Adverse Consequences of Lysergic Acid Diethylamide

Addiction (1993) 88, 1327-1334

REVIEW

Adverse consequences of lysergic acid diethylamide

HENRY DAVID ABRAHAM & ANDREW M. ALDRIDGE

Departments of Psychiatry, New England Medical Center and St Elizabeth's Hospital of Boston, Massachusetts, USA

Abstract The continued endemic use of hallucinogenic drugs, and of LSD in particular, raises concern regarding their short and long term adverse consequences. The epidemiology of LSD abuse is reviewed suggesting an increase in LSD use among the young as the prevalence rates for other substances continues to fall. Evidence supports the association of LSD use with panic reactions, prolonged schizoaffective psychoses and post-hallucinogen perceptual disorder, the latter being present continually for as long as 5 years. Evidence does not support claims of genetic disorders arising from hallucinogens. In light of the foregoing, current data confirm earlier findings of long lasting psychopathology arising in vulnerable individuals from the use of LSD. A hypothetical long term molecular mechanism of adverse effects is proposed.

Introduction steady, somewhat increasing trend in the past This review addresses clinical and neuropharma- decade. In 1990 7.6% of the total US population cological reports on lysergic acid diethylamide had used a hallucinogenic drug at some time in (LSD). First discovered by Hofmann in 1943, it their lives/ 5.5% of a US household population was Condrau who first noted the drug's ability to age 12 and over reported LSD use, about 3% have used mescaline, psilocybin or PCP and 1% alter perceptions and mood in the presence of an peyote." Epidemiological evidence supports the unaltered sensorium, in distinction to other clinical perception that hallucinogen users tend agents such as heavy metals, bromine, cardiac to be the disaffected, Caucasian, male offspring glycosides, and anticholinergics, each of which of white collar workers." There is a positive may cause hallucinations, but usually in the con- correlation with years of completed education 1 text of a toxic delirium. and also greater prevalence in the metropolitan While epidemiological surveys report a decline areas of the Northeastern and Western parts of in use of the majority of classes of abusable the US. substances in recent years, major hallucinogenic drugs, predominantly LSD, have maintained a Acute effects The first use of LSD, an accidental ingestion in Supported in part by US PHS grant ROI DA07l20-01A2 to a laboratory, is described by Hofmann." Dura- H. D. Abraham. tion and degree of intoxication both increase Correspondence to: H. D. Abraham, New England Medical Center, Department of Psychiatry, 750 Washington St., Boston, with dose." The drug passes the blood-brain MA 02111, USA. barrier readily, and exerts its psychological

1327 1328 Henry David Abraham & Andrew M. Aldridge

effects at a concentration of 0.5 ng per grn of smoked. A history of a smoked hallucinogen brain tissue. The drug has a biological half life in should suggest phencyclidine (PCP). Ancillary macaque plasma of 100 minutes, while its psy- factors, such as the effect of the substance on chophysiological effects may extend from 6 to 12 other users, the sophistication of the historian hours. Symptoms correspond to signs of sympa- and the time of ingestion are also important. thetic arousal: increased pulse and blood Commonly, substances sold as 'LSD','mesca- pressure, dilated pupils, piloerection, hy- line' or 'psilocybin', when they include an active perreflexia and slight pyrexia. Following this ingredient, contain LSD but are adulterated. there is a period of increasingly intense percep- Stated quantities are similarly inaccurate. Differ- tual distortion. Hallucinations can occur in any entiation between LSD-like hallucinogens in an sensory modality, the most common being visual emergency setting is of academic interest, since and the least common auditory. Delusions are they produce similar syndromes requiring iden- uncommon. Orientation and cognition tend to tical management. This is not the case when be preserved. The perception of the passage of PCP is suspected, and in which treatment is time is often distorted. Synesthesia, the blending significantly different.'? of sensory modalities, while prevalent in the liter- The clinical picture of LSD intoxication may ature, is unusual in our clinical experience. be difficult to diagnose when only part of the Affective changes are profound and often take history is available. The history of ingestion may the form of an exaggeration of pre-existing be absent when the patient is uncooperative, or mood. In many instances they are experienced as in cases of accidental ingestion or deliberate positive. The feelings of terror and depression poisoning. In these instances blood and urine described by Hofmann, which characterize the toxicology may clarify the situation in retro- 'bad trip', appear in emergency rooms as drug speer." Unfortunately results are seldom casualties. Gradually the intensity of these effects available within the time frame of intoxication. declines, their total duration of action being The pattern may also be complicated by the between 6 and 12 hours. presence of other drugs or concurrent mental There is great variation in the response to illness. LSD both between individuals and in the same The palm test, devised by one of the authors individual at different times. This is related in (HDA), is useful in rapidly differentiating LSD part to the instructional set, setting," and person- from PCP ingestion in the emergency room. ality of the individual. Following multiple doses Here the physician displays his open hand to the tolerance ('Gewohnung') develops.Y' Cross tol- patient, at a distance of about 18 inches, and erance also is seen between LSD, psilocybin and asks for a description of the colors seen in its mescaline.l?'!' There is no evidence of a with- palm. The LSD hallucinator may appear pleased drawal syndrome from LSD.'2 by the question, and commonly describe multi- Acute LSD intoxication commonly presents to ple colors and imagery. This is in distinction to the emergency room as a 'bad trip'. In this the PCP ingestor, on the other hand, who tends instance the diagnosis is fairly straight forward: to react to the test with a labile affect and the patient, or accompanying friends, are able to aggressive behavior. Snarling or attempted biting give a history of ingestion, features of the LSD are not uncommon, yielding a useful diagnostic intoxication described above are present, usually sign. Contemporary toxicology now makes it accompanied by panic or dysphoria. possible to test the validity of this simple It is important to take a careful history, even in maneuver. cases where the diagnosis appears evident, as The management of LSD toxicity historically illicit drugs are frequently mislabeled or involved the use of neuroleptics or emergency misidentified. A description of the substance psychotherapy lasting 4 or more hours ('talking must be elicited; LSD is often supplied absorbed down'). It is now recognized that the former may on small squares of paper, 'blotter acid' (fre- intensify the experience (particularly if PCP has quently printed with fanciful 'new age' designs) been ingested), and while talking down may be occasionally in sugar cubes, aspirin tablets or effective, it is a process which is not always dissolved in water or alcohol. The mode of ad- conducive to the emergency room. On the other ministration is almost invariably oral, ocular and hand, in our clinical experience diazepam 20 mg intravenous routes being rare. LSD is never by mouth is effective within 30 minutes, and is Adverse consequences of lysergic acid diethylamide 1329 to be considered the treatment of choice. There more than 48 hours occurred at a rate of 9 per is no controlled clinical trial of this treatment as thousand." Baker reported 4 out of 150 patients yet. with prolonged psychoses following LSD therapy.22 And McFarling reported a delayed psychosis only once in 281 LSD recipients in US Prolonged psychoses Army experiments which the author doubted In 1960 Cohen described reports of complica- was related to the drug." All told, these workers tions from 44 investigators of LSD therapy.P concluded the incidence of prolonged psychosis Eight cases of prolonged psychosis were de- following LSD in clinical settings falls in a range scribed among 25 000 doses given to 5000 of 0.08-4.6%, with a median of 2.7%. It is also recipients of the drug, with an incidence of noteworthy that the lowest two figures are 0.18% for patients undergoing LSD therapy, and derived from experimental subjects, whereas all 0.08% for experimental subjects. Geert-jorgen- others are from clinical populations. son et al. concluded following 3 years' use of Smart & Bateman reviewed 225 reports of LSD in 129 patients that "complications have adverse reactions, among which were 142 (63%) been so few it seems absurd to tabulate them," cases of prolonged psychotic reactions, noted (adding their cohort suffered two suicides, four with paranoid delusions, hallucinations, and para suicides, one homicide, and several with fear, 19% of these took the LSD in supervised "after-effects ... involving no particular inconve- settings." They concluded that the rates of pre- nience.")16 A similarly benign note was sounded LSD psychosis in LSD users was higher than the by Levine & Ludwig in the same year who wrote general population, but that LSD was precipitat- that "It would seem that the incidence statistics ing prolonged psychoses in otherwise normal better support a statement that the drug is excep- individuals.Most noteworthy was that 30-50% tionally safe rather than dangerous.t''" of cases became psychotic after a single dose, Since then incidence data have accrued in a suggesting a peculiar vulnerability to the drug in number of studies regarding the likelihood of certain individuals. psychosis following LSD, at least eight of which Tietz reported that of 49 patients admitted to report observations of LSD administered in clin- a county hospital as a result of LSD, 57% had ical settings. Opitz described two patients among extended psychoses." A study of 25 patients 66 who underwent LSD therapy and developed seen in the emergency ward of the Kings County prolonged psychotic reactions." In a study in Hospital for LSD related disorders reported that which the drug was given to psychotic subjects, 60% had diagnoses falling within the Fink et al. found that 3 of 65 subjects given LSD schizophrenic spectrum. Two of 13 admissions developed prolonged psychoses for up to 3 had prolonged psychotic reactions." Sanborn & months, characterized by disturbances in mood, Daniels reviewed 53 medical records of LSD affect and thought. Premorbidly this sample of related psychiatric admissions. The largest cate- patients had been hospitalized for a mean of 5.1 gory of diagnosis at discharge was for LSD years, had a mean duration of illness of 14.6 psychosis (42%)? Abruzzi summarized 136 pa- years, and were treatment refractory. Most of the trons at rock festivals who presented for psychotic patients expressed displeasure with the treatment of an acute adverse reaction to LSD, experience. Patients with prolonged reactions and found that 18% continued to have psychotic suffered labile moods, including mania and de- residua at 1 year." And Abraham described a pression, and an aggressive suicide attempt. sample of 105 users of LSD from a psychiatric These workers concluded,"The hazard of LSD outpatient department, 23% of which had diag- administration appears not to be in the precipi- noses of schizophrenia, compared to 12% of the tation of a schizophrenic-like state, but rather usual clinic prevalence." in decreasing emotional and affective controls Seventy-five case reports of post LSD psycho- and inducing a persistent state of altered sis from 16 separate clinical observers yield a consciousness." 19 number of common features of syndromic Leuner described 3 of 82 subjects in LSD significancc.l'":" Commonest symptoms reported therapy suffering prolonged psychoses." included mood swings, visual hallucinations, ma- Malleson surveyed 73 physicians in the UK who nia, grandiosity, and religiosity best conforming had used LSD in patients.Psychosis lasting for to diagnoses of hallucinogen mood, hallucinogen 1330 Henry David Abraham & Andrew M. Aldridge delusion, schizo affective and atypical psychotic schizophrenia, but a younger age for the onset of disorders using DSM-III-R nomenclature. The psychosis, and a briefer period of onset." These most commonly effective treatments were ECT subjects also showed a decrease in CSF 5-HIAA, and lithium. a serotonin metabolite." A 2-6 year follow-up The confounding of these findings with prior study of 15 patients with LSD psychosis found psychopathology has been observed in many, but that two had committed suicide, and half had not all, cases of psychosis following LSD. In a improved. He suggested that LSD might be re- survey of drug reactions in New York County, lated to a genetic vulnerability to an illness in the 77% of LSD psychoses were not predictable manic-depressive/schizo-affective spectrum, im- from previous psychotic disturbances.l? Unger- plicating central serotonergic systems." !eider et al. reported that 27 of 70 patients with Safer found that current substance abusers mixed adverse LSD reactions had previous psy- had statistically higher rates of hospitalization chiatric treatment, including 25 who had prior compared to past users and non-users. Among diagnoses of psychosis." Robbins found that 8 of psychotic patients, users of LSD, phencyclidine, 11 patients with prolonged psychosis following or amphetamines had the highest rates."? LSD had been psychotic prior to use. McLellan & Druley, noting that approximately In a study of 47 subjects who had ingested a 50% of psychiatric patients admitted to a VA hallucinogen within 48 hours of admission, 50% hospital admitted covert substance abuse, inter- had a previous admission for psychosis, and 92% viewed 279 additional veterans who were being were currently admitted for psychosis following treated for psychiatric, but not primarily sub- use of the drug. At discharge 68% carried a stance use, disorders. The hypothesis was that diagnosis of schizophrenia." Frosch found that specific psychiatric diagnoses were likely to be many, but not all, patients with LSD psychoses linked to the specific drugs of abuse. The had prior histories of psychosis. 33 Kornblith sum- findings were that, inter alia, 64% of the patients marized three studies which showed that using hallucinogens had diagnoses of schizophre- previous psychiatric treatment in hospitalized nia, compared to 64% for amphetamines, 45% LSD psychotics occurred from 37 to 49% of the for alcohol, 41 % for heroin, and 22% for barbi- time;" turates.?' Case controlled experimental studies have In a follow-up study McLellan et al. retrospec- likewise yielded mixed results attesting to an tively compared three groups of drug abusers association between LSD use and psychosis. In over a 6-year period for the development of an MMPI study of users and non-users Smart & psychopathology in association with three [ones'" found significant elevations in the LSD specific classes of agents: psycho stimulants, in- group on the schizophrenia, mania and psycho- cluding LSD; sedatives; and narcotics. At the pathic deviance scales. start of the 6-year period there were no measur- Breakey et al. 36 interviewed two groups of able differences in psychopathology between the schizophrenic patients and a group of normal three groups. At the end of the study period, the volunteers matched for age and sex. The patients stimulant group led the other two in measures of comprised 26 users of drugs prior to their first schizophrenia, mania, and paranoia.FWhile this psychotic illness, and 14 schizophrenics with no study was not limited to hallucinogens, their drug histories. Schizophrenic drug users had association with psychoses developmentally over healthier premorbid personalities than non-drug time were consistent with cross-sectional data users, but abnormal ones when compared to reporting the same association. non-psychotic controls. Moreover, the age of In 1982 Tsuang et al. 43 compared 72 hospital onset of psychosis was earlier by 4 years in the records of drug abusers with psychosis to records drug users, as was the age of first admission. The of drug abusers without psychosis, and drugs most commonly used in this sample were schizophrenics without drug abuse. Drug hallucinogens. abusers whose psychoses had predated hospital- Bowers studied 12 patients developing an ization by 6 months or longer had greater family acute psychosis 2-7 days following LSD use, by risks for schizophrenia and affective disorders comparing them to 26 acute psychotics with than those with psychoses for less than 6 negative drug histories. The LSD group had months, which suggested there were several sub- better scores on a scale for prognosis in groups of drug abusers with psychosis. Adverse consequences of lysergic acid diethylamide 1331

Hallucinogens had been abused by 40% of the inantly visual, characterized by altered drug abusers, 58% of the drug abusers with long perceptions lasting from fractions of a second to standing psychosis, and 81% of the drug abusers 5 years in duration." Symptoms included geo- with psychosis of less than 6 months' duration. metric pseudo hallucinations, false fleeting This reflected a 67% increase in hallucinogen perceptions in the peripheral fields, flashes of use by the psychotic group, compared to those color, and positive afterimagery. These visual abusers without psychosis. Supporting Breakey et disorders were stable in half of the sample over a al., ages of first onset of psychosis and first 5-year period, and comprised more enduring hospitalization were significantly earlier for drug phenomena than momentary 'flashes' of previous abusers than for non-drug abusing schizophren- LSD trips. They were precipitated by emergence ics. Seven of eight comparisons of subjects with into a dark environment, intention, marijuana.P psychosis and drug abuse to subjects with neuroleptics, and anxiety states. The disorder schizophrenia were "consistent with the hypothe- was considered slowly reversible or irreversible, sis that drug abuse has a precipitating role in the and could arise from a single LSD ingestion. onset of psychotic illness." Why certain individu- Benzodiazepines ameliorated, and neuroleptics als are vulnerable to LSD psychosis and others exacerbated, visual symptoms. The author theo- are not is an enduring question. rized that these visual disturbances represented a disinhibition of central visual processors brought Post-hallucinogen perceptual disorder about in genetically vulnerable persons. A study Post-hallucinogen perceptual disorder (PHPD) by Moskowitz found haloperidol reduced hallu- (was first described by Eisner & Cohen who cinations in seven of eight patients, but noted an observed spontaneous recurrences of LSD-like exacerbation of flashback symptoms early in states in subjects days to weeks following cessa- treatment. 54 tion of drug use.?' Rosenthal described patients Two additional studies have shed light on the suffering from post-drug visual hallucinations etiology of post-hallucinogen perceptual disor- lasting as long as 5 months from the time of drug der. In one, LSD users were observed to need a use.45 In 1962 Hollister studied a group of 59 larger stimulus than LSD naive controls in iden- experimental subjects receiving hallucinogens. tifying the white color of a test object in a bright Thirty-nine percent continued to describe visual yellow surround. 55 It was suggested that as the hallucinations when examined "when the drug LSD user's eye scanned the field saccadically, experience had cleared. ,,46 Robbins, Frosch & the fovea was stimulated by the yellow back- Stem noted that flashbacks could occur up to a ground, and when gaze fixated on the white test year after last ingestion, and suggested their basis object, the yellow visual signal failed to be inhib- seemed to be both physiological and psycho- ited. This hypothesis was then tested logical."? psychophysically in a second population of users In a survey of 65 LSD users, Holsten found 50 and controls. In this study past LSD users had who described post-LSD disturbances." One decreased critical flicker fusion thresholds, par- and a half to 4 years later, 35% of the patients ticularly in peripheral fields, suggesting that once still experienced flashbacks, although milder a square wave stimulus was perceived, its termi- ones. Horowitz presented seven clinical exam- nation in the environment tended not to be ples of flashbacks, and concluded that they recognized, as if visual information once again represented perceptual distortions, spontaneous was not being physiologically inhibited. Simi- imagery, or recurrent, unbidden images." Shick larly, LSD users had abnormal dark adaptation & Smith described 3 years' experience among curves, requiring more than three times as much LSD users in a clinic with over 50 000 patient light to see a test flash than controls. This obser- visits, and concluded flashbacks were of three vation was consistent with the hypothesis that a types: perceptual; somatic; and emotional. 50 pre-adaptive exposure to light continued to be Anderson & O'Malley suggested flashbacks ap- processed centrally once the subject was in the peared to be a misnomer, describing a case of dark, creating an increase of visual noise which continuous, rather than paroxysmal, visual interfered with proper dark adaptation. 56 The disturbances from LSD.51 chronic, stable nature of; many of these percep- A phenomenological study of 123 LSD users tual phenomena suggest that the term flashback in 1983 described the disorder as being predom- may be but a subtype of a more long lived 1332 Henry David Abraham & Andrew M. Aldridge disorder, now termed post-hallucinogen percep- a potent effect of hallucinogens at the 5-HT1C tual disorder in DSM-III-R. receptor. 70 It is plausible to hypothesize that the pathophysiology of PHPD to a mild degree Genetic effects of the hallucinogens recapitulates the acute LSD experience, implying This topic has been amply reviewed by Cohen & that related neurons may be affected. In animals Shiloh.Y In vitro early studies found that LSD LSD causes an acute drop in 5-HTz receptor was clastogenic, but no consensus could be ar- density, which can be made long lasting with a rived at which supported the hypothesis that continuous eight day infusions," a finding which LSD caused chromosomal breakage in vivo. In has been found in LSD binding of 5-HT2 recep- animal models evidence has been consistent that tors in platelets of drug free PHPD patients LSD is either a weak mutagen, or not mutagenic. (Abraham & Arora, personal communication). LSD is clearly not teratogenic, and no evidence Aghajanian (personal communication) has exists that it is oncogenic. suggested that neurones involved may be small inhibitory cortical interneurones receiving serotonergic inputs, with GABA-ergic outputs. It is Molecular aspects of hallucinogenic hypothesized that LSD causes death of these neurotoxicity neurones by means of an intense, LSD generated Clinical and epidemiological evidence'tinks LSD current.P This hypothesis is consistent with the use to long term alterations in CNS function, the clinical permanence or semi-permanence of clearest link being found in post-hallucinogen PHPD, its partial responsiveness to GABA ago- perceptual disorder. The pathophysiology of this nism, and its transient exacerbation by disorder is unclear, though a number of observa- neuroleptics known to antagonize serotonin re- tions suggest mechanisms which may be ceptors. Further exploration of receptor and operating to bring about this condition. secondary messenger characteristics in psychi- A widely examined hypothesis suggests that atric patients with hallucinogen related disorders hallucinogenic effects are related to the disrup- would appear to be a most promising strategy for tion of central serotonergic activity, based in part deepening our understanding of substance use on structural similarities between LSD and sero- and its clinical consequences. tonin;" and also on observations that LSD antagonized serotonergically innervated peripheral tissues.59,6o This model was undermined by References studies in which LSD was demonstrated as an 1. CONDRAU, G.(1948) Klinische erfahrungen an agonist in other serotonergic systems." Addi- geisteskranken mit Iysergsaure-diathylarnid, Acta tional doubt was cast on the antagonist model Psychiatrica et Neurologica, XXIV, pp. 9-32. when drugs such as 2-bromo LSD, which are 2. NATIONAL INSTITUTE OF DRUG ABUSE (1990) Household Survey. potent serotonin antagonists, were shown not to 62 3. NATIONALINSTITUTE OFDRUG ABUSE (1988) have corresponding hallucinogenic effects. ,63 Household Survey. Work by Glennon et al. 64 in 1984 correlated 4. JOHNSON, L. D., BACHMAN,J. G. & O'MALLEY, P. the affinity of hallucinogens for various receptors M. (1990) Monitoring the Future (University of with their potency in humans. Affinity for the Michigan Institute for Social Research). 5. HOFMfu~N, A. A.(1980) LSD: My Problem Child 5-HT2 receptor related most closely with hallu- (New York, McGraw-Hill). cinogenic potency. The evidence for agonism at 6. ABRAMSON,H. A., JARVIK,M. E., KAUFMAN,M. R., the 5-HT2 receptor is derived from discrimina- KRONETSKY, C., LEVtNE,A. & WAGNER, M. tion studies, in which rats are conditioned to (1955) Lysergic acid diethylamide (LSD-25): 1. recognize administration of an hallucinogen. Physiological and perceptual responses, Journal of Physiology, 39, pp. 3-60. Specific 5-HTz antagonists are then used to 7.SLATER, P. E. et at. (1960) The effect of group block hallucinogen discrimination." Agonist and administration upon symptom formation with partial-agonist activity has been favored by LSD, Journal of Nervous and Mental Disorders, 125, Sanders-Bush et al.,66Sadzot et al.,67 and Shel- pp. 312-315. 8. STOLL, W. A. (1947) LSD-ein phantastikum aus don & Aghajanian.P" while antagonism has been der mutterkomgruppe (LSD-a phantastikum of favored by Pierce & Peroutka. 69 Recently the ergot group), Schweizer Archiv fur Neurologie Sanders-Bush & Breeding have reported finding und Psychiatrie, 60, pp. 279-323. Adverse consequences of lysergic acid diethylamide 1333

9. ISBELL, H. (1955) Tolerance to LSD, Federation a family research approach, International Journal of Proceedings, 14, p. 354. the Addictions, 6, pp. 497-507. 10. ISBELL,H., WOLBACH,A. B., WIKLER,A. & MINER, 28. ABRUZZI, W. (1977) Drug-induced psychosis, E. J .. (1961) Cross tolerance between LSD and International Journal of Addictions, 121, pp. 183- psilocybin, Psychopharmacology, 2, pp. 147-159. 193. 11. WOLBECH,A. B., ISBELL,H. & MINER, E. J. (1962) 29. ABRAHAM,H. D. (1980) Psychiatric illness in drug Cross tolerance between mescaline and LSD, Psy- abusers, New England Journal of Medicine, 302, pp. chopharmacologia, 3, pp. 1-14. 868-869. 12. ISBELL, H. et al. (1956) Studies on lysergic acid 30. MEDICAL SOCIETYOF THE COUNTY OF NEW YORK diethylamide, American Medical Association, (1966) Public Health Committee, Subcommittee Archives of Neurology and Psychiatry, 76, pp. 468- on Narcotics Addiction: New York Medicine, 22, 478. p. 241. 13. MILHORN, H. T., JR (1991) Diagnosis and man- 31. UNGERLEIDER,J. T., FISHER, D. D. & FULLER, M. agement of phencyclidine intoxication, American (1966) The dangers of LSD: analysis of seven Family Physician, 43, pp. 1293-1302. months' experience in a university hospital's psy- 14. MCCARRON, M. M., WALBERG,C. B. & BASELT,R. chiatric service, Journal of the American Medical C. (1990) Confirmation of LSD intoxication by Association, 197, pp. 389-392. analysis of serum and urine, Journal of Analytical 32. HEIKlMIAN,L. & GERSHON, S. (1968) Characteris- Toxicology, 14, pp. 165-167. tics of drug abusers admitted to a psychiatric 15. COHEN, S. (1960) LSD: Side effects and compli- hospital, Journal of the American Medical Associa- cations, Journal of Nervous and Mental Disorders, tion, 25, pp. 125-130. 130, pp. 20-40. 33. FROSCH, W. (1969) in MEYER, R. E. (Ed.) Adverse 16. GEERT-JORGENSON,E., HERTZ, M., KNUDSEN, K. Reactions to Hallucinogenic drugs (NIMH PHS Pub. & KRISTENSEN,K. (1964) LSD-treatment: experi- 1810). ence gained within a three year period, Acta 34. KORNBUTH, A. (1981) Multiple drug abuse in- Psychiatrica Scandinavica, 40, pp. 373-382. volving non opiate, nonalcoholic substances, II. 17. LEVINE, J. & LUDWIG, A. M., J. & A. M. (1964) Physical damage, long term psychological effects The LSD controversy, Comprehensive Psychiatry, 5, and treatment approaches and success, Interna- pp. 314-321. tional Journal of the Addictions, 16, pp. 527-540. 18. OPITZ, E. (1963) Die klinische therapie seelischer 35. SMART, R. G. & JONES, D. (1970) Illicit LSD Storungen mit lysergsaure, Psychiatrie, Neurologie, users: their personality characteristics and psycho- und Medizinische Psychologie, 15, pp. 366-372. pathology. Journal of Abnormal Psychology, 75, pp. 19. FINK, M., SIMEON, J., HAQUE, W. & ITIL, T. 286-292. (1966) Prolonged adverse reactions to LSD in 36. BREAKEY, W., GOODELL, H., LORENZ, P. & psychotic subjects, Archives of General Psychiatry, McHUGH, R. (1974) Hallucinogenic drugs as pre- 15, pp. 450-454. cipitants of schizophrenia, Psychological Medicine, 20. LEUNER, H. (1967) Present state of psycholytic 4, pp. 225-261. therapy and its possibilities, in: ABRAMSON,H. 37. BOWERS,M. (1972) Acute psychosis induced by (Ed.) The Use of LSD in Psychotherapy and Alco- psychotomimetic drug abuse, 1. Clinical findings, holism, p. 101 (Indianapolis, Bobbs-Merrill). Archives of General Psychiatry, 27, pp. 437-440. 21. MALLESON,N. (1971) Acute adverse reactions to 38. BOWERS,M. (1972) Acute psychosis induced by LSD in clinical and experimental use in the psychotomimetic drug abuse, II. Neurochemical United Kingdom, British Journal of Psychiatry, 118, findings, Archives of General Psychiatry, 27, pp. pp. 229-230. 440-442. 22. BAKER, E. F. W. (1967) LSD psychotherapy, in: 39. BOWERS,M. (1977) Psychoses precipitated by psy- ABRAMSON,H. A. (Ed), Second International Con- chotomimetic drugs, Archives of General Psychiatry, ference on the Use of LSD in Psychotherapy and 34, pp. 832-835. Alcoholism (Indianapolis, Bobbs-Merrill). 40. SAFER, D. J. (1987) Substance abuse by young 23. McFARLING, D. A. (1980) LSD Follow-Up Study adult chronic patients, Hospital & Community Psy- Report, US Army Medical Department, US Army chiatry, 38, pp. 511-514. Health Services Command, February. 41. McLELLAN, A. T. & DRULEY, K. A. (1977) Non- 24. SMART,R. G. & BATEMAN,K. (1967) Unfavorable random relation between drugs of abuse and reactions to LSD: a review and analysis of the psychiatric diagnosis, Journal of Psychiatric Re- available case reports, Canadian Medical Associa- search, 13, pp. 179-184. tion Journal, 97, pp. 1214-1221. 42. McLELLAN, T., WOODY, G. & O'BRIEN, C. (1979) 25. TIETZ, W. (1967) Complications following inges- Development of psychiatric illness in drug abusers, tion of LSD in a lower class population, California New England Journal of Medicine, 301, pp. 1310- Medicine, 107, pp. 396-398. 1314. 26. BLUMENFIELD, M. & GUCKMAN, L. (1967) 43. TSUANG, M., SIMPSON, J. C. & KRONFOL, Z. Ten months experience with LSD users admit- (1982) Subtypes of drug abuse with psychosis, ted to county psychiatric receiving hospital, New Archives of General Psychiatry, 39, pp. 141-147. York State Journal of Medicine, 67, pp. 1849- 44. EISNER, B. G. & COHEN, S. (1958) Psychotherapy 1853. with lysergic acid diethylamide, Journal of Nervous 27. SANBORN,B. & DANIELS,J. (1971) LSD reactions: and Mental Diseases, 127, pp. 528-539. 1334 Henry David Abraham & Andrew M. Aldridge

45. ROSENTHAL,S. H. (1964) Persistent hallucinosis tranquilizing drugs on serotonin evoked uterine following repeated administration of hallucino- contractions, Proceedings of the Society for Experi- genic drugs, American Journal of Psychiatry, 121, mental Biology and Medicine, 91, pp. 39-41. pp. 238-244. 62. CERLETTI,A. & ROTHLIN,E. (1955) Role of 5-hy- 46. HOLLISTER, L. (1962) Drug induced psychoses droxytryptamine in mental diseases and its and schizophrenic reactions: a critical comparison, antagonism to lysergic acid derivatives, Nature, Annals of the New York Academy of Sciences, 96, pp. 176, pp. 785-786. 80-92. 63. ISBELL,H., LOGAN, C. R. & MINER, E. 1. (1959) 47. ROBBINS,E., FROSCH, W. A. & STERN, M. (1967) Relationships of psychotomimetic to anti-sero- Further observations on untoward reactions to tonin potencies of congeners of lysergic acid LSD, American Journal of Psychiatry, 124, pp. 393- diethylamide (LSD-25), Psychopharmacologia 395. (Berlin), 1, pp. 20-28. 48. HOLSTEN,F. (1976) Flashbacks: clinical and social 64. GLENNON,R. A., TEITLER, M. & MCKENNEY,J. D. significance 1 1/2-4 years after the 1st admission (1984) Evidence of 5-HT2 involvement in the [Nor], Tidsskrift For Den Norske Laegeforening, 96, mechanism of hallucinogenic agents, Life Sciences, pp. 875-878. 35, pp. 2505-251l. 49.HORO\'Q1TZM, . J. (1969) Flashbacks: recurrent in- 65. WINTER, 1. C. & RABIN,R. A. (1988) Interactions trusive images after LSD, American Journal of between serotonergic agonists and antagonists in Psychiatry, 126, pp. 556-569. rats trained with LSD as a discriminative stimulus, 50. SHICK,J. F. E. & SMITH, D. (1970) Analysis of the Pharmacology, Biochemistry & Behavior, 30, pp. LSD flashback, Journal of Psychedelic Drugs, 3, pp. 617-624. 13-19. 66.SANDERS-BUSH,E., BURRIS, K. D. & KNOTH, K. 51. ANDERSON, W. H. & O'MALLEY, 1. (1972) (1988) Lysergic acid diethylamide and 2,5- Trifluoperazine for the trailing phenomenon, Jour- dimethoxy-4-methylamphetamine are partial nal of the American Medical Association, 220, pp. agonists at serotonin receptors linked to phospho- 1244-1245. inositide hydrolysis, Journal of Pharmacology & , 52. ABRAHAMH, . D. (1983) Visual phenomenology of Experimental Therapeutics, 246, pp. 924-928. the LSD flashback, Archives of General Psychiatry, 67. SADZOT, B., BARABAN,J. M., GLENNON R. A., 40, pp. 884-889. Lvo ,R. A., LEONHARDT, S., JAN, C. R. & 53.FAVAZzA,A. R. & DOMINO,E. F. (1969) Recurrent TITELER, M. (1989) Hallucinogenic drug interac- LSD experience (flashbacks) triggered by mari- tions at human brain 5-HT2 receptors: juana, University of Michigan Medical Center implications for treating LSD-induced hallucino- Journal, 35, pp. 214-216. genesis, Psychopharmacology, 98, pp. 495-499. 54. MOSKOWITZ,D. (1971) Use of haloperidol to re- 68. SHELDON,P. W. & AGHAJANIAN,G. K. (1990) duce LSD flashbacks, Military Medicine, 136, pp. Serotonin (5-HT) induces IPSPs in pyramidal 754-757. layer of rat piriform cortex: evidence for the in- 55. ABRAHAM,H. D. (1982) A chronic impairment of volvement of a 5-HTz-activated interneuron, Brain colour vision in users of LSD, British Journal of Research, 506, pp. 62-69. Psychiatry, 140, pp. 518-520. 69. PIERCE,P. A. & PEROUTKA,S.}. (1990) Antagonist 56. ABRAHAM,H. D. & WOLF, E. (1988) Visual func- properties of d-LSD at 5-hydroxytryptamine2 re- tion in past users of LSD: psychophysical findings, ceptors, Neuropsychopharmacology, 3, pp. 503-508. Journal of Abnormal Psychology, 97, pp. 443-447. 70. SANDERS-BUSH, E. & BREEDING, M. (1991) 57. COHE , M. M. & SHILOH, Y. (1977/78) Genetic Choroid plexus epithelial cells in primary culture: toxicology of lysergic acid diethylamide (LSD-25). a model of 5HT1c receptor activation by hallu- Mutation Research, 47, pp. 183-209. cinogenic drugs, Psychopharmacology, 105, pp. 58. GADDUM,1. H. & HAMEED, K. A. (1954) Drugs 340-346. which antagonise 5-hydroxytryptamine, British 71. KING, W. & ELLISON, G. (1989) Long-lasting al- Journal of Pharmacology, 9, pp. 240-248. terations in behavior and brain neurochemistry 59. GADDUM,J. H. (1953) Antagonism between lyser- following continuous low-level LSD administra- gic acid diethylamide and 5-hydroxytryptamine, tion, Pharmacology, Biochemistry & Behavior, 33, Journal of Physiology, 121, p. 15P. pp. 69-73. 60. WOOLLEY,D. W. & SHAW,E. (1954) A biochemi- 72. GARRATT,1. c., ALREJA,M. & AGHAJANIAN,G. K. cal and pharmacological suggestion about certain (1993) LSD has high efficacy relative to serotonin

mental disorders, Proceedings of the National in enhancing the cationic current Ih: intracellular Academy of Science, 40, pp. 228-231. studies in rat facial motorneurons, Synapse 13, pp. 61. COSTA, E. (1956) Effects of hallucinogenic and 123-134.