Adverse Reactions to Hallucinogenic Drugs. 1Rnstttutton National Test

Home , Bad trip, Cyclizine, Deliriant, Ditran, DOx, Hydroxyzine

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AUTROP Meyer, Roger E. , Fd. TITLE Adverse Reactions to Hallucinogenic Drugs. 1rNSTTTUTTON National Test. of Mental Health (DHEW), Bethesda, Md. PUB DATP Sep 67 NOTE 118p.; Conference held at the National Institute of Mental Health, Chevy Chase, Maryland, September 29, 1967 AVATLABLE FROM Superintendent of Documents, Government Printing Office, Washington, D. C. 20402 ($1.25).

FDPS PRICE FDPS Price MFc0.50 HC Not Available from EDRS. DESCPTPTOPS Conference Reports, *Drug Abuse, Health Education, *Lysergic Acid Diethylamide, *Medical Research, *Mental Health IDENTIFIEPS Hallucinogenic Drugs

ABSTPACT This reports a conference of psychologists, psychiatrists, geneticists and others concerned with the biological and psychological effects of lysergic acid diethylamide and other hallucinogenic drugs. Clinical data are presented on adverse drug reactions. The difficulty of determining the causes of adverse reactions is discussed, as are different methods of therapy. Data are also presented on the psychological and physiolcgical effects of L.S.D. given as a treatment under controlled medical conditions. Possible genetic effects of L.S.D. and other drugs are discussed on the basis of data from laboratory animals and humans. Also discussed are needs for futher research. The necessity to aviod scare techniques in disseminating information about drugs is emphasized. An aprentlix includes seven background papers reprinted from professional journals, and a bibliography of current articles on the possible genetic effects of drugs. (EB) National Clearinghouse for Mental Health Information

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The National list'a of Mental Health i.4,1 C.:11 0 Pr>, 4. 014 43 U.S. MANNA Health Public Roger Chevy with TO WNW. Services Health L Chase, Conference NATIONAL of and Service DEPARTMENT Meyer, Held Mental OF M.D., at ADVERSE Koski Mental Maryland, the Background HEALTH. CLIAIIINONOINM Health Editor National FOR September Papers EDUCATION. institute HALLUCINOGENIC MENTAL Administration 29, REACTIONS AND 1967 of Mental HEALTH WELFARE Health DRUGS INFORMATION Public Health Services Publication No. 18io 1969

For sale by Superintendent of Documents, U.S. Government Printing Dike, Washington, D.C. 20402 Price S1.23 Foreword

The National Institute ofMental Health through itsCenter for Studies of Nar- cotic and Drug Abuseserves as the focal point for support of researchinto the problems of drug abuse. The growingproblem of hallucinogenic drugusage has been of great concern to the staff of this Center. Inthe midst of reports of the spreadingepi- demic of drug misuse and itssequelae, the National Instituteof Mental Health has sought to clarify themany questions and myths that have arisen inboth the lay and scientific press. Consistent with this effort, theCenter for Studies of Narcoticand Drug Abuse sponsored a meeting of scientists inSeptember 1967 to discuss thepsychological and biological sequelae of LSDuse. This volume consists of the proceedingsof that meeting, plus significant backgroundpapers which were available to the participantsin advance of the meeting. While few definitiveanswers emerged from the discussions, the major questionswere clearly defined and some research strategieswere proposed. This book, in a way, servesas a bench mark of our knowledgeat that time. The geneticists were as keenly interested in the deliberationsof the psychiatrists and psychologistsas the latter were intrigued by thefindings of the former. Subsequent to the meeting, the effortsof a number of peoplewere responsible for its preparation in readableform. Miss Arlene Jaffe and MissEleanor Carroll, of the Center for Studies of Narcotic andDrug Abuse, and Miss Marilyn Wilhelmsof the Office of Communications, NIMH,greatly assisted in the editing of themanuscript.

iii Participants at the Conference

Dr. Maimon Cohen Training and Research Department of Pediatrics National Institute of Mental Health School of Medicine 5454 Wisconsin Avenue State University of New York Chevy Chase, Maryland 20015 Buffalo, New York 14214 Dr. Jerome Levine, Chief Dr. Joseph A. Di Paolo Psychopharmacology Research Branch National Cancer Institute National Institute of Mental Health 9000 Rockville Pike 5454 Wisconsin Avenue Bethesda, Maryland 20014 Chevy Chase, Maryland 20015 Dr. Keith Ditman Dr. Hermann Lisco 10921 Wilshire Boulevard Cancer Research Institute Suite 809 New England Deaconess Hospital Los Angeles, California 90024 194 Pilgrim Road Dr. Daniel Freedman, Chairman Boston, Massachusetts 02215 Department of Psychiatry Dr. William McGlothlin University of Chicago School of Medicine Institute of Government and Public Affairs Chicago, Illinois 60601 UCLA Dr. William Frosch Los Angeles, California 90024 Department of Psychiatry Dr. Roger E. Meyer, Acting Chief New York University School of Medicine Center for Studies of Narcotic and Drug Abuse New York, New York 10016 National Institute of Mental Health 5454 Wisconsin Avenue Dr. Kurt Hirschhorn Mt. Sinai Hospital Chevy Chase, Maryland 20015 New York, New York 10029 Dr. Morton Miller, Director Dr. David Hungerford Special Mental Health Programs Institute for Cancer Research National Institute of Mental Health 5454 Wisconsin Avenue 7701 Burholme Avenue Philadelphia, Pennsylvania 19111 Chevy Chase, Maryland 20015 Dr. Robert W. Miller, Chief Dr. Milton Joffe, Chief Abuse and Liabilities Branch Epidemiology Branch Division of Drug Sciences National Cancer Institute 9000 Rockville Pike Bureau of Narcotics and Dangerous Drugs 1405 I Street, N.W. Bethesda, Maryland 20014 Washington, D.C. 20537 Dr. Humphrey Osmond New Jersey State Neuropsychiatric Institute Dr. Martin Katz, Chief Clinical Research Branch Princeton, New Jersey 08540 Division of Extramural Research Programs Dr. Walter Pahnke National Institute of Mental Health Spring Grove State Hospital 5454 Wisconsin Avenue Baltimore, Maryland 21228 Chevy Chase, Maryland 20015 Dr. John Scigliano, Consultant Dr. Sherman Kieffer, Director Pharmaceutical Sciences National Center for Mental Health Services, Center for Studies of Narcotic and Drug Abuse National Institute of Mental Health The Neuropsychiatric Institute 5454 Wisconsin &venue UCLA Medical Center Chevy Chase, Maryland 20015 760 Westwood Plaza Los Angeles, California 90024 Dr. Charles Shagass Department of Psychiatry Dr. Josef Warkany Temple University Professor of Research Pediatrics Henry Avenue and Abbottsford Road Children's Hospital Research Foundation Philadelphia, Pennsylvania 19129 El land Avenue and Bethesda Cincinnati, Ohio 45229 Dr. Julian Silverman Dr. Louis Wienckowski, Director Adult Psychiatry Branch National Institute of Mental Health Division of Extramural Research 9000 Rockville Pike National Institute of Mental Health 5454 Wisconsin Avenue Bethesda, Maryland 20014 Chevy Chase, Maryland 20015 Dr. David Smith, Director Dr. Lyman C. Wynne, Chief Haight-Ashbury Medical Clinic Adult Psychiatry Branch 588 Clayton Street National Institute of Mental Health San Francisco, California 94117 9000 Rockville Pike Dr. Thomas Ungerleider Bethesda, Maryland 20014

vi [ Contents

Page Foreword 111 List of Participants v

Conference Proceedings 1 Introduction: Dr. Roger Meyer, Dr. Morton Miller 1 Dr. Daniel Freedman 2 Dr. Thomas Ungerleider 5 Dr. Milton Joffe 8 Dr. Charles Shagass 11 Dr. Julian Silverman 14 Dr. William Frosch 20 Dr. David Smith 22 Dr. Keith Ditman 26 Dr. Humphrey Osmond 27 Dr. Maimon Cohen 34 Dr. Kurt Hirschhorn 39 Dr. David Hungerford 42 Dr. Josef Warkany 47 Dr. Hermann Lisco 48 Dr. Joseph Di Paolo 49 Summary of the Conference 54

Appendix 57 I. Background Papers 59 "On the Use and Abuse of LSD "Daniel X. Freedman, M D 59 "Patterns of Response to Self Administration of LSD" William A. Frosch, M.U. 74 "Harmful Aspects of the LSD Experience"Keith S. Ditman, M.D 80 "The 'Bad Trip'The Etiology of the Adverse LSD Reaction" J. Thomas Ungerleider, M.D. 88 "Persons with Exceptionally High RiskofLeukemia" Robert W. Miller, M D 95 "Chromosomal Damage in Human Leukocytes Induced by Lysergic Acid Diethylamide"NIaimon M. Cohen, M.D...... 99 "Therapeutic Effects of LSD: A Follow-up Study"Charles Shagass, M.D.. 103 II. Bibliography of Current Articles on the Possible Genetic Sequelae of Hallucinogenic and Other Drugs 109

vii Introduction

Dr. Roger Meyer: On behalfof Dr. Yolles, I grams in the area ofhallucinogenic drug abuse. would like to welcome you to theNational In- Again, I want to thank you very muchfor com- stitute of Mental Health and tothank you in ing. This is a key conference,and I'm very advance for your participation today. Anumber pleased that I have a chance tospend at least of representatives of theInstitute are present some time with youtoday. todayunderlining our tremendous interestin Dr. Meyer: Broadly speaking, ourformat today your deliberations.Dr. Louis Wienckowski, Di- is almost pseudo-Lamarckian,that is, we shall rect.,- Division ofExtramural Research; Dr. be talking about a behavioral disorderthat may Sherman Kieffer, Director, NationalCenter for have genetic implications. Iwould like to draw Mental Health Services, Training andResearch; your attention to aletter we received from Dr. Dr. Jerome Levine, Chief,Psychopharmacology Morton Reiser 1 which was one ofthe stimuli Research Branch; and Dr. MortonMiller, Direc- for this meeting. Dr. Reiser expressed concern tor, Division of SpecialMental Health Programs about possible toxic sequelae ofLSD usage on are seated invarious parts of the room. Before the central-rvous system. Inparticular, he was assuming my role as "David Susskindfor a Day," troubled b) atypical psychotic reactionsin some I'd like to call upon Dr. Miller for someaddi- of his patients. These people did not appearto tional words of welcome. be schizophrenic (as defined inthe traditional Dr. Morton Miller: Speaking bothfor myself nomenclature) and he was alarmedabout the and the Director of the Institute, Dr.Yo lles, and possibility of an epidemic ofheretofore un- for the members of our NationalAdvisory described organic brain syndromes. Mental Health Council, who haveexpressed The possible genetic implicationsof LSD extreme interest in thismeeting, I would very abuse caused us to widen ourformat subsequent much like to welcome you here. I was mostim- to the publicationof Dr. Cohen's article in Science.2 I hope that the formattoday, a round pressed to see how many of you interrupted your the freedom to very busy schedules to come tothe meeting to- table discussion, will give you day, and I think it indeed reflects the concern discuss your findings, both currentand past, very freely. We aretaping the material because of all of us about a very critical topic. attend the confer- Just a few comments about what weconsider we've had such a demand to to be the majorsignificance of this particular ence that we'vehad to turn people away. We meeting. It has been obvious that there hasbeen plan, therefore, to reproduce theproceedings. ourselves a tremendous amountof interest nationally, This morning we sha.1 ;)e addressing both scientifically and politically, in thewhole to the psychologicaland '..)ehavioral problems as- drugs, with particular sociated with the use of LSD andother hallu- area of hallucinogenic have to define reference to the question of adverseeffects, both cinogenic drugs. I think that we short and long term, associated withLSD. This what the problem of LSD is now; todistinguish meeting, I think, is a very important stepfor us between the findings about LSDin the labora- in the Division, particularly inthe Center for tory compared withits use in less formal sur- Studies of Narcotic and Drug Abuse.We hope to define the current stateof the art here today 1 Professor of Psychiatry, Albert Einstein Collegeof Medi- and to utilize your ideas and suggestions as a cine, New York, New York. 2 Cohen, M.M.; Marinello, M.J.; and Back, N. Chromosome base for increasing our own efforts in thede- damage in human leukocytes induced by LysergicAcid velopment of research and intervention pro- Diethylamide. Science, 155:1417-1419, March 17, 1967.

1 roundings. In other words, are adverse reactions very little hope that when most psychiatrists clearly related to the setting in which the drug have their first contact with this drug they are is administered? The reports of Drs. Smith, going to be particularly sensible about viewing Frosch, Ungerleider, Wynne. dnd Silverman on the phenomena induced by LSD. The same illicit users of hallucinogens should be com- problem has occurred each time we've encoun- pared with some of the earlier reports of Drs. tered any intense fluid mental state. Look at the Osmond, Ditman, Freedman, and Shagass in way we've dealt with schizophrenia or hypnosis; various experimental studies. it has taken time to sort out the details and it's Dr. Frosch has delineated three general psy- going to take us time here, especially in the area chological syndromesthe "bad" trips, the re- of adverse reactions. current experiences, and the chronic psychoses. The difficulty of deciphering these new syn- Others have listed suicide and chronic anxiety dromes is particularly complicated by the fact states as special syndromes secondary to LSD. that they may present themselves in different so- Dr. Smith from San Francisco indicated his feel- cial or social-psychiatric contexts. For example, ing that the drug might be implicated in the emergency rooms differ. The college campus genesis of dysphoric feeling states that are being differs from the city hospital. On the cam- observed among some of the hippies. Again, Dr. pus, the clinician has a greater potential for Reiser's letter is fairly spec;fic. He asks whether understanding the youngster who is in trouble adversereactionsarenot new syndromes, and, knowing about his environment, what pre- whether they are in fact toxic sequelae of the ceded his drug taking, and what went on during drug effects on the central nervous system. He the drug episode. It is essential to sort out the feels they are not schizophrenic reactions and several facts from their sum. We also have to that most patients seem inaccessible to ordinary cope with psychedelic philosophy far more of- treatment. He also wonders whether the syn- ten than we have to deal with drug problems; at dromes of black-market patients are different least that's been my experience. from those seen in controlled settings. One of Aside from the questions of somatic changes the questions we would ask Dr. Joffe, from the which we are going to have to come to deal with, Bureau of Narcotics and Dangerous Drugs, is I think we have to recognize that the outcomes, whether contaminants are to be implicated in at least of LSD use, are quite variable and we some of these syndromes that are being observed have to account for the variability. Despite this in the street? Can we better describe the re- variability, many of the outcomes are quite pre- actions that are being observed in the street, or dictable, and one could infer them from the are we really limited to the three descriptive multi-potential fluid mental state produced by states that Dr. Frosch delineated in one of his the drug. I've tried to describe that from time earlier papers? What research strategies need to to time but there's no question that the split of be pursued to further understand the problem? the self, that is, the entire experience of the self What stances are available to the Center, in seeing the self, and the self seeing the self seeing, research, and in professional, and preventive is an astonishing experience. It can also be a education? Finally, can this group make a start banal one. How could Heinrich Kliiver give toward systemization of what is known while mescaline for years and never have a freak-out giving directions for the future? As a start I or even the intimation of a freak-out? 3 When I think I'd like to pass to Dr. Freedman. asked him, he said, "Because during the drug state we paid attention to what's out there.' " The ability to hang on to stable, familiar an- Dr. Daniel Freedman: The view that I've taken chors and clues is crucial. is one advocating caution as to how we interpret I have for a couple of years now been talking and talk about adverse drug reactions because with some of the people in the Native American I think it's really a problem of clinical psychia- 3 Heinrich Kluver, Ph.D.--One of the most distinguished try and clinical description. We have a great experimental biological psychologists and one of the earliest deal of sorting out to do with these drug reac- investigators in the field of hallucinogenic drugs with the tions. publication of his monograph in 1928 entitled "Mescal, the 'Divine' Plant and Its Psychological Effects." Professor of Bio- It's been my view as I've watched abuse de- logical Psychology (Emeritus; Sewell L. Avery Distinguished velop over the past five or six years that there's Service Professor, University of Chicago).

2 Church. A resident, Dr. Robert Bergman, who as he was commuting because the telephone was at the University of Chicago, has been work- poles flashing by the train window bothered ing in the Public Health Service out there and him. He lost the normal suppression of periph- has matic a lot of observations. If we really take eral input. Well, that didn't seem to bother him the Indian experience sei iously it's useful be- too much. I've known people who are function- cause, in another psychosocial context, we have ing well who have had macropsia and micropsia reports of drug-linked psychotic episodes that without LSD. It seems that there is a range of are generally brief and self-terminating. They ways in which we normally habituate and relate have said that the persons who have these are fluidity and constancy in our perceptual be- generally pretty upset people to start withpeo- havior which these drug reactions should be ple who have been psychotic. making us think about. I have a letter from Dr. Bergman reporting I don't know what the barrier isor what the a "bad"trip of an Indian on mescaline; the rea- switch isbetween dereistic and reality think- sons for it seemed to be that this fellow had a lot ing, but LSD and some of the events occurring of problems that he wasn't sharing with the under its influence make you think we haven't group before he took the drug, and yet it was a been focusing on that particular mechanism self-terminating experience. This raises the issue enough, namely, how to switch on and off two of what kind of problems a person does get into orders of reality. Having watched some of these if he pays inordinate attention to what's "in things evolve over time, there's no question in here."The real danger of LSD is that the wrong my mind that the two orders of reality (Freud people seem to be taking it at the wrong time called them the two principles of mental func- and for the wrong purposes. tioning") revealed by this drugand known to While I think I could make a case in terms man in many different forms for a long time of psychodynamic and psychological reasons are hard to live with. alone as to why some adverse reactions would oc- I'm trying to say that in behavior there's a cur, I am aware that some of the syndromes dimension we'll call portentousness, by which I we've seen look like something's wrong with the mean the capacity of the mind to have a psy- brain. I would, however, point again to the fact chedelic experience. Portentousness taps part of that there are no data. Ross Adey observed EEG our experiencewe see more than we can tell changes in the cat for several weeks after LSL, and experience more than we can explicate; we but that cat had been trained to avoid electric experience boundlessness as well as boundaries. shock.4 The changes did not occur if the cat was Of this we're all quite capable. And we have sym- nct so trained. Thus the data do not mean that bolism for it; we speak of the cosmic, the end- thereis hippocampal "damage." They may less, the infinite. I've been struck by the fact mean that there are changes in brain waves that that when somebody takes this drug, he is so im- go along with changes in experience or in learn- pressed by the two orders of realityor the fact ing. Reserpinewith or without painful expe- that this can happenthat he's at least puzzled riencescauses longer-term changes in the cat and may be confused. It takes a lot of time to hippocampus, and we weren't told that we have integrate the experience afterwards. to be wary of this drug because it causes brain With regard to reports of birth defects and damage. chromosomal abnormalities, I think it impor- Thus, while we look for somatic sequelae of tant to initiate a study of native American LSD usage it is important to look for possible Indian groups having long histories of halluci- psychological or psychodynamicprecedents.For nogenic drug use. At the present time, however, example, I have no difficulty recognizing trau- we don't know of any psychedelic monsters be- matic neurosis in those people I've seen who ing born into these native cults. We need a good have trips without the drug. I do, however, have public health survey (including still-births and a lot of difficulty in figuring out why this repeti- fertility) of these people, although I suspect that tive behavior can occur under banal as well as disturbing circumstances. 4 Adey, WM.; I otter, ft.; and Walter, DA. Prolonged ef- I give the example of the scientist who simply fects of LSD on LEG removes during discrimination performance in cats; evaluation by computer analysis.Ekdro- could not suppress his peripheral vision for sev- encephalovaphy and Clinical Nenrophysialagy,11115-35. eral months; he couldn't read hisLondon Times January 1965.

3 any suspicious trend would have struck the local low-up of the volunteers at NIMH who had LSD enemies of peyote who've not picked up that ob- in 1952 or 1953.* I worked with a group of about jection to their neighbors' habits. In any case, ten for a year. These were well-screened people I don't know of any problems that imply chro- in many ways; I knew of no truly bad after- mosomal change among these groups or any effects. other native groups taking the drug. Accord- We have to understand why bad after-effects ingly, I come here prepared with a certain kind don't happen in order to understand better why of skepticism about some of the basic science we are ascribing certain causative factors to the and laboratory indications that there are somatic adverse reaction. This is the reason for trying to dangers to LSD. I also come prepared as a phy- map out what we can about the nature of the .;rian, as I suppose most of us do, to believe experience, its immediate after-effects. and its 4 ft any drug can be harmful. It will take time longer-term after-effects. How are they related? to sort these things out. Obviously, prior set before a trip (or you might I also come equipped with a deep wish that even call it the trip before the trip) what a there would be a dire somatic consequence of kid is going after, where he happened to be mov- the drug, because then we wouldn't have to ing in life as he went into drug takingare im- spend all our time meeting about it, talking portant factors to tease apart. Expectation about it to parents, teachers, clubs, churches. My both conscious and unconsciousas well as social life has changed a good deal due to the guidance during a trip are important. accident that I happened to study LSD ten years Finally, even if we patiently tease out the psy- ago. Given this kind of skepticism, I've looked chological and environmental factors, we may over the somatic data and the only thing I can find that we are dealing sometimes with toxic conclude from looking at the rat and mouse psychoses. If we find this is to be true, we'll still data on still births is that if you're a prudent have to distinguish the "bad" trip from all the woman and yet you're going to take LSD, you other various outcomes, including "good" ones. either ought to be a confirmed virgin or on the We'll also have to remember that panic always pill. "looks" organic. Homosexual panic often, at its I've been confronted from high quarters with height, shows organic features and makes you the question: "How come my child, who was do- think something organic is going on. I think we ing so well at college, is now a dropout?" I've ought to remember Weinstein and Kahn's ap- been confronted with that, however, in 1952, proach to this problem! In other words, I'd 1955, 1957, 1960, and 1964. I really am not sure, urge us, in teasing this apart, to try to be skepti- therefore, whether some very bright people cal clinical psychologists and psychiatrists until (who are exposed to the drug) would indeed we can begin to order the phenomena. So far drop out without the aid of drugs. In other as I'm concerned the people whom I have seen words, I don't know what's concomitant, precipi- who have real trouble over a long period of time tant, accidental, incidental, or whatever. I'm not were headed there. convinced that we have any more problems with I'd like to know now what the usual time borderline states, adolescent turmoil, or the in- period is for the usual adverse reaction and that ability to meet the next life crisis than we have in partwill depend on what the hospital is ever had. I have no question that the drug can doing. If you haul a kid in panic to a state hos- reinforce any behavior pattern the person wishes pital, you've got a person in flux in whom you're or needs to adopt, but in assessing outcome we'll reinforcing a break! If you've got a kid in panic have to sort out what was before the trip. It is and you calm him down and you don't make a important to consider some of this: to remem- "case" out of him, he may, with a few questions ber that there are different motives for trying a and follow-up over the next couple of weeks, be drug, for interpreting its subj:reive effects, for perfectly all right. Even with no follow-up, he maintaining the intake of a drug, for either tak- may be all right. ing it irresponsibly or ritually, for regulating its usage, and for stopping it. volunteers belonged to a man religious group which Asa start, I urge that a project that I proposed does not permit its members to make or drink. Weinstein, LA., and Kahn, ILL. Denial of Illness: Spn- to Robert Cohen about three or four years ago bolic and Psychophysiological Aspects. Springfield, Illinois: now be implemented. This would involve a fol- Charles C ?lentos, 1955.

4 In other words, if you've gota person in a worked with him untilwe felt he was in fairly fluid lute, how you reinforce thatstate may good charge of himself, and thatwas all of the make a great deal of difference, and it'smy im- problem that he had. This adverse trip and flash- pression that we had manymore "bad" trips back was unanticipated. He had been thor- called to our attention after all of the panic pub- oughly screened. All Ican say is that he was licity. I'd like to seea social-psychological study immature. I then began to prefercounter- of newspaper articles and publicity and inci- phobic people who had at least been drunk dence. I think you will find that incidence fol- once in their liveswho with favorable circum- lows publicity. stances could sustain an altered stateand who Well, this is just a range of problems. Ina had firm habits on which to rely. The chief issue sense, they are of basic interest to this Institute, is to know how to reinforce people during the not simply because you are interested in the trip. public health issue, but also because it isa beautiful challenge to tease apart those social,psy- Dr. Meyer: Thank you. Dr. Ungerleider will be chological, and biological variables whichmust our next speaker. be operating in any kind of behavior dysfunc- Dr. Thomas Ungerleider: Dr. Meyer asked for tion. some scientific objectivity in this meeting today, Dr. Meyer: Do you know what dose theywere but as far as I am concerned the words LSD given back in 1952? and scientific objectivityare mutually exclusive, at least at this time. I would like to address Dr. Freedman: Yes, theywere given various dos- some comments to this. I think we would all ages, from 50 to 150 micrograms, as I recall. agree that LSD is a powerful chemical agent. Dr. Wynne: 150 is pretty standard dosage. Perhaps we would alsoagree that LSD can be abused under certain circumstances. Beyond Dr. Freedman: They had patients and also vol- that, I doubt that we would find much, ifany- unteers that were treated. These volunteers got thing, that we here can allagree upon concern- intravenous LSD (whichgave them a more in- ing the LSD situation today. tense experience but in a highly comfortable Some of you may agree with the New York setup).I didn't know then about all the beads Academy of Medicine that LSD ismore danger- and pads and so forth, but the researchnurse ous than heroin. Perhaps some of you would and I would sit there and drink coffee while they agree with the ..uperintendent of the California performed various psychologicaltests for us school system who stated recently that theuse of from time to time. They got the drugat least LSD is the most critical problem in California's once every ten days because I was studying acute schools today. On the other hand, I have heard and chronic tolerance. These people didcome to some of you say publicly that "anyone who can new conclusions about their life, as any young hold his alcohol can hold his LSD," and that kids would have done had theysat around in "the chromosome problem is all dueto the fear the cancer ward fora year volunteering their that adults have because LSD causesyoung peo- services. I think they were interested in the ple to become more artistic. They don'twant to drug, but they were not entranced. work from eight to five at the boring jobs which I saw one bad reaction. Theyoungster had adults want everybody to hold." the drug and went intoa catatonic posture. He Can we even agree on what isan adverse re- later said he heard himself giggle andthought action to LSD? For example, at the last Ameri- he giggled "like a girl." That scared him.He in can Psychiatric Association meeting in May fact was young and somewhat immatureand 1967, in Detroit, a foreign psychiatrist, who has beardless. He stayed in thisposture a few hours made notable contributions in LSD therapy, and we just worked with him until hecame out claimed to have given patientsup to 30 LSD of it. We talked with himover the next weeks treatments without observing any side effects. and did not give himany more drugs. Six When my colleague, Dr. Fisher, later questioned months later, he came back and said he had him, the researcher admitted thatsome of his been looking out of his windowat home and patients did becomepsychoticand others be- suddenly it was like the drugstate; he wondered camesuicidaland required hospitalization, but what that meant. We talkedmore about it and he insisted that these were not side effects but

5 just part of "working through the LSD experi- ditions warrant prompt psychiatric attention for ence." Fif even regarded convulsions with tonic- whatever reason are designated emergencies." clonic mhvements and loss of consciousness as Let me hasten to add that person often seek part of the abreactive experience under LSD help in indirect ways. When taking careful his- and not as a side effect of the drug. tories of those persons who come into our emer- Some of you share the opinion that even ex- gency rooms for help following LSD ingestion, tensive LSD and other drug use in certain sec- we often find that these youngsters have been tions of various cities is not a problem of drug living nomadic lives away from their families. abuse but merely represents an eloquent protest When they begin to have adverse effects from of our' youth to such social problems as Viet LSD, however, they find their way, often hun- Nam, civil rights, and the like. Other physicians dreds of miles, home to their parents. They have informed me with equal sincerity that all know that their parents, being very "straight" LSD use is a giant Communist plot which is and "up- tight," will immediately seek aid for perpetrated by U. S. radio stations which play them. Yet these youngsters, when brought in for various songs such as "Acapulco Gold," and help by their parents, will often say, "I'm only "Eight Miles High." here at my parents' request." They can get help Such lack of basic agreement results in a cli- and still "save face" that way. It is surprising mate of hysteria which has its unfortunate effects how readily they consent to andare relieved by on all of us and on our studies. Certainly those psychiatric hospitalization. of you who have used LSD in research and treat- At UCLA's Neuropsychiatric Institute, in the ment have been especially affected. For example, seven months beginning in September 1965, the the one pharmaceutical company with the ex- first 70 cases of adverse effects from LSD were perience and the equipment to analyze LSD studied. The results have been detailed ina samples has refused to analyze my (black mar- publication entitled, The Dangers of LSD" in ket) samples out of fear of reprisals from the the Journal of the American Medical Associa- Government, particularly our own Food and tion. The predominant symptoms of these pa- Drug Administration. And representatives of tients were hallucinations followed by anxiety, another drug company, which manufactures a depression, and confusion, in decreasing order. tranquilizer used to combat LSD-induced side ef- The word hallucination is used loosely and also fects, recently approached me to arrange a panel includes illusory phenomena. 1...ist_any.-of-.y.911.___ on the treatment of such reactions. They soon be surprised that confusion follows LSD inges- withdrew their offer, again because of difficulty tion (and e of you have expressed surprise with Federal agencies. The representatives of to me in the past),let me refer you to an article the company had told me that they were being by Dr. John MacDonald in the American Jour- bombarded with requests from physicians all nal of Psychiatry' He reports the exper;mental over the country about choice of tranquilizers administration of LSD to 50 persons. Of the 50, and dosage schedules to use in treating LSD re- 29 had some clouding of consciousness which actions. They added that these requests would varied from intermittent slight confusion to stu- have to continue to be answered with a "no com- por. ment" type of statement. Whether their fears During the time that our first 70 patients were are justified or unjustified is not the point. The seen at UCLA, for every person seen we received point is that with such rampant fear, many an additional three or four telephone calls from worthwhile projects are being abandoned, and other people in trouble from LSD who did not LSD research faces a dismal future. subsequently come in for help. Since that time, Now, can we define the "bad" trip, "bum- at UCLA we have actively tried to discourage mer," or "freak-out" following LSD ingestion? I would say yes, or at least sometimes. My def- T GlasKote, R.M., et al.The PsychiatricEmergency. Joint inition of an adverse reaction to LSD is this: Information Service of the American Psychiatric Association and the National Assodation for Mental Health, Washington. "Symptoms following LSD ingestion which D.C., 1966. cause a person to seek professional help." There Ungerleider, J. T., et al. The dangers of LSD.JAVA, is precedent for such a definition. In the book, 197:399-392, August IL 1966. 9 MacDonald, J.M., and Galvin, J.A.V. Experisnenul psy- The Psychiatric Emergency,7 a psychiatric emer- chotic states.American Journal of Psychiatry,112:970-976, gency is defined thus: "All patients whose con- June 1936. 6 r LSD patients from coming to our Neuropsychi- Virgin Marys wandering about on LSD, but atric Institute. In fact, for the first time since our either their culture supported them or they were Institute opened, a blanket rule was passed that not aware of enough difficulty to seek aid. I a certain type of patientwould not be hospi- would therefore exclude them from our def- talized, namely, LSD patients. This is necessary initionof adverse reactions to LSD. This because UCLA is a residency training hospital, also avoids the controversy about value-system and the psychiatric residents were seeing mainly changes with people "turning on" with LSD and one type of patient, the LSDcasualty. Despite then dropping out of society as we know it. active discouragement, since April 1966 another Unfortunately, we do not know and probably 115 patients whose symptoms were directly re- will never know the true prevalence of LSD us- lated to LSD ingestion have been seen at the age in the community. We do not even know the Neuropsychiatric Institute's Emergency Room. incidence of "bad" trips seen in hospitals and This figure excludes those patients who had used by professionals because few statistics exist. We LSD in the remote past and whose presenting are now beginning a questionnaire survey of symptoms did not appear related to theLSD in- professional persons in Los Angeles County to gestion. (Some "flashback" re-creations of pre- try to determine how many adverse LSD reac- vious LSD trips have been included in the fig- tions they have seen in the 18-month period end- ures.) The figure also excludes a number of ing this past July. paranoid schizophrenia who claimed to have Much controversy has arisen as to whether been poisoned by LSD, by the Communists or pure LSD causes adverse effects or whether it is others, but who had little likelihood of exposure the black-market LSD with its alleged impuri- to the drug. It further excludesthe multiple ties and dosage irregularities. I have had several telephone calls and referrals (from five to ten samples spot-checked and analyzed and, in each each week day) that Dr. Fisher and I receive di- sample, where the user claimed he was getting rectly from the community which do not go LSD he always was. These users were chronic through the Emergency Room. "acid heads," who claimed they could tell within It is important to emphasize that the symp- 5 micrograms how much LSD they were ingest- toms I have described, namely, hallucinations, ing. There were no impurities or other drugs anxiety, depression, and confusion, frequently found in these few samples, but the user always are experienced following the ingestion of LSD. thought he was taking much more LSD than he These acute effects only come to be called side really was. effects or an adverse reaction when the user seeks We professionals often debate the etiology of help for them. Many and perhaps most LSD the adverse LSD reaction as well as the defini- users experience some or all of these effects but tion of it. Is it the impure LSD with methedrine they are able to get over them, either by them- or atropine derivatives that causes the adverse selves (often with various aids such as readings reactions? I personally don't think so. Is it set from the Tibetan Book of the Dead) or with and setting with whimsical or kick-type parties the help of a sitter or guide. We do not say then that are responsible for most of the "bad" trips? that these users are having adverse LSD reac- I don't think so. In fact I am more impressed tions. with the set and setting of many of the serious I am excluding many of the chronic changes black-market users than I am with the often ster- due to LSD in my definition of the "bad" trip. ile medical atmosphere and environment in Dr. Fisher and I left the hospital environment which we have given the pure Sandoz LSD. Is early to observe "love-ins, love sessions, and hap- the adverse LSD reaction to be explained by penings" involving LSD throughout the State of psychopathology in the user who is borderline California. These have included serious reli- or emotionallyill anyway? I am most un- gious rites in the Orange County Southern Cali- impressed with this factor. Certainly, existing fornia area, as well as our local Sunset Strip and screening tediniquei have failed to rule out a Hollywood kick-type parties, hippies "dropping number of adverse reactors while many very dis- acid" at Big Sur, and college students experi- turbed persons take LSD in huge doses multiple menting in the San Francisco Bay Area. We times, without apparent adverse effects. have seen many persons on LSD who appeared I would however like to suggest one factor grossly psychotic. I personally have seen several which I do not feel has received enough empha-

7 sis and which may help us to resolve our appar- Scigliano, Center for Studies of Narcotic and ent disagreements about the dangers of LSD. Drug Abuse, NIMH. The average age of the user in our study of the As far as the quotation from Dr. Freedman adverse reactor to LSD was 21. In other studies that "fear of sensationalism in the bureaucracy the age has been reported as the same or even due to the sanction of drug abuse" is concerned, younger. We all know that adolescence is a time he has not dealt with the Division of Drug of instinctual crisis with youngsters trying to Sciences, Bureau of Narcotics and Dangerous handle their sexual and aggressive feelings and Drugs, particularly with Dr. Richards, our so- to resolve their identity problems. I am con- cial psychologist; Dr. Smith, our clinical psy- vinced that using LSD makes this resolution chologist; and myself, a pharmacologist. I think much more difficult, both in the chronic "acid that he will find that we are not afraid to sanc- head" and in the occasional LSD user. The "anti- tion the use of drugs in research. We are trying instinctual" properties of the drug give the LSD to assist scientific investigators in every way that user the illusion that he has no sexual or angry we can. It is true we would like to avoid sensa- conflicts. He can thus postpone or avoid conflict tionalism. I think almost everyone would. We resolution for many months, while he "turns are a Government agency with a regulatory on." function and "a different outlook." Contrary to To my knowledge, virtually all of the work most government regulatory agencies we are also that has been done in both therapy and research responsible for research to determine what the with LSD has been done in subjects over 21 problem is about, what the extent of it is, and years of age. Perhaps, then, the ageor youth what might be done about it. We hope that we of the black-market users explains many of the will be able to foster and extend this point of adverse reactions to LSD. Certainly Drs. Sidney view. Cohen, Ditman, and Grof, to name a few, have As to observations about the illicit sources, I only very rarely administered LSD to persons think if one wanted to know more about these, under 21. I am aware, however, that paranoid he should call on our criminal investigators. I personalities, very compulsive persons, and some can say just a few things about the illicit pro- others in the older age groups have had adverse duction from what I know; I do not make it a reactions to the drug. point to investigate or even to find out about all of the illegal laboratories that investigators Dr. Meyer: Thank you very much. I am certain turn up. The most common type of facility of that Dr. Joffe, representing the Bureau of Nar- this kind is the home-type laboratory where cotics and Dangerous Drugs, might want to re- somebody in a rooming house sets up a window spond to some of your comments about Federal fan for exhausting organic vapors and employs regulatory agencies. unquantitative chemical procedures. Generally Dr. Milton Joffe: I'm rather glad that Dr. the discovery of the laboratory is made because Meyer suggested that I answer some of these in the same rooming house there are people who comments because I wanted to answer them any- are not familiar with the odor of organic sol- way. As to the Government's role in regulation vents and they call the police. of this compound, I think it has changed mark- The product turned out by these laboratories edly in the last year. I wanted to comment that is of course very questionable. The matter that Dr. Freedman and Dr. Osmond, in their pre- Dr. Unger leider brought up concerning the con- pared statements, had been writing in 1966, taminants is a problem which we would cer- some months before those of us who are scien- tainly like to get into, but it would require more tific people were in the Bureau of Narcotics and resources and more study than we can devote to it right now. We don't know whether the con- Dangerous Drugs in the Food and Drug Admin- taminants are due simply to residues from the istration."' I might say that their statements are chemical processing, a breakdown of the actual now rather outdated, that there is a Joint FDA- product, or an incomplete synthesis; the only PHS Psychotomimetic Agents Advisory Com- thing we can tell is that the sample does not as- mittee which will approve the use of psychedelic say to be 100 percent. drugs and provide for their supply. Anyone of to This Bureau was originally under the Food and Drug you can reachthis committee through Dr. Administration and is now part of the Justice Department.

8 In connection with this problem, I have had and I believe that it has a certain status in the a call from one of theparticipants here who subculture which the other drugs do not have. is on the negative side of the chromosomal-break The unpredictability of the "good" versus the investigation; his thought was that perhaps it "bad" trip really puts the user on what the ani- was the contaminants ratherthan the pure ma- mal psychologist would call the "variable-ratio" terial which were producing this break. While or "gambler's schedule." You don't have to be I am in a position to furnish him with illicit reinforced each time, but if you get one or two material, I cannot guarantee what the contami- reinforcements from "good" trips, the user will nants will be. A first step might be todetermine continue to use this material. whether pure LSD does not break chromosomes Another problem that we have had with com- while the illicit stuff does. After this, one can pounds, mainly on the East rather than on the look for identification of contaminants. Apart West Coast, has been with the indole com- from the smaller household laboratories there pounds of dimethyltryptamine (DMT) and di- are also some bigger processorsthat we have ethyltryptamine (DET).These are easily made. come across. One example wasthe laboratory They are, of course, used by inhalation since truck found in Colorado whose owners had a they are inactive orally. And they are used in a rather high level of sophistication. There were peculiar way. It sometimes takes the police quite xeroxed copies of all of Roger Adams' patents on a while to catch on to the fact that the purchase the tetrahydrocannabinols, of John Biel's papers they have made from illicit sources is not obvi- on the anticholinergics, andof course several re- ously illegal. They bring the material to the lab- prints of Dr. Shulgin's work on the mescaline oratory for analysis and are told, "You have been compounds. stuck this time because there's nothing here We don't ever know what's going to turn up but parsley leaves." It turns out to be parsley next. My own particular guess isthat anti- leaves with the liquid DMT spiked on it and cholinergics will not become a large problem. dried. The reaction to them is rather unpleasant. I do The techniques that the illicit -..urces will re- not expect the illicit chemists' level ofsophisti- sort to are rather clever; and I'm sure it's going cation to be such that they will be able to to be a problem for the enforcement people to synthesize tetrahydrocannabinols in any sizable keep ahead of them. From our standpoint of quantity, at least, at present. I personally expect scientific investigation, we are obviously incap- a flood of more phenylethylaminessuch as the able of fostering every type of research that DOM or STP. needs to be done. I think we would all be most These compounds are easily made. The liter- receptive to proposals for work in this area. ture on them is rather extensive, as far as syn- There are times, as I say, when we, partly be- thesis goes. There are no tricks to it;it is a cause of our particular mission, will not beable simplestraightforwardfollowing of known to do anything about the problem. We certainly chemical techniques. I also expect that the users can offer you encouragement and advice con- will gravitate to these substances rather than cerning Government regulation. Our whole seeking out the exotic or compounds unknown mission is to foster research, and we would be today. I don't expect the illicit chemists to go more than happy to try and help youwend your about and synthesize or carry out research on way through the bureaucracy. It's a problem not any new series of compounds. Thereis certainly just for you, but it's a problem for me. There the possibility of the synthesis of the tetrahydro- are other Government agencies which I am not cannabinols since Mechoulam's publication of a a part of, and I have to wend my waythrough rather easy synthesis. Here the problem for the them. investigator is the purchase of starting materials I think that, in looking over what Dr. Smith and the development of a synthesis capable of has submitted concerning STP use, I might an- generating significant quantities of the sub- ticipate him just a little bit. I don't know what stance. At this point in time, it is easier for the he's going to say in regard to the matter of treat- illicit chemist to prepare THC from the plant. ment and the chlorpromazine issue. You will re- In reality, the main problem that we are fac- call that there were reports from Dr. Smith's ing on a long-range basis is that of LSD. It is clinic that chlorpromazine potentiated STP, extremely potent, with generally low toxicity, causing death in one individual, and suggesting 9 that STP therefore acted like an anticholinergic very simply, every tablet that our agents have substance rather than a phenylethylamine. I've been able to obtain or that I have been able not had the opportunity to talk directly with to obtain from scientific peopleevery tablet Dr. Smith about this report. I did, however, talk which was said to be STP and contained to his co-worker, Dr. Frederick Meyers, who was a psychogenic compoundhad only one com- not sure about the findings of the initial report pound in it, namely 2,5-dimethoxy-4-methyl- and the conclusions drawn from it. amphetamine. To my knowledge, there are no I've recently had some experimental work run other psychogenic compounds circulating under off in a human subject. The chlorpromazine was the name of STP. not given as antidotal treatment but rather was Dr. Meyer: Dr. Freedman had one comment to given simultaneously with the DOM, and the re- make, I think. action of the individual was considerably less. This was an individual who had had a full-scale Dr. Freedman: The source of my statement re- reaction to STP when chlorpromazine was not fers back to the Kennedy hearings, in which I administered. His reaction was considerably di- had observed that what I meant by bureaucratic minished upon taking the chlorpromazine si- power was simply the option to make decisions. multaneously. It is my feeling that it is difficult to make con- The general thought of the man who did this troversial decisions when a man has to face Con- work was that we were simply depressing the gress. whole individual; there was nothing specific Dr. Joffe: We are trying to hold up our end of about it and perhaps the tranquilizers should be it. considered as some therapy for an individual Dr. Freedman: Yes, I know. who is in danger of becoming either violent or very panicky. Dr. Smith: Can I ask one question? On what do I don't think I have anything more to say ex- you base your conclusion that tetrahydrocannabinols (THC) will not become a problem? . cept to reiterate that the Bureau of Narcotics and Dangerous Drugs is more than willing to Dr. Joffe: I would say that the present synthesis discuss with anyone the problems involved in is relatively easy as compared with the original scientific investigation. I may say now that, even synthesis of Roger Adams, but it still does not though the Government has the reputation for represent an easy synthesis. As I said, the illegal repressing research in the LSD area, there are sources provided us with a very nice series of at present over 100 individuals who are author- xeroxed copies. If they are taking this literature ized legally to do scientific work with LSD and seriously, are capable of understanding it, and other psychedelics, and this number will in- have the facilities, it would not be beyond their crease, probably significantly, every two months powers to make it. as the special committee meets to approve these Dr. Smith: There have been reports of tet- applications. rahydrocannabinol circulating in the Haight- Dr. Meyer: Dr. Joffe, there has been one report Ashbury. that STP on the East Coast is different from that Dr. Joffe: Can you get me a sample? I would be on the West Coast. Would you care to comment? very glad to have a sample because there are Dr. Joffe: We have had a small amount from really two compounds in one series and a whole the East Coast but most has been from the West flock of compounds in another series that we Coast. There is an individual here who is re- have to worry about. The two compounds in sponsible for providing me with the very first the one series are the L--trans-THC, the tablet on which our structure was established L-A8-trans-THC. There are compounds which and I'm very grateful to him. This tablet, ob- can be isolated from the plant.They are also tained from the New York area, was of a differ- synthesizable and have been tested in man. The ent color and size than the ones from the West other series of compounds is based on the delta Coast. The West Coast ones were blue-green, 3, 4 tetrahydrocannabinols which are Roger the New York one a beige color. This doesn't Adams' compounds. Furthermore, since the sub- really mean too much because we don't know stitutions of R-3 can be of an almost infinite too much about the manufacture of them, but variety, we have here at least a potential for li

10 psychedelic ex- great many compounds.A number of them have ically who would have a so-called been made including synhexyl,synheptal, and perience(Dr. Osmond's term)or insightful longer chain which have a experience, or whatever you want to callit. We ones with an even 10 of higher potency. I don't ask Dr. Smithfor a sam- loaded our group with conduct disorders; referred. They ple out of idle curiosity. Iwould certainly like our first 20 subjects were court this synthetic material is were first given astandardized psychiatric inter- to determine whether classification. Our made by Mechoulam's synthesiswhich would give view schedule for diagnostic the L-trans delta 1 or whetherit is made from LSD treatment method was of the kindthat has would be the been used in the treatment ofalcoholism; the the Roger Adams' series which given intra- delta 3, 4. dose was 2.5 micrograms per kilo venously, which is a large dose in termsof its call on Dr. Meyer: Thank you. I'd like now to effects. Dr. Shagass. Two psychiatrists rated the tapedrecords of have to say this the experience for the presenceand degree of Dr. Charles Shagass: What I divide morning is a background to whatDr. Hunger- insightful response. Thus we were able to ford is going to be saying thisafternoon about our group roughlyinto two segments: those with insightresponders, and those our chromosomestudy. I have had various kinds more evidence of of interest in LSD. I startedgiving it in 1950 with little or noinsightnonresponders. It abreactions in therapy, and for turned out that most of our respondershad been to try to produce by our the next decade I continued togive it sporad- diagnosed as psychopathic personalities responder ically. I was very unimpressed by theeffects and interview schedule. Furthermore, no wondered why the literature was sofull of state- was under 22 yearsold. Parenthetically, we have ments which my observationsfailed to confirm. never seen what wewould call a favorable thera- LSD, and was peutic response to LSD in anybodyunder 22. I was probably not giving enough there giving it to the wrong people; mypatients were Thus, on the basis of age and personality people who didn't displaypsychotomimetic ef- was a way ofselecting in advance those capable fects with small doses. of having an immediate insightful response to Another interest was whether theLSD reac- LSD. The group was a mixedbag of alcoholics, dexedrine tak- tion resembles schizophrenia. Mostpeople don't homosexuals, exhibitionists, and believe this anymore, and in fact,there is a good ers. deal of evidence from various sources tosupport We then did a follow-upstudy. Each patient effects are to be treated with LSD wasdescribed (i.e. symp- the notion that the psychotomimetic found toxic. For instance,if you give the Bender- toms) in advance. From the records we Gestalt test, the people who showthe greatest another patient of the same age, sex, symptom clinical reaction to LSD are thosewho have de- pattern, and socio-economic status.After one terioration of performance. On the otherhand, year we sought outthese individuals, both the and in- LSD, as we showed in anotherstudy, is quite LSD-treated patients and their controls, different from an agent like Ditran,which is a terviewed them and a significantrelative. deliriant. If you take a group ofsubjects and Each symptom was inquired intoand, if they asked give them a performance test,and then test them said there had been a change, they were when they are under the influenceof the agent, to rate the degreeof change on a rough scale. the performance level is maintainedunder LSD. Although our matching for symptom patterns There is a significant correlationbetween the was very close, wedid not control for other treat- pre- and post-drug scores.On the other hand, ments; it turned outthat three of the LSD pa- with Ditran, the performance levelis completely tients had had some regularpsychotherapy, lost; you can't predict what the drugperform- whereas 13 of the 20 control cases hadbeen seen in psychotherapy during the ance is going tobe from the pre-testing. So LSD at least once weekly is certainly not as toxic an agentin that sense one-year follow up.Mean ratings of improve- There are other differences electro- ment in symptoms werecomputed for six as Ditran. retrospective rating) physiologically. months after treatment (a In 1963 we again became interestedin the and at 12 months. The peoplegiven one 200 issue of treatment with LSD. Thistime we set microgram, or 2.5 microgram perkilo, treat- significantly more im- out to determ;newhether we could predict clin- ment with LSD showed 11 provement at both six and 12 months. Those since people do relapse. However, we have who showed the greatest improvement were our retreated some of the relapsers and produced an- eight responders; at six months they were very other six months benefit. Secondly, the electro- much improved, and then they started to show a physiological changes that we have been able to tendency to relapse. The relapse had a remark- measure do not last beyond the acute phase. This able time characteristic. Within seven months is in accord with the notion that there is some after taking LSD the individual started to want kind of toxic reaction. The nature of this reac- to consort with homosexuals again, todrink tion is electrophysiologically interesting, in that again, and so on. We have no idea why there is we are seeing a speeding up of brainactivity. this six month improvement and then the ten- Most toxic agents, such as the anticholinergics, dency to relapse. It raises the question of a pos- of which Ditran is an example, slow brain ac- sible mechanism that is set off by the LSD which tivity. This is one of the few examples we have remains operative for this period of time. of the postulated parabolic relationship between Another finding that came out of this analysis, performance and underlying physiological activ- which may be a chance finding, although it is ity. At the extremes of physiological activity, statistically significant, is that the change in the which could be exemplified by panic and sleep, ratings from six to 12 months showed significant very little intelligent performance can occur. It improvement only in the group of 12 LSD non- has been extraordinarily difficult to obtain a responders. These people just seemed to keep physiological parallel at the panic level,al- on improving gradually. If this is a genuinephe- though it is very easy to record the slow sleep nomenon, what could be going on? Something activity. Now, what we have with LSD is a speed- of a long-term nature must have been triggered. ing up that is associated with decrement of per- Concomitantly with treatment, we studied formance, and this is of some interest. some electrophysiological changes in 17of our Lastly, it seems to me that a lot of things that subjects. We looked at the EEG and at the sen- one sees in working with LSD suggest that this sory-evoked responses to light flash and to elec- drug, or something like it, should be able to tell tricalstimulationofthemediannerve. us a great deal about the basic structure of per- Histograms showing the distribution of wave sonality. Why does a sociopath, having had LSD durations in the electroencephalogram were once, say: "I will not come back for a second computed before LSD was given, at a time close treatment, because when I had my first one, all to the height of the LSD effect, and then the it did was tell me that it was my fault."? Cogni- next day. EEG frequency was generally increased tively, he knew it was his fault before he ever by LSD, as other people have found. It is impor- had any LSD. Apparently the LSD made him tant to note, however, that one day later the know in an affective sense, and this was an ex- frequency histogram was about the same as be- perience to which he was not going to subject fore LSD. It seems that these EEG effects don't himself again. What kind of personality organi- last. zation was shifted by LSD? A paper in JAMA 11 last week, concerning Because of these interests, after I moved to brain damage by LSD in a five-year-old girl, Philadelphia about a year and a half ago, we states that there have been no long-term EEG continued our work with LSD. We have been studies of LSD. We have seen the EEG's of many trying to block what I think is the major toxic patients a long time after they have had LSD; phase of the LSD reaction, that taking place dur- there are no changes evident after 24 hours. ing the first four hours. We give patients a pill, Similarly, the average evoked responses to light which is either chlorpromazine or placebo, be- flash show some definite changes produced by fore giving the LSD. The blocking is of varying LSD, but the records are pretty much back to success; some people just don't block and go to the pre-drug form in one day. The same is true sleep for 12 hours with chlorpromazine. In any of the responses to median nerve stimulation. case, our aim has been to compare blocked and The position that we had to take from our unblocked treatments to see whether the initial results is that, first of all, we do have evidence three or four hours of what I believe to be toxic- suggesting that LSD may produce therapeutic ef- 11 Milman, D.H. An untoward reaction to accidental inges- fects; although this is certainly not anything to tion of LSD in a five-year-old girl. JAMA, 201(11):821-824, get overly excited about as a specific procedure, September 11, 1967.

12 ity is at all necessary for later behavioral change. could be called psychotic, but these are quite We want to know whether the patient will have well controlled. 1 didn't go into detail about the his insightful experience without having to be context. My view, and I go along with Dr. Freed- quasi-psychotic for awhile. This has been our man here, is that we have a very complex inter- purpose. Now, in connection withthis, we were action when we try to use LSD for treatment. really only getting started when Dr. Cohen's re- We have the expectancies of the patient; we port came out. I happened to be talking to a have the expectancies of the therapist; we have biologist at the time who suggested that I do this potent agent which heightens suggestibility; something about this, and referred me to Dr. and we have the setting. I think all of these are Hungerford. This was how we started to collect necessary in order to produce some of these ef- blood samples for chromosome studies in each fects. patient, and that is the background for Dr. Hun- QUESTION: What dosage was it initially in gerford's story. studying psychosis? One final small point I should like to make Dr. Shagass: In another study using a group of concerns reports of LSDdosage. In the JAM/412 14, we went as high as 500 micrograms without article of last week there appears to be uncritical success in producing what we call a psychotic acceptance of the statement that a sugarcube, reaction. impregnated with illicit LSD, which was swal- QUESTION: These included your alcoholics? lowed by a five-year-old girl, contained a standard 100 microgram dose of LSD. How do they Dr. Shagass: No. This was an entirely different know the dose? It was an impregnated black- study. In our use of LSD as a therapeutic agent, market sugar cube which an 18-year-old boy had we have used one of two doses: 2.5 micrograms put in the refrigerator. perkilo or 200 micrograms, whicheveris smaller. We gave it intravenously which, I am Dr. Freedman: What has been your experience told, makes the effect of the drug two and one- with "freak-outs" in the treatment situation? half to three times more rapid in onset. Dr. Shagass: We have had three people become QUESTION: What was the dose that gave you lastingly psychotic. I agree with Dr. Ungerleider up to 50 percent psychosis? that during the treatment session a "freak-out" Dr. Shagass: This wasn't set, but we went from is a very uncommon affair. However, when we 2.5 to 9 micrograms per kilo in that study in an were deliberately trying to produce apsychotic attempt to produce psychosis. What we were reaction, our yield was 50 percent. This was in trying to do, you see, was to compare in the a study we did in 1960. same person a psychotic and a non-psychotic re- Dr. Freedman: What is it you were trying to action to LSD using different tests. This was produce? You and I will have an argument later done with Dan Pauk about 1961.13 as to what psychosis is. QUESTION: Was the incidence of psychoses Dr. Shagass: What we were trying to produce at dose related? that time was something that would meet the Dr. Shagass: Yes. Certainly at one-half micro- clinical criteria of a psychotic reaction as these gram per kilo you get a very low yield of any- were defined in the standard APAnomenclature thing. terms. I am distinguishing between a reaction to a Dr. Freedman: Secondary or permanent? drug which you get in nearly anybody to whom you give it at most dosage levels above amini- Dr. Shagass: Secondary. In 14 patients to whom mum, and a disorganizedbehavioral reaction we gave several doses of LSD, we got sevenim- which fits a syndrome picture. At that time we mediate sudden reactions that were clearly clini- were very much concerned with the questionof cal psychosis, Lut three of them, as I recall, were whether this was really an hallucinogenic drug, organic in the sense that there was disorienta- when actually the phenomena may have been il- tion. There was one clear case of catatonia. One man became sufficiently paranoid to try tokill 12 Mid. the investigator. He was sorry about it later. 13 Pauk, Z.D., and Shagass, C. Some test findings associated with susceptibility to psychosis Induced by Lysergic Acid In our therapeutic context, our experience Dietitylamide. Comprehensive Psychiatry, 2:188-193, August has been that people have a lot of symptoms that 1961.

13 lusions. The term psychotogenic is used and this done any EEG studies of the so-Lalled recurrent implies the notion that the effects are like schizo- experiences without the LSD? phrenia. These are reactions which involve seri- Dr. Shagass: No. I'm just a little skeptical about ous departures from theorganization of the what this means. We recently gave LSD to a mind in relation to what we ordinarily see. We Popular Science writer who is a very anxious per- started out by asking: Are they the same? son. He now feels fine and he has written a very QUESTION: Your feeling is that they are the nice story about his experience for the maga- same? zine." In talking to him later, he brought up Dr. Shagass: For the most part, yes. In the three the fact that he had an anxiety dream one night patients that I have mentioned, we have seen and said it was just like the LSD experience. the development of psychotic reactions which Well, I think if I had focused on a previous were clinically exactly likethe schizophrenic experience that had some kind of dramatic con- syndromes that one sees in the absence of LSD. text, I could have elicited a similar report before One schizophrenic reaction occurred in a man he ever got any LSD. who had a prior history of a brief psychotic epi- Dr. Frosch: We've done EEG's on some of the sode subsequent to leaving an isolated work area. people whom we've labeled as recurrences. We This perhaps should have warned us, but we found no encephalographic abnormalities. But treated him because of his exhibitionism which of course, Dr. Shagass observed no electrocepha- had been refractory to psychiatric therapy and lographic changes unless he did the computer- he did not appear overtly psychotic at the time. ized wave analysis. This patient developed a schizophrenic reaction after his fourth session with LSD. It started dur- Dr. Meyer: Thank you very much. I'd like to ing the experience, and afterwards it required call on Dr. Silverman next. about two months of traditional treatment for Dr. Julian Silverman: I'm going to report on a recovery. The treatment was the same as for a study carried out in collaboration with Drs. schizophrenic reaction which has not been pre- Monte Buchsbaum, Winfield Scott, Douglas cipitated by LSD. Welpton, Lyman Wynne, and Theodore Zahn Dr. Meyer: Had these reactions been seen in of NIMH and Dr. Robert Henkin of NHI. The people who had been previously unstable? subjects in the study were eight male chronic LSD users who ranged in age between 21 and Dr. Shagass: Yes. 33 years, average number of drug experiences- Dr. Meyer: You would feel that a psychological 35; they were examined intensively every day diathesis was there? for a week with an elaborate battery of physi- Dr. Shagass: Yes. ological and psychological tests. Measures of sen- QUESTION And these were the only persist- sory thresholds, perceptual functioning, EEG ing reactions? averaged cortical evoked responses, autonomic Dr. Shagass: Yes. Of special interest was a man reactivity, and a battery of clinical psychological who came to us with a methedrine psychosis. He and personality tests were administered to each wal also a former narcotic addict. The methe- subject under four conditions:(a) baseline drine reaction cleared in three days and he day one, (b) with 15 mg. d-Amphetamineday appeared clinically in excellent contact and we two,(c) with 50 micrograms of LSD-25da decided to take a chance on him with LSD. He four,(d)24 hours after LSD dayday five. had a beautiful psychedelic experience, seemed The baseline measurements made on these sub- to reorganize, became ambitious, and really jects were compared with those of 20 normal looked marvelous. Yet 16 days after his fourth male volunteers of similar age. The overall sig- and last LSD experience, he became floridly par- nificant effects of LSD will be reported, in de- anoid and presented exactly the same picture as tail, by Dr. Henkin at the Eastern meaings of he did under the methedrine. This did not clear the American Federation for Clinical Research up until he was treated, as before (with the in December 1967. Since the main emphasis of my talk is on individual differences in LSD re- methedrine psychosis).On both occasions, he was very difficult to treat. 14 Gannon, R. My LSD trip: non-cop, non-hippie report. Dr. Meyer: To your knowledge, has anyone Popular Science, 191:60-65+, December 1967.

14 actions, I will only summarize briefly our gen- within subjects, between unusually low sen- eral findings regarding LSD effects: sory thresholds and deficient performance on 1. Auditory Thresholds, measured by a stan- tests of perceptual integration.:? This rela- dard audiometric procedure, were lower on tionship is found in both clinically normal baseline day for LSD subjects than for non- and abnormal subjects. dru:4:ed, non-psychiatric control subjects. 6. Pupillary dilation measured after LSD was 2. Following LSD ingestion, auditory thresh- ingested was significantly greater than on any olds were found to decrease even further in other testing occasion. the majority of subjects(5)and not to 7. An interesting electroencephalographic ef- change, but to remain low, in the other sub- fect was observed. Using a newly developed jects. This finding is in accord with the sen- procedure for measuring cortical averaged sory threshold results of otherinvestigators evoked responses (to light flashes),four dif- who have taken special care to establish a referent intensities of stimulation were em- laxed and cooperative attitude on the pan of ployed." The amplitude and latency values their subjects(e.g., Roland Fischer, Ohio of the averaged evoked responses (AER) were State Medical School) . Dr. Henkin, who car- computed for different peaks of the AER ried out the sensory threshold testing, was Waveform. One (and only one) remarkable especially impressed with the performances of effect was noted on one peak of the AER the ISD-drugged subjects. He compared them Waveform which deserves to be elaborated with patients with Addison's disease who are upon.Briefly, among non-drug-user, non- extraordinarily hypersensitive to low intensity psychiatric subjects, increasingly shorter aver- stimulation when not treated with adrenal aged evoked response latencies are recorded as cortical hormone. you increase the intensity of the photic stim- 3. No significant changes were found in taste uli. The slope of the stimulus intensity-AER and smell thresholds under any condition. latency function is linear and very steep for 4. Thresholds for "auditory discomfort" were normal male subjects; that is, AER latencies found to be significantly higher than normal are relatively long at the lowest stimulus in- on baseline day and wereincreased further on tensity and very short at the highest stimulus LSD day. This finding is consistent with re- intensity. (a) For our drug-user subjects, on search reports of decreased sensitivity to pain baseline day, the stimulus intensity-latency under the influence of LSD." The paradoxical function (slope) was significantly less steep positive correlation within the same subjects than that for a group of normal male subjects. of increased sensitivity to low intensity stimu- The average slope score was more similar to lation and decreased sensitivity to high inten- that of a group of normal female subjects. sity stimulation, i.e., to pain, is considered in (It certainly is noteworthy that when sex dif- detail in a paper entitled "A Paradigm for ferences are found on sensory threshold tests the Study of Altered States of Consciousness," and perceptual integration tests, females evidence lower threshold and less efficient per- by J. Silverman." ceptual integrationsimilar to our male, Dr. Lyman Wynne: Let me just underline that LSD-user subjects. The difference in AER la- our subjects' chronic usage of LSD hadbeen in- tency slope scores of normal males and normal terrupted prior to their coming in for the study females is highly significant.)(b) A couple so that there wasn't any likelihoodof an immediate toxic effect or other kind of effect from 15 Kau. E.. and Collins,V.J. Study of Lysergic Add usage during the previous week. Diethylamide as an analgesic agent. Anesthesia and Anal- gesia, 43:285-291, M4y-June 1964. Dr. Silverman: 11 Silvennan, J. A paradigm for the study of altered states 5. On speech discrimination tests designed to of consciousness. British Journal of Psychiatry, 114:1201 -1218, October 1968. measure auditory integration capacity, our 17 Kaswan, J.;Haralson, S.; and Cline, R. Variables in subjects evidenced some deficit in auditory in- perceptual and cognitive organization and differentiation. tegration on baseline day and a highly signif- Journal of Personality, 33:164-177, June 1965. 11. Buchsbaum, M., and Silverman. J. Stimulus intensity icant integration deficit on LSD day. Other control and the cortical evoked response. Psychosomatic investigators have noted a positive correlation, Medicine, 30:12-22, January-February 1968.

15 of hours after ingestion of 50 micrograms of knew that they were receiving LSD on day four. LSD, our drug-subjects' AER latency slope Whereas no remarkable symptom differences scores changed in the direction of, normal were observed between subjects on baseline day, male subjects, and no significant latency slope a rather marked range of symptom scores was score difference was found between ourLSD- recorded on the three other experimental days. drugged subjects and normal subjects. The On the basis of total symptom scores on LSD implications of these AER findings in relation day and on the day following LSD ingestion, to our other results are intriguing but since subjects were differentiated into two groups many AER scores wereanalyzed, the possibil- (Table 1).Analyses of the test battery were then ity must be mentioned that the AER effect carried out on the basis of this two group observed could have occurred by chance. distinction. I would like to turn to a consideration of dif- I. CLINICAL AND PERSONALITY ferences in the ways in which our experimental TESTING subjects reacted to LSD. The literature on the behaviors and subjective reports of LSD- A. Clinical Psychological Testing. The clini- drugged individuals indicates that there is con- cal psychologist (W.S.) on the research team siderable variability in the kinds of experiences was given a list of the subjects in each group, possible. The data to be presented here suggest but not one bit of information regarding that individuals who differ in systematic ways in their behaviors on or off drugs. He was asked personality characteristics also differ in sensory to compose summary descriptions of the per- and perceptual response characteristics and sonalities in the two groups of subjects. The hence in the ways in which they make sense out following is excerpted from the clinical psy- of an LSD experience. chologist's report. His formulation regarding Subjective reactions of each subject were re- two personality types is based primarily upon c.orded by the clinical psychiatrist (D.W.) on the subjects' Rorschach test verbalizations. the resParch team with the aid of the Subjective There was a fundamental difference of ap- Drug Effects Questionnaire (SDEQ) developed proach to the inkblots between type I by Katz Waskow, and Olssen of NIMH. The [Group I] " and type II [Group II] subjects questionnaire, which contains items dealing with a different relationship between the ob- (a) clarity of thinking, (b) degree of ambiva- server and the observed inkblots. While lence,(c)perceptual changes, (d) degree of Group II [Low Symptom report] subjects euphoria, and (e) degree of dysphoria, was ad- acted upon the inkblots, actively analyzing, ministered at the beginning of each of the four dissecting, structuring, and with a strong testing sessions. During the drug days (day two sense of authorship of their own percepts, and day four) the questionnaire was admin- Group I [High Symptom report] subjects istered approximately 45 minutes after ingestion demonstrated an attitude that the inkblots of the drugs. Although doubtful as to the drug authored the percepts, to which they only they were receiving on day two, all subjects gave voice. This difference in attitude is revealed by the way in which responses were Table I.SYMPTOM SCORES FOR EIGHT offered. Subject MC [Group II] consis- SUBJECTS ON THE SDEQ tentlyintroducedresponseswithsuch phrases as, "The very first thing I notice So Wet N.. No. (No. "'volition's that it reminds me of..."; "I do see a. .."; symptoms symptoms am* day) LSD daypast-LSD day "I also see...." In contrast, Subject SN A 95 46 (63) [Group Ij used such expressions as, "This looks like..."; "There are...."; and Group B 71 40 (621 I C 59 36 (70) "Now it's beginning to look like...." D 59 48 (441 Group I subjects seemed to accept un- critically the meaning presented by the E 44 15 (45) inkblots, submitting to the immediate stimu- Group F 40 2 (38) lus without reservation or judgment, letting II 6 33 3 (411 H 33 1 (31) 1. Bracketed words are my inserts.

16 the inkblot change its form and meaning and the Welsh Anxiety Scale. (None of the before their eyes. There was no tension IE measures discriminated between the two created by no meaning, no particular in- types of LSD reactors.") vestment in finding many meanings. The 1. Stimulus Change Seeking Scalethe horrifying was no more rejected than was higher scores of subjects in Group I as the pleasant if it was presented by an ink- compared with those in Group II were blot. Nor was any response rejected because consistent with the clinical psychological it would fail the test of consensual reality. and psychiatric evaluations. Group I sub- In striking contrast to Group II subjects, jects' higher scores were indicative of a whose responses were consistently reason- greater degree of stimulus-seeking behavior able (even at the expense of form appro- and a greater receptivity to novel stimula- priateness),Croup I subjects developed tion during ordinary, everyday situations responses which, while they fit theinkblots (Table 2). well enough, were often unreasonable or absurd....Absurdity or paradox appar- Table 2.STIMULUS CHANGE-SEEKING SCORES ently created no tension for Group I sub- OF TWO GROUPS OF LSD REACTORS jects. They were able to admit absurd, DIFFERENTIATED ON THE BASIS OF paradoxical, or "unrealistic" ideas suggested SDEQ SCORES by an immediate (inkblot) stimulus. ... Grou 1 Group 11 Group I subjects apparently have more Subject Ripm. chg. score Subject Pim. chg. score basic trust in people, and when anxious A 31 E 21 about interpersonal stresses, seek to resolve B 25 F 23 them in interpersonal interaction. Group C 29 G It II S's, in contrast, become distrustful when D 27 H 24 anxious, and rely on their own internal resources to resolve the anxiety. 2. Pleasantness-Unpleasantness Word Use B. Clinical Psychiatric Impressions. The in- ScaleHigher scores tended to predomi- ferences regarding the two personality types nate in Group I. These scores were indica- derived from the Rorschach test were clearly tive of a tendency for Group I subjects to similar to the impressions recorded indepen- use more unpleasant words and to be more dently by the clinical psychiatrist(D.W.) open to unpleasant ideas and affects than who had administered the SDEQ. Group II subjects (Table 3). GroupI. Open, experiencing, able to "let go" of controls and "go with the Table 3.PLEASANTNESS-UNPLEASANTNESS (PUP) WORD USE SCORES OF TWO GROUPS drugs." Score high in openness to OF LSD REACTORS contradictory experience on SDEQ. GROUP 1 GROUP 11 Group II. Analytic,rational emphasis on Subject PUP score Subject PUP score thinking rather than feeling, less open to change. Under the effects A 12 E s of the drugs they report relatively B 16 F 14 C I6 G 5 littlesubjective change. Highly D 10 H 9 motivated to stay in control and to structure their experiences. Rarely experience contradictory feelings. 3. Maudsley Personality Inventory (abbre- viatedversion)Neuroticism Scoreal- C. Personality QuestionnairesSeveral per- though a clearcut difference in Neuroticism sonality questionnaires were administered to each of the subjects on baseline day. The 20 Garlangton, W.K.. and Shimota, H.E. The change seeker index: a measure of the need for variable stimulus input. procedures were the Stimulus Change Seek- Psychological Reports, 14:919-924, June 1964. ing Scale," the Pleasantness-Unpleasantness 21 McReynolds. P., and Ullmann, L.P. Differential recall of Word Use Scale," the well known Maudsley pleasant and unpleasant words as a function of anxiety. journal of Clinical Psychology, 20:79-60, January 1964. Personality Inventory, two other short ques- 22 The Meyers -Briggs indicator was not among the questionnaires of Introversion-Extroversion (IE), tionnaires used.

17 scores was not found between the Groups, hypotheses regarding behavior under the influ- the two highest Neuroticism scores were ence of LSD: found in Group I and the two lowest Neu- A. Subjects in Group I will evidence lower roticism scores were found in Group II. sensory thresholds(i.e., will be more sensi- This is a curious finding in relation to the tive) than subject., in Group IIon the audio- other data obtained in that the more "re- metric threshold procedure. ceptive to stimulation," more "open to B. Subjects in Group I will evidencegreater unpleasantideationalstimuli"subjects (Group I) also had the high Neuroticism impairment than subjects in Group II in their ability to organize and articulate speech stim- scores. High-scoring subjects admitted to uli into meaningful patternson Henkin's (i.e., responded YES to)the six items auditory integration procedure. which comprisetheNeuroticismscale whereas low-scoring subjects responded NO C. Subjects in Group I will evidencegreater to most of the same items: responsiveness to irrelevant, contextualcues 1. Do you sometimes feel happy, some than subjects in Group II onour measures times depressed without any apparent of "anchoring" of psychophysical judgments. reason? D. Subjects in Group Iwill evidence a 3. Do you have frequent ups and downs greater tendency than subjects in Group II in mood, either with or without appar- to reduce automatically the experienced in- ent cause? tensity of strong stimulation. Thisresponse 5. Are you inclined to be moody? disposition, which usually is inferred from 6. Does your mind often wander when performances on a kinesthetic figural after- you are trying to concentrate? effects test, has been studied extensively in 9. Are you frequently "lost in thought" our laboratory and in Aseneth Petrie's lab- even when supposed to be taking part oratory. in a conversation? For each of the four measures,a trend was 11. Are you sometimes bubbling over with found in the predicted direction. On the whole, energy and sometimes very sluggish? " the trends weremore clearly apparent in subjects who were lighter in weight. This latter Tablit 4.--MAUDSLEY PERSONALITY INVENTORY finding was consistent with the results ofa num- NEUROTICISM SCORES OF TWO ber of other investigators' findings" that there- TYPES OF LSD REACTORS lationship between the microgram dosage of GROUP I GROUP II LSD used in the experiment and the body Subject MM score Subject MM score weight of the subject isan extremely important A 0 E +i consideration. It is an especially importantcon- +6 F 2 sideration in low-dosage experiments. In the C +6 6 4 present study in which a 50 microgram dosage D 0 H 0 was employed, differences between the two groups usually were apparent in subjects who Note: A Zero score indicates thata subject answered half YES, half NO. A positive score indicates thatmore items were weighed less than 70 kilograms. It is suggested answered YES; a nosativa score such asa 4 indicates that five items were answered NO and one item was answered YES. 23 The term Neutotidsm is not the term of choice of this investigator for describing individuals with many Yes re- II. SENSORY-PERCEPTUAL TESTING sponses. It is considered misleading and is retained only because it has been used this way by the originators of the Taken together, the clinical and personality MPI questionnaire. testing suggested a relatively clearcut basis for Silverrnan, J. Variations in cognitive control and psychophysiological defense in the schizophrenias. Psychosomatic differentiating subjects into two categories. The Medicine, 29:225-251, May-June 1967. next step was to develop hypotheses regarding Silverman, see footnote 16, page 15. the relationship between the personality-trait 21 Buchsbaum, see footnote 18, page 15. 27 Silverman, J.; Buchsbaum. M.; and Henkin. R. Stimulus patterns of the two groups and their modes of sensitivity and stimulus intensity control. Journal of Per- registering and organizing sensory input. Pri- ceptual and Motor Skills (to be published). marily on the basis of work done by myself and 28 Key. B.J. Effect of Lysergic Acid Dierhylamide on potentials evoked in the specific sensory pathways. British Medi- my colleagues,"-" I formulated the following cal Bulletin, 21:30-33, January 1965.

18 that the lighter-weight subjects weremore af- subject. Recall that all LSD subjects demon- fected by the 50 microgram dosage and thus strated an unusual sensitivityon the au- were more prone to evidence their unique pat- diometric procedure. Perhaps because the terns of adjusting to an LSD-induced altered "range of talent" was so skewed in thegreater- state of consciousness. sensitivity direction, no further differentia- 1. The lowest auditory threshold scorewas tion between the groupswas possible (Table found in a Group I subject; the highestau- 5) ditory threshold was found in a GroupH 2. There was no overlap in thescores of the

Table 5.-AUDITORY THRESHOLD SCORES OFSUBJECTS UNDER THE INFLUENCE OF LSD-25 GROUP I GROUP II Subject Body wt. # Symptoms Auditory Subject Body wt. # Symptoms Auditory in kg. LSO Post threshold in kg. LSD threshold day LSD SCAM day Ls sat day day A 62.0 95 46 -10 E 70.3 44 15 -IS B 67.5 71 40 -20 F 76.4 40 2 5 C 99.3 59 36 -10 G 55.6 33 3 -10 D 72.0 59 48 -IS H 64.5 33 I -10 Note: The higher the negative number, the greater the sensitivity of fla subject,i.e.. the lower the auditory threshold. two groups on the auditory integration meas- ability to organize and articulate speech stim- ure. Group I subjects evidenced greater im- uli into meaningful patterns (Table 6). pairment than Group II subjects in their

Table 6.-AUDITORY INTEGRATION SCORES OF SUBJECTS UNDER THEINFLUENCE OF LSD-25 GROUP I GROUP II Subject Body wt. LSD# Symptoms IntegrationSubject Body wt. # Symptoms Integration inkg. Post SC01111 in kg. LSD Post SCOT. day LSD day LSD day doY A 62.0 95 46 -18 E 70.3 44 15 +4 B 67.5 71 40 -12 F 76.4 40 2 -4 C 99.3 59 36 8 G 55.6 33 3 +4 0 72.0 59 49 -12 H 64.5 33 1 0 Note: The larger the negative number. the greater the impairment in auditory integration.

3. The highest "anchoring" scores, indicative in Group I; the lowest "anchoring"scores of hyper-responsiveness to irrelevant stimuli were found in Group II (Table 7). during perceptual judgment tests,were found

Table 7.-ANCHORING SCORES OF SUBJECTS UNDER THE INFLUENCE OFLSD 25 i GROUP I GRO UP II Subject Body wt. # Symptoms Anchoring Subject Body wt. # Symptoms Anchoring in kg. L SD Post score in kg. LSD Post soon day LSD day LSD day day A 62.0 95 46 IS E 70.3 44 15 2 B 67.5 71 40 14 F 76.4 40 2 7 C 99.3 59 36 6 G 55.6 33 3 12 D 72.0 59 48 5 H 64.5 33 I 1 I 4.Perceptual performancescores indicative Group II evidenced behavior on the figural of a reduction in the experienced intensity of after-effects procedure which was indicative of strong stimulation were clear-cut in three out pronounced sensory input reduction (Table of four Group I subjects. Notone subject in 8).

19 Table 8.--STIMULUSINTENSITY REDUCTION SCORES OF SUBJECTS UNDER THE INFLUENCE OF LSD25 GROUP I GROUP II Subject Body wt. # Symptoms Reduction Subject Body wt. # Symptoms Reduction in kg. LSD Post VANS in kg. LSD Post scores day LSD day LSD day day A 62.0 95 46 2.0 E 70.3 44 15 +0.8 B 67.5 71 40 2.0 F 76.4 40 2 1.3 C 99.3 59 36 2.3 6 55.6 33 3 1.3 D 72.0 59 48 0.3 H 64.5 33 1 0.8 Note: Scores of 2.0 or greater are indicative of significant stimulus-intensify reduction responsiveness. Smaller number negative scores are indicative of less pronounead reduction responsiveness.

In summary, the results of this pilot study are ions which can be drawn from this study. I not inconsistent with the hypothesized relation- believe, however, and with good reason, that fu- ships, especially among lighter-weight subjects. ture investigations in this field will confirm and On the basis of clinical and personality testing, expand upon our work and that the kind of re- it appears that Group I subjects are more open, search strategy described here will contribute in receptive, and seeking of environmental and in- a significant way to our understanding of human ternal stimulation than Group II subjects. On behavior. the basis of the LSD-day sensory-perceptual test- Dr. Meyer:Now we turn to Dr. Frosch. ing, Group I subjects are found to be quite sensitive to low-intensity auditory stimulation and Dr. William Frosch:I would like to start by re- tend to reduce the experienced intensity of ferring to the problem that Dr. Shagass brought strong stimulation to a greater extent than up concerning recurrent experiences. These first Group II subjects. Group I subjects also evi- came to my attention when our research group dence more impairment on tests of perceptual received a call from the admitting office saying, integration and judgment. The greater impair- "We have a crazy guy down here who sounds ment in perceptual functioning which is charac- like he's on a trip, but denies it. Do you want teristic of Group I subjects under the influence to see him?" We did. The patient came up and of LSD is consistent with their disposition to said, "Doctor, there is something wrong with me; yield to the drug experience, to "go along with my wife says I'm beginning to talk crazy. I've it," rather than to counteract its effects. Since never talked this way before and things are be- LSD induces a state in which attention to every- ginning to look funny, just as they did when I day events (e.g., sensations, ideas, memories) is took LSD." He attributed the changes in per- dramatically altered, it is not surprising that or- ception and in self-feeling to his earlier LSD dinary perceptual functioning is impaired and experience. He was terribly worried that he had that it is more impaired in open, receptive in- perhaps permanently damaged himself and this dividuals. The unusual reaction to LSD-25 is was why he had come to the hospital. He insisted typically one in which no impressive impairment that these kinds of experiences had never oc- in perceptual and cognitive functioning occurs. curred to him before. He was a good historian Indeed, a concerted attempt on the part of an and in many ways one of the most stable of the individual to maintain an active analytic intel- people we had seen. He had a wife and children lectual style rather than to yield psychologically and worked as a junior executive and has con- (and physiologically) to the effects of LSD, is tinued to do so. While it is difficult to evaluate probably an important precursor of an aborted such post-hoc reports, it is likely that he had not LSD experience. been psychotic or pre-psychotic prior to his Until further research has been carried out, earlier LSD trip. The drug may have changed all of the above inferences must be considered or triggered something. The presenting symp- as, at the most, tentative ones. The very small toms were not only transient anxiety states, but number of subjects in the sample, the lack of were also very characteristic perceptual distor- clear-cut differences, in some instances, and the tions of the sort that are usually associated with small dosages of LSD-25 employed are just a few LSD (e.g.: kaleidoscopic color changes).These of the factors which limit the kinds of conclus- recurrent states were, however, associated with

20 events in his mental life. Forexample, this man some of the patients thatwe've seen. Once the had a difficult situation with his boss, and ashe acute episode is over, we've been unable to de- looked at his boss' face it would begin to break termine anything that would be described classi- up into kaleidoscopic patterns.He lost his job cally as organicity on either the Wechsler scales as a result of thissituation. In summary, while or the Bender-Gastalt. We've also doneEEG's. some of our patients veryclearly link the onset Within the three days following admission we've of these recurrent experiences to theiringestion seensomenon-specific"drug-effectEEG of LSD, the episodes are frequently triggeredby changes." These are transient and may be re- real events and may represent phenomena or ex- lated to the ingestion of other drugs in the aggerations of phenomena perhaps previously period preceding admission. In fact 90 percent experienced (i.e.: prior to LSD ingestion) . of the patients admitted because of LSD have In viewing adverse reactions generally, we had experience with amphetamines; two-thirds have had an average of two patients a week ad- have taken barbiturates; and, rather surpris- mitted to Bellevue for whom we feel that the ingly, about one-half have tried one of the opi- LSD experience played, at the very least, a pre- ates. As one would expect, there is an almost cipitating role in the admission. As was saidin universal use of marihuana in this group. We've the circulated paper, we've seen many, many seen only one patient who had never usedmari- more people whohad LSD experiences, but who huana. This woman was somewhat unusual in were hospitalizedfor some other reason. These other respects. She was a woman of 34 who went wereusuallyacuteschizophrenicepisodes to a psychologist looking for help. She claims which, as far as we can determine, were unre- that the psychologist said, "Here is some LSD, lated to the previous drug experience. Whether go home and take it." Shehad an acute psy- this average admission rate(two patients a chotic reaction. She is now furious and has an week) really represented a stable admission rate evangelical anti-LSD attitude. is difficult to determine. Initially we sawalmost Several years ago Dr. Korein and Dr. Musac- all of the patients with this problem inthe New chio from our department were interested in the York City area. In the intervening year or so, use of LSD to unmask latentneurological de- some other hospitalshave begun to admit them. fects, similar to the way amobarbital may induce Dr. Hirschhorn tells me that MountSinai has focal weakness. Since many of the effects of LSD now been seeing anumber of these patients, are sensory, they felt thatadministration of LSD and I know that in the last year KingsCounty might induce sensory disturbances in patients has evaluated and admitted many patientswith with neurological disease. They administered this diagnosis. This may represent anincreasing 100 micrograms of LSD intravenously to 14 pa- admission rate. tients with sensory disorders resulting from focal Although my research group hasn't seen all cerebral diseases. These included visual field de- of the LSD patients, we have studied anumber fects and hemisensory defects. of samples over the years. Each sample is essen- All of the patients had symptoms within five tially identical to every other in terms of the to ten minutes. The usualinitial symptom was basic demographic characteristics, as well asthe drowsiness which, as in Hoffman's original de- clinical picture. In contrast with the usualBelle- scription, was described as a feeling of dizzi- vue population, they areall young, middle class, ness and drunkenness.Nine of the 14 patients and almost exclusively white. This is certainly showed anxiety and agitation, three had alter- consistent with our usual stereotype of this pop- nating euphoria and depression. Six had what ulation. It is of interest, however, that the Kings theinvestigators(who wereneurologists) County sample has a relatively high proportion termed clinical psychosisconsisting of halluci- of Negroes and is a lower class population. Kings nations, depersonalization, and marked anxiety. County also feels that their patients' involve- In three subjects the reaction was "violent" and ment with LSD starts with the onsetof a psy- in two the procedure was interrupted with chosis. They seek out the drug in an attempt at chlorpromazine. There were specific neurologi- self cure. This has certainly been true for some cal effects in all of the 12 patients on whomdata of our patients, but doesn't seem to have been could be obtained. In three out of four patients true for all. a mild aphasiabecame worse. There didn't seem We've done routine psychological testing on to be any change in theorganic mental syn-

21 dromes which were mildly present infour to go on to Dr. Smith who will talk about the patients. Five of the seven patients with homon- West Coast scene. ymous visual field defects showed visual changes Dr. David Smith: A number of questions have such as flashing lights, or distortions of color or been raised relative to drug practices in the distance. There were lateralized somatosensory Haight-Ashbury district of San Francisco, and distortions which appeared to be related to the I'll look forward to discussing these questions locus of the cerebral disease in patients with during the question and answer period. In this hemisensory defects. One patient had a localized part of my presentation, I'd like to focus pri- clonic seizure of the upper extremity. The EEG marily on our specific experience with the com- appeared "less abnormal" after administration pound STP. As I'm sure you know, STP .is in of LSD. There was a decrease in the amount effect a "proprietary name" established by the and/or amplitude of slow-wave activity. underground or black market. It means serenity, I would also like to comment on Dr. Silver- tranquility, and peace. The generic name for this man's suggestion that hypersensitivity is an im- chemical substance is DOM or 2,5dimethoxy- pairment of sensory integration. Clinically, in -a, 4-dimethylphenethylamine. Itis a com- those patients whom I have been able to observe pound related to the amphetamines, but it has during a recurrence, this seems to be what's go- some very unusual and different properties which ing on. While sitting with me, a patient will were very surprising to us. In this presentation hear a sound. This distracts him and he will get I'll attempt to describe not only the clinical lost in a perceptual distortion. properties of the drug, but also its introduction One final word, we've seen very little DMT into a highly susceptible drug-using population. (Dimethyltryptamine) or DET (Diethyltrypta- First I would like to describe the population mine) resulting in hospitalization even though into which STP was introduced. We first heard it apparently is present in New York. I wonder reports of STP by "psychedelic leaders" as early if this is related to the length of the trip. Even as February 1967, but the first written reports a "bad" trip doesn't last long enoughfor them appeared in the underground newspapersfol- to get to the hospital. We've also had onedrug sample which was reputed to be STP. It was a lowing a predictable marketing pattern. The green-blue-grey tablet. One-half of this tablet, Berkeley Barb described the compound as being a guaranteed "good" trip that was not yet illegal. which weighed 172 milligrams, was given intra- We heard enough of these reports to know that venously to a dog. Nothing was observed except something was coming. mild fore-limb tremor which may have been re- On June 6,1967, we opened the Haight- lated to the fact that it was a suspension rather Ashbury Medical Clinic which was a general than a solution that was injected. Chemical tests medical facility dealing with the hippies in the have not yet been completed. Haight-Ashbury. The population at risk during COMMENT FROM AUDIENCE: Most of the summer was by no means homogeneous. We these mescaline-type compounds are extremely have a large drug survey going now, entitled difficult to get any kind of evidence and analysis "Drug Practices in the Haight-Ashbury Subcul- on. ture." Our ,lata have not been completely ana- Dr. Frosch: Some of the original descriptions of lyzed bat our impressions to date are that the STP sounded to us like a Ditran effect, but it's population at risk was composed essentially of very clearly not a Ditran-related compound. three major groups. First of all, there was a large group of teenagers who were in Haight-Ashbury The only thing I know of that would distin- primarily for the summer experience. They had guish a mescaline-like drug from a Ditran-like not, by and large, had experience with anydrug compound is whether the patient has a mydria- but marihuana, although some may have taken sis with or without cycloplegia. Dr. Samuel LSD one or two times. In essence this group was Gershon who ran the dogs is very "hep" on anti- oriented toward taking drugs, but had very little cholinergics. I would accept his findings that it experience. The second group consisted of indi- is not a Ditran-like compound. I think that he viduals who had built their philosophy around would know. the mystical and evangelical experiences of LSD. Dr. Meyer: Thank you very much. I would like They are of the "drop-out category," and were

22 fully committed to the hippie philosophy. Many long duration of the STP trip (72 hours)pro- were actively involved in some of the local or- duced a fear and panic withconcerns that they ganizations in the Haight-Ashbury, such as The would "not come down." Therewere marked Diggers, The Straight Theatre (4 community and vividly colored hallucinations. Many of the cultural center), ourclinic, etc. The third group individuals who had taken LSDmore than 100 can be described best as an odd mixture of soci- times, and were therefore very experienced with opathic personalities (including the motorcycle psychedelics, described themselvesas encounter- gangs) that came to Haight-Ashbury for a vari- ing their first "bad" trip with STP. They de- ety of reasons. Certainly amongst this group scribed the experience as beingmore intense, there were a lot of compulsive drug users. Some and lasting so long that eventuallyan adverse of these individuals had a long previous history reaction developed. of multiple drug abuse patterns. We saw almost universally a very rapid tachy- Although we heard reports of the STP being cardia with fine muscle tremors, and dilated used, we did not see a case in the San Francisco pupils that were sluggishly reactive to light and area until June 8, and this seemed an isolated accommodation. I think that at the timewe event. However, on June 21 at a hippie cele- should have been in a better position to describe bration of the summer solstice (one of a series this as not being an atropine-like compound. of events held in the Haight-Ashbury "summer However, we had heard of the possibility of of love festival"),5000 STP tablets were given the Ditran series being introduced into the away without chargeinthe panhandle of community and we were very much concerned Golden Gate Park. Very soon after that we saw because of the high incidence of delirium with a number of adverse reactions to STP. The tab- these drugs. Just prior to this,we had heard lets that were distributed on this occasion were that an agent which had been used for Army all stamped out of the same die. We have reports chemical warfare had been stolen, and these that approximately 15,000 of these aquamarine vague rumors and the physical syndrome that tablets were distributed and that many have we were seeing made us think initially that we since been turned over to the Food and Drug were dealing with an atropine-like substance. Administration for chemical analysis. We have At the end of June wesaw 20 cases enter the evidence that no new STP tablets have been clinic; we had no idea what the compoundwas introduced into the Haight-Ashbury since that which had been ingested. time except for some amphetamine labelled as In the city of San Francisco thousands of ad- STP (in order to get a higher price for that verse reactions to LSD occur. The standard ap- material). proach in institutions is the utilization of large I think it would be advisable for me to de- dosages of intramuscular chlorpromazine. The scribe the clinical STP syndrome to give you first few cases that were treated at San Francisco some idea of how our clinic handled the situa- General Hospital became markedlymore agi- tion of an unknown drug. We have a population tated and very disturbed after the administra- of 10,000 to 20,000 people in the Haight- tion of chlorpromazine. At this timeour feeling Ashbury, but this is a very transient population. was that the clinical syndrome represented that LSD use approaches 90 percent. At least 50 per- of an atropine-like drug. This seemed to explain cent of the population had been there less than several aggravated clinical states in which chlor- two months and had come primarily for the promazine was given and the patient thenap- summer. We estimate that during the summer peared to get worse. We were particularly of 1967 there were at least 100,000 persons pass- disturbed because chlorpromazine isa very im- ing through the community, although the steady portant drug on the Haight-Ashbury black mar- state population would be between 10,000 and ket and we knew that for everyone case that 20,000. Our Haight-Ashbury Clinic saw 10,000 was seen in institutions at that time prior to the medical cases in three months. opening of the Haight-Ashbury Medical Clinic, Now, the clinical STP syndrome, as we ini- at least a hundred cases were treated outside of tially saw it, was of long duration and itwas institutions with self medication. We therefore this long duration that produced many of the published widely in the underground literature "bad" trips. Many of the patients said that they that chlorpromazine was contraindicated, and experienced initially good feelings, but that the that those having STP reactions shouldcome to

23 the clinic where there would be medical assis- sults in calming much of the anxiety and tance without legal repercussions. seemed preferable to chlorpromazine. In July, chemical analysis revealed that this The hospitalizedpatients had a much compound was a substituted phenylethylamine higher incidence of long-term psychological and that this was not an anticholinergic com- problems(depression,"flash-backs,"etc.). pound. However, in reviewing our hospital data One sample case illustrates some of the rea- it would appear from our results that the ques- sons for this. An individual had taken an un- tion of chlorpromazine is still unsettled. Our in- known drug and was admitted to the hospital itial results and impressions with cases that have actively hallucinating. The psychiatrist on the occurred since that time indicate that this phe- ward gave him a large dose of chlorpromazine nothiazine in no case interrupted or shortened and when the hallucinations did not clear, the duration of the hallucinatory experience. gave him progressively increasing doses of this There is at the present time (September 1967) drug to 800 mg. four times a day. The reac- very little STP usage. The majority of the ap- tion became progressively worse and on the proximately 50 cases that we studied in detail tenth day the individual walked out of the came in the months of June and July. Thedrug hospital never to be seen again. rapidly lost favor for a variety of reasons, but I To summarize, in areas where thereis think that we can now come up with some val- a high incidence of psychedelic drug-usage uable recommendations as to a treatment re- there is far too much dependence upon the gime. In a forthcoming paper which Dr. Fred phenothiazines. We would recommend that Meyers and I will publish, we divide the STP when in doubt, the phenothiazines should not cases into the following four majorcategories: be used, that these very extreme hallucina- 1. "Good" trips occurred in a significant tory experiences can be handled with seda- number of people who took STP and who tives and supportive psychotherapy. were able to handle the experience. These In conclusion, I would like to state that it is people were predominantly those who had very disturbing to us that the gap between the had a lot of experience with LSD, and a very psychedelic drug-using population and the sci- low liability to adverse reactions. They con- entific and medical community is widening so sidered the STP experience to be the "caviar rapidly. We are now faced with the introduction of the psychedelic experiences." This group of another hallucinogen in the DOM series. This still takes STP periodically. drug is called MDA. MDA is the chemical 2. Some "bad" trips were handled by the name; the proprietary name for this compound community. was to be FDA but the underground black market decided to change their approach, probably 3. Some "bad" trips were handled by the because the STP got a lot of bad publicity which Haight-Ashbury Medical Clinic which de- essentially killed the market. When the scientific emphasizes chlorpromazinetreatment and community is not in contact with the drug-using emphasizes the use of a non-professional guide population, then the scientific community is hit to sit with the individual and try to talk him with a series of surprise "shock waves." In par- through his experience. We have found that ticular, those of us who are on the psychedelic (as in the LSD experience) the patient can front lines are faced with a mass of patients who be seen by a physician and encouraged to have ingested the unknown compound and are work with either a physician or a sympathetic having a reaction that is very difficult to define. individual to alleviate an acute panic reaction I would like to close by asking that the scien- (the major and dominant reaction seen in the tific community make more of an attempt to Haight-Ashbury). come into contact with the drug-using popula- 4. Some "bad" trips were admitted to the hos- tion. One of the major problems with the popu- pital. At our county hospital the supportive lation in the Haight-Ashbury is that they have psychotherapeutic approach is deemphasized essentially turned away from institutions and because of lack *of personnel, but the regime will not seek traditional medical help. They are of chlordiazepoxide as a sedative and chloral left to their own devices, which tend to poten- hydrate as a hypnotic seemed to have good re- tiate and propagate the patterns of drug abuse.

24 We must realize that a majority of the "adverse plaining of adverse reactions stated that they reactions to hallucinogenic drugs" (which is the were on a "death" trip. Therapid tachycardia title for this symposium) are happening outside induced by the STP led to the fear of a heart of our institutions. If our studies do not empha- attack. Thus. aspects of "What will happen size more research of the participant-observation when I die?" were introduced into their minds, type then our information aboutthis topic will followed by a panic reaction. In our "calm cen- continue in its present state of inadequacy. ter" we have attempted to treat these problems merely by sitting and talking with the patient; Dr. Freedman: I do want to say one thing about chlorpromazine. At Yale we stopped giving it for explaining that all he was having was a rapid heart rate which would go away. In other words, bad reactions several years ago. We gave amytal just as we would in a seizure state if we had by explaining the symptom we have endeavored therapy. As a to divert his mind from thoughtsof death. Many to. Generally we gave supportive times this has been all. that was necessary to stop result, we never had any contaminating psycho- a "bad" trip. On the otherhand, these same in- logical reactions, that is, the chlorpromazine con- dividuals when allowed to progress on the street fusion and the LSD state. In animals it has been shown that you could stop an LSD reactionin might end up at the San Francisco General Hos- the rat with as little as 30 gamma per kiloof pital, running down the street away from some- chlorpromazine where the normal dose is 2 mg. thing in a very acutely paranoid state. The point higher, you got a com- is that if you can reach these patients at a very per kilo. If you went early stage in their psychotic reactions, many pounded reaction, a chlorpromazine reaction times you can interrupt it. However, if the in- and an LSD reaction. While you neverknow what inferences you can make from animals to dividual is forced to go through waiting lines, why we were get- ambulances, police, etc., this merely aggravates man, this tipped us off as to the reaction. I think this is the reason that the ting some confusing reactions. hospital were so severe and The second pharmacological pointthatI cases at the county think should be noted here is that the plasma extreme and sometimes related toself-inflicted level of LSD correlates beautifullywith the wounds. period of acute effects of LSD in animals andin Dr. Meyer: Dr. Frosch, Dr. Ditman, and Dr. man. The waves ofreaction that we sometimes Ungerleideris it your experience as well that get at least from animaldata seem to be due to phenothiazines perhaps are contraindicated in the fact that LSD is sometimes heldin tissues the management of some of the acute adverse and then comes out suddenly into theplasma reactions? several hours later. Dr. Ditman: I would say no. QUESTION: What tissues? Dr. Freedman: We don't know yet. AsI've said, Dr. Ungerleider: Let me say that we have seen we have monitoredplasma concentrations. I six or seven paradoxical reactions to chlor- have wondered whether STP and itsduration of promazine when we gave up to 3,000 mg. per actions shouldn't be monitored as youwould day. One case was described in which the patient any otherpharmacological problemthat is, showed neither improvement nor exaggeration let's get plasma levels and see what'shappening. of symptoms until we stopped thechlorproma- These Can I also just raise one question?What is the zine after which the patient improved. actual length of duration of the STPreaction? paradoxical reactions to chlorpromazine have been reported, however, not only in the treat- Dr. Smith: It was between 16 and 72hours. We ment of adverse LSDreactions but in the treat- had one case of an undiagnosed, prolonged acute ment of schizophrenia aswell. brain syndrome that lasted for 10 days inwhich the individual was activelyhallucinating and Dr. Frosch: We have been impressedwith the out of contact withreality. In this particular fact that many of our patients don't respond to situation the patient had been exposed to pro- phenothiazines. I am not so sure about the para- gressively and increasingly higher doses of phe- doxical reactions. There may be a few but many nothiazine in addition to his previously ingested of them go right on their merry way.Addition- STP. ally, we have hesitated to add somethingwhen The first group who came into our clinic com- we knew so little aboutwhat was going on to 25 begin with. It sounds as though manyof the started. I suppose that we could haveanticipated management problems arebest handled by re- the abuse of LSD, but perhaps not to the extent assurance and bydiscreet use of hypnotics. that it has gone. In 1961, I firstbecame aware illicitly- Back in of a person selling sugar cubes with Dr. Freedman: May I raise one point. made LSD in them. Dr. SidneyCohen and I 1956 Mayer-Gross 29 describedchlorpromazine began reporting on this at that time. This was as apsychotomimetic. This statement actually the beginning of the black marketingof illicitly- appears in oneof his papers. He found that of il- they had made LSD. One of the earliest casualties when it was given to normal people licit LSD that I know of was a 14-year-oldboy. peculiarly colored dreams and in one or two very He had the recurrent symptoms that Dr.Frosch well recorded cases people hadpsychotic-like re- has mentioned. The symptoms went onfor a sponses to it. know what period of a month or more. I also think it is important that we I would like to digress slightly here. It is not we are treating.We are treating panic, depres- only with LSD that you see such"flashbacks." sion, and hallucinations; we are notjust treat- dropped out of law They are reported for CO 2 therapy and we are ing a kid because he has all familiar with the alcoholics' accountof the school. "dry drunk." I suspect that suggestionis an im- Dr. Meyer: At this point, Iwould like to cut portant factor in thissyndrome. off discussion until we hearfrom Drs. Ditman With our card sort we have been trying to and Osmond whose presentationswill round out study the nature of the LSD experience; to com- the morning session. pare experiencesfor those who need treatment Dr. Keith Ditman: What I amgoing to talk afterwards with those who need no treatment, about today is a study in which wetried to de- or even claimbeneficial effects from the experi- termine the harmful aspects of theLSD experience. We obtainedcard sorts on 116 subjects who ence. whom we divided into three groups: those My experience with LSD goesback over the apparently needed no treatment or evenclaimed past 11 years,during which time I have been benefit, those who needed out-patient treatment, interested in LSD as a possiblepsychothera- and those who needed hospitalization.Group I, peutic adjunct, particularlywith alcoholics. I the largest in number, consistedof 52 persons, have also been interested indeveloping instru- none of whomneeded psychiatric care because ments that couldgive us a better understanding of the LSD experience. This groupis of con- of the nature of the LSDexperience. To this siderable interest because a greatmajority of end, John Whittlesey, ThelmaMoss, and I have subjects were functioning either at jobs or as stu- developed a card sort which is aninstrument to dents at the time of testing.Many reported obtain a retrospective descriptionof a person's having had several drug experiences.This pop- LSD experience. It can be usedactually for any ulation was recruited through a varietyof com- consciousness-changing experience, butis par- munity contacts, including students,patients, ticularly useful for the LSDexperience. and colleagues.I cannot state that they are In following the currentrevival of the use of really comparable to the other two groups, hallucinogens and studying theliterature of another than that they claimed that theyhad taken tiquity, I am impressed with thelack of reported LSD. Group II is composed of 27subjects who psychiatric complications amongthe Indians applied either privately or throughclinics for and others who have usedvarious hallucino- psychiatric out-patient care, apparently as a re- genic drugs. This apparent safetyled many result of their LSD experiences. Aswith Group I, search investigators to viewthese compounds a majorityof these subjects were employed at benignly (until recently) . Weshould have been the time of testing and reportedmultiple-drug of 37 sub- more awareof the abuse potential ofthese sub- experiences. Group III is composed stances. Some 70 years agoHavelock Ellis pub- jects seen in psychiatric hospitalsin the Los An- lished on mescaline in Lancet,"predicting that abuse substance. In my 29 Ginzel,K.H.,andMayer-Gross, W. Preventionof it had a real future as an psychological effects d-Lysergic AcidDiethylamide (LSD-25) early experience with LSD I saw someabuse, by its 2-Brom derivative (BOL 148). Nature,178:210+, 1956. even amongprofessionals. I think it was here 30 Ellis, H. A note on the phenomena of mescalintoxica- (among theprofessionals)thattheabuse tion. Lancet, 1540-1542, 1897.

26 geles area where they had been hospitalized as a ture. The only group reporting use of hard nar- result of their LSD sessions. Again a multiple- cotics, however, was Group III, with 23 percent drug experience was reported for Group III, in that category so reporting. We feel that per- but unlike Groups I and II, many of these sub- sonality factors have contributed to the hospi- jects were unemployed. talization of Group III. The percentage of The card sort we used in this study has 156 persons functioning at work or as students de- items descriptive of the LSD experience. The creases from 88 percent in the non-treatment subjects were asked to sort the items into five group down to 39 percent in the hospitalized piles, depending on how descriptive of their ex- group. A Chi Square test of this data reveals periences they were. The headings of these five significance at the .001 level. It should be noted piles we.e: that the level of functioning was assessed just prior to interviewing and not before the LSD 1. Very much like the experience experience. 2. Like the experience I do not have time to go over the 41 items 3. Neither like nor unlike the experience which differentiated among the three drug 4. Unlike the experience groups, other than to say that those who needed 5. Very unlike the experience treatment had experiences indicating marked We have classified, according to our own impres- anxiety, depression, feelings of persecutory para- sions, the items in this card sort into the follow- noia, and fears of going insane. Such emotions ing 12 categories: and thoughts were far more prevalent in the treatment groups than in the non-treatment 1. Strong Pleasant Emotions groups. This was at .01 level of confidence or 2. Self-Understanding and Aesthetic better for all 41 items. The one item which dif- Appreciation ferentiated among the three groups more than 3. Mystical and Paranormal Sensations any other item was, "I felt that I might become 4. Empathy permanently insane." Curiously, the hospital- 5. Religious Feelings ized group(as compared to the out-patient 6. Unusual Though Not Unpleasant Body group) did describe some aspects of their experi- Sensations and Perceptions ences as euphoric. From this data we areunder 7. Somatic Discomfort the impression that it may be the nature of the 8. Depression LSD experiences that is causing the untoward 9. Paranoia after-effects in these individuals. In other words, 10. Anxiety LSD is psychologically toxic, if I may use that 11. Hallucinations term. Complaints of these people after an up- 12. An Evaluation of the Experience setting LSD experience include anxiety, depres- Surprisingly, the frequency of LSD usage shows sion, borderline psychosis, psychosis, etc. I have no significantdifferences among thethree the impression from my experience treating a groups. The percentage of GroupI subjects number of these cases that one is dealing more (the ones who did not need treatment) report- with young individuals who are non-achievers, ing 25 or more sessions with LSD, was 35 per- perhaps schizoid characters or borderline psy- cent as compared with 38 percent inGroup III chotics, and that superimposed on these prob- (the hospitalized group).The percentage of lems there is the traumatic drug experience. I subjects who reported taking [Si) only once was think that a traumatic neurosis may have devel- relatively small in all groups; 25 percent in oped on top of already disturbed personality or Group I to 11 percent in Group III. Similarly, thought disorders. histories of other drugs taken by these 116 sub- Dr. Humphrey Osmond: During the past 15 jects revealed almost parallel percentages in all studies in a three groups; 53 percent in Group I, 67 per- years I have made a number of cent in Group II, and 63 percent inGroup III. variety of contexts, using LSD-25 and other In other words, over half of these people reported substances. Some of these studies were aimed at casual to frequent usage of various drugs, stimu- producing psychotic-like effects; others at treat- lants, sedatives, tranquilizers, and hallucinogens. ing alcoholism and other conditions; still others I suppose that we were sampling the drug cul- at studying more generalpsycho-social effects.

27 Our original subjects were universitystudents. far as our crude test showed. We knew that It was clear that they were far less able to something more refined was needed. We had "handle" LSD-25 than our alcoholic patients found in the HOD test that sensory perception, who seemed very tolerant of it and could take time perception, self perception, and perception four to five times as much as the students. of others were very useful. In our new instru- In those early years of the 1950's oneof ment, the EWI (Experiential World Inven- the bitter and recurring argumentsconcerned tory) we had greatly increased the number of whether or not the LSD experience resembled a items dealing with these last three categories. psychosis, particularly schizophrenia. This ques- Our new test shows that the characteristic which tion has not yet been completely resolved. Itall most clearly differentiates the stateinduced by depends on how you define a schizophrenic-like LSD-25 from clinical schizophrenia is our Dys- state and, of course, onwhether you have some phoria scale. ways of measuring it, onceit is defined. I do not Schizophrenics, as we have shown, are usually believe that we could measure it at that time. as, or even more, depressed than thosediag- We began by using the Rorschach, but manyof nosed as having depressive illnesses, or melan- our subjects could onlydo one card and that, it cholia. LSD-25 takers, on the other hand, are appears, is not enough. Wetried other tests usually much more cheerful. Otherwise the ex- which did not work and then, early in 1960, we periences of LSD-25 takers resemble those Of developed the HOD test, named in jest the severe schizophrenics ratherclosely. It would be Hoffer-Osmond Diagnostic test. This test was difficult to believe that many people would ever constructed following a squabble with our psy- take LSD-25 more than once if it were always chologist friends in which we rashly cast doubts or often accompanied by severedepression and upon the tests which theyhad been using, and despair. The schizophrenic patient has good they suggested rather tartly that if we were so cause to be gloomy becausehe is trapped in his smart we could make one ourselves.We were illness and cannot get out. The LSD-25 taker, trapped into the attempt. whether his experience is pleasant or not, is al- The test is extremely simple; indeed, with our ways buoyed up with thethought that it will lack of knowledge of test making, it could hardly soon be over. Even when hedoesn't enjoy him- be otherwise. It consists of 145 statements on self much, the thought of its ending and his be- cards which the test-taker sorts as true or false. ing able to talk to friends about his experience Many of these statements' are taken from the is a source of hope and comfort. If you cover records or from talks with schizophrenic persons. up the Dysphoria scale,it is not easy to distin- When used by those who have taken LSD-25, guish schizophrenia from the LSD-25 state. we have found it bestfor them to take the test There is one other significant difference: we retrospectively, for if the test cards are given have a scale, the impulse control scale, from during the experience, many such subjects be- which it is clear that many schizophrenic pa- come extremelyparanoid and one actually be- tients feel that the situation is getting out of came catatonic.Luckily,schizophrenics are hand and beyond their control. Most LSD-25 much more obliging. Even "back-wardburnt- takers feel more or less in control, though not out" cases will cooperate splendidly. They seem all are completely sure. We have found that both to be burning fiercely ratherthan to be burnt the HOD and EWI tests can be very usefulif out. Schizophrenics on thewhole take the test patients are asked to do the tests as they are now, with zeal and alacrity. They have a test-retest as they were attheir worst, and as they were at correlation of about 0.9 and seem to enjoy the their best. This saves a great deal of time and test and speak about it asbeing helpful to them. allows one to estimate whether the patient is get- Severely catatonic patients who did not express ting better or worse. satisfaction at the time, emphasized once they By doing our tests over a number of years, were better that it washelpful for them to know show that most patients that someone had some notion of their strange we have been able to have a clear and rather accurate recollectionof predicament. By early 1961 we had a good deal of evidence their illnesses. This is of great value clinically that schizophrenia and the states following the because one of the most difficult decisions facing taking of LSD-25 have many similarities, in so the clinician is that of differentiating someone

28 who is becoming worse from someone who is ords show that her conditionwas not similar to getting better. that of the frequent LSD-25users but closely The success of the HOD and EWI tests seems resembled schizophreniaas seen in her own to be due in part to the fact that patients con- earlier records and that of others. She bemoaned sider the statements on the cards relevant to her bad luck, to which I replied, "Sorry, bad their illness and so are very cooperative. Re- judgment is a more appropriate label." cently we have given our tests to people who I was delighted to find that usingdifferent have been frequent users of LSD-25, or at least methods from ours, Dr. Silverman hascome to substances labelled as such. We now have rec- very similar conclusions. What happens to these ords from eight of these frequent users. Most of adventurers resemblessome aspects of schizo- them are functioning well according to their phrenia but is not identicalto it. I believe that standards. Their ages range from 18 to 42. They one can produce a negative LSD-25 experience are not like schizophrenics even though they do that would closely resemble schizophrenia.One have sensory, time, body, and self-perception of the easier ways is to tella person who is in disturbances resembling those found insome the middle of an LSD-25 experience that hewas schizophrenia. They are overly alert, their per- given a placebo; this is likelyto be very dis- ceptual constancy is impaired, their experience turbing, but could easily be harmful and, there- of time is peculiar, their level of consciousness fore, should not be tried. Ifone adds a good fluctuates, and they have some disturbances in deal of dysphoria to the LSD-25 takers' EWI their body image. One might expect that such records, they look very much like those of schizo- changes would impair conceptual thinking and phrenia. Using our HODtest we have given a indeed, they do complain of some reduction of random mixture of the records of schizophrenia intellectual efficiency, though they feelmore and LSD-25 takers togroups of psychiatrists, creative. Depression is almost always low and asking them to say whichwere which. They did even if they feel mildly depressed and irritable, not succeed, except for one group who did very they claim there is an underlying euphoria and well indeed. At the time,we and they did not that they are intrigued and excited. Paranoid know why they succeeded, but itseems possible features are conspicuously lacking. that they had recognized dysphoriaas being the Just before I left Princeton, my colleague, Dr. key and so were able to do much better thanwe Moneim El-Meligi, checked on a special scale ourselves and others. that we have been developing which we call We are still not at all sure that all psychedelic hyperaesthesia. Seven out of eight of these LSD- substances produce thesame experiences. One 25 takers scored very high on this scale, higher would expect not, as peopleuse rather different than nearly all normals we have studied. Some- words for describing the effects of differentpsy- thing has clearly happened to them. However, chedelics. However, now thatwe have reliable it is only a small group and it is too earlyto ways of establishing a baseline for a person's ex- draw any far reaching conclusions. Theseusers perience we should be in a much better posi- themselves believe that they have hada change tion to explore these matters in depth. Using of personality which they feel is for the better. the Experiential World Inventory, Dr. Bernard I am not quite so convinced of this, but Iam Aaronson has shown that focal disturbances of certain that something has happened. temporal and spatial perception which hepro- Yesterday we had a bonafide schizophrenic duces by post-hypnotic suggestion aimed ata with whom a number of colleagues and I have single perceptual modality tend to spreadto been working for a year; fromour clinical find- other aspects of perception. This is both elegant ings, her reports, and our testswe felt we had and puzzling. We do not yet fully understand largely succeeded in getting her better. Ten days exactly what this means. ago, with an appalling vexatiousness, she ob- One implication of Dr. Aaronson's work tained some LSD--25, so-called, and took it. She which I think we should consider very seriously became very much frightened after taking iton is that before long someone is going to finda her own and went back to her earlier schizo- way of producing psychedelic phenomena by phrenic condition. Our most recent recordsug- post-hypnotic suggestion. I wonder whatour gests that she is now almost completely well position will be when this happens. I can find again, after five days of schizophrenia. Ourrec- good reason now for encouraging people to keep

29 their distance from unauthorized psychedelics, Dr. Osmond: One of our subjects used LSD-25 noting the low expertise of many of the enthusi- seven times, the last trip about two monthsbe- astic amateur chemists involved in this work. fore testing; another used it about 20 times. Our This approach seems to be fairlyeffective sample is not quite so intrepid as Dr. Silverman's. and at least some young people heed the warn- One young man claimed to have used 100,000 ing. It is a soft-sell approach; young folk who micrograms of LSD-25 in about five months, in- would not hesitate about vexing their elders do terspersed with STP on several occasions; we hesitate about becoming the victim of someone tested him some weeks after this last trip. else's inept chemistry. I do not know that this Dr. Meyer: We've now heard from the sched- technique would work in all cultures, but in the uled morning speakers and the floor is open to "brand name" culture of the United States, general discussion. A great deal of new material people seem willing to respond to it. It may not has been presented; particularly dealing with prevent all of them fromcontinuing to take the treatment of adverse reactions. Are there any LSD, but it may get some of them to hesitate and comments in this area? even to stop. It also encouragesthem to use natural products which usually have a lesser de- Dr. Freedman: I think I'll underwrite the fact gree of danger, for natureis a better chemist that the chief abuse of LSD has been selling, than many amateurs. We are encouraging psy- propaganda, and the whole ambience around chedelic users, if they are going to undertake that. We all know this. I also think that you in these hazards, at least to screen out those po- Government should not get into a position tential users who are obviously perceptually un- where you are the Vatican adjudicatory of all stable. The HOD test allows them to do this. proper therapeutic procedures. You don't have chlor- At least some young people are taking careful to be. It's one thing to say, "Look, this promazine can be complicating; some people notice of this. We have also suggested something rather use it successfully, some do not. There areprob- more controversial, namelythat those who in- lems. Some people report antytal or chlor- Ithink that the tend to take psychedelics should have large doses diazepoxide as effective." treatment community needs to know these facts of nicotinic and ascorbic acid available, for these reduce the impact of LSD-25. This has been because part of the reason the hippies move away shown to be the case in animals and in humans, from us is that they are greeted by a combina- though I should like to see more extensive tion of ignorance and the tradition in psychi- studies done in these matters. The effect of the atry that we know everything before we've vitamins seems to depend upon how much is learned anything. This does not mean that you taken and to some extent upon how early in the have to be in a position where you've got to de- experience it is injected. I believe that it is good liver the latest authoritative word. It's a matter for people to have something to take that does of style here. good and will not do harm; this reduces the Dr. Joffe: With respect to what Dr. Freedman chances of panic. Further careful studies will be just said and to what Dr. Smith said before, I'd needed to show how much of this beneficial like to make a plea on our behalf and show what effect, if any, is a placebo effect. If amateur ex- we are doing. The gap between the hippie com- perimenters can be persuaded to screen out the munity and the establishment is great, but not obviously ill and to use measures which will re- any greater than between the Bureauof Nar- duce the chances of prolonged "bad" trips, this cotics and Dangerous Drugs and everybody else. With this as a given, I must depend upon those may serve as a bridge forfurther communica- of you who are in contact with drug using tion, since we know they are concerned about groups to be the intermediaries to furnishin- these matters. Persuading them not to seek and formation both ways. Anytime any of you learn use these substances or preventing them from of a new compound, please send it to me and obtaining them seems to me to be a more diffi- I will get it analyzed, the way we got STP identi- cult matter. fied. The treating physicians need this informa- QUESTION: I would ask Dr. Osmond about tion and the Bureau of Narcotics and Dangerous how many times his chronic users had used the Drugs should have this information. Most of all drug? it is crucial to the afflicted that we know as much

30 then as possibleabout their affliction. In theinterest mine, they're even more depressed. They of the public health it isimperative that we ob- turn to higher dosesand eventually to intra- tain this information whileguaranteeing total venous medication. This is onefactor in am- confidentiality to your sources. phetamine abuse relativeto the particular QUESTION: Would youelaborate on your subculture that we are working with. I would statement with regard tothe identification of like to get some advice, on what Drs. Frosch, black-market materials? Ungerleider, and Ditman are doing with these post-LSD depressions. If possible I'd like them to Dr. Joffe: Yes. Sandoz hassaid that since they discuss the problems of perceptual disturbances, are no longerinvolved with LSD-25, they can- recurrent hallucinosis, and otherchronic dis- not analyze thesubstance. However, as far as the turbances associated with LSD usage. analysis of the material goes, we cando this. In addition, NIMH is supporting aninvestigator Dr. Ditman: I have seen 50 or 60 post-LSD Like Dr. Frosch, I am im- on the West Coast todevelop methods for the cases in treatment. quantities of psy- pressed that these cases do not respond to any identification of microgram regard- chotropic drugs (in particular,hallucinogenic treatment as well as you might expect, less of the diagnostic category that they are put drugs which are involved inepidemics of drug abuse) 31 We hope that thislaboratory will be in, whether it's anxiety, depression, or psychosis. able to identify unknownblack-market com- Some of the cases that come in with the diag- pounds. Thus we will have twolaboratories, and nosis of LSD-induced psychiatric complication NIMH can serve as intermediary,thus preserv- often turn out to be people with problems that ing confidentiality. There arealso certain re- have existed prior to LSD ingestion, but LSD gional laboratories of the Bureauof Narcotics becomes the diagnosis or the excuse. I am think- and Dangerous Drugs which are verycompetent ing of a young man I saw yesterday who has been trying to make it as a rock and rollartist; to do this typeof analysis. be in jeopardy he hasn't succeeded, and now he is usinghis QUESTION: Would a scientist failure. He black-market materials? LSD experience as the reason for his for possession of the is depressed. It may be that LSD had a rolein Dr. Joffe: I'm sorry; I don'tknow the answer to it. He said LSD made him recognize someof that. the things he has done wrong. To summarize, I do not think that manyof Dr. John Scigliano: TheCustoms House Lab- has expertise, and the these are just LSD complications. LSD some- oratory in Baltimore times even has a minor role. Where LSDhas Chief of the Laboratory hasindicated a desire had a major role, I am still very muchperplexed to cooperate inelucidating the composition of Thus, on the East Coast as to what the treatmentshould be. I am im- many of these agents. pressed on a short-term basis with what canbe we have another resourcefor analysis which we done with sedatives, particularly with oneof the can develop. longer-acting ones. Dr. Smith: I'd like to introduce a newsubject I would like to ask you onequestion, Dr. which concerns us inHaight-Ashbury. In our Smith. I keep hearing from patientsabout some- recent drug survey wefound that the population body who has had R "bad" trip andtaken LSD has just about tried everything once.Thirty- again, to erase the after-effects of thebad ex- three percent of our sample had at onetime or perience with good results. I haveheard of this other taken methamphetamineintravenously. a number oftimes, and wonder if this has be- The major drug probleminthe Haight- come a treatmentprocedure in your group. Ashbury is the abuse of theamphetamines. Dr. Smith: This is a verydisturbing phenom- We're seeing a very highincidence of post-LSD enon in ourcommunity. There is a popular depression (presenting as a chronicdepression drug-myth associated with the Leary groupthat in repeated users of thissubstance) suggesting if you've had a "bad" trip, the thing todo is to certain that amphetamine abusers represent a go up againimmediately to rescramble the-ir- segment that gets on toamphetamine abuse because of post-LSDdepression. In this group, am- 31 Craig, John C. School of Pharmacy,University of Cali- phetamines serve as a kind ofself-treatmen_ for fornia, San Francisco, California. MicrogramIdentification of depression. When they stop takingthe ampheta- Psychotropic Drugs (1 ROI MH 14321-01). 31 cuits and get back on the beam. It has beenour There's no such thingas schizophrenia. I can experience that this almost uniformly meets show you that by showingyou types of re- with disastrous results. sponse patterns within the diagnostic category of Getting back to my point about the post-LSD schizophrenia that areso remarkably different depressions, I would like to point to the low from one another that normals who fit intoa state of knowledge in the general medical com- mid-range pattern resemble each of thesetypes munity where many physicians are uniformly more than these discrepant schizophrenic-types putting their patients on chlorpromazine. Fre- resemble one another. Inessence, when we look quently, they are treating post-LSD depressions at these LSD types, we are looking at radically with this drug. As you know, thistreatment may different modes of adjustment afterthe drug has actually worsen the depression. In fact, the only been ingested. I feel certain that the drugtreat- successful cases that I've had inour group are ment or other technique of choice that weuse in those taken off chlorpromazine byour staff. the therapy of the patient experiencingpanic or When the level of knowledge isso low among depressior must dependupon the kind of reac- the medical community that they will prescribe tion which follou& LSD, and the particular daily doses of chlorpromazine for depression, personality or perceptualtype underlying this then I think we've got a real problem. reaction. However, in specific reply to your question,we focus on trying to convince the patients not to Dr. Freedman: I thinkwe ought to remind our- take LSD again. When they take LSD again selves about the depression thatyou are talking without guidance, in approximately thesame about. If you experiencean order of insight or situation as during the first "bad" trip, they revelation, and the world suddenlylooks quite then have another bad reaction that further startlingly different toyou, then you have to in- deepens the depression. In fact, some of the sui- tegrate drab reality with drug-induced paradise. cide attempts that we've had inour community This could very easily setup the ground work have been a direct result of taking LSD again for depression. There is alsomore than depres- after having a "bad" trip. sion. There isthe despair of the character disorder represented by these kids andits rein- Dr. Jerome Levine: I think this discussionun- forcement in thegroups that they are in. I've derscores what I have said on several occasions. never been convincedeven without LSD in To confuse the picture, we've recently completed the picturethat we have donetoo well in psy- a collaborative depression study in which we have chiatry with the tools we have in treatingthis found that, on the whole, chlorpromazine isas order of phenomenon (the character disorder) good as imipramine in the treatment of depres- in young people. Back in the 50'sGreenwich sion; and that both drugs arebets..,than Village was full of chronic middle-aged drop- placebo in treating patients with this symptoma- outs who may have been pot smokers butcer- tology. This should shake up your conceptual tainly did not use LSD. Again, you'vegot to ask system as it will shake up a number of the "more yourself what your therapeutic ambitionsare, as knowledgeable people in the community." It well as what therapeutic skills, includinggroup shook us up. My answer is that your long-term therapy, you can bring to bear. chronic depressions are the difficult ones whom The second thing is that interms of long- you should try and route into treatment with term effects, I've seen a number of compensated some knowledgeable people who can offer them schizophrenics who have what Bleu ler called what is known, and who can offer thema way double registration. They live thisway. I think back to the ordinary community rather than of- the drug can give a relatively normalperson this fering them a pill which will reverse thispro- experience of double registration, of seeingtwo cess. I think each case must be treated by a things at the same time. This could alter dras- competent treatment person, and that he will tically the way these people now tendto per- have to determine what the appropriate treat- ceive the world. Some peoplecan adapt to it ment is. just as many schizophrenics have, and otherscan- Dr. Silverman: To me the notion of LSDreac- not. I think we've got to respect the drug's power tionis becoming as alien as the notion of to do this, and, hence, to give a person a new schizophrenia has been to me for severalyears. task to deal with. Thismay be part of the long-

32 term perceptual changes you've been talking terribly many, who have had "bad" trips. I'dlike about. to know if anybody has seen people in the in- Dr. Osmond: That is a very good point, Dr. volutional period who have taken LSD and, if Freedman. I think we also have to remember so, what the affective response is in such people. that there is a very long history of this in the Dr. Freedman: I've seena few people, maybe a mystical literature. St. John of the Cross, and dozen or so in their 50's, who have taken LSD, many others, give excellent accounts of it. There and none of these that Ican recall have had seems to be a contraction of the world after the bad after-effects. divine revelation which produces great despair and sorrow in many people. There is also in the Dr. Osmond: About threeyears ago I saw the same literature a great deal of information as to oldest man on record, as faras I know, who ever what you do about it. I think that we might look took it. He was 89, an old Australian whocame at the actual way in which it was handled. While to Abe Hoffer and said that he wished to do the experience of that time may not be appli- this. Abe told him that thiswas a very bad idea, cable to our time, it's quite likely that the general that at his age he shouldn't be doing these responses they did observe are applicable today things. The old gentleman said that he intended in a different context, using different ideas. to; he had done everything in his life and he intended to do this. He said that if Abe wouldn't Dr. Freedman: I would like to addressa ques- give it to him, he would go and tion to everyone here. It was introduced by Dr. get it from someone else. They inquired of his physician whosaw Osmond when he said that the alcoholicsseem no particular reason for his not doing so. Indeed to do better after LSD. I have never seen an he took it and had a truly remarkable experi- alcoholic who has had a bad effect due to LSD ence; at one point he looked at the light and in terms of what we've been talking about. I've it suffused the room ina very wonderful man- seen few, only one or two older people, who ner. At the end of the time he came to Abe and have had a bad effect after LSD and I've known said, "I am very grateful for this. This is the a number of such people who are using LSD. greatest moment of my life; I'm extremely These are older intellectuals, and certainly mid- happy. For all of my life I've beena conviured dle-aged people, very few of whom have gotten atheist, but in later years I've been rather doubt- into trouble. It seems to me that this has some- ful about it. Now I know Iwas right all the thing to do with age and the experiencing of time." alteration of consciousness that may be very important in determining whether or not a person Dr. Meyer: I wonder if some of the people sit- has an untoward effect after LSD use. Certainly ting on the sidelines, such as Dr. McGlothlin, older people, perhaps also alcoholics, should Dr. Katz, and Dr. Pahnke who have hadsome have diminished reparative processes. If any- experiences with the drug have some comments thing, they should be the ones who would suf- to make on some of the things that we have been fer most, but apparently they don't, at least not hearing. in my clinical experience. Dr. Walter Pahnke: I have two questions anda Dr. Frosch: I'd like to comment about taking comment. First, regarding the age question. I've LSD again to cure a "bad" trip. We've seen a been treating dying cancer patients, and al- number of patients who have taken other though our series is small so far, we have seen drugs after a "bad" trip. This other drug no adverse reactions to LSD under these con- marihuana,alcohol,oramphetaminewill trolled medical conditions. Dr. Silverman, when sometimes precipitate a "bad" trip similar to the the people took 50 gamma under your experi- original LSD experience. We've also seen a few mental conditions how did their experiences patients who have psychotic reactions to any correspond with those they had using black- drug they take. A number of people who come market LSD? in with an amphetamine psychosiscome back a few weeks later with an LSD psychosis. They Dr. Silverman: I would say that seven out of may also have "bad" trips with marihuana. Drs. eight thought they had minimal psychedelic Freedman and Ungerleider have commented experiences.

1 about age. We've seen a few older people, not Dr. Pahnke: Dr. Smith, if STP lasts for 30 to i

33 72 hours, do these people not sleep for the agents. The basic in vitro approach is to expose whole time? normal leukocytes to the test agent while using Dr. Smith: A majority of the patients do not untreated cultures from the same samples as con- sleep all the time. The popular statement is that trols. The system, for those of you who are not under the influence of STP, a lot of them go into familiar with it, consists of stimulating white a trance-like state which they describe as sleep. blood cells to divide in the culture, adding the They wake up and are still hallucinating. Al- test agent, arresting the cells at the metaphase though it seems highly unlikely that you can stage of mitosis, and scoring chromosomal ab- sleep with a heart rate of 120 and the other phys- normalities. ical signs, they do describe the ability to sleep; The first observation, even before examining but when they wake up they are still actively the chromosomes themselves, is to study the ef- hallucinating. fect of the agent on the mitotic rate. Do the treated cultures differ from the controls in re- Dr. Osmond: Kliiver 32 describes one of his gard to the cell division? Figure 1 shows the re- cases, a man who went to sleep one evening after sults of such mitotic indices." The treatments or a psychedelic experience and then woke upthe the concentrations of LSD used ranged from 10 next day with it still going strong. gamma per ml of culture to 0.001 gamma per Dr. Pahnke: In terms of what has developed ml. The mitotic rate in the control cultures was with LSD abuse and the types of expertise a bit over 6 percent, which is normal using our needed from all different fields, and in terms of method. However, as you can see, with all of understanding LSD as a research tool, as a thera- the dosages of LSD used, there were statistically peutic agent, and as a social-anthropological significant suppressions of mitosis. The longer phenomenon, the situation now begins to re- the drug was in contact with the cells, the mind me of the whole area of narcotic drug greater the suppression of the mitotic rate. The addiction. The drugs are totally different. The data in these in vitro experiments were derived predominant types of individuals who abuse from three males and three females who had no these drugs are very different, but the way in known exposure to LSD, no recent radiation ex- which the community is responding to the phe- posure, and no recent viral infections. The rea- nomenon is very similar. This reminds me of a son for these restrictions will be discussed later. comment that Mitch Baiter of the Psychopharma- 7 cology Division, NIMH, made after visiting Haight-Ashbury recently. He said that the cul- Control 0 0 0 ture there looks a lot more like a wino culture 6 than he had expected. I think there is some similarity there, too, which again makes us think that we may have to bring our experience in 5 dealing with these other types of phenomena to bear on this whole LSD issue. 0.0Iµ 4 Dr. Meyer: We turn now to the genetic area. 0.00Ip Drs. Cohen and Hirschhorn might bring us up 0 I FL 1 FL to date on their work. 3 10 FL I I Dr. Maimon Cohen: I should like to present 4 24 48 additional in vitro data to supplement that re- Hours of Treatment ported in the recent Science paper,33 and proceed to some in vivo experiments that have just Figure 1.Effectof LSD on Mitotic Rates of Leukocytes De- been completed. After presentation of the data, rived from 6 "Drug-Free" Controls. Dr. Hirschhorn will discuss and interpret the 32 Kliier, see footnote 3, page2. 33 Cohen, see footnote 2, page 1. possible significance of these findings. The use 34 Figures 1-3 and tables 9-14 are reprinted with permis- of a cytogenetic approach to the phenomenon sion from theNew England Journal of Medicineand the of chromosome breakage by LSD is the adapta- author, from the article "InVivoand inVitroChromosomal Damage Induced byLSD-25,"by Maimon M. Cohen, Kurt tion of a method that has been used for some Hirshhorn, and William Frosch.New England Journal of time in the screening of various exogenous Medicine,277(20):1043-1049,November 16,1967.

34 FIGURE 2.Types of Chromosomal Abnormalities Observed in Both the in Vitro Experiments and from the Leukocyte Cul- tures Derived from Drug "Users," Showing Chromatid Breaks (a), Isochromatid Breaks (6), Dicentric Chromosomes (c) (Arrows Indicate Acentric Fragments), Exchange Figures (d), Chromatid Breaks Giving Rise to Terminal Deletions and Acentric Frag- ments (e) and Attenuation and Breakage at the Secondary Constriction in Chromosome No. 9 (f).

Figure 2 illustrates the types of chromosomal its centromere. This structure attaches to the abnormalities that can be quantitated. Figure spindle during mitosis and the chromatids sepa- 2-a shows a simple type of break appearing as an rate to the two daughter cells. Figure 2-c repre- area in which the chromatid or the chromatin sents dicentric chromosomes, e.g.,a chromo- material is nonstaining, with a nonalignment of some, with two constrictions or two centromeres the distal portion of the chromatid. In other with the occurrence of acentric fragments. This words, the continuity of the chromatid is dis- has some interest as far as LSD itself is con- rupted. The criterion of nonalignment is used cerned because this aberration isn't seen too fre- to define a breaka distal nonalignment of the quently with other drugs. chromatid. A gapisa nonstaining portion An attempt to localize the breaks to given of the chromosome, which apparently looks areas of the chromosomes indicated that a large broken, but the remainder of the chromosome number of terminal breaks occurred toward the arm is still normally aligned. This type of lesion ends of the chromosome arm (Figure 2-e) .If would not be scored as an abnormality. The fre- such breaks occur in two chromosomes in a quencies of abnormalities included in the study given cell and these two chromosomes are in are those breaks, as defined by the alignment- close proximityto each other and re-heal nonalignment criterion. A chromatid break oc- through the broken ends, this would yield an curs only in one chromatid of the two. An increased frequency of dicentric chromosomes as isochromatid break or chromosome break occurs observed. I have not seen this phenomenon with in both chromatids, giving rise to a double frag- several of the other agents that have been ment (Figure 2-b) . screened this way. However, Dr. Hirschhorn has QUESTION: Could you point out a normal seen a similar phenomenonwith SV40 infection. one? SV40 is an oncogenic virus which induces "end- Dr. Cohen: Here is a normal chromosome with to-end" associations and dicentric chromosomes

35 from terminal breaks. The next type of struc- Table9.-DISTRIBUTION OF CHROMOSOMAL tural rearrangement of the so called quadriradial BREAKS INDUCED IN CULTURED HUMAN LEUKO- figures, or triradial figures, most probably in- CYTES BY VARIOUS DOSAGES AND EXPOSURE volve breakage between two chromosomes and TIMES TO LSD-25.* exchange of genetic material (Figure 2-d). Figure 2-f shows a particular area of certain chromo- HR. BEFORE DISTRIBUTION OF BREAKS WITH DOSAGE INDICATED somes which is affected. These are secondary HARVEST constriction regions, which seem to be not only 10 gglml 0.01 laglml 0.001 gglinl 48 50/398 30/390 77/439 55/515 53/425 affected by LSD but by a whole host ofexo- (12.61 (7.71 (17.51 (10.71 (12.51 genous agents. These seem to be particularly 24 61/530 93/587 73/56(1 81/527 57/519 (11.51 (15.81 (13.01 (15.41 (10.81 vulnerable areas of the chromosomes. 4 95/554 62/587 76/582 81/534 65/578 Table 9 is a composite of the in vitro break (17.11 (10.61 (13.11 (15.21 (11.21 frequencies observed. Again, let me remind you Control 65/1680= (3.91 that this is the pooled study from six individ- Ftgures in parentheses denote of cells v,ith breaks uals. There were no significant differences in frequencies of response either by sex or individ- QUESTION: How does your first figure differ uals, so these figures were pooled. The control from this table? rate which you see at the bottom, the 0.039, Dr. Cohen: The first figure describes mitotic refers to breaks per cell, or if you look at figures rate. We are now discussing chromosomal break- outside the parenthesis, the number of breaks age. Table 10 depicts the uniformity or non- divided by the number of cells examined (65/ uniformity of the action of the drugacross the 1680).This control figure is within the range chromosomes. The question is-do all of the normallyobservedin my laboratory;Dr. chromosomes react in the same wayor is there Hungerford, Dr. Warkany, and the other cyto- an apparent non-random distribution of chrom- geneticists who have had experience with chro- osome breaks? This analysis is done on the basis mosome breakage will bear me out. Control of length of the chromosomes by calculating the figures range between 0.0 to 5 or 6 percent. length of each chromosome or chromosome

Table I0.-DISTRIBUTION OF CHROMOSOME BREAKS ACCORDING TO INDIVIDUALLY IDENTIFIABLE CHROMOSOMES OR CHROMOSOME GROUPS.

CHROMOSOME GROUP UNIDEN111-1ARI E \GMENTS & BRTAKS A I A2 F 10TAI

Observed 154 119 41 93 420 45 41 II 6 930 79 Expected 80.82 75.7(1 63.43 113.0 346.52 93.65 80.26 42.22 34.32 929.9

X' 66.26 24.77 7.93 3.54 15.58 25.27 19.2(1 23.09 23.37 '209.01

df = 8; p <0.001 group. On this basis, it is possible to calculate extremely sensitive to LSD. Outside of this there the expected numbers of breaks in each chromo- are other areas which show a piling up, so to some. It is quite obvious from this distribution speak, of the chromosomal breaks, and this and Chi-Square test that LSD does not break the again is not unique to LSD. These vulnerable chromosomes uniformly. This is not peculiar or areas are the secondary constrictions, hetero- unique to LSD; practically every agent with the chromatic regions, which apparently respond to exception of radiation yields a non-uniform dis- many types of insults more readily than the tribution. euchromatic or darkly-staining regions of the Figure 3 shows an attempt to localize further chromosomes. the breaks within given chromosomes. It ap- So much for the in vitro studies. We have re- pears that in many of the chromosomes or chro- cently completed a collaborative effort with Dr. mosomal groups the centromere regions are Frosch and Dr. Hirschhorn, and I will describe

36 Percent Breaks TableI I.CHROMOSOMAL DAMAGE IN N) A CR 0-1-1-1-1-1-10 0 0 SUBJECTS USED AS NORMAL "DRUG-FREE" CONTROLS.

CASENo. AC& SEX PER CENT BREAKS ti

5 35 Male 5.0 ( 5/ 100) 17 39 Female 4.9 ( 9/ 182) 19 29 Male 5.5 ( 111 200) 24 23 Male 4.3 ( 13/ 300) 25 28 Female 4.1 ( 13/ 314) 27 26 Female 4.5 ( 9/ 200) 30 23 Male 2.8 ( 7/ 250) 33 24 Male 2.3 ( 6/ 257) 35 23 Male 5.0 ( 111 221) 40 55 Male 2.0 ( 4/ 200) 41 23 Male 3.0 ( 6/ 200) 42 22 Male 3.2 ( 8/ 250)

3.8(102/2674) 4 37 Female 31.0t (31/ 100) FIGURE 3.Distribution of Chromosomal Breaks within Given 13 23 Female 14.0t (28/ 200) Chromosomes or Chromosomal Groups (Figures in Paren- theses Indicate the Number of Breaks). * Figures in parentheses denote number of breaks per cells the design of this experiment briefly. The series investigated. consisted of 18 LSD users and was derived from t Viral infection, with high fever & diarrhea, developed within Dr. Frosch's patients at Bellevue Hospital. Dr. 24 hr. of bleeding. Frosch had blood samples drawn in tubes at Bellevue; the coded tubes were given to Dr. Table 12 shows the data from LSD patients. Hirschhorn who propagated the cultures at The subjects are listed in descending order of Mt. Sinai Hospital and recoded the microscope the number of doses or the number of trips, and slides. There were two cover slips to a slide, no since these are all from Dr. Frosch's records, he two cover slips on the same slide coming from will have to defend the numbers involved-300, the same individual. I received the coded slides, 200, and so forth. The next-to-last column con- and carried out the analysis for chromosomal tains the chromosome-break data. There is a damage. Table 11 shows the control subjects. wide range in the responses of these individ- There are 14 listed on this particular table, two uals as far as chromosomal breakage is con- of whom I think we are justified in removing cerned. Several were well within the control from the study. These two females showed high rate of 5 to 6 percent, but the vast majority of rates of chromosomal breakage, but within 24 them were two to four times higher than the hours after bleeding for the cultures, both came controls. Again, to emphasize the point made re- down with diarrhea, vomiting, and high fever; peatedly this morning and to quote Dr. Frosch's a picture compatible with the diagnosis of a phrase, "Most of the LSD users are inveterate viral infection. Virus infections are known to experimenters with other drugs," you can see cause increased chromosomal breaks, but this from the last column of this table, the other damage is of a transient nature. We examined drugs usedA's are the amphetamines, B's are these individuals ten days later and the breaks the barbiturates, and so forth. All of these in- had disappeared. These two girls have been used dividuals had ingested some other drugs. Of for controls in other experiments as well, and course this is a confounding parameter in the their break rates are within the normal fre- whole study. What effect, if any, do these other quencies. The remainder of the controls ex- drugs have on chromosome breakage, and, if in hibited chromosomal breakage rates ranging vivo, is this due to LSD itself? To this end, Dr. anywhere from 2 to 5.5 percent, which is within Frosch collected a group of patients who were the normal range for individuals without drug not taking LSD but who were ingesting some of ingestion. the other drugs.

37 CASE AI.E SEX NO. OE INIERVkl BE- PER CEN I BREAKS OTHER DMA Ac- No. I)osE% TWEEN 1.ASI columw., TO HISTORY* DOSE & Hi Euu- INC,

yr.

TO 19 Male 3(K) 2 wk. 9.0 (181200) A,M.0,13 3 24 Male 2(K) I mo. 9.8 (28/285) A,H ,M,0 34 22 Male 100 I mo. 25.1 (44/175) A.H 9 28 Female 100 2 mo. 11.0 (22/200)t A.B,C.H,M,P 22 29 Female 30-6(1 I mo. 15.3 146/300) A.M.P 29 22 Male 50 I mo. 5.5 (10/183) H.M.O,P 7 24 Male 50 7 mo. 11.6 (29/250) A,B,C ,H .13 32 20 Male 35 I mo. 12.0 (30/250) A.13 6 19 Male 20-25 4 mo. 10.3 (19/184) A.H,M,P$ 20 22 Male 15-20 4 mu. 12 6 (35/278) A.H.M 37 52 Male IS 8 mo. 13.0 (39/300) P 14 25 Female 15 I mo. 20.3 (61/300) A,H,M 36 26 Male 15 I mo. 22.0 ( 58/264) A,H ,M ,P 39 23 Male 6 7 mu. 24.0 (36/150) A,H,M,O,P 2 21 Female 4 2 mo. 6.4 ( 5/ 78) A.B.C,H,M,0 26 20 Female 4 I mo. 14.0 (42/300) M 38 22 Male 3 6 mo- 9.8 (28/285) A.H.M 28 21 Female 2 1 mo. 5.3 (16/300)t A.C.M,P$

13.2 (566/4282)

*A indicates amphetamines. II barbiturates. C cocaine. H hallucinogens. M marijuana. 0 opiates. & P phenothiazmes. tLow dose (50-100 tql. #Phenothiazine at time of bleeding.

Table 12.CHROMOSOMAL DAMAGE IN PATIENTS INGESTING LSD.

QUESTION: Is there any relationship to the after his last dose and he still had 13 percent doses? chromosome breaks, but the important thing is that he also showed the structural rearrange- Dr. Cohen: No, as far as we could ascertain, ments. there was no apparent relationship between the Table 13 will show the so-called LSD drug- number of doses, the time of exposure of the positive controls. There were six subjects and last dose prior to the time of bleeding, other the first three individuals who were on chlor- drugs, frequency of other drug use, and the rate promazine atthe time of bleeding showed of chromosome damage. chromosomal breakage as high, if not higher, QUESTION: What about individual dosages? than the LSD users. The fact that these individ- Dr. Cohen: These were all between 300 and 600 uals were on chlorpromazine at the time of micrograms. bleeding may be significant. This appears to be akin to the transient virus infection. We are now Dr. Frosch: They mostly claim to take 500 mi- in the process of setting up experiments to test crograms. A few people who were asked claimed chlorpromazine and similar tranquilizers in vitro only to have taken low doses, 50 to 100 micro- first and secondly in vivo with a series of pa- grams. It's important to remember that this was tients to be examined before, during, and after a black-market calculation. One of the persons who took the drug the chlorpromazine treatment. Some of you have undoubtedly seen the press longest time ago, seven months, had one of the coverage of the National Foundation-March of highest break rates, 24 percent. Dimes meeting that was held several weeks ago Dr. Cohen: Let me modify a statement I made (September 1967) in New York at which chlor- earlier. These are not all of Dr. Frosch's patients. diazepoxide and diazepam were also implicated The one individual who is 52 years old, mid- in chromosome damage. These were results by way down the table, was the patient origin- Dr. Morton Stenchever from Western Reserve ally described in the Science paper." This University, who isinterested in these drugs patient was a schizophrenic who was on non- when usedduringpregnancy.Hisresults black-market LSD therapyforafour-year period. We took his blood sample eight months 35Cohen, see footnote 2, page 1.

38 Table 13.CHROMOSOMAL DAMAGE IN Table I4.--CHROMOSOMAL DAMAGE IN PATIENTS INGESTING DRUGS OTHER THAN LSD. OFFSPRING OF MOTHERS WHO INGESTED LSD DURING PREGNANCY.

CAM /WE six Rig r DettA.s PERUtsr Nu. BREAKS ( AM SU. Ot At.t Six No.ofPut(E% 1 Stumm Oixua No MOTHER% Dusts Datu.s yr. Ix estois li rim' 8 20 Male W Chlorpromazine. 200 17.4 04/1951 Una° mg/day. for I mo. i 2 I I mo.Female 4 19.01 57/ 3001 A.C.M until day of Needing IS 14 24 yr.Male I (3.01 39/ 3001 - II 16 34 Fe-nale N NI` - 10- yr. dura- 21.5 (43/2001 12 9t 54 yr.Female 2 7.S115/ 2001 M lion: chlorpromazine. I I 9t 2 mo.Male 4 4.018/ 2001 C.M 50 mg/day for 2 days until day 11.9 1119/10001 of bleeding. 31 30 Male N Chlorpromazine. 200 13 (28/2051 mg/day. for 3 wk. * See key to Table 12 for abbreviations until day of bleeding. t Low dose (50-100 pg). 18 11 Male W A' - 4-yr. period up to 9.0 (18/200) I gm/day (Fast dose 2 wk. before Dr. Frosch:It varied. Overall, I would say it bleeding): 0* - 6 yr.: malnourished group. Ms - 15 yr : IV - was certainly not a intermittent. Dr. Meyer:Dr. Hirschhorn, we are now anx- 21 9 Male N Diphenhydramine. 10.0126/2611 100 mg/day for ious to hear your comments. 1 mo. up to time of bleeding. Dr. Kurt Hirschhorn:There are just a few com- 23 9 Male N Chlorpromazine & 4.0 (12/3001 ments I want to make on theinterpretation and thioridazire for 14 yr. up lo ; ino. possible significance of these data. I think the before bleeding: di- first point (which I will come back to later) is phenhydramine for 1 wk. hefere bleed- that we did find a variation in apparent sus- ing: patient ad- ceptibility to chromosome breaks. I think some dicted to opiates at birth - exposed of the previous discussion about psychological throughout pregnancy. reactions was hedging around this point to some extent, and all I woulddo at this particu- *See key to Table 12 for abbreviations. lar time is to remind you of a rapidly growing are from in vitroinvestigations at this point. field that the pharmacologists here will be ac- He had not yet actually looked at the in vivo quainted with, the field of pharmacogenetics. situation. I think probably one of the more in- One must remember to account for individual teresting points of the in vivo LSD study is differences before making general statements shown in the next table. We were able to study about anything, since these individual differ- four children who were exposed to LSD in nitro ences may in fact be on agenetic basis. With (Table 14). The last two children in this series reference to the potential dangers of the type of were carried by one motherwho, as Dr. Frosch chromosome breakage that we have seen, the pointed out, was receiving low dosages. Accord- particularly important aberrations are the ones ing to the pregnancy history, she took the LSD which result in rearrangements, that is, . chro- late in pregnancy as opposed to the first two who matid exchanges and dicentrics. took it earlier in pregnancy, in the second Let me first emphasize that we have no evi- trimester. The two children, exposed in the dence at this time that the dangers I'm going second trimester to LSD with the normal dose to talk about do actuallyexist in the human (500 gamma),showed significantly higher break population. This question can only be settled by rates than the other two (exposedlate in preg- a large epidemiologicalstudy, which I hope can popula- nancy),and in these children as well, we saw be put into effect with the rather large morpho:ogic rearrangements of the chromo- tion available at this time. The potentialdan- somes. One child is twoand one-half years old, gers are the following:(a) To the individual and adding the time in nitro, showed significant himself. It is well established and I think it will breakage approximately three years after the be discussed later that chromosome breakage single dose. I may make a comment later on this and rearrangement induced either by radiation point when we talk about teratogenicity. or spontaneouslyoccurring in certain genetic QUESTION: What was the nutritional status? diseases, such as Fanconi's anemia, and so on,

39 are associated with quite a high incidence of leu- but the chromosomes heal immediately. With kemia and other neoplasms. This will have to this in mind I now begin to wonder whether be looked into in the future. (b) To the unborn LSD itselfis breaking the chromosomes or child who is exposed to the drug in utero. There whether perhaps it has some metabolic effecton are now three studies, one by Alexander in the cell (possibly by way of serotonin metabo- rats," one by Auerbach in mice, ; and, perhaps lism, or by one of its metabolites, which inturn the best, by Geber in hamsters," that have dem- either unstabilizes the lysosomes which contain onstrated the teratogenicity of this drug if given destructive enzymes that could break chromo- at a particular point in time during the preg- somes) or alternatively interferes with the heal- nancy. Again this is something that will have to ing process that normallyoccurs in preventing be studied in man. It must be pointedout that permanent chromosomal damage in normal in- most of such chromosome damage is probably so dividuals. severe that it will not result in teratogenesis but Let me for a moment come back to theques- rather in spontaneous abortions, possibly quite tion of individual differences. Wenow have early in pregnancy; here again the epidemiologi- genetic evidence that some peopleare more sus- cal study is the one that is important. (c) The ceptible to chromosome breakage than others, genetic damage to future generations. The im- some to an extremely great extent. I think this portant aspect of this is the chromosome rear- too will have to be looked into very carefully. rangement, which results in a so-called translo- If one does find that thereare some individuals cation, in other words, a new chromosome who are susceptible and others whoare not, I consisting of two parts of two different chromo- think that we will find here the clueas to what somes. There results from this a high risk of is going on. I would also urgeyou in terms of having abnormal children or children who will the psychiatrically-oriented studiesto look at die in utero, in the next generation, or ofpro- this problem in a similarway; that is, your clue ducing carriers of such translocations who will may come by comparing reactors to nonreactors, show such abnormalities in the third generation. rather than by comparing LSD takers tonor- Whether this is true or not will depend to a mals. great extent on the presence or absence of these chromosomal rearrangements in the cells that Dr. Frosch: I'd like to add two clinicalnotes to are going to make sperm and eggs. We now have this study: (a) In this patient sample therewas testicular biopsies planned in order to try this, no correlation that I could discover between to see whether the germ cells carry the damage. chromosome breaks and the presenceor absence There is an analogy with drugs called streptoni- of overt behavioral disturbance. (b) The physi- grin and mitomycin C, both of which produce cal and psychological examination of these four effects on chromosomes quite similar to those children has not as yet revealedany gross physi- produced by LSD. There is now evidence that cal, behavioral, or mental abnormality. How- in the germ cells there is the same kind of dam- ever, they are very young and it is very difficult age as that produced by streptonigrin; whether to do accurate testing. LSD does this, I don't know as yet. Prelim- QUESTION: Can you demonstrate this in ani- inary data from the laboratories of Cohen and mals, and if so, don't you have a quickway of Philip 31-4° indicate that the germ cells of LSD- finding out about the damage? treated mice do carry the breaks and rearrange- 3. Alexander, G.J.; Miles, B.E.; Gold, G.M.; et al. LSD: in- ments. jection early in pregnancy produces abnormalities in off- The next point I want to discuss is the ques- spring of rats.Science,157:459-460, July 28, 1967. tion of mechanisms. Chromosomes can probably 37 Auerbach, R., and Rugowski. J.A. Lysergic Acid Diethyl- amide: effect on embryos.Science,157:1325-1326, September be broken by a variety of mechanisms, possibly 15, 1967. by direct damage to the chromosome as by ioniz- 3$ Geber. W.F. Congenital malformations induced by Mes- ing radiatiod: possibly by way of cytoplasmic caline, Lysergic Acid Diethylamide, and Bromolysergic Acid in the hamster.Science,158:265-266, October 13, 1967. enzyme release. This has been postulated for 39 Cohen. M.M.. and Mukherjee, A.B. Meiotic chromosome some of the agents, including perhaps some of damage induced by LSD-25. Nature, 219:1072-1074, Septem- the viruses. Another possible mechanism is by ber 7. 1968. inhibiting the healing of broken chromosomes. 40 Skakkebaek, NM; Philip. J.; and Rabeben, 0.J. LSD in miceabnormalities in meiotic chromosomes.Science,160: Breakage probably occurs normally all the time, 1246-1248, June 14, 1968.

40 Dr. Hirschhorn: Chromosome studies are now sity of Iowa, in the Department of Obstetrics and being done in animals, but the results are not Gynecology, and regards a recent fetus with a yet known. Such studies have been done in ani- phocomelia anomaly. "...the mother and fa- mals with a variety of other drugs producing ther were on daily doses of LSD prior to preg- similar chromosome breaks, but jet me again nancy and during the first three months. The warn of trying to derive information purely mother, father, and baby exhibited the typical from animal studies; it has been done, but such chromosome breaks." There is another observa- interpretation is fraught with great danger. In tion. terms of teratogenicity,I am sure that Dr. Warkany, who is probably the leading expert in Dr. R. Miller: I have two questions. First, it this field, would bear me out in saying that if seems to me that LSD does produce a tremen- aspirin and thalidomide both had been sub- dous fright in some people; maybe this experi- jected to animal tests before being put on the ence is releasing a whole lot of things that cause market, thalidomide would much more likely these breakages. It seems that control studies have been put on the market than aspirin. comparing those people who have very rough experiences and those who don't might be in or- Dr. Freed_man: Could I just inject a contro- der. Secondly, what do these abberrations in the versial note. I am dismayed at the lack of con- chromosomes relate to, other than some drug trols before this was published. You've still got that might have been taken? In other words, if a lot of interesting work ahead of you. you find a high incidence of leukemia, what Dr. Cohen: As far as the controls in the in vitro meaning does that have? study are concerned, I think the proper controls Dr. Hirschhorn: In answer to the first question, are there. The cells were from identical blood there was no apparent correlation between samples drawn from the same individuals and whether they had a "bad" trip, a "good" trip, then split into treated and untreated groups. or otherwise. In terms of the second question, This is the only type of comparison you can this is exactly what I was getting at; we don't make in this particular type of situation; there- know. All we know is that with similar chromo- fore, as far as the in vitro experiments are some breaks after radiation there is a higher in- concerned, I think that there were adequate con- cidence of leukemia; with similar chromosome trols; these are replicate samples, one treated breaks with patients with increased susceptibility and one not. The control rates which we got to breaks there is a higher incidence of leuke- compare well with control rates gotten for un- mia. With the same kind of chromosome breaks treated cultures in any cytogenetic laboratory caused by other drugs there is a higher rate of engaged in chromosomal studies. abortion and of a variety of other things. With Dr. Di Paolo: What about buccal smears? regard to LSD, we only know one thing: teratogenesis occurs in some animals when LSD is ad- Dr. Cohen: Buccal smears? They are good for ministered during certain times of pregnancy. distinguishing males from females, but they are What the story is in man can only be derived not going to help a bit in this particular situa- from a large epidemiological study. tion. Dr. Meyer: Do you know what the rates of As far as in vivo system is concerned, then I breakage are in the community? In other words, admit we really do have a problem with controls if you have a high rate of breakage, you may except for the people who were not exposed to have some problems in assessing the cause and the drug, who were the overall controls for the effect or other relationship between high rates whole group. I will grant you that this is a prob- of breakage and leukemia. lem. They are not the ultimate control, but they were the best control that we could find. I don't Dr. Hirschhorn: What "community"? know what better control you can ask for. I'm Dr. Meyer: In the total population. open to all suggestions of how bean to control these things. Dr. Hirschhorn: Yes we do. And that is around While I have the microphone I would like to 4 percent, and this has been consistei.t. read one sentence from a letter that I received Dr. Meyer: We can now go on to Dr. Hunger- yesterday. it is from a physician at the Univer- ford's presentation.

41 Dr. David Hungerford: I'dlike to say that the Thom dofinitions were derived primarily from: done by Jacobs, PA; Brunton, M.; and Court-Brown, W.M. Cyto- largest single portion of this work was gonotic studios in leukocytes on ill. generalpopulation: Dr. Kenneth Taylor who isin the Biology De- subjects of ages 65 years and more. howls of Hama partment of San DiegoState College and was in Generics, 27:353-365, Juni 1964. my laboratoryfor a year on a special NIH Fel- Other discussions of classification of aberrations are in: lowship. Four other cytologists,including my- Evans, H.J. Chromosome aberrations induced by ionizing has already re- radiations. Interactional Review of Cytology, 13:221-321, self, were involved." Dr. Shagass I962. counted to you the opportunity we had tostudy Swift, M.R., and Hirschhorn, K. Fanconi's Anemia:inherited his patients. It arose last Apriljust after Dr. susceptibility to chromosome breakage in various tissues. Cohen's paper appeared in Science42 and for Annals of Internal Makin, 65:490-503, 1966. of Chicago Conference:Standardizationin Human Cyfo- that reason and because there was a prospect gonotics. firth Defects: Original ArticleSeries. Volume 2. doing an almost completely prospectivestudy, Now York: The National Foundation-March ofDimes, De- we set out todo this. We have so far looked at cember 1966. four patients. They were sampledin general three times for each dose and theyreceived three We have to begin with twocontrols(see doses per course of treatment. They werealso Table 15) which were matched initiallyfor age, sampled on follow-ups. If you look at thecables sex, and samplinginterval; the same scoring pro- you can see this. Agood place to start is with the cedures were followed for them. It'sinteresting classification of chromosome abnormalities.It in this respect that the youngerpatient shows shows our scoring methods andcriteria, which some of the effectsof prior exposure to diagnos- started but are very muchlike Dr. Cohen's. tic radiation. We knew this when we neither he nor we knew how muchradiation he had had, and you can see thatit is consider- CLASSIFICATION OF CHROMOSOME ably elevated in comparison to the35-year-old ABNORMALITIES control in the second row. He had atleast one consistent chromosome change, a cloneof cells A. No structural abnormality in which there was a pericentricinversion. I. Normal diploid If we turn to Table 16, we can seethe fre- 2. Hypodiploid or hyperdiploid quencies of breaks plus the moreserious kinds 3. Polyploid of rearrangement, including those which are un- a) Triploid or tetraploid, or neartriploid or interpret this near tetraploid stable in subsequent mitosis. To b) Endoreduplication table briefly for you: the frequencies are numbers of rearrangements over numberof cells in B. Gaps or breaks which these have occurred. The items in paren I. Chromatid gap(non-stainingregion in one theses are the total number ofmetaphases in chromatid) each sample. If we sum the numeratorof these 2. Chromatid break--(non-alignment oraxial dis- frequencies across rows, we end up with,in the placement of broken ends) first case, 23 over 300 cells, whichgives us 7.7 3. Isochromatid gap(non-staining region at same percent, etc., down. position in both chromatids) Table 17 shows the same cells. Here wemake axial dis- 4. Isochromatid break(non-alignment or an attempt tomaximize the effect, if any, of placement of broken ends, less serious break point at same posi- LSD. We have included also the tion in both chromatids) aberrations, of types indicated as itemsB.1. and (Gap is a region entirely or partiallyachromatic B.3. in the classification, whichgive a little bit and with or without constriction) higher percentaps, and in both casesthe percentages in the lastcolumn should be com- C. Other structural abnormalities pared for three of the four patientswith the pre- I. Acentric fragments,dicentrics,rings,multi- LSD samples in table 17 column 1;maximizing radiak-(classicallyregardedasunstable, Roble the data, we have 8 percent versus9.3, 8 per- to be lost or to undergo furtherchange at mitosis) 2. One or more morphologicallyabnormal chromo- 41 Hungerford, D.A.; Taylor, K.M.; and Shards, C.Cyto- somes resultingfrom multiple breaks leading to in- geneic effects of LSD-25 therapy in man.JAMA, 206: versions, deletions, or translocations4regarded as 2287-2291. December Z 1968. stable at mitosis) 42Cohen, see footnote 2, par I.

42 Table 15.CONTROLS Frequencies of Structural Rearrangement of Chromosomes/Cells Involved; and Total Chromosome Aberrations/Cells Involved

Cells Aberrant Cu. Studied Calk

28yr. old 8/1/67 8/8/67 8/22/67 control 7/6; 13/12 To be studied 2/2; 9/9 200 21/200=10.5% 54411 (100) (100)

35 yr. old 8/28/67* 9/5/67* 9/18/67* control 0; 5/5 0; 5/4 0; 4/4 300 13/300 =4.3% 545H (100) (100) (100)

500

Numbers in parentheses aro total number of rat/Upham Anhui per sample. 4$ hour and 72 hour intenrak in culture; all others 72 hour. N.I. 544H had diagnostic X-rays to leg and spine 1952-54 and 1960. Clone is prangs, with pericentric inversion in one chromosome #2. cent versus 8.7, and 10 percent versus 8.2. These tic leukemia. The Ph 1 is about 60 percent of a can be compared with the controls in table 15, normal small acrocentric. We have done a little where we got 10.5 percent for the irradiated con- bit of cytophotometric work on this abnormal trol and 4.3 percent for the unirradiated con- chromosome and have found that about 40 per- trol. cent of the DNA is gone. I think that Dr. I should say that the statistical analyses have Egozcue's chromosome is a little too small, and not yet been done. This is one thing that Dr. that the construction that is being put on this Taylor is undertaking at the moment. We all in the press is misleading. think that if there is any significance here it is Dr. Cohen: I don't think there's any doubt borderline. about the last point made by Dr. Hungerford COMMENT: Well, this is an interesting set of that the chromosome referred to by Dr. Egozcue data to co: -ire with the results of Drs. Cohen is Ph 1. Those of us who saw his Science article 4° and Hirschhorn 43 and with Drs. Irwin and would have a great deal of difficulty telling what Egozcue.44 it really was, and I don't think it was all his Dr. Hungerford: I do not think that we neces- fault, for the photographic plate was a very poor sarily have real discrepancies here; we are deal- reproduction. Also I don't think that any of us ing with two different kinds of material, and seriously think that the fragments of chromo- there is some question about the integrity of the somes we observe are Philadelphia chromo- compound that the hippies are taking. I think somes, because the diagnostic parameter of one could draw a little bit of reassurance from the leukemia is absent. So, it is apparently a frag- therapeutic experiences, with pharmaceutical- mentation phenomenon, and not the formation grade LSD, by physicians, but there seems to of the specific Philadelphia chromosome. The be a clear need to investigate the nature of pos- problem is the general association of chromo- sible contaminants in illicit batches and their somal breakage with neoplasia and leukemia. effects specifically on chromosomes. This is a question, which, as Dr. Hirschhorn has

I would like to turn briefly to the leukemia 43 Cohen, see footnote 34. page 34. question. Dr. Egozcue 45 has found in some of 44 Irwin, S., and Egozcue, J. Chromosomal abnormalities in this materia! a minute chromosome, which he leukocytes from LSD-25 users. Science, 157:313-314, July 21, 1967. thinks is like the Philadelphia (Ph 1) chromo- 45/bid- some found in most cases of chronic granulocy- 46Ibid.

43 I Table 16.PATIENTS CASE pro Dose I Ipost hr. Frequencies of Structural Rearrangementother of postChromosomes (Rearrangements/Cells Involved) pro Dose postI hr. 2 otherpost pro r Dose 3 Ipost hr. otherpost Follow-up studied Cells Total rearrange-monis LSD after 522H A 10 clays24 hr. (50)1/1* (50)1/1 (50)6/5 4824 hr. hr.(50)7/4 48 hr. 28 clays26 clays (50)6/5 75 clays3 mos. (50)2/2 300 23/300=7.7% 523H 9 12%)(50)1/1 (50)4/3 24 hr. (50) 1/1 (50)5/4 (50) 0 24 hr. (50)2/1 (50)6/5 (50)4/3 (50)2/2 2 mos. (50) 0 2/2*(50) 550 26/500=5.2% 528H C (100)(2%)2/2 (50)2/2 24 hr. (25) o (50)4/3 3/3*(50) 24 hr. (50)I/I (50)2/2 (50)I/I 24 hr.24 hr.(50) 0 (50) 0 525 13/425 = 3.1% 550H E 14°/.1(50)2/2 (50) 0 (50)3/3 (50) 0 (50)5/3 (50)1/1 (50) 0 (50)1/1 (100) 0* 1875500 10/450=2.2% All*Numbers samples4$ hour inandtaken parentheses between are total number of metaphases studied 72 hour intervals in culture; all others 4/3/47 and 11/26/67. 72 hour. per sample. Frequencies of Total Chromosome Aberrations/Cells Table I7. PATIENTS otherPost Pro Dose 2 IPost hr. otherPost Pre Dose 3 PostI hr. otherPost Involved Follow-up studiedCells Total aberrant cells after LSD 10 days 3/3*(50) (50)9/9 19/14(50) 10/7(50) IIIIMM1 IMINIMI1 OIMIIM 26 days 12/10(50) 75 days (50)2/2 300 45/300 = 15% 24 hrs. 3/3 (50)8/6 (50)3/3 48 hrs. (50)3/3 13/12(50) 13/8(50) 48 hrs. (50)9/9 28 days (50) 0 3 mos.(50)5/5* 550 54/500 = 9.3% (50)8/6 (50)4/4* 24 hrs. (50)717 (50)7/7 (50)5/4 24 hrs. (50)2/I 2 mos. (50)2/2 525 37/425 = 8.7% (50) (50)3/3 (50)7/5 24 hrs. (50)3/3 (50)4/4 (50)6/5 24 hrs.(100) 8/8* 500 37/450 = 8.2% All* 4$Numbers samples hour and in taken parentheses 72 hour between intervals 4/3/67 in culture; and II126/67. are total number of metaphases studied per sample. all others 72 hour. 1875

,,...... m.sally...... 1M already pointed out, is going to take a lot of Dr. Cohen:You did not get a pre-dose sample? time and epidemiological study to clarify. Dr. Hungerford:Patient A had started treat- Now, going back to your data for a minute, ment a week before we started this study. I'd like to ask several questions concerning the patients themselves. I'm sorry to say I didn't Dr.Cohen: Well, I think really then that the entirely follow Dr. Shagass' presentation this important point in the entire discussion is the morning about how he obtained these patients comparison between rearrangement types. You and if they had any LSD before he started treat- do show an increase in the LSD-treated individ- ing them. uals, and from my own personal experience I don't see chromosomal Dr. Hungerford: rearrangements in un- They had not. treated cells. Were these individualson any- Dr. Cohen: ifI interpreted your Table 16 cor- thing else before coming in for the study? rectly, in the pre-LSD sample that you got, th, Dr. Shagass:No, these happen to be moreor was one cell with a rearrangement. What do less drug-free patients. Now, Dr. Hungerford these rearrangements mean? Are these quadri- didn't mention that we havea table, Table 18, radials? on the hippies who were on everything under Dr. Hungerford: No, by 'structural rearrange- the sun. These are small samples for hippies, 50 ment" is meant, in Table 16, all abnormalities cells per hippie. It has been commented that except gaps. In the pre-LSD samples from pa- this is a very small sample in Table 18, for the tientsBand E, only breaks were present. In the hippie population in Philadelphia, and thatyou pre-LSD sample from patient C, there was one are running three or four of them over 10 per- break and one acentric fragment. The various cent. You should note that the one who had the other types of rearrangement did not appear in highest drug consumption also had the lowest the patients until after therapy had begun. No percentage of chromosomal breaks. statement can be made concerning patient A In your in vitro studies, did you use bloodsam- prior to therapy. ples from hippies?

Table 18. HIPPIES

Frequencies of Structural Rearrangement of Chromosomes/Cells Involved; and TotalChromosome Aberrations/Cells Involved

Case 72 Hr. Cultures Aberrant Cells Claimed Drug History S.E. 6/2/67 6 16 trips 533H 0; 7/6 -1-0 = 12% + other hallucinogens a (50) D.S. 6/2/67 5 20 trips 534H 0; 6/5 = 10% -I- other hallucinogens 9 (50) 50 M.A. 6/2/67 7 9 trips 535H 0; 7/7 = 14% -I- marijuana 50 a (50) N.S. 6/2/67 100 trips 1 536H 1/1; 2/1 = 2% + other hallucinogens d' (50) 50 + some hard narcotics Numbers in parenthesis are total number of metaphases studiedper sample.

Dr. Cohen: No, these included two technicians, what happens was in regard to whetheror not secretaries, and myself; we used pure Sandozma- I should go on giving people LSD and breaking terial. I don't think there is any question here up their chromosomes. Now for the data that about the in vitro findings. we have in the in vivo studywe know what Dr. Shagass: Of course my interest in seeing the blood was like before and what itwas like afterwards. The results suggest that not much is removed; four rats were allowed to deliver and happening. The fact that in vitro and in vivo raise their young. data are very different sometimes is borne out The mean litter size of the 21-day fetuses and by this discussion. I think that themajor issue the mean weight of the fetuses were not signi- in this situation concerns the in vivo findings. I ficantly different from those of control animals. was interested in thedata presented by Dr. We obtained 508 fetuses, and of these, 504 were Cohen, which suggest that we really ought to found to be normal on external inspection; 409 stop giving people chlorpromazine.According were dissected and 95 cleared for skeletal exam- to these data chlorpromazine seems tobe just as ination and no abnormalities were found. Only dangerous as LSD. four fetuses were considered abnormal; one had hydrocephalus, one had short extremities and Dr. Hungerford: I just want to talk about leu- syndactylism, and two fetuses were small. These kemia once more. I wasn't taking issue with Drs. fetuses appeared in litters which were otherwise Hirschhorn and Cohen about the relationship normal. No dose dependence could be recog- of their data,47 and Fanconi's syndrome data to nized, and there was no common pattern in the leukemia, but simply about this one observa- abnormalities of the four young. The four tion of Egozcue 48 and the subsequent play in the treated rats that we let deliver had 44 apparently press. normal young, some of which could be raised Dr. Meyer: I'd like Dr. Warkany to tell us and bred. No abnormalities could be demon- about his work at this point. strated, as they developed and there was no tendency to disease or early death. Since an inci- Dr. Josef Warkany: We've been interested for dence of about one percent of congenital mal- a number of years inthe effect of various terato- formations in the offspring of untreated Wistar gens upon chromosomesin the embryo. Con- rats is not unusual, our pilot experiment did not versely, we've also been interested in possible prove that LSD is teratogenic in rats.Even a teratogenic effects of substances known to bring dosage as great as 300 micrograms given to preg- aboutchromosomalchanges.Thus,when nant rats did no harm to the embryos. Such Cohen, et al." found in 1963 that streptonigrin dosage is comparable to human dosage. On a causes muchchromosomal breakage and rear- weight basis it is more than 200 times larger. rangement in cultured humanleukocytes, we After these experiments were finished we thought that this drug could be helpful in our learned of the results of Alexander, et al.52 who studies of chromosomal aberrations and terato- gave single injections of LSD to ratsearly in genesis. We found indeed 5° that many interest- pregnancy (fourth day of gestation) andob- ing and unusual congenital malformations can served resorption of one litter and some still- be produced in rats with streptonigrin. It's unborn stunted young in others. On the fourth or derstandable, therefore, that we became inter- fifth day of pregnancy we gave 34 rats doses estedin LSD when Cohen and co-workers ranging from 1 to 100 micrograms of LSD and announced in 1967 that this drug was producing obtained from 32 females a total of 335 young. chromosomal abnormalities." Of these, 296 were removed on the 21st day by We applied to the NationalInstitute of Caesarean section. With the exception of one Mental Health and obtained Delysid (Sandoz/ fetus that was small, all were normal on external batch 65002) ampules containing 0.1 milligrams inspection, dissection, or clearing. Thirty-nine LSD per milliliter. A pilot experiment was be- young were deliveredand raised. They remain gun injecting various amountsof the solution alive and healthy. Two of the 34 rats had no intraperitoneally or administering it orally during periods of organogenesis. Single doses were 47 Cohen, see footnote 34, page 34. 48 Irwin, see footnote 44, page 43. given on the seventh, eighth, or ninth day of 49 Cohen, M.M.; Shaw, M.W.; and Craig, A.P. Effects of gestation, or multiple doses from the seventh to streptonigrin on cultured human leukocytes. Proceedings of the twelfth day. Total dosage to individual rats the National Academy of Sciences, 50:16-24, July 1963. ranged froM 1.5 to 300 micrograms. Fifty-five 50 Warkany, J., and Takacs, E. Congenital malformations in rats from streptonigrin. Archives of Pathology, 79:65-79, pregnant rats were treated. Fourlitters were January 1965. completely resorbed; 47 rats were sacrificed on 51 Cohen, see footnote 2, page 1. the 21st day of pregnancy and their young were 52 Alexander, see footnote 36, page 40.

47 litters A resorption rate of 5.9 percent is not dif- several years on chromosome aberrations in ferent from that for pregnant Wistar rats in- blood lymphocytes in a number of humanpop- jected with saline solution. ulations exposed to ionizing radiations, suchas Although most of the doses administered in the Marshall Islanders exposed to fallout radi- these experiments were very large (the highest ation 57 and others. We were persuaded to look single doses administered by us were about 80 into the possibility of LSD-induced chromosome times larger than those given by Alexander, et damage primarily for the purpose of making al.), wefound no abnormalities other than re- comparisons of types of chromosome aberrations duction in size of one of the young. There were seen with these drugs and radiations. some differences between the experiments of Let me briefly summarizeour observations to Alexander and ours. They used a dry LSD dis- date. They were madeon three individuals who solved in saline while we administered Delysid. had taken LSD only, on four others who had We were puzzled by the animals used by Alex- taken LSD in combination with psilocybin, and ander, et al. since they mentioned that their con- on four persons who had been given psilocybin trol offspring weighed an average of 64 grams in the course of an "experiment" undercon- at 10 days. We could not find such rats. In our trolled conditions. Control datawere used from laboratory, rats weigh about 19 grams at 10 days. normal subjects examined in some of the other Donaldson " cites weights of 15 grams for 10- studies referred to above. day -old rats. If the LSD-treated rats of Alexan- Cultures of blood lymphocyteswere made by der, et al. weighed 44 to 46 grams at 10 days, it conventional methods. Whenever possible, cells would appear that these treated rats weighed were fixed after 48 to 51 hours in culture, since more than twice as much as rats in other lab- with radiation-induced chromosome aberrations oratories weigh at that age. it has been demonstrated that there isa reduc- Thus, we didn't find LSD teratogenic during tion in the yield of chromosome-type aberra- the organogenetic period, and we found no ab- tions with increasing culture time from 48to 72 normalities in the offspring of rats injected on hours and longer. In most cases 200 cellswere the fourth or fifth day of pregnancy although scored as follows:(a) aneuploid, (b) chromo- the doses administered to some of the pregnant some aberrations, and(c)chromatid aberra- rats were as high as those used by human beings. tions. Karyotypes were made of most of the cells We draw no conclusions from the negative re- with chromosome-type aberrations and of cells sults with rats concerning teratogenicity of LSD with equivocal chromosome morphology. in man since it is known that a drug teratogenic Before describing separately our findings on in one species may not be so in another. This the three groups of people, some commentsmust general rule applies also to results in mice 54 and be made on certain featurescommon to all of hamsters.55 them. In almost all cultures here studiedwe have QUESTION: When you repeated this study, observed stickiness of chromosomes inmany what day did you inject one cells. This stickiness frequently led to the for- Dr. Warkany: We did it on the fourth and fifth mation of dicentric-like configurations. These days. dicentrics were composed of two otherwise in- tact chromosomes that were firmly attached to Dr. Meyer: I'd like to go on to Dr. Lisco, Dr. each other in an end-to-end association. Theter- Miller and Dr. DiPaolo before we proceed to a minal portions of the chromatids general discussion. were perfectly in line with each other, but frequentlya small Dr. Hermann Lisco: Stimulated by the interest- overlap could be seen. Such chromosomesap- ing observations of Cohen, et al. on the effects peared to be firmly joined. Oncursory examina- of LSD-25 on human chromosomes in vitro,56 53 Donaldson, H.H. The rat: data and reference tables for and encouraged by a number of highly moti- the albino rat and the Norway rat. Memoirs of the Wistar vated young volunteers anxious to donate their Instituteof Anatomy and Biology, No. 6.Philadelphia: blood, we embarked during the summer of 1967 Wistar Institute, 1924. 54 Auerbach, see footnote 37, page 40. on studies of chromosome aberrations produced 55 Geber, see footnote 38, page 40. in vivo by LSD and psilocybin. This investiga- 56 Cohen, see footnote 2, page 1. tion was made in the course of a larger study 57 Lisco, H., and Conard, R.A. Chromosome studieson Marshall Islanders exposed tofalloutradiation.Science, that has been under way inour laboratory for 157:443-447, July 28, 1967.

48 tion many of these structures appeared like bona dose of psilocybin (40 and 30 mg) from18 to 20 fide dicentrics as seen in radiation-induced chro- months prior to examination also showedin- mosome aberrations, but on close examination it creased rates of aberrations, includingboth was evident that no chromosome material was types of dicentrics and of rings. Chromatid aber- lost, and there were no accompanying frag- rations were within normal limits.To our ments. knowledge these four individuals hadtaken no These structures have been scored and classi- other hallucinogenic drugs eitherbefore or fied as a special category of dicentrics, and they after the ingestion of psilocybin. are included in the overall aberration rates. It The results from this limited numberof in- should be mentioned that such dicentric chro- dividuals support the observations ofCohen and mosomes are occasionally seen in controls, but of others since then that LSDcan produce chro- we have no estimate of their rate of occurrence mosome damage in human lymphocytes. Fur- at present. However, they have been observed in thermore, they provide evidence thatanother the present material with such frequency that hallucinogenic drug, psilocybin, has similar ef- they must be included in the estimate of aber- fects and that these effectscan persist for 20 rations. Another feature worth mentioning is months and probably longer aftera single dose the fact that translocations and inversions have of 40 mg. Lastly, these observations indicatethat not been observed in excess of what would have the mechanisms of production ofchromosome been expected in the 3,189 cells scored in this aberrations by these drugsmay be different in population as compared with a similar number some important respects from those involved in of cells in the controls. Onewas found in each radiation-induced chromosome damage. group. Dr. Meyer: Could Two young men who had taken we move on to the last two a total of 980 speakers? Dr. Miller. micrograms and 480 micrograms of LSDrespec- tively in several small doses for abouta year and Dr. Robert Miller: I'm Dr.Robert Miller of one-half prior to examination showed nothing the National Cancer Institute.As an epidemi- unusual, with the exception of a single dicentric ologist, the rare breedto which Dr. Hirschhorn of the sticky type in 200 cells inone of the men. has alluded, I would liketo talk at length, but Chromatid breaks were within normal limits will not. I'll hardly talkat all. I would like to with 2.5 and 6 percent respectively. Several reserve the time during which I would have months later the previously aberration-negative spoken for some discussionas to important roles person and a companion took a single dose of that the NIMH can play in exploringsome of about 500 micrograms of LSD; they experienced the questions raisedat this meeting. I would sug- marked psychic effects lasting several hours. Ex- gest, however, that epidemiology playsa very amination of both individuals five days later large role. Almostevery presentation this morn- showed an incidence of 16.5 and 25 percent ing and this afternoon either concernedan ep- chromatid breaks, increased numbers of acentric idemiological studyor had implications for fragments, and also a few dicentri, s of the sticky them. type in each. Reexamination of one of the in- Dr. Joseph Di Paolo: I wishto make reference dividuals 16 days and three months later showed to the carcinogenic, teratogenic, and blood stud- a decrease both in chromatid breaks and in ies which have been in the literaturefor some chromosome aberrations but nota return to time. In addition, I should liketo add com- normal. ments concerning some of our own results. The four persons who had ingested both LSD In 1959, Berenblum, et al." reportedthat al- and psilocybin in varying doses from 10to 36 though LSD was a powerful antagonist against months prior to examination also showed in- the anesthetic effects of urethan, itwas ineffec- creased rates of chromosome aberrations butno tive in eliciting any antagonism againstthe excess numbers of chromatid breaks. There were carcinogenic actionon the lung or against the increased numbers of dicentrics of the sticky initiating phase of skin carcinogenesis induced type as well as of the classic type, some of them 58 Berenblum, I.; Blum, B.; and Trainin, N. Failure ofthe with fragments; one individual showed ring chro- urethan antagonistLysergic Acid Diethylamide (LSD -25) mosomes. to inhibit lung carcinogenesis or the initiating phase of skin carcinogenesis in mice. Biochemical Pharmacology, 2:197-199, The four individuals who had takena single September 1959.

49 by urethan in mice. A single injection of LSD specimens. With practice it should be possible failed to potentiate or minimize the effect of to obtain cellular immigration within a few urethan. days after cultures are set. These then could be In reference to teratology studies, I should analyzed for chromosomal anomalies. In addi- like to point out that there has been a recent tion, embryonic and/or fetal tissue from a vari- paper in Science by Dr.Auerbach." This work ety of sources should be exposed to LSD. appears to have been wellcarried out. The fre- Dr. Meyer: Thank you. I would like to focus quency of malformationsis high but it should our discussion now on comments, namely,ini- also be taken into consideration that the con- tiatives that the Institute can take and the role trols have 10 percent abnormalities. In all cases of epidemiological studies in defining the prob- the malformations involved brain defects.It lems raised here today. would be nice to see this work expanded, particularly since it had been reported by Auer- Dr. Freedman: There are several people here bach that one dose level of LSD appeared to be who were given LSD in the 1950's, and it may be possible to ascertain the state of their chro- ineffective. I have commented at length on the reported by Alexander mosomes. I would recommend that Dr.Miller, rat studies which were who has great experience in doing such studies and I understand that these comments will ap- all over the country, could get in touch with pear as a technical notein Science.° Our own attempts to demonstrate teratogenic response the people here or others whom he may know with LSD have involved two strains of mice and and let us find out the status of their leukocytes and their offspring. one strain of hamsters.In no instance were we able to demonstrate that LSD produced malfor- Dr. Smith: I'm in full agreement that epidemi- mations. The amount of LSD we used varied ological studies are necessary, but I think that by astronomical figures from that reported tobe the gentlemen here have to realize what has successful by Auerbach. happened relative to the drug-using population. The next reference I wish to point out is a Certainly if we did demonstrate that chromo- paper by Sack ler, et al.81which showed the ef- somal abnormalities were produced by LSD and fects of acute and prolonged administrationof that they did have teratologic effects, then at LSD on white blood-cell count, bodyweight, that moment in time the issue would still not and organ weight. "Tail blood samples were be settled for the drug-using population. Our taken immediately prior to autopsy.Marked or community of several thousand people who con- significant decreases were noted in total white sistently use LSD from one time per month to blood cell counts as well as lymphocyte and two times per week have beenwidely refuting eosinophil frequencies. Food consumption was the initial reports about LSD and chromosomes. affected more adversely during thefirst week. In fact there have been a series of recent articles Analyses of the absolute organ-weight data re- published in the underground press; one under vealed significant reductions in the thymus the esoteric title, "Acid Burned a Hole in My weights of both test groups, with consistentbut Genes," openly stated that the data that has been smaller decreases in the thyroid and uterine presented was a Government-sponsored plot to weights of the test animals. Although adminis- stamp out the use of LSD. I think we've got to tration of LSD to female Wistar ratsdemon- realize that we can get a great amount of epi- strated greater resistance and less pronounced demiological data, but the credibility gap is so effects than those noted in males, the resultsstill wide that we also ought to address ourselves to indicated stimulated adrenal activity with sug- putting this data in a form that the drug-using gestions of hypothyroidism and hypogonadal population will believe. If we prove that there is function." Because of this effect on white count, chromosomal abnormality secondary to LSD us- in particular lymphocytes, I think it wouldbe age, then the only way to preventit is to have interesting and desirable to attempt to culture 59 Auerbach, see footnote 37, page 40. other types of cells in the presence of LSD or 60 Di Paolo, J.A. LSD: effects on offspring. Science, 158:522, to take biopsies or any fluid such asamniotic October 27, 1967. 61 Sack ler, A.M.; Weltman, A.S.; and Owens, H. Endocrine fluid which has been in an LSD environment. and metabolic effects of Lysergic Acid Diethylamide on fe- There are techniques such as the cellophane male rats. Toxicology and Applied Pharmacology, 9:324-330, method which may be utilized for small biopsy 1966.

50 the individual stop taking LSD. If the user be- Dr. Levine: With all due respect to epidemio- lieves that your data is epidemiologically false logical studies it might be a lot less expensive and that it's designed specifically to induce him to do a really controlled study of whetherthe to stop taking LSD (as is the currentand domi- drug results in chromosome breaks. In looking nant attitude now inHaight-Asbury),then the at the results here, one wonders how onefinds Institute should address itself not only to epi- controls for so-called hippies. In other words, demiological studies but also to techniques of how does one find controls for people who live education that the drug-using population will a very peculiar kind of existencein which a believe. great deal of abuse of the organism goes on aside from LSD? I think one can't be convinced Dr. Hirschhorn: First of all, there seems to be by these kinds of controls. The one study in a difference in attitudesbetween the East Coast and West Coast. The East Village Other had a which there is a pre- and post- kind of thing is the potential much too small to draw any conclusions; two of very favorable article regarding the four patients actually go down in regard to dangers of chromosomal damage. It was recently chromosome problems and two go up. I don't determined that a great number of individuals in the New York area have in fact gone off the think there's any hard evidence with regard to drug on the basis of this article. I think how- chromosome breakage in humans from the data ever that publication aloneis insufficient. The that we've seen today. type of contact that Dr. Smith canhave and Dr. Osmond: Just two points. We see quite a that some of us have had directly with these peo- lot of agreement that LSD could be usefully and ple, in which we do not tell them "it's going safely given to people whose perceptions have to cause damage," butsimply describe the pos- become stabilized and who are probably beyond sibilities, is extremely effective. their reproductive life. This seems to be rather Dr. Meyer: Apropos of that in terms of the epi- surprising. The other point is that I would demiological studies, there are two questions we strongly agree with Dr. Smith that what is needed with this information is a "soft-sell"; the have to be concerned about. First, if in fact these attempt of battering at the hippies and others drugs do have long-term effects, this would raise for about five years with a club has simply pro- serious questions in terms of the research efforts with the drugs; the second issue is that there is duced obstinacy. They are not sure that the drug is very good for them; perhaps if we change a credibility gap not onlybetween the Haight- will seep into Asbury and the professional community but our ground here, it gradually I them that there are dangers, and they will think within the professional community itself. about these and then gradually change. If, how- think we've uncovered here a degree of disagree- through, we'll research people ever, we try to bulldoze our way ment among various competent run into all those qualitiesthat we actually ad- as to what thesefindings really mean. I also think that we do have a position that we must mire in people whose views are being attacked. upholtl, which is to find out what these things Dr. R. Miller: I too think that epidemiology mean. I think we can onlyfind out through epi- isn't going to be the answer by itself. There has demiologic and other research. I see some other to be a close interaction betweenlaboratory, hands up so I'd like to pass the microphone to clinical, and epidemiological observations, but Dr. McGlothlin, and then to Drs. Levine, Os- the final application to man of concepts devel- mond, and Robert Miller. oped at the bedside or in the laboratory will be Dr. William McGlothlin: I just wanted to men- determined by epidemiologic study. We're not afraid to report studies which are negative. We tion briefly a study that we are carrying out now, which is a follow-up on 300 persons who took do it all the time. And such negative findings should be reassuring to persons who want to use LSD six to ten years ago through a physician who did an experiment in therapy. It looks as these drugs for therapeutic purposes. though about a third have continued to take Dr. Wynne: I'd like to raise for further study LSD to some extent. We are looking at birth and consideration the problem that was sug- defects and miscarriages, etc. If any of you have gested in some of the data about other drugs some ideas of otherthings that we should be such as chlorpromazine which seem to have sim- looking at, I'd appreciate it if you'd contact me. ilar effects. That kind of finding would pose

51 N problems, I think, for epidemiological studies a basis for reassurance; surely the data are small where you have people who have a great variety but, so far, I haven't seen anything that con- of life experiences with drugs, with therapeutic vinces me that I don't have a basis for reassur- and diagnostic X-rays, wiLh malnutrition, with ance of a mild degree. virus infections,etc.I'm greatly concerned, Dr. Meyer: I think that what we're aiming for therefore, that if these studies are going to be here is a definition of some of the questions. Per- definitive, the problems of adequate controls haps it is the Utopian fantasy of a Government must be very carefully scrutinized. I think this scientist sitting in this building which makes me is of the utmost importance. feel that getting people together of the compe- COMMENT: I'm going back to the question of tence that's in this room will clarify questions the effects of publicity, whether it is good or (if not provide answers).Additionally the Cen- bad. It was mentioned that it may be good be- ter is interested in supporting research and get- cause it will scare a few or perhaps many young ting people of different research competencies people from taking LSD. There is a reverse side. together, specifically the way you and Dr. Hun- There are many pregnant girls now who have gerford have done in Philadelphia. These are taken LSD, and you know what it can do to a the kinds of observations that need to be made, pregnant woman to be told that she has to ex- and I think that only by finding out some of the pect an abnormal child. Secondly, I think there data that are available, as we have today, can may be abortions being done right now because we begin to look more systematically at the some women have taken LSD. problem. We're looking at it from several differ- Dr. Hirschhorn: As I understand it, none of ent levels; when the meeting started this morn- the data on subjects receiving chlorpromazine ing it appeared almost as though the people who showed rearrangements. These were chromatid were giving LSD for treatment would be on one and isochromatid breaks and not rearrang- side and the people who observed adverse reac- menu. The other issue is that these people were tions would be on the other side. I think what's currently receiving chlorpromazine and had emerging is that we have many levels of obser- blood levels of chlorpromazine. It has not yet vation and that they aren't contradictory; rather, been determined whether this is a long-lasting I think that they are complementary. effect; we're doing a study to see if it it. These Dr. Freedman: I think there's only one posture were the features which distinguishedthe ISD that you can take and that is that you're in a subjects from the chlorpromazine subjects. Bureau now, but that you came from traditional Dr. Shagass In response to your comments, we institutes which fostered research. You should do have an enormous number of people in invite research; make it clear that you'll re- whom we deliberately maintain a high chlor- ceive research proposals and that you'll program promazine level, and we get very worried when research. You're in danger if you program all it isn't maintained, because they relapse into a the research from here by contract. I think psychosis. there's some that you can do best. The question I'd like to address a question to the chairman of posture is governed by somebody who con- regarding what sort of postural issues he wants trols the budget; you have to have enough funds to discuss. It seems to me that we've got a num- to disperse to extramural scientists for those ber of things here. The most important one, studies considered by you and your advisors to however, is that an otherwise small, yet impor- be useful and important. tant(but not sensational)scientific finding Dr. Silverman: I'm not sure of just how to go about the chromosomes was precipitated into a about this, but it ought to be possible to develop furor by virtue of publicity in a climate of con- P safe atmosphere within which hippie types cern. Certainly, as far as my own investigations could take their own drugs under NIMH super- are concerned, I am hit negatively because my vision. The aim of such a project would be to subjects are not hippies; they are not people who get a line on the contaminants in LSD which are drug users, but they are very frightened are being used in its manufacture in the various about being treated with LSD, and I have to re- areas of the country. At present there is no way assure them. My motive in getting Dr. Hunger- of getting people into our laboratories to study ford to do this work was to know whether I had them while they are on their own drugs.

52 Dr. Joffe: I think we've got tofacilitate infor- that's an epidemiological word) and maybe we'd mation exchange. We can getthe material for better focus our attention on that. you; you get thevolunteers. Dr. Hirschhorn: What has to be remembered about the difference between the findings with Dr. Shagass: I just wanted to saysomething LSD and radiation as against the findings with about this problem of communication.I got viral infection: and probably chlorpromazine is these four blood samples fromhippies by simply that with LSD and radiation the finding.- ire saying to our student healthpsychiatrist that I long lasting; the findings contain chromosomal would like to get some and he said,"Well, will rearrangements. In regard to transient viralin- you pay them?"and I said, "No, just tell them fections, the findings occur for a few days and that I'll let them know if theyhave any chro- they have been shown not to aact other somatic mosomal abnormalities." I got acall the next tissues (which radiation does) . The .-hlorpro- day and he offered me ten subjects, andhe asked mazine studies so far do not show rearrange- how many I wanted. I don't thinkthat's an at- ments; the transient viral infe.:tiensproduce titude of massive denial. These kids arerunning simple breaks and not rearrangements, whereas scared. I think that what's beenreported is not the oncogenic viruses, for example, in tissue cul- inconsistent with that, but our responsibilityis ture do cause rearrangementsand are long last- not to feed them scareinformation, but infor- ing in culture, similar to the in vivo studies with mation. - radiation and with LSD. There's a world of dif- Dr. R. Miller: I would like to suggestthat a ference between the kind of finding that you role for NIMH is to try to identify gapsin our get in someone who has a transientviremia and knowledge to be filled either throughdirect re- someone who has had LSDeight months ago. search by NIMH, through contractresearch, or You just can't put the two in the same basket. grants; NIMH, perhaps,would want to reserve QUESTION: How about things like hepatitis? for itself studies which cannot bedone so ef- Dr. Hirschhorn: Hepatitis, so far as I'm con- fectively by other organizations, such asuniver- cerned, has some questionable effects on chromo- sities or drug companies. somes, and again, whenthey're there, they're Dr. Hungerford: A just wanted to ask one ques- very transient. experiments QUESTION: These findings are all based on a tion. It seems to me that one of the times? Are these the that needs to be done is to administer illicit LSD group that's had LSD many results presented by Dr. Cohen? to hitherto unexposedpatients, but I wonder how many physicians would consider this to be Dr. Hirschhorn: No, we've heard today about ethical? You can't do it in vitro because as we've permanent and long-term chromosomalaberra- learned today Sandoz LSD has essentiallythe tions in persons exposed on one occasion to same effect in vitrothat illicit LSD has. Work psilocybin in an experiment. It's unrealistic to with primates might not be entirely relevant, think that you're going to be able to track down because monkeys aren't people either. There all the contaminants in these kinds of things. might be human volunteers from various You can't get an answer to the question ofim- sources, conscientious objectorsand prisoner pure substances. populations, for example. Dr. Pahnke: I'd like to make apractical sug- Dr. Joffe: I think perhaps with a little more gestion. I would say that anyone who's working digging we would have the model system that with LSD at the present time might be encour- biology could present to study this particular aged to do some collaborative studies with a ge- and we may be able to utilize neticist. For instance, at Spring Grove we hope group of drugs sample to get the sort of an animal model. to study a host blood COMMENT: I'm neither an epidemiologist thing that Dr. Hungerford has done. I think we nor a geneticist but I wasintrigued today by the need a lot more studies like that. finding that it looked as though the highest rate Dr. Meyer: Thank you all very, very much.I of abnormalities in these cells was noted in two think you have done a magnificent job of defin- control patients who were dismissed as being un- ing the significant questions and suggesting rele- important because two days later they came vant research strategies. I hopethat we can be down with a viral ir. cection. It seems to me that as successful inimplementing these investiga- viral infections are a lot more prevalent (I guess tions. 53 Summary of The Conference

The extent and characteristics of hallucino- Evidence of pert:sti-;:i psychological damage genic drug abuse among middle classyoung from chronic LSD a;.12.aiiiisirk-Conwas minimal. adults is at this time unknown. Preliminaryre- This negative finding may be "real"or may reports of grant-supported surveys in the spring of flect a lack of sophistication in outmeasur- 1967 indicated that 15 to 20 percent of the college ing instruments. Whilesome psychological tests population had used marihuana and approxi- done on persons who have used LSDmany mately u to 8 percent of thissame population times suggest borderline evidence of organicity, had used LSD (and/or other hallucinogenic electroencephalographic findings subsequentto drugs). Much of this could be characterizedas LSD administration (but not during the LSD "experimentation." Within hippie gathering trip) are generally normal. Dr. Julian Silver- places, however, drug usemore clearly approxi- man, reporting on a study done with eight mates drug abuse with persons regularly taking chronic LSD users at the National Institute of multiple and more dangerous compounds. Mental Health, indicated that amplitudes of Some clinical and research observers of the EEG evoked responses(secondary to photic LSD scene have observeda discrete pattern of stimuli) were elevated insome ch-onic LSD psychopathologic behavioramong chronic users users (while not under LSD).These higher of LSD and persons on "bad" trips. Thesepro- amplitudes paradoxically returned to normal fessionals have been concerned about possible levels when 50 micrograms of LSD was admin- outbreaks of new forms of organic psychosisre- istered. Of some interest was the observation lated to hallucinogenic druguse. Preliminary that these chronic users (when not on LSD) reports from various biological laboratories have showed uniformly lower thresholds to auditory also suggested the possibility that LSDmay be stimuli, and that these thresholds resembled implicated in serious chthmosomal aberrations. those of Addisonian patients being withdrawn These observations have ledsome to conclude from steroid maintenance. This suggests thepos- that LSD may be leukemogenic and/orterato- sibility that sensory overloadmay be a problem genic. Concerned with these reports of psycho- for some chronic LSD users, even when they are logical and biological damage, the Center for not on the drug. It was speculated that, in some Studies of Narcotic and Drug Abuseon Sep- way, this phenomenon may be related to the tember 29, 1967, conveneda meeting of leading absence of goal-directed behavior among the research investigators in this area. This report chronic users of LSD. summarizes the proceedings of this meeting. Dr. Humphrey Osmond of the New Jersey Most participants deplored the complication Neuropsychiatric Institute and a pioneer in of reasonable research deliberation byexaggera- early research efforts with LSD confirmedsome tions in the popular press and the tendencyto of Dr. Silverman's findings by his own observa- draw conclusions from preliminary data. Some tions at the New Jersey Neuropsychiatric Insti- participants confirmed the spread of intravenous tute. methedrine abuse in some of the hippiecom- Other participants focused on the treatment munities and described the outbreak of STPuse of the "bad" trip. Some noted that chlorproma- which took place early in the summer of 1967. zine has been ofttimes ineffective and, that in The original reports which had indicated that some centers, routine sedation and psychological chlorpromazine potentiated STP trips in a dan- support is the preferred treatment. Most partici- gerous manner were specifically refuted by sev- pants agreed, however, that the psychiatric com- eral participants. This drug (STP) was feltto munity should gain increasing familiarity with be more typically adrenergic, consistent with its this new syndrome and that each psychiatrist chemical structure. should develop familiarity with a treatment pro-

54 gram that could include phenothiazines and/or ing the circulating lymphocytes ofsome hippies the use of sedative drugs and psychologicalsup- in the Philadelphiaarea but failed to confirm port. Several clinicians present noted that "bad" Dr. Cohen's findings. On the other hand, Dr. trips are seen almost exclusively amongpersons Hermann Lisco of Harvard University observed in the 15 to 25-year age group. One postulated similar chromosomal changes inpersons who that this relationship might represent the poten- had been given psilocybin ina psychological ex- tiation, by LSD, of adolescent adju3tment prob- periment. Persons attending this meetingwere lems into severe acute crises. unclear as to the ultimate significance of these Several participants described the phenome- findings. Dr. Robert Miller of the Epidemiol- non of recurring psychedelic experience without ogy Branch, National Cancer Institute, noted recurrent ingestion of the drug. Of particular that time would be the significant factor in ob- concern were descriptions of recurrent paranoid serving the evolution of possible leukemia-type episodes, at times accompanied by vivid halluci- syndromes. Underlying all of the discussionwas nations, in some users of LSD. There were the concern that these reported chromosomal neither psychological nor pharmacological exchanges have also been observed in survivors of planations of this phenomenon, but the LSD ex- the Hiroshima attack and otherpersons exposed perience generates powerful emotions and any to high doses of ionizing radiation, all of whom effectively rich experience is bound to recur in have an increased likelihood of developing leu- the mental life of the individual. kemia-type syndromes. Dr. William Frosch, of Bellevue Hospital in Early reports from Dr. Auerbach 413at the Uni- New York, reported the continuing admission versity of Wisconsin noting teratogenic effects of two patients per week to the Psychiatric Ser- of LSD administered to mice (plusan increase vice secondary to LSD use. Dr. Thomas Unger- in the rate of spontaneous abortions)were not leiderof UCLA indicatedthatthelarge confirmed in studies doneon rats by Dr. Josef number of LSD admissions to the emergency Warkany of the Children's Hospital, Cincin- room at UCLA caused the Psychiatric Service nati. Subsequent reports of teratogenic effects in to close its doors to those experiencing "bad" the hamster suggest species differences in fetal trips. While some have reported that the fre- response to LSD. quency of "bad" trip admissions to general hos- Some reports cubsequent to this meetingsug- pitals and other institutions has been decreasing, gest that the chromosomal changes secondary to it appears that this is still a continuing problem LSD may be transient phenomena similarto for mental health professionals. Additionally, a those observed in viral illness and thereforenot number of participants pointed to the phenone- analogous to the chromosomal changes observed non of depression among chronic users of LSD. after radiation exposure (whichare permanent). This depression has been particularly refractory Atthistimeourinformationaboutthe to traditional psychiatric treatments and the par- biological hazards of LSD and other hallucino- ticipants were not agreed on the nature or treat- genic drugs must be considered incomplete. One ment of the phenomenon. Unfortunately, many observer at the meeting said that he almost chronic LSD users have turned to amphetamines wished that some of thesereports about chro- in an effort at self-treatment of the depression. mosomal damage were trueso that we could Relative to the question of leukemogenic or stem the increase in illicit hallucinogenic drug teratogenic properties of LSD, Drs. Maimon use. But the jury is still out. We would certainly Cohen and Kurt Hirschhorn summarized their continue to warn potential mothers about the data relative to LSD and in vivo and in vitro possible hazards of LSD exposure; being always chromosomal aberrations. Since their initial re- clear about our facts while avoidingscare tech- port in Science 62 they have also observed chro- niques. The group was unanimous in feeling mosomal damage secondary to chlorpromazine that scare techniques only alienate the drug- and certain other tranquilizing drugs. They using community so that they may not atsome noted, however, that these aberrations were not future time listen to scientific facts aboutcon- as severe as the dislocations and translocations firmed hazards of hallucinogenic druguse. observed secondary to LSD administration. Dr. David Hungerford of the Cancer Research In- 62 Cohen, see footnote 2, page 1. stitute in Philadelphia also reported investigat- 63 Auerbach, see footnote 37, page 40.

...... maa. APPENDIX Background Papers andBibliography Reprinted with permission of author and publisher from theARCHIVES OF GENERAL PSYCHIATRY,March 1968, Volume 18, pp. 330-347 Copyright 1968, American Medical Association

On the Use and Abuse of LSD

DANIEL X. FREEDMAN, MD, Chicago

While scientists may debate the appropriate use do and do not selectively enhance suggestion and of hallucinogens, history records our unceasing urge various psychological and ideological phenomena. to cope with dreary reality or dread with theaid of The reported consequences of drugs such as LSD magic, drugs, drama, festival rites, and (with bi- range from isolated awe or benign or evenbored ological regularity) through dreams. The need to surprise to shifts of values. They range from transi- transcend limits also finds a voice in utopian ideol- ent to long-term psychoses to a gamutof confusional ogiesbe they of the inner world, of this, or the states and depression to varieties ofreligious or next; the promise of omnipotent mastery isalways aesthetic experience and insight, to clique forma- either implicit or readily inferred. Thus whether tion and ritual? There are now conflicting reports it is the proletarian masses, or youth mesmerized of therapeutic effectiveness in alcoholism, depres- by mellow yellow banana, or the princes of the sion, character disorders, and severe neurosis.3-12 land of genital primacy, or the meekeach is prom- There is also a mushrooming psychedelic culture. iced the inheritance of what probably will be a This underlies the tribal motions (or brownian rather crowded earth. Given the prevalence of these movements) of young and aging dropouts, rebels motives it is not surprising that drugs play a role disavowing society's "games" if not all (nonmusi- not only in the behavior of individualsbut also in cal) instrumental behavior. The paraphernalia of social and ideological processes. fringe fashions, music, and art comprise the trap- With the appropriate mctives and occasion, al- pings and trippings commercialized as psychedelic most any psychoactive drug canprovide a brief "go-go." Some serious theologians, some "hippies" "ego disruption"producing a moment of being as well as our peripateticprophets now seek the out of it.' This disruption in itself may promotethe drugs as a promoter of love, of religious or self- release of powerful affects and this ego state will enhancement. Some view the drug as transforming be welcomed for its novel value as a remarkable western society into a Zen Elysium.Some are sin- trip from reality. Etched upon it may be the spe- cere and private in thesepursuits, some pro- cific pattern of the drug. I believe that the action vocative and evangelistic, and there are variant of drugs such as LSD extend and accent this pri- subgroups whose rapidly evolving habits, ideolo- mary ego state in a salient andsustained way. In gies, and behavior are as yet unrecorded. any event, scrutiny of the social use ofdrugs cannot Of course, gentle and ferocious reformershave infallibly discriminate the "basic" pattern of effects. often held that special visions were not only their We first have to distinguish the range of effects inspiration but their expl; -it guide. Theelite of "ego disruption" and what is commonly called threaten misery for those who do not accurately the power of suggestion. With this in mind, we assessie, agree withtheir claims of value. Truly can focus on the ways in whichhallucinogens dispassionate assessmentthe exercise of judgment may deprive one of access tothe mysteries revealed in special states; there is only one way to Submitted for publication Oct. 13,1967. if one is From the Department of Psychiatry, University of Chicago, be "in" on the truththeir wayand Chicago. "in" there may be no way out! The only answer to Reprint requests to 950 E 59th St, Chicago 60637. such dilemmas posed by any cult is exposure to ex- 59 perience, to knowledge, and assessment over time had taken mescaline, wrote that there are potential ie, perspective. forms of consciousness which with ...the requi- site stimulus and at a touch... arethere in all The "Psychedelic" Dimension in Behavior their completeness...somewhere(they)have their field of application and adaptation ...How The recurrent theme in historical records is that to regard them is the question ...they may de- certain drugs are compellingly related to "learn- termine attitudes though they cannot furnish for- ing," to self-revelation, and that they are involved mulas and open a region though they fail to give a in some mystical, often ritual, use.12 The American map (Italics mine) . Indian often states that "peyote teaches." This What about the experience of this "region" of major theme does not dominate ordinary accounts the mind is so striking? Two features are obvious, of marijuana usage. The potent preparations of the nature of the experience and the contrast with cannabischaras and ganjaare an exception and ordinary experience. It is my impression that one have been used in India to enhance contemplative basic dimension of behavior latently operative at states as well as for a "high" and are not without any level of function and compellingly revealedin paranoid and other psychotomimetic effects1 +.1a LSD states is "portentousness"the capacity of the Apparently, there is a continuum of effects along mind to see more than it can tell, to experience the dimension of self-revealing and ritual usages. more than it can explicate, to believe in and be To the extent that there are classes of agents impressed with more than it can rationally justify, which reveal normally suppressed components of to experience boundlessness and "boundaryless" the mindexposing these dimensions to our atten- events, from the banal to the profound. If we were tionwe can say that both use and abuse stem to relate this to psychoanalytic theory, we would from an amazed response to a drug-induced sub- say that an ego (or cognitive) consequence of the jective experience. If this is what Humphrey Os- primary process and its hypothesized mobility of mond meant by the term "psychedelic" (or "mind energies is this dimension of "portentousness." Af- manifesting"),it is an apt though not novel defects are equally mobile; fragmentations and fus- scription. Whatever the outcome, the mode of func- ions--plasticityare, as Freud describeditfor tioning and experiencing called "psychedelic" dreams, characteristic. or "psychotomimetic"reflects aninnate capacity To this disjointed world of clear perceptions one (like the dream) of which the waking human mind can react with awe rather than tempered judgment, is capable.16 The fact that a certain class of drugs or even with irrational and boundless affectecs- so sharply compels this level offunction .(with all tasy or terror. The sense of truth is experienced the variability inherent in less organized states) as compellingly vivid but not the inclination to test and does so for a chemically determined package the truth of the senses. Unlike the sleeping dreamer, of time is what so intrigues the biobehavioral sci- the waking dreamer is confronted with the coexis- entist. tence of two compelling and contradictory orders From our work over the past nine years,17-12 we of realitywith the interface of belief and the now know that the indole andcatechol derivatives orderly rules of evidence. which are psychotomimetic in man can induce a James saw this as a region of the mind which response in the brain of animals, alteringbrain knows both mysticism and madness; "...there serotonin metabolism and probably increasing the seraph and snake abide side by side." But experi- utilization of norepinephrine. Most of these drugs ences of this realm of the mind cannot be totally show crosstolerance. In contrast, psychotomimetic disconnected from normal life; how they are con- agents such as atropine or piperidylglycolates (eg, nected is the crucial issue. As James remarked, what Ditran) which produce amnesia and delirium20-22 comes from this inner world must, ". ..eventually primarily affect brain acetylcholine rather than run the gauntlet of confrontation with reality just monoamines.19 This indicates that we are dealing as what comes from the outer world of our senses." with agents for which some exquisite molecular 23 The "trip" back to reality after "tuning in" to this and biological specificity exists; each of the brain region may be discordant or harmonious; one's monoamines appears to be lawfully related to spe- sense of both the inner and outer world may be cific, largely polysynaptic neural systems and it is revised in the service of the ego or altered to suit not unlikely that with autoradiography, and fluo- the requirements of irrational needs. There are, rescence and electron microscopy,13.24 ourknowl- then, modal and characteristic forms of mental op- edge of the involved neural systems and chemical erations which can underlie behavioral states and changes induced by these drugs can be ever more experiences of widely different consequence, intent, finely specified. and meaning; and these modal operations are com- At the behavioral and experiential level this spe- mon both to madness and mysticism which must be cificity has intrigued many. William James,25 who differentiated on other grounds." To summarlie,

60 I believe that there are few drugs which can so un- dosage J1 With doses of 200to 1,000y there is, with hinge us from the constancies which regulate daily increasing dosage, an increasing loss ofautonomy life, or so clearly present us with unevaluated data and control of critical and discriminative functions. from the "inside world" and from the many nor- Usually, one "trip" produces "psychological satia- mally useless perceptions potentially available to tion" 13 and is sufficient formost people forever and us. It clearly has been tempting to snatch some for others, at least fora few days, months, or years. good from this. It also can do little harm, given such an ample smorgasbord of claims, to seek perspective by concentrating on whatif anything The Drug Experience is common to all of these varied effects of LSD. It is the intense experience without cloudedcon- What must be described is a multipotential state sciousnessthe heightened "spectator ego" witness- which, in its most general sense, can underwrite a ing the excitement, which is characteristicfor these variety of outcomes: religious feeling and conver- drugs in usual dosages. Thus there isa split of the sions, states of hyperperception leading to inspira- selfa portion of which isa relatively passive moni- tional insights, to psychosis, to exalted states, or tor rather than an active, focusing, and initiating perhaps to behavior or value change. The more we force, and a portion of which "receives" vividex- can grasp some of the intrinsic features of this state, periences. Some peopleseem to repeat this long the more we will be able to predict and under- after the drug state; standingapart from life and stand why such drugs can be properly called psy- its "games" or relyingon the group to direct events, chotominietic, psychedelic, or "cultogenic" agents. they turn away from the prosaic worldorelse are itwill also be clear that some of the modes turned away by society. The striking self-centered- of experiencethe styleswhich characterize the nessthe experience of the self seeingthe self drug experience can be linked to the outcome or can be elaborated in a variety of ways, from detach- to the style of life commonly centered around drug ment to symptomatic narcissism. The dominantex- taking: whether this frequently persistent "hang- perience of seeing can be expressedas convictions over" of drug effects represents new learning, or of revelationie, psychological, mystical, aesthe- reinforcement of the ongoing trend of goals and tic, or religious "insights." adaptations, or more complex mechanisms is not During the drug state,awareness becomes in- now known. Beyond impressions which are hardly tensely vivid while self-controlover input is di- sanguine about long-term use, evaluated data are minished, fragile, and variably impaired. Thus still lacking. there is always the lurking threat of loss of inner controlloss of control of integral stability. This Pharmacological Features isvariably experienced and symbolized. At its height, it has been called "dying of the ego" and The sequence of effects following the usual doses is often reported in bad tripsor in phases of mysti- has been described elsewhere.27 During the first 41/2 cal experiences with the drug. Forsome, such ex- hours there is generally a clear-cut self-recognition perience is dread transcended; for others, itis of effectsan internal "TV show" (marked by unwelcome or denied anxiety and dyscontrol. shifts of bodily sensations, affect, and percepti:ni) Many anxious concerns and problems after the which is followed by another four- or five-hour drug state center around issues of control,auton- period in which the subjective sense of change is omy, self-directedness, and decision making. less marked but during which heightened self- In the drug state, customary boundaries become centeredness, ideas of reference, and a certain fluid and the familiar becomes novel andporten- "apartness" are observed. At 12 to 24 hours after tous. Any event or category of events which comes drug there may or may not be some letdown and to one's attentionsensory, sexual, or cognitive slight fatigue. There is no craving to relieve this takes on a trajectory of itsown. Qualities become aini no true physiological withdrawal. intense and gain a life of theirown; redness is Contrary to previous myth, the acute stagecor- more interesting than the object which is red, relates with the biological half-life of the drug in meaningfulness more important than what isspe- plasma in rat 29 or man 29; and the duration of cifically meant. Connotations balloon into cosmic what can be identified clearly as drug related effects allusiveness. This can be experienced religiously, is dose dependent, lasting generally 8 to 12 hours. aestheticall,,sensually, or in a variety of clearor There is a dose-contingent tolerance in both rat and confused frames of reference. man requiring three or four daily doses for maxi- After the drug state, we may find pseudoprofun- mum effect and about four days for a loss of tol- dity 2'32 or omniscience as wellas more tolerance erance 30; with high dosage there is an unexplained for the novel, the unusual,or for ambiguity. We cyclicity of tolerancea sudden loss after eight also can find an associated inability to decide,to days and then a gradual build-up with continued discriminate, to make commitments. Th;s occurred

61 as a Rorschach pattern in Indian peyote users." seen in man 37 and animal 38 su : ests vividness more Such a i.endency to avoid distinctions could lead to than powerful discrimination of the complex. Cre- alienation and retreatism, even if these were not ativity requires some facility not only for seeing preexisting traits (as they often are).For many, the but for implementing new meanings; but, as we drug experience may represent a beginningan at- shall stress, it is the need for synthesisnot the tempt to feel intenselywhich without luck or ex- ability to synthesize with due account for real limits pertise, cannot easily come to a useful conclusion which tends to be reinforced in the drug state. (just as neurotic acts may be viewed as unguided attempts at self-cure) . "Cultogenic" Effects of LSD Certainly when hidden meanings perpetually contaminate the response to the explicit conven- An important feature of the state is an enhanced tions of everyday life, "focus" and goal-directed ef- dependence upon the environment for structure ficiency are impaired. Judgment is not enhanced and support as well as enhanced vulnerability to during the drug state and isolation or apartness thenow novelsurrounding milieu. With the bring their own problems: accordingly persons who loss of boundaries, persons or a group are used for continually overvalue the modes experience of the such elemental functions as controlfor helping drug state could develop and reinforce poor practi- one to know what is inside and what is outside, cal habits. Pseudoprofundity, philosophical naivete, for comfort and for binding and balancing the impractical detachment, and inadequate foresight fragmenting world. and judgment or impulsiveness in dedicated users With the fusion of self and surroundings, some were already evident to an observer of the Harvard of the strain caused by the exertion of personal scene of 1963.32 The consequences of long-term and strivings and their conflict with what is projected frequent use of the druginvolving possibly 5% as harsh authority, can (for the moment) be tran- to 15% of those experimenting with LSDwould scended or dissolved. At the same time there is a probably have to be evaluated in this context. leaning on others for structure and control. Hence, when the drugs are taken in a group setting, the Immediacy, Novelty, and Creativity With LSD breach with reality canand mustbe filled by the directive mystique and support of the group. This In the drug stage, the experience of compelling is, in part, why I have termed these drugs "culto- immediacy diminishes the normal importance of genic." past and future. One's organized anticipations of Many successful self-help groups are peer groups time dissolve and the anticipatory factor, so impor- or form around a common flaw. If they are uncriti- tant in the psychophysiology of pain, is similarly af- cal of weakness, less masking of inadequacy can fected. (Thiscoupled with effects of suggestion- - ensue. With such arrangements, the distance be- may be why the drug experience could be reported tween authority and the miscreant is diminished as "replacing" narcotics in dying cancer patients.) and so, too, is the inner tension. The cost is a sur- Dehabituation (ie, a response to the familiar as if render of a certain order of autonomy to the group, it were novel) was noted in early studies of the a certain passivity, and dependence upon the con- drug in cats 84-36 crete presence of a group to share the burdens of The overvaluation of "nowness" is not unrelated initiative. The surrender of a conflictful autonomy to the fickle pursuit of the novel apparent in cer- (reflecting a prior instability, isolation, or diffu- tain youth subcultures. The ability to see old and sion)may be preferabletothe compensatory familiar events in a new light is also a facet in the delusional autonomy seen in proselytizers who ag- poorly understood processes related to creativity. gressively threaten the establishment with love and But the impairment of goal-directed efficiency and drugs. Of course, a compulsive tendency to exter- sustained focused attention carries with it the im- nalize the conflict with authority can be reinforced pairment of integrative and synthetic functions. by peer-grouping. Nor are all the tribal affiliations Thus the mere mergings of sensory objects(the we call groups endowed with the competence to synesthesias,theplastic rearrangements orthe guide; many are loose alliances based on the denied dear focusing upon fine details or usually disre- mutual despair of their members. garded perceptual elements)or the elisions of thoughts and concepts hardly are the same as an Object Relations and Values organized building and arrangement in which "boundaries". and distinctions are essential. Sharp- Actual persons in the environment have positive cned or "heightened" perception and consciousness cr negative value in terms of quite elemental func- is not equivalent to adaptive perception, nor is ab- tions, eg, as threats or as anchors in maintaining normal brilliance necessarily to be equated with a primary self-control (quite as in the so-called psy- beauty. Indeed, the primitivization of perception chotic transference) and intensities of affect can

62 mercurially escalate and .'iminish in the absence difficult since the distinction of inside and outside of normal boundaries. Persons are self-centeredly tends to diminish. Accordingly there are frequent seen and usedeither to be clung to, or to be con- mislocationsormisconceptionsprojectionsof templated in terms of what essentially is a self- motives and sensations. This tendency is reinforced centered ..ensory, aesthetic, or ideologic frame of when one must exert energy to account for even reference; they may become vivid objects of highly slight changes in the environment; slight details not personal transferences. At best there may be a nar- only capture attention but also can gain the patina cissistic shifting of one's relationship to others and of portentousness and are linked to the ever pres- to one's own ambitions which, as Kohut has noted, ent threats of dissolution. The eventual outcome of can lead to outcomes which are socially valued this hypervigilance, inefficient scanning,42.43 and wisdom, humor, perspective. But such internal mislocation is called paranoid behavior. syntheses never guarantee socially pleasant behav- There is also a remarkably heightened sensitivity ior, and pathological outcomes are also probable. to gestures,inflections, and nonverbal sensory- motor cues which normally are in the background; Model Psychosis in the Drug Experience however, the ability accurately to judge these cues and appropriately lodge them ill contextjust as The elements of a model psychosis are present. in schizophrenic sensitivityis easily impaired. This does not mean identity; rather it is an ap- The altered relationship of figure and ground also proach to certain processes which are variably pres- means that metacommunications fail; the context ent in both the drug state and psychoses. The no longer predicts the relationship of parts to the conditions for either state have similarities and whole. obviousdifferences(justas do dreams and Similarly the component affects can be enhanced psychosis) .40 under the drug state but are difficult to focus upon. In the first hour after LSD most people refer Thus several contrary feelings coexist; or they fluc- their altered perceptions and relationships to the tuate (just as sensations do) ; this is reminiscent of body and its parts; this period of changed bodily ambivalence. Subjects later refer to the total state sensations and perceptions could be called hypo- as a pleasant-unpleasant experience. Those seeking chondriacal (with all this connotes as a prodromic mystical experience speak of heaven and hell. symptom) or simply altered body image, depending Euphoria mixed with tension may be seen. on the context. The point is that there is auni- Laughing or crying or both in the first three form change in the experience of the relationship hours are common. With care, one observes that of the body, the self, and their normal environ- following the initial perceptual changes referred to mental coordinates. the bodythere is a primary need for elemental The basis for hallucinations can be analyzed.41 tension-dischargea welling up which requires For example, what is impinging on an ongoing per- laughing or crying for relief. Subjects have to ception is a vivid memory of what has just been laugh or cry and they then seem to find the ap- perceived; these coexisting images can compete for propriate setting to rationalize this. attention and thus give rise to illusions. (In our However these experiences may be represented laboratories we have observed monkeys under LSD and symbolized, they are evolved from a ground- who may respond to serial stimuli as they had been work entailing a coexistence, heightening, and frag- trained to respond to overlapping stimuli.) This is menting of component urges and feelings. Thus, marked usually two to three hours following 200pg changes in ego organization and capacity seem to or less of the drug and following the period of occur first: this is usually manifest in the perception altered perceptions referred to the body and its of bodily changes. A tension or need for discharge boundaries. With the increasing loss of distance, then becomes apparent; perception of affective such illusions can be imaginatively or regressively changes and changes in the self and relationships elaborated into hallucinations. Similarly, memories with objects in the milieu supervene and dominate can emerge as dear images competing for the status the experience. These changes in the first three or of current reality. This failure to suppress the prior four hours underlie the varied experiences of "in- perception or memory or thought is reminiscent of sight."Expectations and preconscious fantasies what Bleu ler called "double registration" in schizo- certainly stamp the content and even influence the phrenia or what, in Rorschach parlance, is called capacity to exert control during the drug state, but contamination. Similarly the failure of identities with the loss of structure a "program" of vulner- and categories to be maintained underlies most of abilities and needs seems to be "released" 44 or com- the descriptions of paralogic in schizophrenia. pelled by the drug. The capacity selectively and relevantly to direct The enhanced value and intense attention placed one's focus is impaired; allocation of the source of on the self, the narcissism, ego splits and regres- a feeling, a sound, a sight, or a thought becomes sion; the loss of boundaries; the "double registra- 63 dons"; the ambivalence; the heightenedtension; tranced or totally absorbed. But with increasing the diminished control and problemsof focus 45; dosage the experiencing ego can be overwhelmed. the unstable (or inappropriate) affect;all can rep- At any level, defensiveness can appear; the spec- resent the primary symptomsof a psychosis. Given tator shuts his eyes and ablind struggle for con- this state of affairs one can see avariety of "psy- trolmaydominate.Basicattitudinalshifts, chotomimetic" or "psychedelic" phenomena elabo- redirection of attention, projection denial, displace- rated and expressedall of which requiresuch ment, affective explosions, panic,confusion, with- basic shifts in ego organization. Whether or notthe drawal, or magical and delusional syntheses may be "observing ego" keeps touch with reality maybe seen as persons attempt to cope.Rarely there is an crucial to outcome, but is irrelevant to theclassifica- acute loss of judgment orimpulsive and primitive tion of a psychotomimetic state. Catatonicschizo- thinking manifest in attempts to fly or defy gravity phrenics often maintain a silent observing era which results in a concrete and fatal confrontation monitoring reality during their psychosis." with the real world. One protection isnotto fight The appearance of peak experiences (or acute the experiences during the drug state. An upsurge psychedelic experiences) in clinical psychosishas of the traditional defensive operations requires long been documented 47; early phases of acute psy- extra vigilance and may lead to temporarypanic choses often cannot be differentiated from accounts even in relatively stable people. of drug experience." In the hoursfollowing the It is striking that when self-examination or con- acute flux, as adaptations tothe first phase begin, frontation with personal problems is the motive we can note thesubject's attempts to structure for illicit drug-taking, effects are not infrequently while still impaired by the drug. Where energyfor bad. Both licit and illicit drug users note that un- scanning and testing the reality of unwantedinput stable surroundings or confused motives lead to is required, delusional simplifications, ideasof ref- "bad trips." When problems are aptly externalized erence or passionatebeliefs occur and provide an or shared there is less panicand subsequent upset. economical explanatory anchorage. Those who are unable to tolerate the flux by shift- We have with these drugs at least a toolwith ing attention from it or enduring it (or "guiding" which to study the genesis and sequence of a num- it by delusional, mystical, or aesthetic revisions) ber of familiar phenomena in psychiatry.Whether may retreat into catatonic-like postures.Thus a cer- it can lead us to a better sorting anddescription tain yielding and surrender of ambition and per- of the varied elements which are presentin the sonal autonomy helps some individuals to have a range of dinicaldisorders is yet unanswered; for good experience; but this requires if not group sup- example it is obvious that differencesin .outcome port, a certain personal strength, or atleast a faal- of LSD states depend upon. specific priorstrengths ity.It also requires stable groups. as well as varyingcircumstances. It is also obvious Those who are encouraged or equipped tonot that a time-bound state such as a drug state can- attend to the fragmented disparate elements, let not demonstrate symptomaticphenomena which them flow into the sway of a mystique, steered by develop over time and are embedded in confusing latent guiding interests or memories. Thus all that life circumstances." Indeed, the role of thesefactors occurs is given a toneor a verydiffuse direction. in symptomatology could be more readilydistin- With higher dosages and the increasing loss of de- guished by appropriate comparative study ofclini- tailed focusing, the importance of guiding "sets" cal and drug-induced alterations ofconsciousness. (music, mystique, affective expectation such as the Comparative studies of drug-induced states could doctine of boundless love)is enhanced. Indeed, also be useful in determining factors and sequences under LSD it is the positive or negative attitudes related to outcomes of such a multipotentialand and postures toward the ego's varied experiences fluid state. Finally, it bears upon our thinking which are most vulnerable to suggestion. The about any psychosis to recognize thatwhatever "maps"the formulas and specific ideologies sup- the role of motivationprimary or secondary shifts plied by guidesare actively sought because ofthe in such elemental ego functions as attention and vulnerability of the ego and therelativeloss of discriminationthe adaptive control of sensory in- synthetic and higher cognitive functions (such as put and percept.on 42-0canunderlie a range of goal directedness).Accordingly panic states may be "psychotic" symptoms. "guided" by redirection of attitudes, or attention and by provision of structure. Adaptations During the Drug State Summary of the Drug State Some persons endure all this without es dent harm. The spectator ego can simply be interested Thus we may say that in the presence of a height- in the reversal of figure and ground, the visual ened sense of awareness, there is a diminished role tricks, orwith higher dosesthe spectator is en- of the array of functions related to cognitive control

64 and discrimination of complexities. The ego may be drug state; it is not uncommon that there is an said to be less autonomousless reliablein the equivalence of value for what is at the periphery deployment of focused and sustained attention. It and what is normally perceived at the center of is vulnerable to being guided by a widened and the visual field. He commuted daily, reading dur- more variable range of both internal and external ing the trip. For months after the drug, he was factors. In order to anchor the drug-induced period bothered by the telephone poles which flashed by of flux, direction of attention and basic orienting his train window. He could no longer suppress what attitudes can be supplied either by the now im- normally is background rather than compelling fig- paired ego (with its defenses and prior expecta- ure. Similarly, the unconscious "background" to tions) or by the setting. Such expectations may be thoughts, gestures, and feelings can emerge. explicit and implicit, conscious and unconscious; There are numerous anticipatory sets or con- accordingly, prediction and control over outcome stancies which operate to keep the body oriented in especially in self-experimentation are inherently space and ready to meet the environment as we ex- unreliable. Similarly, the utility, fittedness, and re- pect to experience it; the mind provides constancy liability of the setting will, in fact, vary widely. wherever the sense organs deal with variability. We The extent to which the experience of a specific anticipate or correct for the images on our retina "trip" is related to outcome requires finer study. to keep the world stable and ordered; the hand So, too, does the fact that one good trip does not stretched 8 inches before one, may appear small, predict a second. Accurate studies in this area are though on the retina or camera it is large. Com- important to our understanding of outcome. Nev- ing off a boat one may still waddle, maladaptively ertheless, the primary changes described are the anticipating the roll of the ship. Such habits or sets background state from which a number of diver- can smooth out our perceptions and actions; but gent outcomes and adaptations ensueadaptations they can persist when they are not useful and lead both during and after the drug experience. No to inappropriate and confused responses. LSD ap- doubt the rearrangements of reality which occur pears to affect these stabilizing perceptual anticipa- during this state produce a memorable experience, tions. It rearranges and unbalances our ideas of but one is reminded of Sidney Cohen's remark that order, whether the self and its defenses or percep- most people get what they "deserve" 0 or what tions are a referent. they are equipped at the time to experience as modified by set, equipment, and setting. The Need for Synthesis and Outcome

Restoration of Constancies After the Drug The intensity of the drug experience manifest in the change of constancies can lead to a number Two realities have been exposed in startling con- of repetitive behaviors. The search for synthesis trastprivate and public reality, both of which are may take the form of attempts to reexperience the a part of experienced reality. Anyone who has ex- intensity of elements within the drug experience in perienced this intense episode must come to deal order to master it, just as with the traumatic neuro- with it; some judgment about the significance and sis with its breaching of the "stimulus barrier." It utility of these realms of the mind must be made. is an old theme in psychopathology that in a state Our dreams are an episode in a sequence of states of altered consciousness in which control over which we usually can somehow integrate into the awareness is diminished, there is no way to bind normal fabric of living; similarly something must the intensities experienced and symptoms may en- now be done to represent and cope with the total sue. Breuer (and more reluctantly, Freud) referred drug experiencenightmare, illusion, or ecstasy. to this as the hypnoid state; explanations of the Some borrow stability from ready-made explana- consequences of early pregenital experience to re- tions or isolate the experience. Still others will de- petitive neurotic symptoms in later development cide that the experience of cosmic comprehension have been placed in this context." is equivalent to self-mastery. Still others, lacking While "bad trips" occurring without the drug any other means of mastery, will be compelled re- may be explained in the model of the traumatic peatedly and unexpectedly, to confront what was neurosis or hypnoid state, it is astonishing to see experienced. We see this in students who come in an entire sequence of heightened sensations as well for help weeks after a tripexperiencing anxieties as altered perceptions occurring with apparent sud- or brief unwanted trips in the absence of drug." denness weeks after the drug. This obviously evokes The breakdown of those constancies and habits comparison with psychomotor epilepsy; but this which normally smooth over the disparate details connotation is as yet without foundation in facts. of our perceptions and actions can persist in fright- The psychodynamics preceding these lapses from ful but also benign ways. One sdetnist experience s reality also require close scrutiny; yet these reports his peripheral vision to be enhanced during th, appear to present us with evidence that the "bar-

65 rier" against dereistic thinking and altered states order to diminish their own doubt, isolation, and (or the "switch" permitting a shift ofmental guilt. At best, they may do this not only to share states)is a factor which in itself merits intensive but in order to reachieve union with those from investigation. There are schizophrenic patients who whom they have been separated by their unique appear eventually to have learned ordiscovered vision and experience, and to synthesize these that there was some control which they could exert breaches with important others. against "slipping" into such states. Whatever the explanation for either the loss or the mastery of The Role of Groups in Outcome such controls may be, it is evident that the experience of the LSD state withits intense clarity in Some kind of continuity with the gap in reality the presence of diminished control can have a is sought. The bridge may be a book as it was with range of consequences which cannotalways be an- Huxley, a silent synthesis, or change of values and ticipated simply by monitoring the apparent in- tastes, or the understanding of a group or person. tensity of the ongoing drug state. In the Native American Church, the Indian uti- Repetitive symptomssuch as acting outmay lizes religious explanation and adherence, specific occur. In part, these may beviewed as unsuccessful ceremonies, and the group with its ideology to in- attempts to restore or find constanciesand bound- tegrate the experience which serves a purposein aries. Such behavior, which invites control and the total fabric of his life.2 guidance, frequently appears as a provocative ac- There are mixed consequences with the reli- cusation against authority andby provocation ance on groups. In some chronic users one sees a prr...lerves a tie with it. Othersaggressively and end- bland impulsivenessan indifference to the habitual and customary which may border on a super- lessly talk about their experiences as if they were 11 trying to put them together. cilious posture of superiority. The elect of many For some, reflection about the sharp contrast of cults either assume this attitude or the outsider drugged and real life may evoke mild or severe feels this to be the attitude of those who know rumination and depressionrelated to an urge to something he does not. This benign or irritating recapture the lost illusionaryand brilliant drug posture has also been remarked upon in theAmeri- world. The extent to which primitive and regres- can Indian peyote users who are often asubculture sive fusion fantasies will dominate these reactions not infrequently at odds withestablished groups. varies.Conflict and confusion about "what is Nevertheless, the observed reliance of drug users on reality" or the experience of normally repressed cults can permit at least a measure of authentic thoughts and urges by the unprepared ego can lead self-involvement at a level which is realistically to mild or severe symptomatic states,perplexity, available to the persons involved. Where these and disorganization. "cults" are but loosely juxtaposed cliques con- In any event, variably determined needs or ca- nected by common rationalizations, there is still pacities to cope with the split or breach of normal some comfort and protectionfrom a ruminative experience can be expected. This may be a simple self-concern which is enhanced by isolation. "sealing over," or even an enlightened anduseful Mystical or religious representations also are thought formation we call insight. Some react with remarkably apt for synthesizing the experience. Re- a denial of inadequacyand anxiety about loss of ligion can relate man to his limits while taking ac- control; borrowing the enhanced omnipotence of count of his boundlessness which occursin all the drug state, they show a delusional autonomy. aspects of this realm of the mind. It maybe that This may lead to various outcomes: that of the be- religious symbolism aptly represents the transforma- nevolent and foolish prophet, or the defensive, tions characteristic of this latent part of the mind. alienated therapist, angry at those who prevent his Against fragmentation and directionlessness, some- curing the rest of the world. Any threat to the val- thing coherent lends continuity to experience. ues of the illusory experience ofunion and omni- Against dread, transcendent love can prevail; lov- potencesuch as undrugged realitycould evoke ing like redness can apparently be enhanced and defensive denial and strident proselytizing. is remembered. The "lovingness" and "strongness" It is interesting that classifications of pathological of a parent can be parted from the particular per- outcomes of conversion 52 (includingirresponsibil- sons and transcendentallyrepresented in various ity and omniscience) startlingly resemble patterns forms of power ascribed to deities. we see with LSD. Indeed, we mustseriously wonder There are, then, a number of features of this why those who find salvation are so implacably gen- multipotential state related to its intensity, its erous and so ready to advertise!Implied are un- novelty, its boundlessness which account for some solved problems with authority figures. Salvation of the expectable occurrences within it and some often involves renunciation of previous ties; those of the expectableand observeddangersand vari- who are saved must repetitively convince others in able outcomes.

66 LSD in Psychiatry In the so-called psychedelic therapies as they are now being tested, there is an awareness of an im- There are a number of psychotherapists who mense amount of preparation, of salesmanship with have attempted to we the loosening of associations an evangelical tone in which the patient is con- and the intense experiencing produced by the fronted with hope and positive displays of it before drug in order to influence behavior change in in- he has his one great experience with a very high dividual as well as group therapy (and the drug dose of drug. The drug experience is structured by obviously is useful for the study of group pro- music and by confident good feelings. With the sup- cesses) .53.54 There are a few ongoing controlled port of the enthusiastic therapist, the patient is en- projects and a long history of experience with couraged to see his life in a new light, to think of the use *.**and abuse "of LSD in therapy. In his future accordingly. There now tends to be a the late 1950's some physicians thought they had rather long period of follow-up and support before discovered a new reality of the mind and were not the patient is discharged. An earlier mode of in- only struck by the drug-induced phenomena, but tervention attempted to avoid the tangled problems apparently addled by them. Perhaps they were sim- of relationship between therapist and patient 10 with ply jealous of the subject when they insisted upon but a single high-dose drug session as the chief taking the drug concurrently with him therapeutic contact; the current approach is more Today, two major serious modes of treatment explicitly ritualized(in the model of nativistic prevail. That employed by many European workers movements) ; the person and attitude of therapist (called "psycholytic" by Leuner 44)represents a tends not to be analyzed but incorporated. It is method by which certain defenses are breached. speculated that the egocentric problems of the With a strong drug-enhanced tie to the therapist, alcoholic may be specificallytailoredforthis feelings, memories, and transferences are allowed "ego-dissolving, ego-building" technique. Other ap- to emerge vividly and unforgettably before the eye proaches, eg, employing hypnosis,*/ lie somewhere of the consciousness and their strength discharged. between these two. It is interesting that peyote The events are later worked over with care. Dos- cultures also report cures of alcoholics but the ef- ages are regulated in part by the capacity of the fects may not persist without sustained group sup- patient to steer a course between being utterly lost port and leadership.2 The effectiveness and selectiv- or overly constrained by habitual defenses. A kind ity of current therapies is far from settled and of active participation in the presence of a general research is still ongoing.* Obviously careful follow- loosening is sought. As issues in therapy arise, up is essential since the immediate glow which dusters of intense affects directed towards early ex- occurs with drug-induced personality changes in periences and objects are encouraged; thus, fanta- such contexts can be deceptive. The fact that under sies involving rebirth, early transference strivings, LSD the therapist can often readily suggest posi- and trauma can emerge with sensory intensity. The tive or negative attitudes toward life experiences therapist lends support and later interprets. and promote a state in which struggle may be di- Certainly, people are initially less guarded under minished should arouse our fundamental curiosity the drug and can experience a range of "insights" not only about LSD therapy and its effectiveness, they might normally disown. Yet they also can react but about the mechanisms, utility, resistances, and quite defensively under the drug when what is seen pitfalls in behavior change achieved through per- is, for personal reasons, overly traumatic. To an suasion ...As extent they can ward off self-recognitions with affective outbursts and they can dearly distort them The Scope and Dangers of Illicit Use by basic attitudinal shifts, displacements, redirection of attention and projections, denial, confusion, We should recall that the increasing problem of withdrawal, or magical and delusional "syntheses." drug abuse in most countries is alcohol, followed For quite vivid self-encounters there is usually no by the barbiturates, amphetamines, opiates, and postdrug amnesia. The integration which follows mild tranquilizers. In this context the consequences is a collaborative venture requiring the active par- to national health of hallucinogens are not as yet ticipation and the output of the patient. During truly startlingeither in terms of the utility of LSD treatments, a sequence of defensive memories, or its harm. In the long run, debates about whether transferences, and distortions commonly arises and or not to use LSD are as socially consequen- requires further drug sessions and work. Illicit tial as the use of "the Pill." The agent most fre- drug users also encounter "hang-ups" but have lit- quently used by youth for illicit purposes and with tle guidance to work them through sequentially. lethal effect is the automobile; and the most faith- The therapists find this absorbing and exhausting; ful monitor of the scope of such social problems is they generally work with inpatients and severely ill the prevailing high insurance rates for young men. or characterologically impaired patients. The actuarial superego of our society has not yet

67 instituted insurance wate changes for medical,psy- wagon effectconfidently announce that growing chiatric, or mortician'scoverage in response to hordes of youngsters are independentlydedicated these chemicals. This is an interesting generation chronic users. To the mature, theirmessage is that but they have not as yet gone completely to pot! this is a revolution in which adultsare helpless; Not all users are youth nor are all youthful to the young it is a subtle invitation to revolt under users initially unconventicaul and utipmductive. A the sanction of inevitability. The establishment few current illicit self-helpgroups reportedly em- then reacts with. irritation and fright.As the ploy the drug and religion to achievea conven- advertising escalates and the empiricalproblem in- tional outcotne; eg, a group of exconvicts anda deed grows, the young and their frequentlycon- group of homosexuals. Several religious and lay fused and permissive parentsmust enter the debate groups have set up agencies to be phoned when and assess the claims of value. Physicians hysteri- panics are encountered. Weseem to be living in an cally crying alarm join the melee, lumpingall bad era when many practices (half-way houses, group reactions into one dire outcome:permanent mad- therapies, cathartic therapy, confrontation therapy) ness. They can now also cite somatic dangers. built into the fabric of psychiatric workare imi- Reports of chromosomal changes in preparations tated by ever proliferating self-helpgroups which of lymphocytes raised in tissue cultureare not iden- frequently tap our society's long tradition of dis- tical with "genetic damage"or dinical disease. trust of medical science. Unfortunately, nonscien- Apart from unwarranted biological inferences,the tific searches for cures are too easily dismissedas reliability of such findings isnot established; nor fanaticism, eccentricity, or ignorant superstition. do we as yet know the relationshipto dose, to com- Yet these social responses in part reflectupon the mon stimulants, or to drugs related by structureor ability of the health professions to deliver relevant behavioral effect.Similarly, a finding of LSD- services, to treat irrational anxieties,or to be com- induced stillbirth or stunted growth inrats is not petently aware of and responsiveto the issues and identical to fetal anomaliesor germ cell damage; consequences of different patterns of drug abuse. effects in mice may differ; rodentsmay differ from Reliable estimates of the incidence of psychedelic man; similar reports of effects of other drugs (in- drug "use" (however defined)are always vulner- cluding reserpine) should be evaluated priorto able to criticism. They range from 1%to 15% on sanctioning alarming reports about LSD. Nor does certain campuses. Figures higher than 5% probably the persistence of hippocampal dischargesfor sev- do not distinguish single trials from habitualuse eral weeks following LSD (in cats trainedto avoid nor LSD from other drugs of abuse; eg, prosely- shock) indicate long-term brain changesnor brain tizers frequently tell us about the "inevitable" "damage" in man; reserpine, in fact, producesmore growing use of "marijuana and LSD." Onlya small dramatic persisting effects in the hippocampus to fraction of persons who have taken the trulypotent and without the intervention of shock. Neither the hallucinogenic drugs could be saidto constitute a history of folk usage of psychedelicsnor the past 20 reliable base for study of long-termusers. Groups years of medical and lay use of LSD haveas of persons who drift in andout. of the category of yetproduced dear and reliable evidence ofsomat- users are not easy to identify and are hardly reliable ically dangerous consequences of the drug inman. reporters. The problem is that some are always first While such important research continues,caution discovering the drug (availablenow for 20 years) about publicity is warrantedon both scientific and and acclaiming it while the silent othersare humane grounds lest we further panic thesuscepti- experiencing disillusion aftera year or two of ab- ble. A single past indiscretion with LSDnow leads sorption. Still others actively seekor passively ac- to serious brooding over the shape of what the cept one or two self-experiments. We clearly require young parents fear will be a psychedelic monster. a study of the fad element in usage; cydes of inter- No doubt the social problems presented by LED est may well be shown to follow certain pressre- could easily be diminished ifa dearcut son: tic leases and to vary sharply with opportunity and danger is established;we might, however, have yet the ethos of different settingseg, hippiecenters to cope with this phenomenon without the aid of or campuses or enclaves of middle-aged imitators such facile warnings! who mourn their lost youth. Clearly themotives for experimenting, maintainingor self-regulating the intake of any drug differas do the conse- Psychiatric Complications of LSD quences of these varied patterns of use. The facts are that dangerous and tragicpsycho- Complications for research also arise fromsen- logical consequences arenow unequivocally es- sational publicity. The selectas well as the popular tablished,a47 and it is just this fact whichusers press provide a structure for the curious, restless, deny (as if it were concoctedto attack their auton- and lost as they compete toannounce or denounce omy and self-esteem).From our own campus ex- drug usage. The psychedelic huckstersfora band- periences it appears thatusers who end up in 68 hospitals with prolonged and serious psychoses are the possibility for the impairment of good sense initially a quite unstable group. They are, in any and maturation. In this sense, the drug can rein- event, a small group. Suicides and violence are also force a dissociative trend, leading to acute reactions uncommon. More frequently one sees atransient or insidious disorganization and failure successfully panic occurring during the drug state from which to integrate life crises. recovery (without theadministration of often complicating phenothiazine medications) occurs within The Risk of LSD "Trips" 24 hours. If other than supportive and reassuring treatment is required, adequate barbituratehyp- Impressions gathered from various observers in- nosis or a sedative tranquilizer such as chlordiaze- dicate that the experiencethough not necessarily poxideisa simple regimen. A few visits for the outcomeof approximately 10% of any batch follow-up can be instituted when required. Others of trips (whether or not it is an initial one) can do not require hospitalization but often seek treat- be potentially upsetting. With skilled guides per- ment because they are concerned abouthaving haps many of these potentially unpleasant experi- taken the drug. They are upset or depressed about ences are warded off or redirected. With skilled some of their thoughts and experiencesduring the therapists, 1% or less of drug experiences may be drug state, or about their basic life dilemmawhich unexpectedly traumatic. Certainly under these cir- in many instances is obviously serious. And a few cumstances less than 1% is traumatic in outcome. others, as noted, may have serious "nondrug" in- With proper immediate follow-up most of these re- duced panics some weeks after the drug state veyy actions should be therapeutically resolved. This ap- much as a bad dream recurs. Occasionally a com- pears to have been the case even though attempts plicated history of multiple drug intake by a root- to screen subjects in order to predict reactions have less youngster leads to a picture of toxic psychosis. not yielded clear-cut guidelines 5"; and it has not We must make a distincolon between an un- been established that the drug is necessarily trau- pleasant tripeven one which might leadto matic when given to severely mentally ill persons emergency room referralsand variouspsychiatric with the structure and follow-up available in thera- complications of drug use which may or may not peutic settings. In all probability older subjects be contingent on a bad episode. Such unpleasant (past 26 years) are less likely to have prolonged episodes have "turned off" those who try a casual reactions linked to a single bad experience. experimenta socially valuable response! When While such impressions require research, we can patients are brought to physicians by drugged or un- be confidentfrom the experience at responsible stable friends, or in disorganized circumstances, research centers in the 1950's and in European clin- physicians should be aware not only of the role of icsthat the setting and the ability to manage the momentary panic (and the fact that any escalating experience and its aftermath are crucially impor- panic can look like a toxic state) but of the pos- tant. We can also be reasonably certain that the sibility of complicated drug-taking patterns, of risk differs when the drugs are taken under unsu- prior instability if not mental disorder. Similarly, pervised circumstances; or with unwise therapists we should note that classical instances ofidentity or guides;or by adolescents attemptingself- diffusion, of borderline phenomena and adolescent analysis; or in specifically therapeutic experiences turmoil mayin contemporary lifebe associated or in sensibly controlled researchconditions. There with LSD; this is hardly a basis for citing the drug is no question that good sense and trained skills as totally causal. can help to control bad LSD experiences and out- We now see little scare literature presenting an comes. The inescapable problem isthatexcepting unevaluated snapshot of steroid psychoses, because within narrow limitsa bad experience and an un- we can now predict with more confidence what the welcome outcome need not be associated and results will be and evaluate the risk. Similarly neither can always be predicted. we shouldin timebecome familiar with these drugs. The facts are that a fair number of people The Drug Mystique have had LSD without serious untoward effects. The majority of acute untoward reactions with My current opinion is that the chief abuse of LSDwhile severely troublesomeare not as yet LSD is irresponsible, alluring, and provocative ad- proven to be inevitably permanently crippling. The vertising. Havelock Ellis' enthusiastic report of the suggestibility, despair, confusion, and latent dis- effect of mescaline,'0 while evoking alarm about pos- organization of those who unwisely take LSD is, I sible abuse,71 did not flower into a cult or into believe, as crucial a variable as the chemical which a topic for the bored mass media. Anideology renders themunexpectedlyvulnerable to more couched in the language of drugs has been insinu- trauma than they can handle. The habitual long- ated into youth culture by a band of quite articu- term use of LSD for pleasure or escape produces late writers and vagrant professionals. These have 69 replaced the old medicine show of yesteryear with it is a civil matter) when irresponsible proselytiz- an updated campusversion complete with readings ingborn from the spirit of oedipal revengeleads and tempting arguments if not pills to sell: "tune to a number of drug-related casesin children and in, turn on, ant: dropout." A drug mystiquehas young adults requiring psychiatric carefor either been welded to the underlyingly serious shifts and brief or long periods of time. It is often forgotten strains inherently experienced by the most poten- that the real momentum for such claims arose when tially unstable group of any societythe adolescent a few psychologists who peddledthe dreg resented and young adult. the notion that medical or even nurses training We need not determine whether this is indeed were required for the responsibleadministration of a "now" generation valuinghonesty, love,di- potentially toxic agents. The problem, of course, is rect confrontation and uncomplicatedaction, and that the psychedelic guruswhile promoting fre- avoiding ideologies in favor of simple justice. netic advertisements for themselvesare not in a These values, however germane to the LSD experi- position to manage the consequences of their ideo- ence, were not born from thedrugged mind. The logical schemes. When they do admit the drug Pied Pipers of LSDpeddling a drug which can might be dangerous, they do so by insisting that enhance poor judgmentwould lure youth from only the very courageous should take the drug! The the acquisition of competence (or even from the rationalizations which prevail among those who ex- serious study of man's attempts to deal with the periment with LSD are often borrowed from these two orders of reality in his personaldevelopment various preachings. and in his religious, artistic, philosophical, and scientific endeavors). Motives for Use If we make the distinction between the psychedelic mystique and issues about the utility of LSD, The motives for LSD use are varied. Sociologists and if we attempt to account for the fact that the refer to problems of commitment and alienation greatest abuse has been among thewell-educated and at least add thereby to the younger genera- or those who might bewewould in all honesty tion's verbal mythology. We might remember that have to question the strange tolerance for these wild analysis and "psyching"probing into one psychedelic follies in campus cultures. Forgetting another's supposedly unconscious motivescharac- both Freud and James, many of our teachers and terized youth of previous generations, as did self- intellectuals are either entranced or perplexed by experiments with hypnosis even in the 19th century. stories of LSD-induced revelations. They appear Curiosity about the mind, about what can be neither to have learned from nor to teach from ex- experienced, about who one is and is to be can perience. be expected. All the crises of adolescence 72the We seem to have forgotten that there are trained fluidity, shift of primal objects, narcissism, somatic persons who in fact have more experiencethan the changes, inexperience, and identity issuesplay self-appointed gurus in coping with adolescent tur- into the drug-taking culture. moil and the more serious dysfunctions. There are Of the college users I have studied, a "need to scholars and disciplines knowledgeable about man's feel"to gain access to themselves and others--a attempts to understand subjective experienceand pervasive sense of being constricted seem charac- its manifold aesthetic, literary, and intellectual ex- teristic. In a recent report of a group in which pressions. The social psychology of groups, cults, Rorschach and other studies were available, this conversion, enthusiasm, and utopias is hardly a new theme dominated even though outcomes sharply discipline. None of this seems to have crucially per- differed: these ranged from psychosis, to instability, meated our campus cultures in terms of new cur- to a reaction of bemused enlightenment :faOne ricula or opportunities for both confrontation and wonders whether the consequences of a "boundary- reflection. In brief, much of this advertising may less" or destructively permissive upbringing leads "take" because in exploring new frontiers we have to a lack of distinctions, a deficientrecognition of lost confidence in our traditions and seem to have self-experience especially when drugs or authori- avoided dealing both with the rationalizations and tarianism (masked as rebellion) are common ways the honest probings of the drug cultists and other to achieve feeling and a sense ofdistinctiveness. youth on campus. In any event it is dear that "edu- Some college students dearly tried the drug as cation" of the drug-prone young will require more part of clique activity; taking the drug puts the than a troop of physicians. Some sophistication student one-up--he has "been there." This is a chal- about the vicissitudes of man's gullibility might lenge evoking interest among friends and can pro- render our institutions less vulnerable to sophistry. vide the basis for a loose group cohesion. For this The psychedelic apologists insist they have the group, magical transformationof reality, omni- civil right to take any agent which does not harm scient union rather than painful confrontation of others. It is, of course, hardly a private matter (and separateness and effort is a lure. Old limits canbe

70 dissolved andwith a singlegulpphilosophical chemicals could have attained somespiritual equi- infants are transformed into sages.The frustration librium seems apparent, but whether noalternative of years of inexper'ence are replacedby an intense means exist within a cultureis another question. arcane experience;it is as if the secrets of the paren- That startling examples of new learning or even tal bedroom are instantly transcendedby the mys- conversion can occur cannot be denied; butthat we teries of the drug! The tables areturned as the can as yet control andsystematically reinforce drug- young turn on; nowit is the parents who stand by induced insights is uncertain. is really in perplexed, uncomprehending,and fascinated We must ask whether a stable person impotence. under sufficient control of his motives and shifting Others sincerely feel they shouldconfront an ex- circumstances let alone the dosage to takethese perience advertised to be so important.They can drugs as a civil right for whatever personal reasons be dared by accounts of pleasant orassertedly pro- he wishes:15 If so, who has to care forthe conse- found experiences. They see the drug as an emo- quences of his misjudgments?How can the stability tional fitness test, somewhat analogous tophysical of religious custom protect drug-takerswho have fitness. The issue for many is "control."They ex- little authentic orientation to religion andunstable periment with the right to drink and testtheir abil- groups and barelyreliable leaders upon whom to ity to stop. At this age they aredoing the same lean. If we learn from the effects ofdrugs on much often with cigarette smoking, studying, orwith mas- simpler biological systems, some side effects of any turbation. In general, they are rehearsingtheir chemical cannot be avoided. Few of theadvocates strength and autonomy at a timewhen their lives of unsupervised use seem to appreciatehow difficult drug adminis- are largely unwritten.Many behaviours of this age it often is to assess risk and value in constitute a probing for consequencesanimpa- trationeven in the best practice ofmedicine and tient attempt to leap the barriers oftime, to come psychiatry. to grips with life andseize the fruits and risks prom- We should not forget to assess the cost of sus- ised in the future, the threshold ofwhich is now tained euphoria or of pleasure states. We canseri- just barely visible. This underlies manyof the ously wonder if man is built to endure morethan grimmer statistics of the 18 to 25 age group,includ- a brief chemicallyinduced glimpse of paradise. ing accidents and suicide. One wonders ifthese Many authors have stressed that we areendowed and represent the inevitable costsof learning the lesson with mechanisms with which to filter input of consequences, of limits, of mortality. structure and use the fluidand irrational components of behavior. HeinrichKltiver 76 concluded his systematic and pioneering series ofneuropsycholog- Summary and Conclusions ical studies of mescaline with speculationsabout With respect to the LSD experience, weknow the drug's differential action on those vastsubcorti- that many serious persons have reported some cal areas characterized by emotionalityand varia- transient or even long-term value in it.There is bility and those anchoring sensory-motor systems some objectiveevidence that aesthetic appreciation which aid in constancy. The question is perhaps can be enhanced; eg, an LSD groupbought signifi- not so much "expanding"the mindit is expanded cantly more records for a period of sixmonths.'* enoughbut to see if there are drugs (ordevelop- If, though, we search for major productionsof art, mental experiences) which can enhance abetter letters, music, or visionary insight fewclear-cut and more creative coordination amongthese so- monuments to the drug areavailable. Related to called regions. creativity, the effects of the drug do not seem to Thus etched upon the variabilities of cultureand have compelled it. Huxley's greatest output pre- personality are drugs with a certain skew toward ceded his mescaline states; he thereafter, as Iread that mystical realm of the mind which knowsboth him, tended to write about drugs, not to createwith psychosis and religion, both heightened anduseful them. If we ask whether there have been cultures self-insight and impaired and distortedjudgment which have eradicated mental disorders anddisease about both the drugged and everyday world.Per- with these drugs, or groups which have seenthe haps similarities and differences of thesevarious dissolution of deviant behavior, we find someslight chemicals and their effects couldif analyzed23 association but no clear-cut overall differences that reveal means for finer control of theseexperiences I know of in the general titer of humanmisery. In at least in terms of theirintensities. The possibil- fact, the extensive use of these drugs is often ity or impossibility of such manipulations are ques- associated with some form of psychosocial depriva- tions of basic importance to our notionsof how tionan equivalent form of which is marked priv- neurobehavioral mechanisms are intrinsically re- ilege (as in Brahmins and college students) .That lated and the extent and means by whichthey can private satisfactions might have been achieved, selectivelybe dissociatedandcontrolled.17,77,78 that groups with the presence of these plantsand In general, then, it seems that we havebeen more 71 awed than aided by our experience with these This is an expanded version ofa lecture given at the drugs. They still remain agents which reveal but Michael Reese Hospital and Medical Center, June6, 1967. do not chart the mental regions; to do that we must Itis a revision of a paper, "Perspectiveson the Use and employ our mental faculties available in the un- Abuse of Psychedelic Drugs," published in Ethnopharmaco- drugged state. Accordingly we should do better logic Scgrch for Psychoactive Drugs, D. H. Efron(editor-in- than simply be amazed, repeating thereby the on- chief), US Departmels: of Health, Education, and Welfare, togeny of past encounters with mind revealing Public Health Service Publication No. 1645, 1967, withthe drugs. With these drugs we could learn to analyze permission of the editors. Sectionson the Definition of a how behavior is organized, disrupted, and influ- "Psychedelic" Dimension, Model Psychosis, and the Scopeof enced and see what nature can teach us about the Contemporary Problems have been extensively revised and that on Inherent Problems in Ethnopsychopharmacology ond ways in which the chemical organization of the the Use and Abuse of Conversion omitted. Work with brain is related to the dimensions of experiencing the drug in man and animal over thepast ten years has been and behaving which comprisetouse an archaic supported by Public Health Service grants MH-03363, 13186, termthe study of the mind. and Career Investigator Awards M-1204 and K3-18566.

References

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73 Patterns of Response to Self Administration of LSD

WILLIAM A. FROSCH, M.D.

Authors of magazine articles and popular books with unstable or psychotic personalities. In addi- about LSD have, until very recently, heralded pri- tion, the conditions of an experiment minimize the marily its beneficial effects. They have stressed its likelihood of bad reactions, such as panic or more capacity to "expand the consciousness" and to open prolonged complications. There has been careful the way to greater self understanding, increasedar- supervisionoftheexperimentalsubjects and tistic powers, and in general to a richer, fuller life! prompt psychiatric intervention when indicated. (1).This popularization of the drug has resulted Despite this, there are a number of reports in the in widespread, indiscriminate self-administration of literature of brief or more prolonged adverse reac- illegally obtained compounds reputed to be LSD. tions occurring as a result of an LSD experience The increasing popularity of the drug and the avid- during the course of an experiment. The incidence ity with which it is now used would appear to be of these appears to be quite low; certainly consider- a testimonial to the hopes and expections of the ably less than 1 percent (3). takers. Less is known, however, of the incidence of ad- This situation is reminiscent in some ways of verse reactions in settings where there is no screen- what happened to Alice in Wonderland (2): ing or supervision. The only two incidence figures By this time she had found her way intoa tidy are those provided by Blum (4) and by Fink (5). little room with a table in the window, and on Blum's data suggests a minimal hospitalized psy- it (as she had hoped) a fan and two or three chosis rate of 2 percent and indicates that the over- pairs of tiny white kid gloves, and was justgo- all psychosis rate may be as high as 3.3 percent. ing to leave the room, when her eye fell upon These figures are based on a population of 300 who a little bottle that stood near the looking-glass. received LSD under institutional auspices. Two of There was no label this time with the words these were LSD institutions per se. Fink, in a re- "DRINK ME," but nevertheless she uncorked cently published study, reports that 2 percent of it and put it to her lips. "I know something psychotics who are given LSD have prolonged ad- interesting is sure to happen," she said to her- verse reactions. He feels these are separate from the self, "whenever I eat or drink anything:so I'll ongoing psychotic process. They were related very just see what this bottle does. I do hope it'll specifically to the ingestion of LSD and showed make me grow large again, for really I'm quite characteristic clinical findings, different from the tired of being such a tiny little thing!" classical symptomatology of schizophrenia. After an Such curiosity sometimes has unfortunate results. initial period of confusion, they showed an exag- In experimental work with LSD there has usually gerated emotional and affective lability. been careful screening of subjects to exclude those During the past two years, there have been an estimated 200 admissions to the Bellevue Psychia- The author is with the Department of Psychiatry, New tric Hospital directly resulting from ingestion of York University School of Medicine and the Bellevue Psychi- LSD. This number does not include those who give atric Hospital, 550 First Avenue, New York, New York. a history of having taken LSD but who are ad- Portions of this work were done in collaboration with Edwin S. Robbins, M.D., Marvin Stern, M.D. and Moya M. mitted for other reasons. We would estimate, based Groeschel, M.S.W. The author would also like to express his upon a recent survey, that 5 percent of the Bellevue thanks for the technical assistance of Paula Frosch and Psychiatric Hospital admissions have had at least Joan Gertz and for the thoughtful criticism of Murray Al- one experience with LSD. Our data suggests that pert, Ph.D. this is almost unheard of in the general hospital This work was supported by Public Health Service Grants population. Of the psychiatric patients who have MH-08618 and MH-04669 from the National Institute of Mental Health. used LSD, 15 to 20 percent were admitted as a di- Presented at the 5th Annual Meeting of the American Col- rect result of the LSD experience. Thus the in- lege of Neuropsychopharmacology, Puerto Rico, December 7, cidence of LSD use as a cause for admission is a 1966. little less than 1 percent.

74 Of this large group of admissions, we have most groups over 30. There were almost as many women carefully studied three samples of LSD users. These as men. This sex distribution differs significantly were the first 12 2atients admitted to the hospital from that reported in most other addiction prob- early in 1965 (6),the first 22 successive admissions lems, such as with the opiates or with alcohol. Al- in 1966 (7),and the most recent 23 admissions. though less than 10 percent of the LSD takers were The first two samples included only patients ad- married at the time of admission this may be pri- mitted as a direct result of LSD ingestion, the last marily a function of their relative youth. In contrast sample induded all patients we were able to find in to the Bellevue Psymiatric Hospital population the hospital who had taken LSD. The age, sex, mar- there were almost no Negroes or Puerto Ricans in ital status and race of the samples are shown in this group. In striking contrast to both the Bellevue Table 1. The three samples, taken at different times, population and the public stereotype of the drug are remarkably similar to each other. The median addict, they tended to come from a middle and age is 22; there were almost no patients in these upper socio-economic group.

Table 1.VITAL STATISTICS OF LSD USERS ADMITTED TO BELLEVUE PSYCHIATRIC nownAL

dekmp I Semple U Semple M EarlyMS Early 1111 Late NU Combined 24 = 12 2f = 22 N = U 24 = 17 Agein years median 23 21 22 22 range 18 32 15 43 16 33 15 43 Sea N I % N 1 % N % N %

male 7 58 11 50 14 61 32 56 female 5 42 11 50 9 39 25 44

Marital Status married 1 6 2 9 2 9 5 9 unmarried 11 92 20 91 21 92 52 91

Race white 12 100 21 96 20 88 53 93 negro 0 0 1 4 2 $ 3 5

oriental 0 0 0 0 = 1 4 I 1 2

Table 2 presents the number of times that LSD level of 100) before ingestion resulted in hospital- was taken by these patients. This ranges from a ization. Of the third sample, which includes all pa- single experience resulting in hospitalization to tients in the hospital who had taken LSD, seven took claims of several hundred experiences (coded to top the drug mdy once before hospitalization.

Table 2,NUMBER OP TIMES LID WAS TAKEN

Ilemple I DiliII lample M Early MI5 Early 13U Late WU Combined firetiefriri Dees N = 12 N = n 24 = 13 24 = 17 N 4d, N lb N % N % 1 5 8 67 10 I 46 13 56 31 54 6 10 2 17 2 9 3 13 7 12 11 30 1 I 8 4 13 4 17 9 16 31 100 1 8 6 27 3 13 10 ; 18

We are able to say little about the dosage of LSD had previously taken marijuana. Almost all had ex- taken by these patients. It was usually taken as a perimented with amphetamines or another of the sugar cube impregnated with the drug. The users' stimulant drugs. In addition, many had taken bar- estimates of the amount ingested have ranged biturates and one of the opiate derivatives. They from 100 to 5,400 micrograms. Most patients appeared to use drugs in an attempt to embrace claimed to have taken 400 to 600 micrograms each life rather than to get away from it. Drugs gave time. However, without chemical identification we them a sense of liberation from conventional cul- are unable to be sure that they have actually in- ture and a feeling of having undergone genuine gested LSD. experiences. Almost all of the patients who had ingested LSD Although LSD is publicized for its beneficial ef-

75 fects, a surprisingly small number of our LSD takers well as patients who show evidence of confusion. said they took the drug primarily for these benefits. These are transient episodes not extending beyond Only two of our first 34 patients took LSD to the period of activity of the drug and the symp- achieve personality improvement via psychedelic toms appear to be dosely related to the direct ac- experience. Fourteen sought "kicks" or "highs." tion of the drug. For example, in response to The rest, although primarily interested in excite- grandiose or persecutory delusions the individual ment or companionship, said theywould not have may expose himself to danger. This was seen in minded being helped psychologically in addition to the case of a young man who thought he was in- achieving an experience. Almost all of these pa- vulnerable and walked up the center of 5th Avenue tients had some degree of personality disorder be- against traffic. He was brought in by the police. In fore taking the drug. other cases an individual may be unable to cope with conflictual material that may appear under the Syndromes influence of LSD. A man in his mid-thirties took LSD while mourning the recent death of his wife. Although the patients were admitted for a variety Under the influence of the drug he experienced un- of reasons, it is useful to distinguish three somewhat realistic guilt about her death and the return of a overlapping categories. We have previously de- series of traumatic memories from his earlier life. scribed these as panic reactions, reappearance of While under the influence of the drug, he sla.hed drug symptoms without reingestion of the drug, his wrists. For both these patients lack of adequate and overt, prolonged psychosis. Cohen (8) has sug- supervision during the period of drug action re- gested a somewhat more complex classification, sulted in behavior which was dangerous to them- with major classifications of psychotic disorders, selves or others. Those patients who show confusion nonpsychotic disorders, and neurologic complica- at the time of admission have only an indistinct tions. We would, at this time, suggest a classifica- memory of their LSD experience. tion of acute reactions; recurrent reactions, in which Panic ReactionsPanic is often seen at some there is a return of symptoms without reingestion stage of the LSD experience Whereas the symp- of the drug; and prolonged reactions. wins in the psychotoxic reactions appear to be the Table 3 is a compilation of the number of pa- direct effects of the drug, panic appears to be the tients with each of these syndromes in our first two response of the individual to the drug induced samples. There were no significant differences be- symptoms. In our patient population, panic reac- nveen the patients in each of the classifications with tions occurred both in the novice taking his first regard to any of the patient characteristics previ- trip and in the more experienced drug user. The ously described. A number of the patients first patients present with overwhelming anxiety, fear of appeared with acute reactions and later returned going crazy, a sense of helplessness and loss of con- to the hospital because of recurrent drug symptoms trol. They are often afraid they will not return --) without reingestion of the drug. This accounts for their pre-drug state. Both the setting in which the the number of reactions being larger than the N of drug was taken and the psychological state of the the sample. person at the time of ingestion were important in precipitating panic A confused, chaotic or lonely Table S.NUMBER Of PATIZNTS HAVING EACH TYPE setting, or anxiety or depression at the time of tak- OF RESPONSE ing the drug, are more likely to result in a panic reaction. Some patients came to the hospital them- I Simple I Sample n Early 1N11 Early INS Coselbisel selves seeking relief from their terror; others were N = 12 N = n N = 24 brought by friends who felt they could not control Type of Reaction N % the patient or could not prevent him from harm- Acute 7 II Ill 33 ing himself. One person cut his wrists in a suicide Recurrent 3 S II 33 attempt; another jumped or fell from a window. Prolonged 3 8 II 33 A subgroup within the panic reactions consists of those patients who have been given LSD without their being aware of it. Under these circumstances ACUTE REACTIONS even those patients who have previously had LSD The acute reactions arise with ingestion and are may experience panic One patient expressed this short lived. They include psychotoxic and panic re- as, "Now I'm experiencing this without taking the actions. Fifty-three percent of the patients admitted drug. I must really be going crazy." She then came as a result of LSD ingestion presented with such to the hospital. acute reactions. Recovery from these acute psychotoxic and panic Psychotoxic ReactionsThis groupincludes states was rapid, usually within three days. In our those Cohen has labeled acute paranoid states as experience a supportive environment and a sympa-

76 thetic nurse are adequate for the treatment of these they had previously known. Feelings of terror were patients. When these are available, medication has rapidly replaced by ecstasy. In the isolation of the not seemed necessary and we have hesitated to add transcendental state they believed that they had another variable to a drug induced state about achieved a resolution of their problems; they felt which we know so little. they had achieved a new self. As the effects of the drug wore off these patients were faced with the RECURRENT REACTIONS problem of returning to the real world and ac- The spontaneous return of perceptual distortions commodating to it. Conflict arose as they found or feelings of depersonalization occurred in one- that their new understanding was not readily third of our patients. These were similar to those grasped or responded to by others. Rather than previously experienced under the influence of LSD. give tip their new self, the psychotic patients strove They occurred up to a year after the last previous to maimain their sense of uniqueness, and with- use of the drug without further ingestion of it. drew from the world. These reactions respond to They varied in length from a few seconds to 30 treatment as do similar reactions unrelated to LSD minutes, from transient "aesthetic" experiences to ingestion. trancelike states occurring sufficiently often to in- terfere markedly with the individual's reality adap- OTHER CHANGES tation. Recurrence tended to appear inthose Many of our patients in each of these categories individuals who had been preoccupied with the showed a general alteration of values of the sort effect of LSD upon them before the experience, and that Cohen has included in his subgroups"dis- who thought of it often. Although some patients social reactions'' and "antisocial reactions." For ex- enjoyed their newly found "aesthetic" appreciation, ample, many patients felt a lessening of ambition. others became terrified when they became aware This was often accompanied by the formulation that the symptoms were no longer dependent on that life is a game. Withdrawal from competition drug use or even dosely related to previous inges- and social interaction followed. To some a down- tions. It was our impression, and that of the pa- ward movement in the social scale was justified by tients, that recurrent symptoms were correlated with the insight and empathy they felt they had derived periods of stress or anxiety. The frequency of their from taking LSD. appearance appears unaffected by the administra- Despite their unfortunate experiences with the tion of phenothiazine compounds. drug, nearly 40 percent of the patients claimed beneficial effect from their transcendental experience; PROLONGED REACTIONS however, 20 percent emphatically said they felt One-third of our patients presented with pro- worse after taking LSD. We were able to find no longed reactions. These indude chronic anxiety objective evidenr- for such claims as "increased in- states and chronic psychotic states. Although some- sight" or "greater love of fellow man." Most of the times descriptively identical with similar states (e.g., women said they felt less social constraint after depression, schizophrenia) unrelated to the inges- taking LSD, one going so far as to change her oc- tion of LSD, these patients' symptomatology is most cupation from office work to prostitution. In the lit- often colored by the LSD experience. They show a erature on LSD the effects of the drug are described preponderance of visual phenomena, depersonali- in great detail, and in addition, communication be- zation, and body image distortions. tween users further serves to disseminate knowledge Chronic Anxiety StatesThese appear to be com- about typical reactions. It is difficult to find an un- mon and may be accompanied by depression, soma- informed user. The role of anticipation and ex- ticsymptoms,anddifficultyinfunctioning. pectationcolors both the experience and its However, the individual remains in contact with interpretation and makes it difficult to evaluate his surroundings and reality testing is not grossly these claims. impaired. In our experience these chronic anxiety states may last many months and are relatively re- Comparative Smve sistant to the phenothiazine drugs and to other medication, as well as not responding well to psy- A recent survey of 102 randomly selected psychia- chotherapy. tric hospital admissions and 48 randomly selected Psychotic StatesThree of the patients who de- general hospital admissions may be used to com- veloped extended psychoses were not felt to have pare these groups with the people who use LSD. been psychotic prior to ingestion of LSD. The pa- Table 4 presents the age, sex, marital status and tients who did become psychotic had expected in- race of these groups as well as the combined LSD creased self understanding from taking LSD. They group presented earlier. considered the recent experiences to be more vivid The groups differ in a number of ways. It is dear and of greater personal significance than anything that those who use LSD are considerably younger

77 Table ALMAL STATISTICS OF THREE PATIENT Table LDRUG USE HISTORY SAMPLES General Psychiatric Hospital Population General Prichiatric LSD Hospital Hospital I Hospital Users without with LSD N = 48 N = 102 N = 57 marlins=marijuana U N = 48 N = 72 N = 80 N--=2$ Agein years Dr IWO 16 9h lh median 44 33 22 53 43 range 16-60 16-80 15 -43 Analgesia 73 64 Antacids 60 21 37 26 Sex % % % Laxatives 33 44 43 17 male 73 55 56 Alcohol 71 83 90 74 female 27 45 44 Tobacco 77 78 83 83 Marital Status Stimulants 0 10 47 91 single 71 82 91 Sedatives 17 25 43 65 married 29 18 9 Narcotics 6 4 43 47 Race Marijuana 10 100 96 white 62 60 93 LSD and 0 1 16 100 negro 33 37 6 Mescaline other 4 3 2 If one examines the drug histories of those who than the other hospital populations studied. There have utilized marijuana or LSD, it is different from is a preponderance of whites among the LSD users. the usual stereotype of the drug addict. The classic Although not induded in this table, it should also drug addict is reported to utilize opiates exclusively be noted that in marked contrast to the Bellevue or with occasional use of barbiturates assubsti- population there were no LSD users who had been tutes. The hallucinogen user is the drugequivalent born in Puerto Rico. The psychiatric hospital pop- of polymorphous perverse. He is drawn to experi- ulation and the LSD users had the same percentage ment with ary drug which has major central ner- of men and women. In contrast to the other Belle- vous system effects. vue Hospital samples the LSD userstended to come from middle and upper socio-economic groups. Conclusions These last two are in striking contrast to the usual stereotype of the drug addict as a male fromthe 1. The patients admitted to the hospital with a his- lower socio-economic group. tory of ingestion of LSD appear to be a population Table 5 is a summary of the drug histories of significantly different from both the general hospi- these populations. The randomly selected psychia- tal and psychiatric hospital population. They also tric hospital sample has been divided intothose differ from the classically described opiate addict who have and those who have not used marijuana. or alcoholic. The composite LSD takeradmitted to Analgesics and antacids are used primarily by the the hospital might be described as a 22-year-old general hospital population. Laxatives are used less white man or woman with one year of relatively un- by those who take LSD. There appears to be little successful college work. He is likely to have come difference in the use of alcohol and tobacco between from a lower middle dass family and to have some the various populations. There is a consistent in- history of rebellion against family norms. He has crease in the use of stimulants, sedatives,narcotics, taken LSD for "kicks" or experience rather than marijuana and the major hallucinogens, as one pro- for self-improvement. He will previously have ex- ceeds from the general hospital population to the perimented with marijuana, amphetamines, and psychiatric population who have not used mari- perhaps a barbiturate or an opiate. juana, to those who have used marijuana; and fi- 2. These patients present with one of a variety of nally to those who have taken LSD. This is most syndromes of an acute, recurrent or chronic sort. striking for the stimulants. None of the general 3. Although some of these patients claim subjec- hospital population had used them in contrast to tive improvement as a result of their drug use, there 91 percent of those who had taken LSD. Almost has been no objective evidence of this change in one-half of the hospitalized patients who used mari- our selected sample of patients hospitalized for in- juana or LSD also had used one of the opiate deri- gestion of LSD. vatives. The difference in marijuana use by the gen- Our continuing evaluation of the results of tak- eral hospital and psychiatric hospital populations is ing LSD substantiates our earlier impression that it greater than appears in the table. Of the 10 percent is a potentially dangerous drug when self adminis- of the general hospital population who used mari- tered. Because these are clinical observations rather juana, most had used it only once or twice. Most of than well controlled experiments, we have little in- the 30 percent of the psychiatric hospital popula- formation about these patients' predrug state. The tion who had used it had done so on many changes we observed may represent the natural occasions. course of an ongoing neurotic or psychotic process.

78 However, LSD appears to be implicated for several the hospital; and (c) the drug experience appears reasons: (a) We have reasonableevidence that they to have colored their ongoing psychiatric difficul- actually took the drug; (b) it seems to have played ties. The exact nature of the relationship between at least a precipitating role in their admission to the drug and the reaction remains to be explored.

References

1. Cole, J.0., and Katz, M.M. The psychotomimetic drugs, adverse reactions to LSD in psychotic subjects. Archives of an overview. Journal of American Medical Association,187: General Psychiatry, 15:450-454, 1966. 182-185, 1964. 6. Frosch, WA.; Robbins, ES.; and Stern, M. Untoward 2. Carroll, L Alice's Adventures in Wonderland, Chapt. IV. reactions to Lysergic Acid Diethylamide (LSD) resulting in hospitalization. New England Journal of Medicine, 273: 1235- 3. Cohen, S. Lysergic Acid Diethylamide: side effects and 1239, 1965. complications. Journal of Nervous and Mental Disease, 130: 7. Robbins, E.; Frosch, WA.; and Stern, M. Further obser- 30-40, January 1960. vations on untoward reactions to LSD. American Journal of 4. Blum, R.N., ed.Utopiates, and the Use and Users of Psychiatry, 124:393-395, September 1967. LSD-25. New York: Atherton Press, 1964. 8. Cohen, S. A classification of LSD complications. Psycho- 5. Fink, M.; Simeon, J.; Hague, W.; and Itil, T. Prolonged somatics, 7:182-186, May-June 1966.

79 Reprinted with permission of author and publisher from THE JOURNAL OF NERVOUS AND MENTAL DISEASE, Vol. 145, No. 6, pp. 464- 174,1968 Copyright 1968, The WilliamsWilkins Co., Baltimore, Maryland 21202, U.S.A.

Harmful Aspects of The LSD Experience

KEITH S. DITMAN, M.D.,1 WALTER TIETZ, M.D.,2 BLANCHE S.PRINCE, M.S.W.,3 EDWARD FORGY, PH.D.3 AND THELMA MOSS, P.H.D.4

Why is it that some people, sometimes after only seen by trained interviewers who obtained the one lysergic aciddiethylamide (LSD) experience, needed biographical information and administered become victims of depression, paranoia, psychosis the card sort. There were 98 men and 18 women, and even suicide, whereas others, even after numer- ranging in age from 15 to 47. Occupations varied ous LSD sessions, appear tosuffer no ill effects but from unskilled laborer, student, housewife, artist, often even claim substantial benefits in personalin- to professional people. The number of times the sights, functioning and creativity? Prolongedad- drug was taken ranged from once to well over 100 verse reactions to LSD usagehave been reported times for an individual. The dosage reported varied and dassified by Cohen and Ditman (4) , more from 75 to 1500 pg, but the dosage can be consid- recently by Frosch et al.(8) and by Ungerleider ered as only a poor approximation, since the drug and Fisher (13) . Conversely, there has been conwas usually obtained from illicit sources. However, siderable interest in the use of LSD as an adjunct our experience with controlled dosage studies leads to psychotherapy and as a means tofurther crea- us to believe that these subjects ingested enough of tivity (1, 2, 5, 12) .5 How can this apparent para- the drug to have a "massive LSD alteration of con- dox be explained? sciousness." It occurred to the authors that an understanding Subjects were divided into the following 3 might be found by exploring the nature of the drug groups: experience in those people who suffered ill effects Group I: The largest in number, this group con- from their LSD sessions and comparing it with sisted of 52 persons, none of whom needed psychia- that of those people who daimed no harm. To this tric care because of his LSD experience (s). This purpose, a standard card sort of156 items descrip- group is of considerable interest, because the great tive of the LSD experience, a number that allows 'Department of Psychiatry, UCLA School of Medicine; that experience to be evaluated quantitatively, was Brain Research Institute, Los Angeles, California; Vista Hill I retrospectively administered to LSD users who re- Psychiatric Foundation, San Diego, California. quired psychiatric care (either hospitalization or This research was supported by a grant-in-aid from Wyeth Laboratories; by the Alcoholism Research Clinic, Department outpatient treatment) and to a number of other of Psychiatry, UCLA, which is supported by a grant from the users of the drug who (lid not require treatment. State of California Department of Public Health, Division of Alcoholism; and by the Vista Hill Psychiatric Foundation, Procedure San Diego, California. Computations were done at the Health Sciences Computing Facility, UCLA, under the support of SUBJECT'S AND GROUPS MR Grant FR-3. 1 USC School of Medicine, Los Angeles County Hospital, We selected subjects who had reported taking Los Angeles, California. LSD one or more times and were willing to be in- ' Alcoholism Research Clinic, Department of Psychiatry, terviewed for pertinent biographical data and then UCLA School of Medicine, Los Angeles, California. be administered the card sort, as a means of de- Neuropsychiatric Institute, UCLA Center for the Health scribing their drug experience (s) . In all, 116 sub- Sciences, Los Angeles California. jects participated in the study, all of whom were 3 Personal communication, S. Grof, 1965.

80 majority were functioning at the time oftesting, aesthetic appreciation (20 items) ; 3) mystical and either at jobs or as students. Inaddition, many re- paranormal sensations (14 items) ; 4) empathy (6 ported having had several drug experiences.This items) ; 5) religious feelings (7 items) ; 6) unusual group was recruited through avariety of commu- body sensations and perceptions, not unpleasant nity contacts, including students, patients, andcol- (33 items) ;7) somatic discomfort (1.2 items) ; 8) leagues. depression (7 items) ; 9) paranoia (6 items) ;10) Group II: This group consisted of 27 subjects anxiety (19 items) ;11) hallucinations (6 items) ; who applied privately or to clinics forpsychiatric and 12) evaluation of the experience (9 items) . outpatient care, apparently as a result of their LSD The DWM card sort, with its 156 items listed experiences. Here, too, the majority were employed under 12 categories, is furnished in Appendix A. at the time of testing,and reported multiple drug experiences. Results Group III: This group consisted of 37 subjects in psychiatric hospitals in the Los Angeles area, BIOGRAPHICAL DATA where they had been hospitalized as a result of Table 1provides a comparison of the three their LSD sessions. Again, multiple LSD experi- groups in relation to levels offunctioning, fre- ences were reported, but unlike groupsI and II, quency of LSD usage, and drug histories.SurpIis- many of these subjects wereunemployed. ingly, frequency of LSD usage shows no significant difference among groups: 35 percent of the subjects TEST INSTRUMENTS in group I reported 25 or more sessions with LSD, In the interview, biographical information re- as against 38 percent in group III.And the per- garding age, sex, education, employment, number centage of subjects who reported taking the drug of LSD experiences, approximate dosages, and his- only once is relatively small in all groupsfrom tories of drug taking was obtained. The "DWM 25 percent in group I to 11 percent in group III. card sort," containing 156 items descriptive ofthe Similarly, drug histories reveal almost parallel LSD experience, was originally designed and as- percentages across groups. It is pertinent, if odd, sessed by three investigators (Ditman, Whittlesey that there is a high percentage in all groups of and Moss (5, 6) ) over a period of 9 years. Origi- multi-drug users: 53 percent in group I, 67 per- nally over 300 items were compiled, which seemed cent in group II, and 63 percent 'group III. In to exhaust descriptions of the LSDexperience. This other words, over half the people in all groups (and original card sort had been administered to more thus, in this population) reported casual to fre- than 200 subjects, who were asked to rate each of quent usage of various drugs: stimulants, sedatives, the items on a five-point scale, ranging from "very tranquilizers and hallucinogens. Apparently this much like the experience" to "very much unlike study sampled "the drug culture." However, it is the experience." Gradually those items which did pertinent to point out that the only group report- not seem relevant or did notevoke a differential ing a history of "hard narcotics" usage is the hos- response were eliminated, andduplications were pitalized group, with 23 percent in that category so dropped. The remaining 156 items were classified reporting. We wonder whether the use of hard nar- into the following 12 categories: 1) strong pleasant cotics (or personality factors) contributed to their emotions (17 items) ;2)self-understanding and hospitalization.

Table LCOMPARATIVE DATA ON GROUPS STUDIED

No Treatment Outpatient Hospitalised Group I roup II Group III (N = 52) (N = 27) (N = $7) Levels of functioning Working in jobs or as students 44(88%) 16(62%) 11(39%) Unemployed 6(12%) 10(38%) 17(61%) Unknown 2 1 10 LSD usage 5(19%) 4(11%) 1 session 13(25 %) 2 to 24 sessions 18(35%) 16(59%) 19(51%) 25 or more sessions 18(35%) 6(22%) 14(38%) Drug history Only LSD 10(20%) 0(0%) 2(5%) Marijuana and LSD 14(27%) 8(33%) 3(8%) Multi-drug use 27(53%) 16(67%) 22(63%) Narcotics use 0(0%) 0(0%) 8(23%) Unknown 1 3 2 The difference between group I and group III is significant beyond .001level. 81 Finally, the percentages of persons functioning at items in the depression category, five items signifi- work or as students decreases from 88 percent in cantly discriminated these groups: group I to 39 percent in group III. Achi-square test shows that this is a significant difference,well "I felt like committing suicide." (p < .01) beyond the .001 level of probability. Before draw- "I felt as if life had lost its meaning conclusions from these data, we should note ing." (p <.05) that the level of functioning was assessed just prior "Everything seemed hopeless." (p <.05) to the interview or hospitalization and notbefore "I had a feeling of complete de- the LSD experience (s) . spair." (p <.05) "I felt that life was not worth CARD SORT living." (p <.05) For purposes of evaluating the LSD experience quantitatively, each of the 156 items of the card Furthermore, three of the six paranoia category sort was rated on a five-pointscale, with the fol- items distinguished the treatment groups from the lowing numerical values: 1 = very much like the nontreatment group; groups II and III reported all experience; 2 = a little like the experience; 3 = three items with greater intensity than did group I: neither like nor unlike the experience; 4 = a little unlike the experience; 5 = very much unlike the "At times I had the sensation of experience. Each subject scored all of the items someone spying into my mind." (p <.05) from 1 to 5, according to his reported experience (s) "I felt that other people were in- with the drug. For each of the three groups of sub- fluencing my thoughts." (p <.05) jects, it was then possible to obtain the mean re- "At times I felt as if I were being sponse for each item. One-wayanalysis of variance persecuted." (p <.05) was used to determine thespecific significant differences which occurred in the natureof the LSD ex- Anxiety, depression, and paranoia were also re- periences, as described by the three groups. ported with far greater intensity by the treatment The most relevant finding in the card sort analy- groups II and III than by the nontreatment group sis is that of the 16 items significant beyond the .01 I. It might be interpreted, on the basis of these level of probability, 10 items were characterized by findings, that the characteristics of the harmful LSD strongly disruptive emotions (see Table 2) . And on experience include such specific concerns as immi- all 10 of those items, subjects in groups II and III nent death, disgusting sexuality, permanentinsan- all of whom required psychiatric care as a result of ity, despair to the point of wishing for suicide, and their LSD experience (s) described significantly persecutory paranoid ideation. Thesedevastating more unpleasant emotionalfeelings in their drug emotions, experienced in a nonmedical and per- sessions than did those in group I, who required haps nonsupportive setting, might be presumed to no treatment after their LSDexperiences. precipitate the need for psychiatric treatment. In all, 41 items differentiated groups significantly In contrast, these five items, which reflect a posi- beyond the .05 level of confidence. Seven of these tive,beneficial experience, were reported more items were from the anxiety category. They are: strongly by the nontreatment group I than by either of the other groups: "I felt I might become permanently insane." (p <.001) "I am much more satisfied with "I felt on the fringes of sheer life in general now." (p < .01) horror." (p <.01) "I can remember very clearly "I kept thinking terrible everything that happened dur- thoughts." (p < .01) ing the experience." (p < .01) "I became afraid I might die." (p < .01) "I have been greatly helped by the "Certain things did frighten me." (p <.05) experience." (p < .01) "I felt something dreadful was "I would like to try this again." (p < .01) about to happen." (p <.05) "I felt more alert and alive than I "I was disgusted by some sexual have in a long time." (p <.05) ideas that came to mind." (p <.05) Generally, it might be concluded that the non- In addition to these fears, treatment groups II treatment group experienced more beneficial, con- and III reported far greater intensity of feelings of structive sessions than did the treatment groups. despair and hopelessness than did the nontreatment Further analysis of the individual groups reveals group I. Surely it is pertinent that of the seven interesting differences between the outpatient group

82 Table 2.-ITEMS DIFFERENTIATING THE LSD EXPERIENCE

Rank Statement No. Statement Probability 18 I felt I might become permanently insane. < .001 1 < .001 2 138 There was humor and a jolly atmosphere. 3 99 I felt like committing suicide. < .01 4 70 I feel as if I "missed the boat" or somehow failed to get out of the < .01 experience what was potentially there. 5 7 I felt on the fringes of sheer horror. < .01 6 33 I am more satisfied with life in general now. < .01 7 53 I can remember very clearly everything that happened to me dur- < .01 ing the experience. 8 75 Certain things did frighten me. < .01 9 76 I have been greatly helped by the experience. < .01 10 78 I kept thinking terrible thoughts. < .01 11 133 I would like to try this again. < .01 < .01 12 47 This was like a bad (alcohol) hangover. 13 31 I felt something dreadful was about to happen. < .01 14 106 I learned what it is like to be really dead. < .01 < .01 15 137 Everything seemed too bright, too harsh, too loud. 16 159 I felt closer to God. < .01 17 109 I felt as if life had lost its meaning. < .05 18 141 The experience was nothing unusual. < .05 19 101 I felt as if I were traveling in time. < .05 20 124 Everything seemed hopeless. < .05 21 34 One side of my body felt different from the other side. < .05 22 88 I was disgusted by some sexual ideas that came to mind. < .05 23 153 I had a feeling of complete despair. < .05 24 36 I saw myself as I really am, and I did not like what I saw. < .05 25 59 I became afraid I might die. < .05 26 39 At times I had the sensation of someone spying into my mind. < .05 27 144 Words had strange new meanings. < .05 28 4 I felt supremely happy. < .05 29 86 I felt that other people were influencing my thoughts against my < .05 will. 30 61 I felt that life was not worth living. < .05 < .05 31 6 I felt more alert and alive than I have in a long time. 108 I felt as I do when I need a drink (alcohol) . < .05 32 < .05 33 29 At times I felt as if I were being persecuted. 34 74 Hours went by like seconds-or one second seemed to last forever. < .05 35 119 Everything seemed to have a place in life, even the "good" and < .05 "bad." 36 69 It was an experience of great beauty. < .05 37 80 I kept thinking of my problems. < .05 38 44 In the future, the appreciation of beauty will play a greater part < .05 in my life. 39 72 I understood some things far better than before. < .05 40 90 I felt drowsy. < .05 41 46 I felt that I knew what would happen before it did-like being a < .05 lump ahead of time.

H and the hospitalized group III. The outpatient jects seems to extend all along the continuumfrom subjects showed more intense anxiety in relation despair to ecstasy. For example, the hospitalized to permanent insanity, terrible thoughts, and fear group III reported aboutthe same degree of emo- of death, whereas the hospitalized subjects reported tion as the nontreatment group I on theseitems: greater feelings of hopelessness and paranoia (specifically, the desire to commit suicide, complete de- "There was humor and a jolly spair, and feelings of persecution) .It might be atmosphere." (p < .001) construed that the outpatient group, withits "1 felt closer to God." (t) < .01) stronger anxiety about permanent insanity, indi- "It was an experience of great cated enough contact with reality to seek help. But beauty." (p < .05) the hospitalized group seems to have crumbled "I felt supremely happy." (p < .05) under the impact of the drug experiences, so that its subjects could no longer defend against the Such extremes of feeling-fromeuphoria to dys- powerful emotions of depression and paranoia. phoria-are typical of the unstablepersonality. It Actually, this vulnerability of the hospitalized sub- is conceivable that the unsupervisedLSD experi- 83 ence could regress suchpersonalities into acute psy- procedure was to let them experience the psychosis, choticepisodes.The oneitem which most but then, within a day or two, to provide them with significantly differentiated the treatment groups another LSD session so that they could overcome from the nontreatment group is the fear and experience catharsis, after which, he "1 felt I might become perma- claimed, the therapeutic recovery proceeded rap- nently insane." (p < .001) idly. This method of LSD therapy is more extreme Actually, this item, which heralded psychological than that developed by Ling and Buckman (11), difficulty to come, was felt more keenly by the out- who combined LSD with methylphenidate (Rita- patient group than by the hospitalized group. lin) and claimed to achieve abreaction and cathar- Again, this might be construed as an indication that sis without the danger of acute anxiety attacks or those victims of a bad LSD experience who felt the psychotic episodes. It might be that other tech- danger of permanent insanity were still in enough niques can be employed in therapy, such as com- contact with reality to seek therapywhereasthose bining LSD with other drugs to prevent or work Who suffered depression and/or psychotic episodes through anxiety, to eliminate the experiencing of as a result of their experience hadlost the capacity deep depression, suicidal ideation and psychotic to test the bounds of reality. Actually, it wasfound breaks. impossible to test these patients during the first few Second, other hallucinogenic drugs, such as mari- days of hospitalization because of their lack of con- juana, its more potent counterpart, hashish, pey- tact. ote (mescaline) and the mushrooms (psylocibin) , Finally, these two items, significant beyond the have been used for centuries by primitive peoples .05 level of probability, are provocative: without the disastrous effects our society has ob- "I felt as if I were traveling in time." served with LSD. L. has been noticed that mari- "I felt I knew what would happen before it did juana and hashish increase appetite and have a like being a jump ahead of time." sedative influence, whereas LSD characteristically The treatment groups experienced both of these decreases appetite and provokes sleep disturbance. items more profoundly than did the nontreatment It may be that there are qualitatively different group. This will be elaborated in thediscussion psychopharmacological effects between LSD and which follows. thec.e other drugs. Again, it is suggested that for experimental and therapeutic purposes, it might be Discussion profitable to combine LSD with sedative or tranquilizing drugs to eliminate the majority of unde- Repeatedly it has been stated that the psychiatric sirable reactions, such as panic and depression. We illnesses resulting from the "massive LSD experi- do have reports of panic reactions from LSD which ence" run the gamut from anxiety, panic reactions, have been successfully terminated with antianxiety and depression, to borderline and acute psychoses drugs without subsequent discernible untoward ef- with occasional reports of suicide as well. Our data fects.6 also show that the disruptive LSD experience itself Third, it is well known that other methods of is characterized by anxiety, depression, paranoia, altering consciousness have produced disruptive feelings of futility and loss of reality testing. Surely emotional states similar to those produced by LSD. such overwhelming fears as those of death, perma- For example, sensory deprivation and sleep depri- nent insanity and disgusting sexuality couldprecip- vation have resulted in many untoward effects, itate severe and sometimes prolonged psychiatric including dissociation, hallucinations, and even disorders. That certain people experience such in- temporary psychosis. The well known "placebo ef- tense fears under the influence of LSD has been fect" can also produce untoward reactions. For amply illustrated in this study. However, some example, even distilled water, when injected in- salient points should be considered in this context. stead of the anticipated LSD, has been known to First,thereisconsiderableliteratureextant result in a temporary psychotic state (2) .6 And of which describes the use of LSD as an adjunct to course it has been repeatedly reported that the non- therapy (1, 2, 5, 9-11) .5 Repeatedly in these works medical use of hypnosis has resulted in regression, arereportedvividdescriptionsofabreactions abreaction, dissociative states, and even acute psy- involving "disgusting sexuality," such as incest, chosis. It may be within the bounds of probability sadism and homosexuality, which, when inter- that LSD, alone, is not responsible for the psychi- preted by the therapist and patient, are claimed atric disorders here reported. It seems evident that to have considerable therapeutic value. Grof 5 even the LSD experience is influenced by the individual's reported that some patients have suffered a psy- personality, his set and the setting, just as are the chotic breakdown under LSD, usually when they experiences with placebos, hypnosis and sensory de- were overpowered by traumatic materialbrought out in therapy with which they could not cope. His Personal communication, K. Ditman.

84 privation. Such a powerful drug as LSD, with its The latter point should not be construedas a consciousness-changing effects, can easily be destruc- plea for the unsuperviseduse of LSD! The authors tive to an emotionally unstable personor even to deplore the messianic attitude of those LSDtakers a healthy individualin an unsupervised setting. who advocate the indiscriminate(ab)use of the LSD, in sufficient dosage, seems to have theca- drug, just as muchas we deplore the emotionalism pacity to strip the individual of his defenses, in- and sensationalism against the drugper se, which tensify his awareness and thus make him more could lead to the banishment of the drugfrom con- vulnerable. This capacity seems evident in the trolled research, despite encouragingevidence that "time-loosening" aspects of the LSD experience. it has value as a therapeutic adjunctand aids in Orientation in time seems characteristic of the the investigation of the potentials of themind. Nor stable individual, whereas the neurotic is disturbed do we wish to ignore the possibilities,recently re- by the demands of time, as in many obsessions and ported, that brain or chromosomal damagemay re- compulsions. Thus, "traveling in time" may be, for sult from LSD ingestion (3,7). Certainly these the emotionally unstable person, an especially stress- reports must be intensively researched; and until ful experience. they are, clinicaluse of LSD in human beings Further, in this study it was significant that per- should be severely limited. Butat this time our sons functioning in jobs or as students just prior data on the LSD experiences of thosepersons who to testing were far less likely to be psychiatrically have continued to function without theneed of disturbed by their LSD experiences. If similar levels psychiatric care suggest that the toxicityof LSD of functioning also existed in these persons prior may be psychological rather than organic in origin. to their LSD use, then this suggests that a person committed to a regular program of activity (other Summary than drug taking) is somehow less likely to have a disruptive LSD experience. Thus, the question Some people have had disastrous reactionsto the arises: is it the temporary situational state of being LSD experience, including psychotic episodesand unemployed and unoccupied which helps trigger even suicide. Others claim no bad effects, but rather the bad LSD experienceor is it an already exist- benefits from their LSDusage. In an attempt to un- ing psychiatric malfunction (of which the lack of derstand this anomaly, the authors studied116 sub- employment is merely a symptom) that renders the jects from three populations: 1) thosenot requiring person more likely to have a bad LSD trip? In this therapy after their LSD experiences, 2)those need- regard, the role of the use of hard narcotics needs ing psychiatric outpatientcare as a result of taking to be determined. These are areas for further study. LSD, and 3) those hospitalized after LSDusage. All Still another hypothesis presents itself. Suppose subjects were interviewedto obtain biographical the lack of regular activities in the disturbed group data and were administered the DWMcard sort did not appear until after LSD usage (as with the (consisting of 156 items descriptive of theLSD ex- "drop-outs"),then it is reasonable to assume that perience),which they were requiredto evaluate on the LSD is part of the disruptive process, rather a five-point scale, ranging from "very much like the than a noncontributing factor. Unfortunately, for experience" to "very much unlike the experience." most of our sample, we do not know the actual Statistical analysis revea'ed that the LSDsessions time sequence of events. were far more unpleasant for those groups requir- Two findings do seem clear, however. First, in ing psychiatric care than for those requiring accord with previous reports, LSD in our study is no treatment. Specifically, the appearance of such fears likely to be disruptive for some unstable,noncom- mitted individuals who take the drug in a setting as those of death, permanent insanity and disgust- without medical support and protection. Second, ing sexuality and feelings of despair duringthe there is indication from this study that the non- LSD experience discriminated thetreatment groups treatment group, many of whom describe essen- from the nontreatment group well beyond the .01 tially beneficial and insightful LSD experiences, level of probability. In addition, the hospitalized supports the belief that the mind-altering proper- group experienced far more depression and para- ties of LSD offer potential value for research into noia than did tl,,.. other groups. Interpretations of psychotherapy and esthetic appreciation. these results are offered.

References

1. Abramson, H. A., ed. The Use of LSD in Psychother- 3. Cohen, M. Chromosomal damage in human leuco- apy and Alcoholism. Bobbs-Merrill, New York, 1967. cytes induced by LSD. Science, 14-17, 1967. 2. Abramson, H. A., ed. The Use of LSD in Psychother- apy. Josiah H. Mary Foundation, New York, 1959. 4. Cohen, S., and Ditman, K. Prolonged adverse reactions

85 to lysergic acid diethylamide. Arch. Gen. Psychiat.(Chi- 9. Leuner, H,, and Holfield, H. Psycnutherapy under the cago) , 8: 475-480, 1963. influence of the hallucinogens. Physician's Panorama, 2: 5. Ditman, K. Psychotoznimetics: Pharmacodynamic and 13-16, 1964. Psychotherapeutic Properties [Proceedings of the Western 10. Levine, J., and Ludwig, A. Alterations in consciousness Pharmacological Society]. 6: 13-17, 1963. produced by combinations of LSD, hypnosis, and psycho- 6. Ditman, K., Hayman, M., and Whittlesey, J. Nature therapy. Psychopharmacologia (Berlin), 7: 123-137, 1965. and frequency of claims following LSD. J. Nerv. Ment. Dis., 11. Ling, T., and Buckman, J. Lysergic Acid (LSD-25) and 134: 346-352, 1962. Ritalinin the Treatment of Neurosis.Lombardo Press, London, 1963. 7. Egozcue, J., and Irwin, S. Chromosome aberrations re- 12. Savage, C., Harman. W., Savage, E., and Fadiman, J. ported in LSD users. Med. News, 1: 3, 1967. Therapeutic effects of the LSD experience. Psychol. Rep., 8. Frosch, W., Robbins, E., and Sterin, M. Untoward re- 14: 111-120, 1964. actions to LSD resulting in hospitalization. New Eng. J. 13. Ungerleider, T., Fisher, D., and Fuller, M. The dangers Med., 273: 1235-1239, 1965. of LSD. J.A.M.A., /97: 389-392, 1966.

Appendix A

1. Strong Pleasant Emotions (17 items) 150 I fund I could just sit and look at something for 1 I could not control my laughter hours 4 I felt supremely happy 6 I felt more alert and alive than I have in a long time 3. Mystical and Paranormal Sensations (14 items) 33 I am more satisfied with life in general now 23 I could make an object turn into something else just 40 I had a feeling of excitement and anticipation as when by wanting it to something very important is about to happen 46 I felt that I knew what would happen before it did 48 I enjoyed being in this state so much that I will want like being a jump ahead of time it to last for days 56 The whole experience seemed to have happened before 51 This experience was the greatest thing that ever hap- 57 I felt as if I were several different people, only one of pened to me which was the usual "me" 52 I had wonderful sexual feclings 66 I felt I could communicate with others in the experi- 83 I felt a tremendous energy ence without words or gestures 131 I was tremendously relaxed 74 Hours went by like secondsor one second seemed to 138 There was humor and a jolly atmosphere last forever 146 I have a new capacity for love 97 I felt as if I could read other people's minds 148 I now have more enthusiasm for things 101 I felt as if I were traveling in time 154 I felt in contact with unknown, wonderful forces in 106 I learned what it is like to be really dead the universe 110 I was able to influence people and objects with my 155 I felt like talking it out thoughts 157 I felt more free 117 I became very open to suggestion and did what I was 158 The whole universe was like a tremendous joke told 127 Past, present and future seemed to be all one 2. Self-understanding and Esthetic Appreciation (20 items) 132 1 now have more belief in things like telepathy, rein- 12 I actually seemed to return to certain moments in carnation, spiritualism, foreseeing the future, etc., as childhood and experience myself there possibilities for research 36 I saw myself as I really am, and I did not like what I 151 I felt as if I could change past events saw 43 It is easier now to decide what I want 44 In the future, the appreciation of beauty will play a 4. Empathy (6 items) greater part in my life 24 I felt at one with those around me 58 I wanted to sit and meditate 54 I felt the people here understand me 65 I had the feeling that I have much work to do to set 71 I found it enjoyable when certain people were with me me straight 140 I am more sensitive to the feelings of others even 68 I became more self-accepting when their feelings are not expressed 69 It was an experience of great beauty 142 The touch of someone's hand seemed important 72 I understood some things far better than before 152 Doing something for someone else's happiness seemed 79 I felt more creative than usual easier 85 I now have a new feeling regarding my marriage and family 5. Religious Feelings (7 items) 116 Things I remembered threw new light on some of my 27 I felt a sense of wonder, joy, and peacefulness in the problems world 118 I felt I knew the real meaning of existence 35 I saw all the mysteries of the universe in certain ob- 119 Everything seemed to have a place in life, even the jects "good" and "bad" 50 I felt that we are all one in this universe 122 I had a higher evaluation of myself 64 I was on the verge of au important revelation, but not 128 I felt serene, content and knowing able to express it 134 I was able to express how I felt without shame or care 126 I had levels of thought I can't express in words 144 Words had strange new meanings 159 I felt closer to God 145 I felt the beauty and meaning of music as never before 160 I felt as if I had been reborn

86 6. Unusual Body Sensations and Perceptions, Not Unpleas- 89 I felt remorse over things in the past ant (33 items) 99 I felt like committing suicide 3 My mind was flooded with thoughts 109 It felt as if life had lost its meaning 8 My hearing seemed much sharper than usual 124 Everything seemed hopeless 10 The walls and floor moved and flowed 153 I had a feeling of complete despair 11 I felt as if I were floating in space 9. Paranoia (6 items) 17 Walls or other objects seemed to be breathing 15 People thought what I said was not important 21 With my eyes closed I saw multicolored moving de- 29 At times I felt as if I were being persecuted signs 39 At times I had the sensation of someone spying into 25 Colors seemed brighter my mind 30 Music affected my mood much more intensely than 86 I felt that other people were influencing my thoughts usual against my will 32 I became another object or another person and yet re- 104 I was worried that something within me showed what mained myself I didn't want seen 34 One side of my body felt different from the other side 107 I resented what was being done to me 53 I can remember very clearly everything that happened to me during the experience 10. Anxiety (19 items) 55 I had a strange taste in my mouth 2 I felt confused 60 My thoughts kept shifting rapidly from one idea to 7 I felt on the fringes of sheer horror another 14 I felt anxious or tense 67 My hands and feet felt light, or as if they were not 18 I felt I might become permanently insane attached to my body 26 I felt separated from everyone and everything 73 Other peoples' faces seemed to become changing masks 28 I felt upset and distraught 92 I kept seeing things after I'd stopped looking at them 31 I felt something dreadful was about to happen 90 I felt drowsy 37 I was easily distracted and was not able to control my 94 Objects seemed to glow around the edges thoughts 98 I lost interest in what I started saying so that a sen- 38 I felt choked or found it hard to breathe tence was left unfinished 49 I had trouble understanding what was being said 100 I was especially talkative 59 I became afraid I might die 102 I had intense swings from "high" to 'low" 73 Certain things did frighten me 103 I saw music 78 I kept thinking terrible thoughts 112 My body seemed to grow younger or older all on its 80 I kept thinking of my problems Own 84 I tried to fight off what was happening 113 I had difficulty talking 88 I was disgusted by some sexual ideas that came to mind 114 My sense of smell became more acute 93 I couldn't keep from crying 115 I felt the need to stretch or move 120 My conscience bothered me 123 I had "x-ray vision" 136 I felt paralyzed 125 My body seemed to change its size all on its own 129 My "I" or "self" seemed to leave my body 11. Hallucinations (6 items) 139 My mind sometimes became a complete blank and my 13 I heard things that I knew were not real thoughts seemed to stop 19 Solid objects changed their shapes and even disap- 143 My eyesight seemed blurred peared 149 I had peculiar sensations on my skin at times 62 Sounds seemed to affect what I saw 196 I felt as if I had no body at all 63 My own face in a mirror looked quite different; it even turned into dale: -rat faces 7. Somatic Discomfort (12 items) 93 I saw people or animals in motion who weren't really 5 I felt unsteady and uneasy there 9 I felt cold or had chills 156 I saw faces or little animals coming out of the walls 16 I felt like I was shaking or trembling or other places 41 My head ached 47 This was like a bad (alcohol) hangover 12. Evaluation of the Experience (9 items) 77 I felt hot or flushed at times 45 This experience had no therapeutic value 81 My stomach hurt 70 I feel as if I "missed the boat" or somehow failed to 87 I had nausea, headache or other physical pain which get out of the experience what was potentially there dominated the experience 76 I have been greatly helped by the experience 91 I had a craving for food 82 I now fed more ambitious 108 I felt as I do when I need a drink (alcohol) 130 I felt I was not able to give myself up completely to 111 My hands kept perspiring the experience 137 Everything seemed too bright, too harsh, too loud 133 I would like to try this again 135 None of these cards really can describe what I ex- 8. Depression (7 items) perienced 42 I felt depressed 141 The experience was nothing unusual 61 I felt that fife was not worth living 147 There is no good reason to LAC such drugs

The "Bad Trip"The Etiology of the Adverse LSD Reaction

J. THOMAS UNGERLEIDER, M.D., DUKE D. FISHER, M.D., MARIELLE FULLER, AND ALEX CALDWELL, PH.D.

In an attempt to identify the factors responsible try have reported a similar increase. The demo- for adverse reactions to LSD and to elucidate the graphic characteristics of the first 70 such patients rising incidence of hospital admissions associated seen at UCLA have previously been reported (9) . with use of the drug, the authors compared 25 psy- These patients came most often with hallucina- chiatric inpatients hospitalized following LSD in- tions, followed by anxiety to the point of panic, gestion with 25 members of a group who took LSD by depression, often with suicidal thoughts or at- together regularly without reported difficulty. Al- tempts, and by confusion. though some differences were found between the The question has thus been raised why these per- groups, there were no outstanding historical or cur- sons should have experienced difficulty from LSD rent clinical features which could be used to pre- when others claim to take the drug regularly and dict an individual's response to LSD with accuracy. apparently have no adverse effects. A number of These findings support the hypothesis that LSD in- pertinent additional questions are then raised. First teracts with schizoid trends, unsteady reality test- of all, how do we know the persons who get in ing, and related factors in a complex way that trouble from alleged use of LSD are really taking makes accurate prediction of response virtually im- LSD? Since Sandoz Pharmaceuticals, the one legiti- possible. mate manufacturer, discontinued production, all LSD that is available is black market, with all the Since approximately the fall of 1965 the incidence impurities and dosage confusion that is attendant of adverse LSD reactions throughout the country upon such illegal supply. Secondly, how do we has mushroomed. At the UCLA Neuropsychiatric know that those persons who have difficulty from Institute prior to September 1965 one problemcase LSD were not already emotionally disturbed? (In associated with LSD ingestion was seen approxi- our original study 37 percent had had psychiatric mately every two months. Beginning at that time care previously and 33 percent were unemployed, the incidence increased gradually from five to 20 which were perhaps gross indices of mental illness.) cases a month, with three to five telephone calls There is no applicable chemical test for LSD being received, for every person seen, from other once it is inside the body and no pathognomonic persons in trouble from LSD who were not subse- signs or symptoms on which to make the diagnosis. quently seen. Other hospitals throughout thecoun- Although most typically passive, the ISD user may Read at the 123rd annual meeting of the American Psy- present with almost any kind of behavior. However, chiatric Association, Detroit, Mich., May 8-12, 1967. beyond the history of LSD ingestion, there are no The authors are with the department of psychiatry, UCLA unique features although dilated pupils along with Center for the Health Sciences, Los Angeles, Calif. 90024, the peculiar "I feel sorry for you nonusers" smile where Dr. Unger 'eider is assistant professor, Dr. Fisher is a are characteristic. resident in psychiatry, Miss Fuller is research associate, and Dr. Caldwell is assistant professor of medical psychology. LSD users describe the perceptual changes fol- The authors would like to express their appreciation to lowing drug ingestion in intense and often charac- Nancy West, R.N., for her assistance in obtaining the ques- teristic ways. When one hears about visual and tionnaire data from the comparison group. auditory "unfolding" of nature it is typical of LSD

88 and other psychedelics alone.In addition, the most ion. There were pictures of Buddha and Jesus on common sideeffects reported by these subjects were the walls. Every Wednesday night the group gath- consistent with those describedelsewhere following ered to have a non-LSD religious experience con- experimental administration of LSD(3, 4). We had sisting of prayer and meditation. The drug-taking several drug samples spot-checkedfor LSD content. sessions were scheduled for the weekends. Although the user always overestimatedthe amount The group did not go along with the "drop out" of LSD in his sample, all did containLSD (8). part of the "turn on, tune in anddrop out" that Dr. The entire issue of predictabilityfor the adverse Timothy Leary advocates. They claimed to be LSD reaction is unsettled. Thisis particularly co- working, making money, and to have rehabilitated gent in view of the factthat some researchers have themselves. Most of the members of the group said advocated the use of LSD not onlyexperimentally that they were "ex-criminals and drug addicts" who but in clinics where "creative and normal" persons were now finding a new anduseful life through could receive the drug in order to create apsyche- LSD. delic experience for them. This studyis a prelimi- After we observed a number of their "love ses- nary attempt to try to assess someof the factors in sions" and all-day LSD experiences, the group the etiology of the "bad trip,"the adverse LSD agreed to psychiatric interviews, induding mental reaction. status examinations and the Minnesota Multiphasic Personality Inventory (MMPI).We examined the first 25 who were available on one weekend. We Methodology then compared these data to corresponding data Of the previous 70 patients reported upon,25 from the 25 hospitalized patients. were hospitalized and the rest weretreated as out- patients. This group of 25 inpatients, hospitalized Results in following adverse LSD reactions, are compared Background. There were no significant differ- this study with 25 other frequent LSD users who reported no difficulties from the drug. Thislatter ences in race, sex or age between the two groups. comparison group claimed to have ingestedthe Both groups had comparable amounts of curly pa- drug in doses of from 250 to 1200 pg. from once to rental deprivation.' Both groups resided predomi- should nantly in the Los Angeles area. three times a week for up to 18 months. It Marital status. There was a highly significant dif- be emphasized that these 25 subjects were panof who took their LSD ference (p less than .001) in marital status between an existing "religious" group the two groups. No inpatients were married at the together. when time of admission to the hospital (84 percent of the We initially made contact with this group inpatients had never been married) versus 60 per- one of their memberssought us out following a and cent married (with 19 children) inthe comparison lecture which two of the authors U.T.U. examined (see Table D.D.F.) were giving on the LSD situation to a com- group at the time they were munity service organization in a suburb of Los 1) Angeles. The member had initially tried to read a statement advocatingunlimited use of LSD dur- Table LMARITAL STATUS ing a question and answer session following the parison lecture. Afterwards, he approached us and insisted Inpatients Subjects that there were many persons who were taking the Status Number Percent Number Percent drug without difficulty. They had formed a group, Single 21 84 10 40 to be referred to as the "Disciples,"which consisted Married 0 15 60 Divorced 2 8 of 100 regulars with as many as 500 total members Other (widow) 1 4 who met regularly and took LSD. This was before No data 1 4 possession of LSD was made illegal in California. Total 25 100 25 100 After we agreed to observe the group, we were "screened" by five members at the Los Angeles Air- port. They were satisfied that we were notlaw en- Employment. Only 20 percent of the inpatients forcement officials and we were invited to observe were earning a living at the timeof admission, some of their LSD "happenings." while over 70 percent of the controls were work- Numerous subsequent visits were made to the ing; this was a highly significant difference (p less headquarters of the "Disciples." This was located than .01).The comparison subjects were mainly in a suburb of Los Angeles where about a dozen blue-collar workers and their jobs included those of the group were living in a large house on spa- of plumber, longshoreman, gas station attendant, cious grounds. They were literally tilling the soil 1 Separation from one or both parents for over six months and had decorated the house in psychedelic fash- before the age of 16(2) . 89 grocery and drug store clerk, janitor, construction of 72 percent who were at least high school gradu- worker, truck loader, tractor mechanic, aircraft ates. The remaining twenty-eight percent were high plant worker, stockboy, gardener, and surfboard school dropouts. For the inpatient group 64 per- renter. The average length of time working was cent had finished high school, 32 percent were drop- three years for this comparison group (see Table outs, and one patient was a high school student. 2) This difference was not significant. Previous psychiatric history. Seventy-six percent Table toOCCUPATION of the comparison group had no previous psychiatric history(see Table 4).Sixteen percent had Comparison Inpatients Subjects been in outpatient treatment and eight percent had Status Number Percent Number Percent been inpatients. This is not significantly different Unemployed 13 52 5 20 from the 44 percent of the inpatient group who had Housewives 2 2 8 had previous psychiatric care. Students 5 20 0 White-collar jobs 2 0 Table 4 PAST PSYCHIATRIC HISTORY Artists 3 12 0 Blue-collar jobs 0 18 72 Total 25 100 25 100 Com Inpatients Sugjaletsigim Treatment Number Percent Number Percent Outpatient 8 32 4 16 Religion. We could not obtain religious infor- Inpatient 3 12 2 8 mation for the comparison group. They had formed None 13 52 19 76 a new religion, and they all denied having any pre- No data 1 4 0 vious religion or that their families even had any Total 25 100 25 100 religion. In fact they had repudiated orthodox re- ligions totally until they "found God under LSD." Drug history. Half of the inpatient group were Thirty-two percent of the inpatient group said they taking only LSD at the time of admission and the had no religion. other half were taking both LSD and marihuana or Police records. Table 3 shows the histories of LSD and other drugs, in approximately equal num- criminal behaviour-64 percent of the comparison bers (see Table 5).The comparison group was tak- group had police histories. The major crimes that ing either LSD alone (44 percent or LSD and mar- the comparison group had been involved in were ihuana (56 percent). It was part of the "Disciples" forgery, stealing, carrying concealed weapons, man- religion not to take other drugs. slaughter, grand theft auto, and aiding a fugitive. As for past drug history prior to six weeks before Disturbances of the peace, delinquency, minor being seen in the emergency room, 40 percent of fights, and petty thefts were classified as minor the inpatient group had taken only psychedelics. crimes. Only eight percent of the inpatient group Twenty percent of the inpatient group had taken gave histories of police records, which was a sig- multiple drugs excluding heroin, while 20 percent nificantly smaller proportion (p less than .001). had used multiple drugs including heroin. Thus 40 percent were chronic multiple drug users. Twenty Table 3.POLICE RECORD percent had never used any drugs in the remote past. In the comparison group in the remote past Comparison Inpatients Subjects (before joining the "Disciples") 32 percent had Conviction For Number Percent Number Percent taken only psychedelics, 44 percent were multiple Major crime only 3 12 drug users excluding heroin, and 24 percent were Alcohol only 2 8 multiple drug users induding heroin. Thus 68 per- Drugs only 1 4 2 Minor crime only cent were chronic multiple drug users. It should (induding be noted that none of these differences was statisti- delinquency) 1 4 cally significant. Major crime plus Diagnosis. As recorded in the hospital charts, the drugs, alcohol resident psychiatrists diagnosed 40 percent of the or minor crime 5 20 Minor crime plus inpatients as psychotic and 28 percent as neurotic; drugs or alcohol 4 16 diagnoses of character disorder, borderline psy- None 23 92 9 36 chotic, and multiple diagnoses accounted for eight Total 25 100 25 100 percent each (see Table 6) . Four percent each were diagnosed as addict and adolescent adjustment re- Education. Fifty-six percent of the comparison actions. We compared these diagnostic frequencies group finished high school and an additional 16 with a random sample of 95 other inpatients in the percent had had some college education, for a total same hospital. The differences in frequency were

90 Table 5.DRUG HISTORY

Inpatients Comparison Subjects Drug Used Number Percent Number Percent Current history Marihuana + LSD 7 28 14 56 LSD only 12 48 11 44 Other 6 24 0 Total 25 100 25 100

Past drug history (Over 6 weeks before seen) (Before joining Disciples) Only psychedelics (marihuana. LSD, mescaline, psilocybin) 10 40 8 32 Multiple(excluding heroin) 5 20 11 44 Multiple (including heroin) 5 20 6 24 None 5 20 Total 25 100 25 100 More than one of amphetamines, barbiturates, alcohol, psychedelics. and tranquilizers.

Table 6.DIAGNOSIS

Comparison Inpatients' Inpatients* Subjects" DiarIMAS Number Percent Number Percent Number Percent

Psychotic 3 12 1 4 Toxic (organic) 2 8 Functional 8 32 Neurotic 7 28 1 4 0 Character disorder 2 8 6 24 12 48 Borderline psychotic 2 8 6 24 4 16 Addict 1 4 0 Adolescent adjustment reaction 1 4 0 Multiple diagnoses 2 8 6 24 3 12 Invalid (extreme F) 3 12 Undiagnosabk 5 20 Total 25 100 25 100 25 100 * Diagnosis via hospital chart. " Diagnosis by MMPI testing. small and appeared to be random; greater differ- tions of proverbs and one subject could not sub- ences would occur by chance seven times in ten. tract sevens or threes serially. The latter subject No attempt was made to dassify the comparison subsequently volunteered that he had been "out of group diagnostically since so many were function- my head with pot" at the time of the examination ing without symptoms, were not in psychiatric and then did the subtractions correctly. treatment, and were working at the time they were One of the subjects who was unable to abstract seen. Their indices of psychosocial disturbance stated that he often could not think straight since were: previous school trouble (28 percent dropped he had begun to take LSD, but he had held his out of high school),police trouble (64 percent), job as mechanic for 18 months without difficulty. He past psychiatric history (24 percent had had previ- had never seen a psychiatrist, but had been addicted ous outpatient or inpatient care) , and past history to barbiturates and dextroamphetamine sulfate in of symptoms (one person admitted to hallucina- the remote past and had been arrested several years tions while on LSD and another person had had previously for drunk driving. His MMPI revealed anxiety symptoms prior to but not after taking a definite personality disorder associated with pas- LSD).Eighty percent of the group claimed to have sive-aggressive, antisocial, paranoid, and sexually extrasensory perception when under LSD, but this deviant trends. was considered to be a part of their religious be- The other comparison subject who was unable to liefs and not truly delusional. abstract proverbs was a 24-year-old married father We did, however, assess psychopathologyon the of two who had no previous psychiatric history. He mental status examination(for the comparison had been on marihuana, barbiturates, and dex- group) and by the MMPI (for both groups). On troamphetamine sulfate before joining the religious mental status examination two comparison subjects group two months prior to the initial interviewing. showed a clinical concreteness in their interpreta- He had a drug and theft police record and daimed

91 to have had trouble talking (stammering) which ambiguously defensive. However, none of these five was cured by LSD. He had used LSD approximately were openly schizoid patterns; rather, all were of 40 times in reported doses of up to 900 Ag. Before a controlled and potentially paranoid type. he joined the group, LSD had caused "the past to 4. The comparison subjects obtained character come rushing forth," and occasionally "suspicious disorder types of patterns quite consistently, but thoughts," but this was never true after joining the many of these were well within the normal range. group. Although character disorder elements occurred con- About ten months after the initial interview one sistently in the profiles of the inpatients, they were of us (J.T.U.) reveived a call from this man's wife. complex, mixed, and predominantly psychotic pat- She stated that he had been using LSD almost every terns. day for several months, and that she had just signed To summarize our results, the inpatient and com- papers to have him committed to the hospital. How- parison groups did not show significant differences ever, he was refusing to talk to anyone but the in race, sex, age, education, or early parental de- senior author, and the judge had acquiesced. His privation. Significant differences were found in wife stated that he had quit his job and often marital status, occupational history, and police rec- stayed away from home, wandering about in the ords. Severe psychopathology was seen clinically in woods for days at a time. He refused to eat any- the inpatient group while hospitalized. No com- thing colored red and threw out everything red in parable clinical psychopathology was evident in the their house, and he frequently told her to shut up comparison sample. The MMPI profiles clearly cor- while he conversed with Jesus and the saints. The responded to these results, although the comparison final "straw" for her was when he refused to pick group was much more defensive toward the testing. up the unemployment checks. (MMPI profiles are shown in Figure 1.) When interviewed, he detailed his plans for beginning a new church. He spoke about green vapors interchanging from his body into the atmosphere looNsole (20 soh/ polho) C0000nso suloodh through the umbilicus and leaned forward to whis- per, "You wouldn't eat anything red, would you?" He denied having any problems, however, and claimed total happiness. Another MMPI was obtained and compared with that from the previous year's comparison group testing.HisinitialMMPI (presymptomatic) showed a paranoid personality pattern. The second testing yielded a very similar profile with even more guardedness, denial, and evasiveness. A comparison of the MMPIs on both groups revealed: 1. Most of the comparison subjects were quite de-

fensive toward the MMPI (two-thirds at least Scam Iss 0 op PO /1 Pe Sc Ms mly 0 my P4 PoPeSclb moderately so),and they did not exaggerate or hopoocy0 13 3 0 2 2 o I S14 I 00 "fake sick." The inpatients did overstate; three profiles were clearly invalid, and several others were Figure 1.Frequency of Highest Elevations Among the Two Groups on the Eight Basic Clinical Scales of the MMPI borderline. Only one inpatient was notably defen- (Hypochondriasis, Depression, Hysteria, Psychopathic Devi- sive. ate, Paranoia, Psychasthenia, Schizophrenia, and Hypo- 2. Pd (psychopathic deviate) was the predomi- mania) nant peak in the comparison group and Sc (schizophrenia) was the most frequent peak of the Discussion hospitalized group (see Figure 1).All 25 inpatients had one or more deviant scores (elevations at or It can be asked whether all those who had over a T score of 70) . In contrast, only 11 of the chronic adverse LSD reactions were emotionally 25 comparison subjects had one or more patholog- predisposed or were to some degree emotionally ill ical scores. Eight men among the comparison cases prior to LSD ingestion. This is very difficult to and none of the inpatients had the specific sexual answer. Well known at many hospitals are the deviation pattern (Code 45 or Code 54). anecdotal reports of local interns and residents who 3. A majority of the inpatients obtained mixed, were carefully screened before taking LSD (or had borderline, and overtly psychotic patterns; only five even been psychoanalyzed) but who subsequently of the 25 comparison subjects appeared borderline had severe adverse reactions from LSD. In addition psychotic on the testing, although a few others were there are now a number of reports of nonprofes-

92 sional persons screened by psychiatric history and/ friends or with an experienced sitter or guide pres- or psychological testing who have had adverse ent; LSD reactions. Although 44 percent of our inpa- The room has soft lighting and a thick carpet tients with a history of previous psychiatric care is or mattress to sit on; a high figure, it is certainly less than 100 percent. One is listening to the Indian music of Ravi None of the 24 percent of the comparison group Shankar and reading reassuring phrases from the who had previous psychiatric treatment had diffi- Tibetan Book of the Dead; and perhaps if one has culty from their ingestion of LSD. a "downer" or chlorpromazine pill at hand. Among psychiatric patients with LSD histories, we are now seeing at the hospital fewer chronic, But we have hospitalized many persons who had multiple drug users who are obviously emotionally taken these precautions and who also had had up disturbed. Instead we are seeing more teenagers who to 100 previous good LSD experiences. Our inpa- tried LSD once, for example at a party, got over tient group took their LSD in many varied settings, its effects in 12 to 16 hours, but then presented from kick-type, acid-test parties (56 percent) to iso- at a hospital some months later with recurrent lated ingestions in their rooms (16 percent).How- symptomatology without ever having taken the ever, some (8 percent) were most careful and serious drug again. A decreasing proportion of our patients about the preparations for taking LSD. (There are chronic drug users. However, it is not clearly were no data for setting in 20 percent of the inpa- demonstrable whether this is due to a change in tient group.) Despite their hospitalizations a large incidence or to a shift in selective referrals to our proportion of the inpatients persisted in claiming hospital. benefit from the drug and many returned to it after This brings us to a consideration of set or, spe- discharge. cifically, the attitude with which one approaches How reliable were the data from our comparison the LSD experience and the setting or environment group? Obviously they were proselytizers of LSD. in which one takes the LSD. Everyone recognizes This could explain why they all claimed no previ- the importance of these factors in the LSD experi- ous religion and even no religion for their parents. ence. In fact people now have "psychedelic experi- It also could explain why they claimed to have de- ences" in groups in the proper setting where they veloped "ESP" as well as to have found love from hallucinate, etc., but never take drugs at all (5). LSD and also why they identified themselves as a The parallels between the LSD subject and the "bunch of ex-criminals and drug addicts" before good hypnotic subject are striking, particularly in using the drug. the realm of passivity and suggestibility. Our comparison group dressed alike and even used identical phrases in answering questions. One of their fav- Summary orites was "for sure," chanted over and over. They obviously received a tremendous amount of sup- Twenty-five hospitalized psychiatric patients with port, both during and between trips, from the adverse LSD reactions were compared to a sample group itself. The average length of stay with the of 25 subjects who had not had adverse reactions group was eight months, and 24 of the 25 controls from the repeated use of LSD. claimed that LSD (taken with the group) had led In all of our comparisons there were no histori- them to "God, love, or peace of mind." They may cal elements or current clinical aspects that were thus have been successful LSD users because the unique to either group. Clearly there is no single group support outweighed or overcame the adverse factor that guarantees immunity from an adverse potentials of the drug. LSD reaction. The prediction of successful versus We should not conclude, however, that set and unsuccessful users is further complicated by the oc- settings are the only determinants of the type of currence of cases in which subjects used LSD 100 trip one has. There is ane study reported where all times or more with no adverse reactions and then subjects expected psychosis, but all felt only re- subsequently developed psychiatric symptomatol- laxed and friendly after LSD (1).There is an ever- ogy. Set and setting appear to help but not to guar- growing LSD mythology, too, much of it having to antee against adverse complications. do with set and setting (6, 7).For example, one One hypothesis, strongly supported by our test commonly hears that a bad LSD experience will not data, is that the LSD interacts with schizoid trends, result if: unsteady reality testing, and related psychological factors. Such a complex interactionwhich is diffi- One is in a calm frame of mind (no fights cult to anticipate even with the best of clinical that day with spouse or employer) ; and test datawould predict that adverse LSD reac- One takes the LSD with one or two good tions will be with us for some time to come. References

I. Blum, R., ed.: Utopiates: The Use and Users of LSD- 5. Hoffman, R.: The Psychedelic Game, Mademoiselle, 25. New York: Atherton Press, 1964. March 1966, p. 179. 2. Brill, N. Q., and Liston, E. H., Jr.: Parental Loss in 6. Ungerleider, J. T., and Fisher, D. D.: LSD: Research Adults with Emotional Disorders, Arch. Gen. Psychiat. 14: and Joyride, The Nation 202:574-576, May 16, 1966. 307-314, 1966. 7. Ungerleider, J. T., and Fisher, D. D.: LSD: Fact and 3. Cohen,S.:LSD: Side Effects and Complications, J. Fantasy, Arts and Architecture 83:18-20, December 1966. Nero. Ment. Dis. 130:30-40, 1960. 8. Ungerleider, J. T., and Fisher, D. D.: The Problems 4. Cole, J. 0., and Katz, M. K.: "The Psychotomimetic of LSD and Emotional Disorders, Calif. Med. 106:49-55, Drugs: An Overview," in Solomon, D., ed.: LSD: The Con- 1967. sciousness Expanding Drug. New York: G. P. Putnams' Sons, 9. Ungerleider, J. T., Fisher, D. D., and Fuller, M.: The 1964. Dangers of LSD, J.A.M.A. 197:389-392, 1966. Reprinted with permission of author and publisher from CANCER RESEARCH, Vol. 27, Part 1, pp. 2420-2423, December 1967

Persons with Exceptionally High Risk of Leukemia

ROBERT W. MILLER

Epidemiology Branch, National Cancer Institute, Bethesda, Maryland

Summary probability is about 1 in 5 that he will develop the Epidemiologic research has helped to identify 5 disease usually within weeks or months after his twin falls ill(17). classes of persons whose probability of developing There is no such risk among leukemia within a relatively short time is 1 in 100 fraternal twins. This finding has not been con- or greater. Common to all is a distinctive genetic firmed in England and Wales (14),but additional or cytogenetic characteristic, eith,,. inherited or ac- cases have been observed in the U. S. (R. W. Miller, quired. These observations suggest studies to iden- unpublished observations).The near-simultaneous tify additional high-risk groups and to clarify the onset of the disease among both members of the role of genetics in leukemogenesis. twin-pair adds to the belief that these occurrences are not due to chance. The evidence to data suggests that the risk among identical twins may not Introduction extend beyond 7 years of age. This point will be Epidemiology has helped to clarify the origins of clarified when the 15,500 male twins who served leukemia(a)by testing hypotheses developed in the U. S. Army during World War II have been through laboratory experimentation and (b)by classified as to probable zygosity (15),and a deter- generating hypotheses through descriptive studies mination made of the concordance rates for leu- and the identification of persons at exceptionally kemia. It is, of course, important to continue to high risk of the disease. My present purpose is not seek confirmation here and abroad for the previ- to review comprehensively information we have ously reported concordance rate of about 20% for published elsewhere (12, 19, 20),but to examine leukemia among identical twins in childhood. Ad- recent developments concerning high-risk groups to ditional data in the U. S. will be sought through a evaluate how they relate to one another and to recently established national registry of birth and future epidemiologic research on leukemogenesis. death certificates for all children who have died of The advantage in identifying groups of persons cancer since 1960. especially prone to a disease is that onecan seek Recognition of the extraordinary risk of leuke- among them features in common which may be of mia in the young child whose identical twin has etiologic significance. In the past decadea variety developed the disease provides investigators with of circumstances have been defined which carrya the opportunity to study the as yet unaffected twin high risk-1 in 100 or greaterof developing leu- in regard to cell kinetics, immunity, virologic status, kemia within a relatively short time. This informa- and chromosomes with the expectation that, on the tion is summarized in Table 1. average, in one out of five instances the child will develop the disease within a short time. Retrospec- Identical Twins tive investigations may reveal why 80% of co-twins escape the disease, although both members of a pair At the greatest risk thus far known is the child are genetically identical and share the same envir- whose identical twin has developed leukemia. The onment.

95 Inherited Tendency to Chromosomal Breakage was still elevated when last reported, twenty years after exposure (3).In both studies, acute leukemias Eloom's syndrome inherited through an auto- and chronic granulocytic leukemia were induced somal recessive gene, is characterized by photosensi- by radiation, but chronic lymphocytic leukemia was tive telangiectasia of the face and an unusual not.In neither study coulditbe determined susceptibility to acute leukemia. Though the data whether there was a radiation dose below which no are as yet scarce, they suggestthat 1 in 8 persons leukemia was induced; the sample size, large as it with the syndrome will develop leukemia over the was, was still too small to evaluate aneffect below first 30 years of life [3 leukemics among 23 persons about 80 rads(7). Further observations are re- with the syndrome (26)]. In Bloom's syndromethere quired to determine how long the rates among is excessive chromosomal breakage and rearrange- the atomic-bomb survivors remain elevated, and ment on cell culture, a traitshared with Fanconi's whether the rates in either study will rise again as aplastic anemia and ataxia-telangiectasia, inherited the latent period lengthens or as environmental disorders which also apparently predispose to acute circumstances change. Time will tell also if chronic leukemia (5, 13) . As experience with these congen- lymphocytic leukemia is a long delayed sequel of ital defects increases and as diagnoses aremade radiation exposure. earlier in life, a more accurate estimate of leukemia It should be noted that the risk of leukemia fol- occurrence will be obtained.Should excessive chro- lowing heavy exposure to the atomic bomb (within mosomal breakage be recognized in other geneti- 1000 meters of the hypocenter) was about 1 in 60 cally induced diseases, study of affected persons and over 12 years, substantially less than that in Bloom's their families for the occurrence of leukemia will syndrome or for the child whose identical twin has be informative. developed leukemia. The marked predisposition to leukemia in poly- Acquired Chromosomal Breaks cythemia vera (16% of patients treated with X-ray, Chromosomal breaks can be produced by a va- 32P or both) has been attributed by Modan and riety of agents to which man is exposed (4, 9,24, Lilienfeld (22) to a radiation effect, since leukemia 30),and 2 of these, ionizing radiation and benzene, developed in only 1.6% of patients who were not have been implicated in human leukemogenesis. treated with radiation. Kay et al. (16), however, Observations on the Japanese survivors of the have since described aneuploidy in 7 of 11 cases be- atomic bombs provide convincing evidence that fore treatment, a circumstance which may contrib- whole-body radiation in sufficient dosage is leuke- ute to leukemogenesis. It should be noted that, as mogenic in man (3) . Study of patients given radio- shown in Table 1, the frequency of leukemia in therapy for ankylosing spondylitis indicates that radiation-treated polycythemia vera(1 in 6) was partial-body exposures may also induce leukemia substantially higher than it was among persons (10).In both studies, the frequency of the neo- heavily exposed to the atomic bombs in Hiroshima plasm was proportionate to the radiation dose, and (1 in 60) or among British patients given X-ray the peak incidence occurred about 6 years after ex- treatment for ankylosing spondylitis(1in 270). posure. In the spondylitisstudy the elevation in The implication is that persons with polycythemia leukemia rate disappeared 15 years after X-ray vera are much more prone than usual to the leu- therapy, but among the atomic-bomb survivors it kemogenic effect of ionizing radiation.

Table 1.GROUPS AT EXCEPTIONALLY HIGH RISK OF LEUKEMIA

Group Approximate Time interval References risk Identical twins of children with leukemia 1 in 5a Weeks or months MacMahon and Levy (17) Radiation-treated polycythemia vera 1 in 6 10-15 years Modan and Lilienfeld (22) Bloom's syndrome 1 in 8b <30 years of age Sawitsky et al. (26) Hiroshima survivors who were within 1000 meters of the hypocenter 1 in 60 12 years Brill et al. (7) Down's syndrome 1 in 95 <10 years of age Barber and Spiers (2) Radiation-treated patients with ankylosing spondylitis 1 in 270 15 years Court Brown and Doll (10) Sibs of leukemic children 1 in 720 10 years Miller (18) ; Stewart (29) U. S. Caucasian children < 15 years of age 1 in 2880 10 years U. S. Vital Statistics (23) Of 22 identical twins with leukemic the co-twin was affected in 5 instances. b Three leukemics among 23 persons with Bloom's syndrome. The evidence that benzene is leukemogenic in gator with access to workers heavilyexposed to this man depends largely on anoccupational cluster of chemical to conduct a prospective study to estimate cases among Italian shoe workerswho used benzene the magnitude of the risk. in their trade (31) .It remains for some investi- In the search for other leukemogens, attention

96 should be directed to agents, chemical or viral, enough (1000 or more sibs).The excess over nor- which produce chromosomalbreaks. A prime mal expectation is about fourfold. Other investiga- suspect at presentislysergic acid diethylamide tors have described 2 families in which aggregation (LSD-25), which has been widely used for its hal- of leukemia or a leukemia-like disease was geneti- lucinatory effects. It induces long-lasting chromo- cally influenced: ataxia-telangiectasia with acute somal abnormalities ("quadriradials") which charac- lymphocytic leukemia in 2 sibs (13),and a myelo- terize Bloom's syndrome and Fanconi's aplastic proliferative disorder simulating myelogenous leu- anemia (8).It will be of interest to study the kemia among four sets of sibs in a kindred (25).It frequency of leukemia not only among adults who is to be expected that acute leukemia may also ag- have taken LSD-25, but also among children ex- gregate among sibs in families with other heritable posed in utero when their mothers took the drug. leukemia-prone disorders: Bloom's syndrome, Fan- coni's aplastic anemia or congeaital(X-linked) Extra Chromosomes agammaglobulinemia. These possibilities indicate that, when leukemia is found in sibs, the family be The risk of leukemia is increased not only in cer- studied cytogenetically and immunologically for tain conditions with excessive chromosomal break- the characteristic abnormalities of the known in- age, inherited or acquired, but also in Down's herited diseases which predispose to leukemia. It syndrome (2),which typically has an extra chromo- would also be of value to determine if the morphol- some in the G group. Whether persons with other ogy or natural history of leukemia in these families congenital aneuploidy are also prone to this neo- differs from usual. plasm is as yet uncertain. An accumulation of case The association of acute leukemia with the dis- reports su:4:ests thatKlinefelter's syndrome, in eases mentioned above apparently is influenced by which there is an XXY sex-chromosome comple- the action of rare recessive genes. The role of in- ment, predisposes to leukemia (12).Conclusive evi- heritance may be further defined by study ofa dence of a relationship between the two diseases series of cases in Japan with respect to the fre- awaits(a)the results of a prospective study by quency of parental consanguinity. An inbreeding Court Brown et al. (11) based on a registry of per- effect would be revealed if cousin marriages had sons with abnormalities of the sex chromosome occurred more often than usual among the parents complement, or (b) the demonstration of an exa.bs of leukemic persons [about 4% of the marriages in of Klinefelter's syndrome among persons with leu- Japan involve first cousins (28) ]. The elevatedcon- kemia. Another form of congenital aneuploidy, cordance rate for leukemia in identical twins under D-trisomy, rare as itis, has been described with 7 years of age (17) suggests that leukemia early in leukemia in 2 instances despite the short life-span life may in particular reveal a consanguinity effect. of infants with the syndrome (27, 32). These observations suggest that cytogenetic study Table 2.DISTINCTIVE GENETIC FEATURES OF of leukemic children in remission might reveal an GROUPS AT HIGH RISK OF LEUKEMIA excess frequency of chromosomal abnormalities. Among 25 leukemic children so studied, Borges High-risk category Genetic feature et al. (6) found 3 with congenital aneuploidy on ex- Identical twin of child withGenetically identical amination of the skin and blood: XXY, probable leukemia XYY, and F-trisomy. The study is being extended Bloom's and Fanconi's syn-Genetically induced chromo- to obtain a more precise estimate of the frequency dromes somal fragility and variety of chromosomal aberrations present be- Radiation-treated polycythe- Aneuploidy prior to radia- mia tion;chromosomal breaks fore the onset of leukemia. subsequently Case histories indicate that congenital chromo- Exposure to ionizing radia-Long persisting chromosomal somal aneuploidy and leukemia may aggregate tion or benzene breaks more often among sibs than can be attributed to Down's syndrome Congenital aneuploidy chance (21).Definitive evidence through epidemiologic study is difficult to achieve because of the Perspective large sample size required to demonstrate an excess of such clusters even if the frequency were several There is a surprising diversity of cytogenetic find- times greater than normal expectation. ings among groups at high risk of leukemia. Yet, as shown in Table 2, there is a common denomi- Sibs of Leukemic Children nator in that each high-risk group has a distinctive genetic or chromosomal feature which may well Two published reports (18, 29) leave little doubt play a role in leukemogenesis. that aggregation of childhood leukemia in sibships Though certain viruses alter chromosomes, in- can be demonstrated when the sample size is large duce leukemia in experimental animals, and cause

97 human tissue culture to undergo malignant trans- agents which predispose toleukemia do not also formation (1), novirus has yet been implicated in predispose to lymphoma (12) . On the other hand, the genesis of human leukemia. A large arrayof genetically induced disorders characterized by se- epidemiologic tests have failed to show that the dis- vere immunologic deficiency carry ahigh risk of ease is transmitted from one person toanother in lymphoma and probably of acute lymphocytic leu- either a vertical or horizontal fashion which sug- kemia, but, so far as we know, there is no predispo- gests an infectious spread (19) .The negative epi- sition to granulocytic leukemia. These observations demiologic results to date do not disprove the viral indicate that in etiologic studies it is desirable to origin of leukemia, for subtlety in the modeof separate the various forms of leukemia from one transmission may defy present technics to reveal it. another and from solid tumors of the lymphoid It is noteworthy that diseases or environmental system. References 1. Andrewes, C. Tumour viruses and Virus-tumours. Brit. 16. Kay, H. E. M., Lawler, S. D., and Millard, R. E. The Med. J., 1: 653-658, 1964. Chromosomes in Polycythemia Vera. Brit. J. Haematol., 12: 2. Barber, R., and Spier.% P. Oxford Survey of Childhood 507-528, 1966. Cancer; Progress Report II. Monthly Bull. Minist. Health 17. MacMahon, B., and Levy, M. A. Prenatal Origin of (London),23: 46-52, 1964. Childhood Leukemia. Evidence from Twins. New Engl. J 3. Bizzozero, 0. J., Johnson, K. G., and Ciocco, A. Radi- Med., 270: 1082-1085, 1964. ation-related Leukemia in Hiroshima and Nagasaki, 1946-64. 18. Miller, R. W. Down's Syndrome (Mongolism), Other I. Distribution, Incidence and Appearance Time, NewEngl. Congenital Malformations and Cancers Among Sibs of Leu- J. Med., 274: 1095-1101, 1966. kemic Children. New Engl. J. Med., 268: 393-401, 1963. 4. Bloom, A. D., Neriishi, S., Kamada, N., Iseki, T., and 19. Miler, R. W. Radiation, Chromosomes and Viruses Keehn, R. J. Cytogenetic Investigation of Survivors ofthe in the Etiology of Leukeuia: Evidence from Epidemiologic Atomic Bombings of Hiroshima and Nagasaki. Lancet, 2: Research. New i.ngl. J. Med., 271: 30-36, 1964. 672-674, 1966. 20. Milks, R. W. Etiology of Childhood Leukemia: Epi- 5. Bloom, G. E., Warner, S., Gerald, P. S., ;..;id Diamond, c' 'etiologic Evidence. Pediat. Clin. North Am., 13: 267-277, L. K. Chromosome Abnormalities in Constitutional Aplastic 1966. Anemia. New Engl. J. Med., 274: 8-14, 1966. 21. Miller, R. W. Relation between Cancer and Congeni- 6. Borges, W. H., Nicklas, J. W., and Hamm, C. W. tal Defects in Man. New Engl. J. Med., 275: 87-93, 1966. Prezygotic Determinants in Acute Leukemia. J. Pediat., 70: 22. Modan, B., and Lilienfeld, A. M. Polycythemia Vera 180-184, 1967. and Leukemia-the Role of Radiation Treatment. A Study 7. Brill, A. B., Tomonaga. M., and Heyssel, R. M. Leu- of 1222 Patients. Medicine, 14: 305-344, 1965. kemia in Man Following Exposure to Ionizing Radiation: Summary of Findings in Hiroshima and Nagasaki, and Com- 23. National Center for Health Statistics. Vital Statistics parison with other Human Experience. Ann. Intern. Med., of the United States, Annual Report,1964. Washington, 56: 590-609, 1962. D.C.: U. S. Govt. Print. Off., 1964. 8. Cohen, M. M., Marinello, M. J., and Back, N. Chro- 24. Nichols, W. W. Studies on the Role of Viruses in mosomal Damage in Human Leukocytes Induced by Lysergic Somatic Mutation. Hereditas, 55: 1-27, 1966. acid Diethylamide. Science, 155: 1417-1419, 1967. 25. Randall, D. L., Reiquam, C. W., Githens, J. H., and 9. Cohen, M. M., and Shaw, M. W. Specific Effects of Robinson, A. Familial Myeloproliferative Disease. A New Viruses and Antimetabolites on Mammalian Chromosomes. Syndrome CloselySimulating Myelogenous Leukemia in In: Tissue Culture Association: The Chromosome; Struc- Childhood. Am. J. Diseases Children, 110: 479-500, 1965. tural and Functional Aspects; a Symposium Organized by 26. Sawitsky, A., Bloom, D., and German, J. Chromosomal George Yerganian, Miami, June 1-4, 1965 In Vitro, Vol. 1., Breakage and Acute Leukemia in Congenital Telangiectatic pp. 50-66. Erythema and Stunted Growth. Ann. Intern. Med., 65: 487- 10. Court Brown, W. M., and Doll, R.Mortality from 495, 1966. Cancer and Other Causes after Radiotherapy for Ankylosing 27. Schade, H., Schoeller,L., and Schultze, K. W. D. Spondylitis. Brit. Med. J., 2: 1327-1332, 1965. Trisomie(Patau-Syndrome) mit kongenitaler myeloischer 11. Court Brown, W. M., Harnden, D. G., Jacobs, P. A., Leukamie. Med. Welt., 50: 2690-2692, 1962. MacLean, N., and Mantle, D. J.Abnormalities of the Sex 28. Schull, W. J., and Ned, J. V. The Effects of Inbreed- Chromosome Complement in Man. (Med. Research Council, ing in Japanese Children. New York: Harper & Row,1965. Spec. Rept., Series No. 305.) 239 pp. London: Her Majesty's 29. Stewart, A. Aetiology of Childhood Malignancies.Con- Stationery Office, 1964. genitally Determined Leukaemias. Brit. Med. J., 1:452-460, 12. Fraumeni, J. F., and Miller, R. W. Epidemiology of Human Leukemia: Recent Observations. J. Natl. Cancer 1961. 30. Tough, I. M., and Court Brown, W. M. Chromosome Inst., 38: 593-605, 1967. Aberrations and Exposure to Ambient Benzene. Lancet,1: 13. Hecht, F., Koler, R. D., Rigas, D. A., Dahnke, G. S., Case, M. P., Tisdale, V., and Miller, R. W. Leukaemia and 684, 1965. Lymphocytes in Ataxia-Telangiectasia. Lancet, 2: 1193, 1966. 31. Vigliani, E. C., and Saita, G. Benzene andLeukemia. 14. Hewitt, D., Lashof, J. C., and Stewart, A. M. Child- New Engl. J. Med., 271: 872-876, 1964. hood Cancer in Twins. Cancer, 19: 157-161, 1966. 32. Zuelzer, W. W., Thompson, R. I., and Mastrangelo,R. 15. Jablon, S., Neel, J. V., Gershowitz, H., and Atkinson, Chromatid Exchange and Breakage in the Pedigreeof a G. F. The NAS-NRC Twin Panel: Methods of Construction Child with Leukemia and Partial D-Trisomy: Evidencefor of the Panel, Zygosity Diagnosis and Proposed Use. Am. J. a Genetic Factor inLeukemogenesis and Congenital Mal- Hum. Genet., 19: 133-161, 1967. formations. (Abstr.). Blood, 28: 1008, 1966.

98 Reprinted with permission of author and publisher from SCIENCE, Vol. 155, No. 3768, pp. 1117 -1119, March 17, 1967

Chromosomal Damage in Human Leukocytes induced by Lysergic Acid Diethylamide

MAIMON M. COHEN, MICHELE J. MARINELLO and NATHAN BACK

Abstract. Addition of lysergic acid diethylamide Each concentration and exposure time was repeated to cultured human leukocytes resulted in a marked twice. The controls consisted of untreated cul- increase of chromosomal abnormalities. The distri- tures from these two individuals as well as from bution of chromosome breaks deviated significantly four additional persons, two males and two females. from random, with an accumulation of aberrations Several slides from each culture were prepared in chromosome No. 1. Cytogenetic investigation of and coded by individuals who did not participate a patient extensively treated with this drug over a in the microscopic scoring of the cells. It was hoped 4-year period for paranoid schizophrenia showed a that 25 metaphases per slide could be obtained to similar increase in chromosomal damage. yield a total of 200 cells for each concentration and time period. However, in some of the treated The induction of chromosomal abnormalities by cultures, we could not find this number of cells. various exogenous agents has been studied exten- Well-spread mitoses were selected under low mag- sively (1, 2).In addition, compounds with specific nification (X 250), and chromosomes were scored pharmacologic and chemotherapeutic value cause under oil-immersion phase-contrast microscopy (ap- chromosome damage(3).The psychotomimetic proximately X 1560). Once a cell was selected agent lysergic acid diethylamide (LSD-25), when under low power, it was included in the study. added to cultures of human peripheral leukocytes, Abnormalities were scored as breaks only if a produces a marked increase in the frequencies of dear discontinuity of the chromatid was visible. chromosomal breaks and rearrangements compared Breaks were classified as "chromatid" if only one to untreated cultures. chromatid was affected and "isochromatid" if both Chromosomal preparations were made from cul- sister chromatids were broken at the same location. tures of whole blood with a microtechnique and Both of these types of abnormalities were scored as standard procedures (4).All cultures were incu- single breaks. Single fragments were induded with bated for 72 hours at 37°C, and colcemide (0.05 chromatid breaks while "double' fragments were pg/ml) was added for the last 2 hours of culture scored as isochromatid breaks. Dicentric chromo- to arrest cells at metaphase. Lysergic acid diethyla- somes and "translocation" configurations were con- mide was dissolved in sterile distilled water and sideredas containing two breaks. Attenuated, added to the cultures in various concentrations pale-staining chromosomal regions, other than the (100, 50, 10, 1, 0.1, 0.01, and 0.001 pg/m1 of cul- normal secondary constrictions, were scored sepa- ture) for different periods of exposure before har- rately as "gaps" but were not induded in the vest (48, 24, and 4 hours) . Concentrations of 100 calculation of breakage rates. Whenever possible, and 50 pg/ml caused cellular degeneration and sup- each break was assigned to a given identifiable pressed mitosis so that the number of analyzable chromosome or chromosome group according to cells was insufficient. Leukocytes obtained from two the Denver classification (5). healthy individuals (one male and one female) Since there was no observable difference in the were treated with LSD-25 at final concentrations of responses of the two individuals, the data for each 10, 1, 0.1, 0.01, 0.001 dug /ml for 48, 24, and 4 hours. treatment were pooled. Table 1 illustrates the dis-

99 tribution of chromosomal abnormalities observed an indication that the longer exposure may have for various exposure times and concentrations of caused cellular destruction. The same effect is also the drug. At least a twofold increase in the rate of noted with a concentration of 1.0 pg /ml in the 48- chromosomal breaks over the control rate was evi- hour treatment. Conversely, with 0.001pg/ml, dent for all treatments (except 0.001 pg/m1 for 4 more chromosomal damage was evident at longer hours). A relationship between dose and response exposure times, while, with the 4-hour exposure existed; however, this appeared to be time depen- with this dosage, a direct reduction in the number dent. The highestconcentration(10pg/ml) of chromosome breaks was observed. caused greater damage in shorter incubation times, Table 2 depicts the distribution of chromosome

Table 1- DISTRIBUTION OF CHROMOSOMAL BREAKS INDUCED IN CULTURED HUMAN LEUKOCYTES BY VARIOUS DOSAGES OF AND TIMES OF EXPOSURE TO LSD-25. DATA ARE GIVEN AS BREAKS PER NUMBER OF CELLS. FIGURES IN PARENTHESES DENOTE BREAKS PER CELL

Time before Don* (M/mi) harvest (hours) 10 1 0.1 0.01 0.001 48 15/164 13/194 41/125 19/200 27/195 (0.091) (0.067) (0.328) (0.095) (0.138) 24 22/200 46/125 34/175 28/175 72/175 (0.110) (0.368) (0.194) (0-160) (0216) 4 38/150 18/200 23/200 28/200 10/200 (0.253) (0.090) (0.115) (1.148) (0.050) Control 34/925 = (0.037)

Table 2.-DISTRIBUTION OF CHROMOSOME BREAKS ACCORDING TO INDIVIDUALLY IDENTIFIABLE CHROMOSOMES OR CHROMOSOME GROUPS. THERE WERE 35 UNIDENTIFIABLE FRAGMENTS AND BREAKS. DATA ARE GIVEN AS NUMBERS OF BREAKS. Distribution by chromosome group Total Al A2 AS Observed 74 28 18 33 161 15 16 7 2 354 Expected 30.8 28.8 24.1 43.0 131.9 35.6 30.6 16.1 13.1 354.0 Chi-square test 60.6 1.5 2.3 6.4 11.9 7.0 5.1 9.4 1042 Lt. 3=0 P < .001. breaks among the various identifiable chromosomes ing these longer exposure times, while 4 hours be- or chromosome groups. The test of significance in- fore harvest the cells are in the G2 period (after dicates a nonrandom distribution of breaks (P < DNA synthesis) of the cell cycle. Since in most cases 0.001),with a disproportionate accumulation of the lowest frequency of breaks was observed after anomalies in chromosome No. 1. The array of ex- this 4-hour exposure (except where the dose was 10 pected values is based on random breakage per unit pg/ml), LSD-25 may cause chromosome breaks of chromatin as calculated from the Denvermea- during the Gl or S period of the cell cyde. Figure surements (5).Studies of other agents inducing 1, a-d, illustrates typical chromosomal aberrations nonrandom breakage of human chromosomes have observed in vitro. demonstrated "hot spots" in the heterochromatic We also studied the leukocytes of one patient regions of chromosome No. 1 [for example, thecen- who had undergone extensive treatment with LSD- tromere and secondary constriction (2)]. Lysergic 25 in conjunction with psychotherapy for paranoid acid diethylamide also shows an apparent affinity schizophrenia. This patient is a 51-year-old male for these chromosomal regions. who, with the exception of his schizophrenia, is At most concentrations, the greatest damagewas physically healthy with no history of malignancy, induced by 24- and 48-hourexposure periods. viral infection, or radiation treatment other than Although the leukocyte system is notan absolutely routine diagnostic procedures. From 30 September synchronized cell population, a large proportion 1960 to 9 March 1966 he had a total of 15 treat- of the cells seen at metaphase after 72 hours of ments with LSD-25. The ingested dosages were 80, culture must have been in either the GI (before 100 (three times), 150, and 175 pg for the first six DNA synthesis) or S (DNA synthesis) period dur- treatments, while the last nine treatments were

100 i rib ipak- #

Ivie elk 0.4202

Figure 1.Partial cells with various chromosomal abnormalities induced by LSD-25 (approximately X MOO).(a) Arrows indicate dicentric chromosomes seen in two cells. In the cell on left notice twodouble fragments and one single fragment. (b) Chromatid exchanges from three different crib. (c) Single chromatid breaks. (d) Isochromatidbreaks. (e) Chromosomal anomalies in leukocytes of the patient treated with LSD-25 (quadriradial and two chromatid breaks). with 200 pg. Leukocyte cultures were initiated for exchange figures also are frequently observed in chromosomal preparations 8 months after the last tumor cells as well as cells that haveundergone treatment. There was no other known ingestion "malignant transformation" by the oncogenic virus of drugs of any kind during thi3 interval. The SV40 (9).It is also of interest that patients with chromosome breakage rate of 200 cells in meta- Bloom's syndrome and Fanconi's anemia demon- phase was 12 percent compared to the normal 3.7 strate an increased frequency ofdeveloping neo- percent. Figure le demonstrates some of the chro- plasia (10). mosomal anomalies seen in the patient. Of ex- Since the patient we studied had been treated treme interest is the one quadriradial formation for short periods of time with the tranquilizing observed between two No. 1 chromosomes. Such drugs chlorpromazine (thorazine) and chlordiaze- figures are seen in only extremely low frequencies poxide (librium) before and during treatment with in untreated, normal cultures but may be induced LSD, our cytological findings should be interpreted routinely by treatment of human leukocytes with with caution. However, screening of chromosomes mitomycin C (6). The genetic consequences of this from 35 schizophrenic patients, some of whom were phenomenon have been discussed(7). "Quadri- treated with these tranquilizers in a double-blind radials" and increased chromosomal breakage also study, revealed no increase in the frequency of characterize the cytogenetic picture in two syn- chromosome breakage over that in untreated indi- dromesBloom's syndrome and Fanconi's anemia viduals (11). caused by autosomal recessive genes (8) . Such The significance of these findings cannot yet be

101 assessed fully. However, LSD-25 is apparently an- cells that may give rise to subsequent leukocytes, other agent which is capable of quickly producing or (ii) damage in the G1 period to long-lived lym- chromosomal damage in vitro, perhaps in the first phocytes, the damage not being observed as chro- or second division of culturedleukocytes. Moreover, mosomal abnormalities until mitosis. The latter the observation of increased chromosomal damage may be the more likely hypothesis. in the patient suggests an additional long-term ef- MAIMON M. COHEN fect of the drug. Individuals accidentally exposed MICHELLE J. MARINELLO to irradiation (12) ,therapeutically irradiated (13) , Department of Pediatrics, School of Medicine, State or treated with thechemotherapeutic agent 1, 3bis University of New York, and Buffalo Children's (2chloroethyl)-1nitrosourea (14) and then stud- Hospital, Buffalo ied long after the initial exposure still manifest increased frequencies of chromosomal abnormalities. NATHAN BACK Such studies suggest two possible mechanisms of Department of Biochemical Pharmacology, School LSD action:(i)permanent damage to the stem of Pharmacy, Stale University of New York

Referencesand Notes

1. For reviews of induced breakage of chromosomes see: (1965) ; G. E. Bloom, S. Warner, P. S. Gerald, L K. Diamond, S. H. Reveil,Heredity 6(suppl.), 125 (1953); B. A. Kihlman, New Engl. I. Med.274, 8 (1966) . Advance. Genet. 10, 1 (1961) . 9. T. C. Hsu and G. K. Manna,Amer. Naturalist93, 207 2. M.M. Cohen and M. W. Shaw,In Vitro(Waverly Press, (1959) ;M. Fraccaro, A. Mannini, L. Tiepolo, C. Zara, Baltimore, 1965) , vol. 1, p. 50. Mutation Res. 2, 559(1965) ; S. R. Wolman, K. Hinchborn, 3. P. E. Conen and G. S. Lansky,Brit. Med. 1.2, 1055 G. J. Todaro,Cytogenetia3, 45 (1964). (1961); F. E. Arrighi, T. C. Hsu, D. E. Bergsagel,Texas Rep. 10. S. Garriga and W. H. Crosby,Blood14, 1008 (1959); Biol. Med.20, 545 (1962) ; M. M. Cohen, M. W. Shaw, A. P. G. E. Bloom, S. Warner, P. S. Gerald, L. K. Diamond,New Craig, Proc. Nat. Acad. Sci. U.S. 50,16 (1963) ; P. C. Nowell, Engl. J. Med. 274,8 (1966); A. Sawitsky, D. Bloom, J. L. Exp. Cell Res.33, 445 (1964) ; M. M. Cohen and M. W. Shaw, German, Ann.Intern. Med. 65,486 (1966) . I. Cell Biol. 23,386 (1964) ; T. J. Ryan, M. M. Boddington, 11. A. A. Sandberg, unpublished data. A. J. Spriggs,Brit. J. Dermatol.77, 541 (1965) ; M. K. Jensen, 12. M. A. Bender and P. C. Gooch,Radiation Res.16, 44 Acta Med. Scand.177, 783 (1965). (1962). 4. Cultures were initiated in commercially available diro- 13. K. L Budcton, P. A. Jacobs, W. M. Court-Brown, R. Island Biological Co., Doll,Lancet1962 II, 676 (1962); J. Visfeldt, Acta Radiol. mosome microculture tubes from Grand Nucl. Grand Island, N.Y. (chromosome media IA). Chromosomal 2, 95(1964) ; M. M. Nofal and W. H. Beierwaltes, I. J. Med.34, preparations were made by following a modification of Moor- Med. 5,849 (1964) ; W. D. Macdiarmid, Quart. 133 (1965) ; A. Dekaban, I.Nucl. Med.6, 740 (1965) . headet al.[P. S. Moorhead, P. C. Nowell, W. J. Me lhnan, Proc. Soc. D. M. Battips, D. A. Hungerford,Exp. Cell Res.20, 613 14. K. Harrod, J. Cortner, A. A. Sandberg, Pediat. Res.(1966). (1960) ]. 15. Supported in part by US. Children's Bureau Project 5. Denver Report,Lancet1960-I, 1063 (1960). No. 417. We thank Dr. R. Bircher, Sandoz Pharmaceuticals, 6. M. M. Cohen and M. W. Shaw, J.Cell Biol.23, 386 for the supply of LSD given to N. Back; Dr. Eleanor Jacobs (1964) . for referral of the patient; and Dr. Margery W. Shaw for 7. M. W. Shaw and M. M. Cohen,Genetics 51,181 (1965) . critical reading of the manuscript. 8. J. German, R. Archibald, D. Bloom,Science148, 506 14 December 1966 i Reprinted with permission of author and publisher from THE JOURNAL OF NERVOUS AND MENTAL DISEASE,Vol. 144, No. 6, pp. 471-478,1967 Copyright 1967, The Williams e.: . Wilkins Co., Baltimore, Maryland 21202, USA.

Therapeutic Effects of LSD: A Follow-up Study

CHARLES SHAGASS, M.D.1 AND ROBERT M. BITTLE, M.D.2

Lysergic acid diethylamide (LSD) has been used altered his perception of his relationships to the to treat many psychiatric patients, but its status as world; if he related these memories and fresh per- a therapeutic agent remains uncertain and contro- ceptions to his present problem; and if he made a versial. Specific indications for therapy with LSD convincing resolution to change his future behavior have not been established, although there is some as a consequence of his new understanding. evidence that patients with conduct disturbances, Patients who responded to LSD therapy with in- e.g., chronic alcoholics and sexual deviates, tend sightful experiences of this kind were distinguished to respond favorably even to limited treatment (3, from those who showed no such response by rater5 4).The present investigation was carried out in an who listened to tape recordings of the sessions. attempt to define some indications for LSD therapy Eight patients were classified as "responders," and and to develop prognostic indicators. The study 12 were classified as "nonresponders." was divided into two phases: the first focused on the Seven of the eight responders were found to be relationship between insightful experiencepro- among nine patients who had been diagnosed as duced by LSD and swift clinical improvement; the psychopathic personality because they showed five second extended the study to evaluate the stability of 15 criteria for this diagnosis designated in the of this improvement by studying the patients a year Small (10) structured interview. The results, dem- after LSD treatment. onstrated a significant relationship between psycho- Results of the first phase have been reported pre- pathic personality characteristics and a tendency to vicusly by Eggert and Shagass (6).This aspect of react to LSD with an insightful response. It was the study was designed to test the assumption that also found that no subject under 22 years of age patients who react to LSD with an insightful re- was classified as a responder. sponse are more likely to show favorable behavioral The present report deals with results from the change than those who do not. One aim was to de- second phase of the study, a follow-up evaluation termine clinical criteria predictive of insightful re- of the same 20 patients after one year. Obviously, sponse.Other authors have usedtermssuch the prognostic value of predicting immediate in- as "mystical," "cosmic," "psychedelic" and "con- sightful response to LSD depends upon the later sciousness-expanding" to designate the insightful clinical course associated with the type of immedi- response (7, 8). For the purposes of this study an ate response. Although the answer to this question insightful response occurred if, during an LSD ses- rests on comparisons of outcome in the responder sion, the patient experienced early memories and and nonresponder groups, the design of the follow-up study also permitted comparison of outcome 1 Temple University Medical Center and Eastern Pennsyl- vania Psychiatric Institute, 3300 Henry Avenue, Philadelphia, in all patients treated with LSD with that of a Pa., 19129. matched group of patients who were not given LSD. This study was conducted at the Psychopathic Hospital, Iowa City, Iowa. The cooperation of the medical staff, di- Methods rected by Dr. Paul E. Huston, is gratefully acknowledged. SUB JECTS Sandoz Pharmaceuticals supplied the LSD. 2 Psychopathic Hospital, University of Iowa, Iowa City, Subjects were 20 psychiatric inpatients at the Psy- Iowa. chopathic Hospital, Iowa City, Iowa. All submitted

103 voluntarily to treatment and signed a special exper- of the LSD session totaling about 60 to 90 minutes. imental treatment release form. A deliberate at- Ratings were on a scale from 0 to 3+. The raters tempt was made to recruit patients with conduct had available full routine case material about each disturbances. Ten subjects were court-referred or patient but not the structured interview data. A 3+ had some legal problem related to psychiatric con- rating was assigned to sessions in which there was tact. Ages ranged from 16 to 36 years (median, 24) ; reliving of forgotten childhood experiences, inte- 13 were men. Selection procedures were designed gration of this material, and realistic self-acceptance to exclude subjects with overt psychoses, mental re- with the resolution to improve. Ratings of the two tardation and brain syndromes. Small's (10) struc- observers were identical in 11 of 20 cases anu within tured interview was used to clinically evaluate one point in 18 of 20. Ratings were skewed toward patients prior to LSD administration. All responses the zero end of the scale, but it was possible to to standard questions were recorded verbatim on a divide the cases into those responding more and protocol sheet; these were then used to complete a those responding less by taking a mean rating of check list of diagnostic criteria, which led to classi- 1.0 or more to indicate a responder. fication according to predetermined rules. Although the classification system differs in some respects FOLLOW-UP PROCEDURE from that of the American Psychiatric Association, Case histories were reviewed, and a list of symp- use of the Small procedure insures greater reliabil- toms and deviant behavior characteristic of each ity because it reduces variability. By this method LSD patient was compiled. For every patient the patients were grouped in the following diagnos- treated with LSD the hospital records were searched tic categories: psychopathic personality, nine cases; to find a patient treated by means other than LSD, exogenous depression,five;psychoneurotic reac- who would match the LSD case closely for age, sex, tion, four; schizophrenic reaction, one; no diag- marital status, years of education, psychiatric diagnosis, one. The patient diagnosed as schizophrenic nosis, and for his pattern of symptoms and deviant reaction was not at the time obviously psychotic, behavior. Due to the large number of hospital although later observation verified this diagnosis. cases available, it was possible to achieve satisfac- No patients received drugs for at least 48 hours tory matching. Two examples presented in Table 1 before test injections; only five had taken medica- illustrate the similarity of clinical features in LSD tions for their present condition. and control patients. All LSD cases and their matched controls were contacted by letter; letters TREATMENT PROCEDURE were also sent to significant relatives such as parents LSD was administered intravenously at a dose of and spouse. If the letter did not elicit a response, 2.5 mg/kg body weight. In this group it was given telephone calls were placed. Appointments were only once. The intravenous method was used to then made for both the patients and their relatives speed the action of the drug and to reduce variabil- to be seen and interviewed. Those who could not ity of response due to absorption differences. Prep- come to the hospital were interviewed by telephone, aration for the drug sessions consisted of at least as were the relatives. In one instance, the where- six interview hours over a seven- to 14-day period. abouts of the patient was unknown, so only his wife In these interviews current problems were explored was interviewed. In another case, the patient was in and subjects were informed that the drug session prison, and an interview was conducted by the could lead to unusual and important experiences. prison psychiatrist, v.ho followed a prescribed in- Sessions took place in the office of the investigator terview schedule. who administered the drug and stayed with the pa- Each patient and relative was asked to rate tient almost continuously from 9 A.M. until evening; changes in symptoms and deviant behavior listed he attempted to maintain a supportive, interested for that patient at six months and 12 months fol- and generally nondirective attitude. At bedtime lowing treatment with LSD, or following discharge chloropromazine, 25 to 50 mg, was administered. from hospital in the group not treated with LSD. Twelve patients also received 20 mg of metham- The patient and his relative were also asked to note phetamine intravenously on another day (alternate improvement in any particular aspect of behavior. order of administration) in an attempt to compare If there had been improvement, they were asked to the effects of the two drugs. However, it was found rate its degree on a 4-point scale wi..h steps defined that observers could easily distinguish between LSD as 25, 50, 75 or 100 per cent. A 100 per cent im- and methamphetamine. provement was indicated if the behavior or symptom in question was no longer a problem to the CLASSIFICATION OF INSIGHTFUL RESPONSE individual or hisfamily. Improvement ratings Degree of insightful response to LSD was rated were coded on a scale from 0 to 4, and the ratings independently by two psychiatrists, not otherwise of the patient and his relative were averaged for involved in the study, from tape-recorded samples each manifestation.

104 Table 1.TWO EXAMPLES OF CASE MATCHING who had insightful responses during the LSD session were considered much more improved at six I Manifestation Rated LSD Case Control months than those classified as nonresponders (p Case 1 < .001) . The LSD responders were stillsignifi- Dexedrine habituation cantly more improved than the nonresponders at 12 Overt homosexuality months (p < .02)but the difference was not as Excessive useother meds. Poor relationship to females great. Anxiety and depression Table 2 also shows the mean change in ratings of Feels sexually inadequate improvement between six and 12 months and the Case 2 significance of the difference. Only the LSD non- Checks with insufficient responders showed acceptably significant continu- funds ing improvement (p < .01) . Clinical improvement Embezzlement (S13,000) tended to recede between six and 12 months in the Extorting money from peo- LSD responder group. ple Lying The data were examined to determine whether Excessive drinking particular behavior or symptom areas showed Sexual promiscuity greater change in response to LSD; responders and Conflict with authority nonresponders were also compared along these Poor work record Gambling lines. Table 3 shows some comparisons in three be- Irresponsible to family havior areas. The small number of cases precluded Feels inadequate meaningful statistical tests on these findings. How- Indicates presence. ever, the LSD responders showed more improvement than any other group in the areas of sexual behavior and excessive use of alcohol or drugs. On Results the other hand, in ratings of school, home or job In view of the diversity of symptom andbehav- performance, the considerable improvement of the ioral manifestations, it seemed reasonable to com- LSD responder group at six months had largely pare overall ratingsof clinical change. The change vanished by the 12-month period, so that these pa- ratings from 0 to 4 were averaged to achieve asingle tients had the same mean change rating as the overall change rating at six and 12 monthsfor each group which did not receive LSD. patient. Mean ratings were then comparedfor the LSD-treated and non-LSD-treated group andfor Discussion the LSD responders and nonresponders.A summary of the follow-up results is shown in Table2. Statis- The results indicate that, as a group, patients tical significance was evaluated by means of t-test treated with LSD showed more improvement than (two-tailed).It is seen that the LSD-treated group similar patients not so treated. Furthermore, the at six months was ratedsignificantly more im- LSD patients who showed the greatest clinical improved than the control group (p < .05). At12 provement were those who displayed an insightful months, the LSD group still showed greater im- response during or within 24 hours of the single provement (p < .02) . Withinthe LSD group, those LSD treatment session. These patients, most of

Table 2.FOLLOW-UP RESULTS i

Mean Ratings of Overall Change Subject Group At 6 mos At 12 mos LSD (N = 20) 1.69 ± 0.39 1.94 ± 0.30 No LSD (N = 29) 0.82 ± 0.20 1.03 ± 020 p < .05 < .02 LSD responders (N = 8) 3.09 ± 0.45 2.51 ± 0.46 LSD nonresponders (N = 12) 0.76 ± 0.32 1.55 ± 0.38 p < .001 < .02 Change from 6 to 12 mos

Mean P LSD responders (N = 8) 0.58 ± 0.27 .10 LSD nonresponders (N = 12) 0.79 ± 0.19 < .01 No LSD (N = 20) 021 ± 0.12 .10 *Stands-d error of mean. 105 Table 3.COMPARISONS WITH RESPECT TO SOME tion of the ratings of change given by the patient BEHAVIOR AREAS and his relatives. Different clinical outcomes also could have resulted from differential motivation for Mean Rating of Change treatment. However, this seems unlikely since ten Behavior Area patients of the LSD group were court-referred or 6 mos 12 mos had some legal problem relevant to hospital admis- A. Sexual sion, such as threat of divorce; and similar legal LSD responders (N = 6) 3.83 2.83 problems were present in nine of the patients not LSD nonresponders (N = 5) 2.00 2.00 No LSD (N = 11) 1.64 1.64 treated with LSD. It is also obvious that the group B. Excessive alcohol or drugs was small and that any generalizations based on a LSD responders (N = 5) 2.80 2.40 small sample must viewed with great caution. How- LSD nonresponders (N = 4) 0.25 0.50 ever, similar findings have been obtained by other No LSD (N = 7) 0.00 0.00 C. School, home or job perfor- workers from different countries. For example, mance Johnsen (7) noted in his large series of cases that LSD responders (N = 5) 3.20 1.60 sexual perverts and psychopaths frequently had LSD nonresponders (N = 8) 0.00 0.88 "deep emotional reactions with cosmic and mystic No LSD (N = 13) 1.08 1.62 experiences" to LSD, whereas compulsive neurotics Homosexuality, frigidity, impotency.promiscuity. rarely reported such experiences. Some LSD patients interviewed in the follow-up whom had disorders of conduct, were initially di- study indicated that they had recently begun to re- agnosed as psychopathic personalities with the lapse and asked for additional treatment. One such Small structured interview (10).The findings sug- case was a 25-year-old homosexual man who had gest that Small's criteria for this diagnosis can be achieved his first heterosexual intercourse six weeks used to select candidates for LSD therapy. An im- after his LSD treatment and had managed to estab- mediate check on the adequacy of selectionis lish a relatively stable relationship with a woman provided by the LSD treatment session itself; for until about eight months following thistreat- those patients who experience an insightful re- ment. At this point he had begun to have homo- sponse can be expected to show relatively swift sexual fantasies once again and stopped dating. He clinical improvement. Since only those patients was readmitted for another LSD treatment session, who were 22 years of age or older showed insightful after which he felt that he had solved his problem. responses to LSD, age may also be an important But he returned again after one month saying that variable. he feared a relapse. He was readmitted once again Although results from the follow-up study clearly for an additional treatment. At this time he stated indicated that the LSD group showed more im- that he was certain that his problem was solved. provement than the matched control group, it Following this third LSD session he left the hospital seemed possible that the difference might be due to confident that he could maintain a heterosexual ad- other forms of psychiatric treatment. That is, pa- justment and he has succeeded in doing so for many tients in the LSD group might also have had more months. Such cases suggest that follow-up contact follow-up treatment than control patients. When after LSD treatment is desirable and that readmis- case records were examined to check this possibility, sion for further sessions should be very seriously the results confirmed the opposite conclusion: three considered when there is impending relapse. It is LSD cases had weekly psychotherapy in the year noteworthy that most cases of relapse did not occur following treatment, but 13 control cases had suddenly; as in the case cited, an interview would weekly psychotherapy during this period. be likely to disclose the change in fantasy content It is of interest that the patients given LSD and which could be used as indication for further classified as nonresponders tended to show signi- therapy. ficant improvement in a more gradual manner, so It is also possible that a series of concentrated that they were rated as more improved at 12 months LSD sessions may yield results superior to those ob- than at six months. In contrast, the LSD responders tained with single treatments. In an LSD study cur- improved dramatically almost immediately but rently in progress we have found several patients tended to show signs of relapse at a mean interval in whom insightful response appeared only with a of about seven months following their LSD session. second or third injection of LSD. In no case did Certain aspects of the study are clearly open to a fourth treatment produce an insightful response criticism, particularly the fact that the interviewer when the first three had failed to elicit one. knew which patients had received LSD. It would be Workers using LSD for psychotherapeutic pur- extremely difficult to avoid this problem, because of poses have frequently introduced adjunctive proce- the distinctive effects of LSD. It can only be stated dures, such as intensive psychotherapy and hypnosis that the interviewer attempted to avoid interpreta- (2) or sensory stimulation, such as music and pic-

106 tures into the LSD sessions. We used no procedures havioral change?" The tendency of those who of this kind. We deliberately refrained from inter- showed the greatest immediate behavioral change pretive comments, assumed a nondirective attitude, to relapse after several months gives the impression and allowed the patient to arrive at his own in- that, in some way, effects of the drug could have sights during the LSD sessions and subsequently. continued to be present for several months before Despite this nondirective approach, the responses of they gradually disappeared. Observable neurophysi- the patients, e.g., insights concerning their rela- ological changes produced by one dose of LSD in tionship to the world and realization of the need to man are usually no longer evident after 24 hours respect other persons' dignity, were similar to those (9).However, Adey et al.(1) observed some elec- recorded by other observers using more forceful psy- trical effects lasting for about a week after LSD in chotherapeutic intervention (4) . Many of our pa- the hippocampal regions of the cat, so that long- tients were motivated by external pressures to seek lasting functional changes in some brain areas seem treatment for problem behavior, and, in our psy- quite possible. chotherapeutic preparations for the LSD session at- Results to date support the view that immediate tempts were made to define the behavior problem and subsequent reaction to LSD may be predicted which required assistance. The working hypothesis from clinical observations and that the drug has underlying this approach is that the probability of favorable therapeutic benefits in a category of pa- favorable behavioral change with LSD is increased tients otherwise very difficult to treat. Further ex- in individuals in whom the behavior to be changed ploration of the use of LSD in treatment appears can be specified. It follows that problems, such as indicated; and research elucidating the mechanism homosexuality or consuming too much alcohol, of action of the drug should contribute in an im- might be more amenable to change than those portant way to psychiatric pathophysiolugy. which involve multiple activities and which can be described only in a general way, e.g.,passive- Summary aggressive behavior. Our results support this expec- Twenty psychiatric patients treated with a single tation. large dose of LSD were studied to determine degree General personality assets of patients may also of improvement in symptoms and problem behav- furnish prognostic cues for LSD treatment. Patients ior six months and one year after treatment. Clin- with good ego assets in spheres other than their ical change in the LSD-treated group was compared personality deviation appeared to show more favor- with that in a patient group matched for age, sex, able change. The apparent relationship between education, marital status, psychiatric diagnosis and favorable result and age may also be a function of clinical manifestations. The LSD group was divided the level of personality development. into two groups: those displaying an immediate in- It is important to emphasize that LSD treatments sightful response to LSD (responders) and those were administered to hospitalized patients under failing to do so (nonresponders). The responder closely supervised conditions and that careful ob- group was found to consist mainly of patients with servation was maintained for at least 24 hours after diagnoses of psychopathic personality and all were the treatment. These conditions were instituted at at least 22 years old. the beginning of our work with LSD in accordance Patients treated with LSD showed greater im- with a general attitude of caution and maximal provement than those in whom LSD was not used, safety. The necessity of such careful supervision is even though two-thirds of the non-LSD group re- documented by recent reports of prolonged adverse ceived systematic psychotherapy compared to only reactions to LSD (5). Although careful selection of one-sixth of the LSD group. The LSD responders patients will, hopefully, minimize possible compli- showed significantly more improvement than the cations of LSD therapy, they can be recognized and LSD nonresponders. However, the responder group dealt with only in a controlled setting. Further- showed a tendency to relapse after six months, more, it seems possible that the supervised setting, whereas the nonresponder group showed progres- designed to diminish the patient's anxiety as well sive improvement between six and 12 months. as to promote safety, may be an essential condition It was concluded that patients with specific con- for therapeutic benefit. duct disorders, who otherwise have reasonably well Several observations raise questions about the developed personality assets, are probably the most duration of LSD effects and their relation to the favorable candidates for LSD therapy. Although the immediate response. The fact that the LSD-treated probability of relapse is high after six months, suc- nonresponder group showed continuous improve- cessful retreatment has been demonstrated. Several ment between six- and 12-month follow-ups raises possible shortcomings of the study, including the the question, "Can one LSD experience facilitate small number of cases, invite caution in interpreta- personality growth over a long subsequent period tion of results, but they clearly encourage further of time, even though there is little immediate be- study of the use of LSD in treatment.

107 References

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108 Bibliography of Current Articles on the Possible Genetic Sequelae of Hallucinogenic and OtherDrugs

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109 Hazardsof drugprescribinginpregnancy. LSD and chromosomes. British Medical Journal, British Medical Journal, 3:220-223, July 22, 1967. 4:124-125, October 28, 1967. HEMING, A. E., and BROWN, J. H. Chemical LSD and chromosomes. British Medical Journal, mutagenesis. Science, 163 (3873) :1361-1362, March 2:778-779, June 29, 1968. 21, 1969. MARTIN,P.A.Cannabis and chromosomes. HIRSCHHORN, K., and COHEN, M. M. Nonpsychic Lancet, 1 (7590) :370, February 15, 1969. effects of Lysergic Acid Diethylamide. Annals of McCoLL, J. D. Drug toxicity in the animal fetus. Internal Medicine, 67:1109-1111, November 1967. Applied Therapeutics, 9:915-917, November 1967. HOFFELD, D. R.; WEBSTER, R. L.; and MCNEW, J. McCoLL, J. D. Teratogenicity studies. Applied Adverse effects on offspring of tranquilizing drugs Therapeutics, 8:48-52, January 1966. during pregnancy. Nature, 215:182-183, July 8, McCoLL, J. D.; ROBINSON, S.; and GLOBUS, M. Ef- 1967. fect of some therapeutic agents on the rabbit fetus. HUNGERFORD, D. A.; TAYLOR, K. M.; and SHAGASS, Toxicology and Applied Pharmacology, 10:244- C. Cytogenetic effects of LSD-25 therapy in man. 252, March 1967. Journal of the American Medical Association, 206: MYERS, W. A. LSD and Marihuana: where are 2287-2291, December 2, 1968. the answers. Science, 160:1062, June 7, 1968. IRWIN, S., and EGOZCUE, J. Chromosomal abnor- NEU, R. L.; POWERS, H. 0.; KING, S.; and GARD- malities in Leukocytes from LSD-25 users. Science, NER, L.I. Cannabis and chromosomes. Lancet, 157:313-314, July 21, 1967. 1 (7596) :675, March 29, 1969. IRWIN, S., and EGOZCUE, J. Chromosome damage NIELSEN, J.; FRIEDRICH, U.; and JACOBSEN, E. Ad- not found in leukocytes of childrentreated with verse effects and complicationsof LSD. Ugeskrift LSD-25. Science, 159:749, February 16, 1968. for Laeger, 130:1381-1384, August 22, 1968. JACOBSON, C. B., and MAGYAR, V. L. Genetic eval- NIELSEN, J.; FRIEDRICH, U.; and JACOBSEN, E. Ly- uation of LSD. Clinical Proceedings of Children's sergide and chromosome abnormalities.British Hospital of the District of Columbia, 24:153-161, Medical Journal, 2:801-803, June 29, 1968. May 1968. NIELSEN, J.; FRIEDRICH, U.; and TSUBOI, T. Chro- JARVIK, L. F., and KATO, T. Is Lysergide a tera- mosome abnormalities and psychotropicdrugs. Na- togen. Lancet, 1:250, February 3, 1968. ture, 218:488-489, May 4, 1968. KING, C. T., and HOWELL, J. Teratogenic effect PERSUAD, T. V., and ELLINGTON, A. C. Teratogenic of buclizine and hydroxyzine in the rat and chlor- activity of cannabis resin. Lancet, 2 (7564) :406- cyclizine in the mouse. American Journal of Ob- 407, August 17, 1968. stetrics and Gynecology, 95:109-111, May 1, 1966. PETERS, J. M. Factors affecting caffeine toxicity. KRUSKAL, W. H., and HABERMAN, S. Chromosomal A review of the literature. Journal ofClinical effect and LSD: samples of 4. Science, 162:1508, De- Pharmacology, 7:131-141, May-June 1967. cember 27, 1968. SATO, H., and PERGAMENT, E. Is Lysergide a tera- KUHLMANN, W.; FROMME, H. G.; and I- IEEGE, togen. Lancet, 1:639-640, March23, 1968. E. M. The mutagenic action of caffeine in higher Cancer Research,28 (11) :2375-2383, SAX, K., and SAX, H. J. Radiomimetic beverages, organisms. drugs and mutagens. Proceedings of the National November 1968. Academy of Sciences U.S.A., 55:1431-1435, June LARSSON, K.S., and ERIKSSON, M. Salicylate- induced fetal death and malformations in two 1966. mouse strains. Acta PaediatricaScandinavica, 55: SCHLEIERMACHER, E.; SCHROEDER, T. M.; and AD- LER, I. D. Chemically inducedmutations in mam- 569-576, November 1966. mals and man. In vivo and in vitro cytogenetic LARSSON, K. S.; IVEMARK, B.; and ENGFELDT,B. A studies. Deutsche Medizinische Wochenschrift, 92: microradiographic study of salicylate-induced skel- 2343-2350, December 22, 1967. etal anomalies in mouse embryos. ActaPathologica et Microbiologica Scandinavica, 66:560,1966. SKAKKEBAEK, N. E.; PHILIP, J.; and RAFAELSEN, 0. J. LSD in mice: abnormalities in meiotic chro- LOUGHMAN, W. D., and SARGENT, T. W. Chromo- mosomes. Science, 160:1246-1248, June 14,1968. some damage by LSD.Science, 159:1493, March 20, SLATIS, H. M. Chromosome damage by LSD. 1968. Science, 159:1492-1493, March 20, 1968. LOUGHMAN, W. D.; SARGENT, T. W.; and ISRAEL- STAM, D. M. Leukocytes ofhumans exposed to SMART, R. G., and BATEMAN, K. The chromosomal Lysergic Acid Diethylamide: lack of chromosomal and teratogenic effects of Lysergic Acid Diethyla- damage. Science, 158:508-510, October 27, 1967. mide: a review of the current literature. Candian

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