MEGAVITAMIN THERAPY

THE AMERICAN PSYCHIATRIC ASSOCIATION TASK FORCE REPORT ON MEGAVITAMIN AND ORTHOMOLECULAR THERAPY IN PSYCHIATRY

Canadian Schizophrenia Foundation August 1976 MEGAVITAMIN THERAPY

This is the second report published by the Canadian Schizophrenia Foundation to give wider dissemination to its members and to members of similar organizations in the U S A of corrections to the findings of the American Psychiatric Association Task Force Report #7, Megavitamin and Orthomolecular Therapy in Psychiatry The findings, opinions, and conclusions of these reports do not necessarily represent the views of the officers, members of the board, or all members of the Foundation Each report does represent the thoughtful judgment and consensus of Dr A Hoffer and Dr H Osmond who prepared it, and it is considered a useful and substantive contribution to the ongoing analysis and evaluation of problems, programs, issues, and practices in a given area of concern: orthomolecular psychiatry A. Hoffer, M13., Ph.D,, F.A,O.P., F,R.S.C.(C) President Canadian Schizophrenia Foundation MEGAVITAMIN THERAPY

In Reply to the American Psychiatric Association Task Force Report on Megavitamins and Orthomolecular Psychiatry

A Hoffer, PhD ,MD, F AO P ,R C P(C)

H Osmond,MB,MRCP,FRCPsych

Canadian Schizophrenia Foundation 2135 Albert Street Regina, Saskatchewan S4P 2V1

ACKNOWLEDGEMENT

The authors gratefully acknowledge the assistance of the Academy of Orthomolecular Psychiatry which made publication of this book possible with a grant of $2,000 An Examination o

Summary

Addendum

Section I - Brief Abstract of Orthomolecular Treatment by Saskatchewan Group

Section II - Brief Abstract of Corroborative Reports

Section III - Pauling Paper

Section IV Letters to the Editor

Section V - Comments on B. J. Wyatts Comment (1974) on L. Paulings Report

Section VI - Comments on the Double-Blind (Placebo) Methodology

Section VII Efficacy and Toxicity

Section VIII Letters

Section IX References

Section X Reading List in Orthomolecular Psychiatry

Section XI - REAL Attempts to Corroborate with Failure to Confirm to Original Studies

Copyright 1976 by Dr. A. Hoffer and Dr. H. Osmond. Published by the Canadian Schizophrenia Foundation. 2135 Albert Street. Regina, Saskatchewan S4P 2V1. No part of this book may be reproduced by any mechanical, photographic. or electronic process or in the form of a phonographic recording, nor may it be stored in a retrieval system transmitted. or otherwise copied for public or private use without written permission of the authors We decided to answer the American studies might have been differently Psychiatric Association Task Force written However, having completed our Report on Megavitamins and Ortho- critical study of our critics we feel that it molecular Psychiatry with some reluc- has been worth the effort and hope that tance since this kind of controversy is our readers will agree tedious and not really productive—there As far as the Task Force members are are many other things to do connected concerned we would remind them of with the well-being of schizophrenic Bernard Shaws aphorisms: "If you would patients which should have higher injure your neighbor—better not do it by priority than answering the criticisms of a halves " committee none of whose members Since the report was clearly intended appear to have had direct clinical charge to injure us it was doubly botched of a single schizophrenic patient treated because, according to the American by orthomolecular psychiatric therapy Psychiatric Association, it was supposed- However, colleagues have pointed out ly a fair inquiry and as such it was a to us that we had a special responsibility failure from the start The moment that for replying to these critics, and if we we doubted the impartiality of the failed to do so it would be assumed that chairman and committee members our default indicated that we accepted (presumably selected by him) it ceased to some or perhaps most of their criticisms be an unbiased inquiry The APAs duty Our reluctance as we shall note later on was to ask us whom we would consider has been much more on account of the to be unbiased among their 25,000 multitude of errors than upon the high members or so, or how undue bias, one quality of the criticisms There is much to way or another, could be assured against be gained from the observations and Their arbitrary assumption that they even strictures of an intelligent, fair knew best is far more serious than the critic. We are not so conceited or so errors of Lipton, Mosher, Ban, et al provincial as to deny that, especially That four-fifths of the committee came with the benefit of hindsight, experi- from two institutions and that the other ments might have been done differently member was a rival experimenter in- and papers discussing and describing our dicated ineptitude and insensitivity. an examination of the american psychiatric association task force report "megavitamins and orthomolecular therapy in psychiatry" american psychiatric association, 1973

The Task Force To attain their stated objectives, a lack This report begins by stating that " we of bias and prejudice was essential It shall examine carefully and critically the may surprise those who believe that the claims, the supporting evidence, the American Psychiatric Association would theoretical basis and the contrary never allow its name to be attached to a evidence in detail." It is wholly proper document which did not meet these for a professional association to study a criteria to learn that three years before new treatment in this way The report this report was published the chairman of ends with these words, "this review and that Task Force was conducting himself critique has carefully examined the in a manner which did not suggest literature produced by megavitamin pro- impartiality Indeed, his behavior in- ponents and by those who have attempt- dicated to many who heard him speak ed to replicate their basic and clinical that he had already made up his mind work " It concludes that in this regard and was not inclined to change it "the credibility of the megavitamin At a public meeting in California proponents is low " The value that one arranged by Mr Joe Desilva of Local 770 attaches to the Task Force conclusions in Los Angeles, Dr. Morris Lipton read a depends largely upon the intelligence, paper on the theoretical aspects of zeal, honesty, and detachment with megavitamin therapy and touched briefly which its members approached the on treatment At this time none of the objective which they had set for them- Ban-Lehmann studies had been reported selves In this paper, we shall examine and Wittenborns work was still in the composition of the Task Force, the progress Nevertheless, Dr Liptons con- nature of its report, and the manner in clusions, which he expressed then, which it set out to examine megavitamin closely resembled what was published and orthomolecular therapy in psy- later by the committee of which he was chiatry, chairman We are not the first to have questioned manner, and, finally, explain, reason, the propriety of using this report as a and argue with other members of the source of information Linus Pauling, committee. It is with this in mind that in 1974, wrote: "The APA Task Force democracies government committees Repoft, Megavitamin and Ortho- always include members of the major molecular Therapy in Psychiatry, dis- political parties One-party committees, cusses vitamins in a very limited way however admirable their members may (niacin only) and deals with only one of be, are always suspect If a minority of two aspects of the theory Its arguments members believe that a report is in- are in part faulty and its conclusions are correct or unfair they can then register an unjustified " j Hoffer, 1974, following a official dissenting view which is pub- long and detailed examination, com- lished with the majority opinion The mented: "It is a mistake to use it as a presence of members experienced with reference source in evaluating mega- the treatment under review means that vitamin therapy because it is a mine of those appearing before the committee misinformation " These remarks may know that they will be questioned by any disappoint those who had supposed that one - of its members This deters people the APA would provide a useful and from presenting mere hearsay evidence reliable document, but they are less or opinions which cannot be backed with unexpected when one studies both the personal experience composition of the committee and its Second: Proponents of opposing views modus operandi may be allowed to cross-examine each When a committee is formed to report other. This is a procedure which was on a controversial issue, one assumes eventually done in the prolonged and that the matter is important enough to controversial F D A vitamin hearings warrant a careful, scholarly, and held in Washington recently Dr Miles detached examination. The APA Robinson, M D , asked to be allowed to Council on Research and Development cross-examine some of the witnesses was correct in appointing a Task Force to appearing before the hearing examiner examine megavitamin therapy for this This right was at first denied him, but Dr was a matter of interest, concern, and Robinson took the matter to court The discussion among both psychiatrists and examiner was then rebuked and ordered the public However, the Council erred to re-open the hearings to allow the gravely in failing to instruct the sub- cross-examination. The United States committee, chaired by Dr M Lipton, Court believed that a public inquiry that not only must the committee be fair should make every effort to determine and objective, but they must also appear the truth and decided that cross- to be so examination, which had been denied A committee can appear to be fair earlier, would further this process Either even when they are not truly so by using of these approaches alone increases the two procedures either alone or together. chances of objectivity, but to have even First: It may include among its an appearance of fairness and so warrant members those who have had direct public and professional confidence, both personal experience with the new treat- should have been employed. ment These knowledgeable members of In fact, neither was used Consequent- the committee can examine the data, ly the committee appears to have been question witnesses in an intelligent biased, and as we shall show, this appearance is not misleading No pro- vision was made to ask any physician experienced in the use of megavitamin Lord Devlin. a former British Law Lord (roughly the therapy to appear before it, even though equivalent of a Supreme Court Justice in the U.S.A.), was quoted in the London Times, June 26, 1975, as there were plenty available and willing to saying in his Charley Lecture that "a judges most so Yet it has been reported that i mportant qualities were impartiality and second. the do appearance of impartiality sessions were held in which members Of the committee consulted other psy- its Task Force There can be no question chiatrists and sought their views, even that the Associations highest officers though they had never published any knew that there were cogent objections data on megavitamin treatment to the subcommittee chairman whom An official or legal body which they had appointed They made no conducted its affairs in such a manner attempt to remedy this in the meantime, would be promptly discredited The long before the Task Force had made its APAs posture is the more questionable final report, Dr Lipton was circulating a since it has always been very strong for preview of it, a copy of which came into constitutional and personal freedom and our possession frequently advocates the humane and It is a poor augury when the chairman sensitive conduct of governmental and of an important Task Force appears to be social affairs Perhaps the APA has prejudiced, but it is worse still if several forgotten that charity begins at home other committee members should also be suspect Dr. Morris Upton, The Chairman In all committees the choice of Dr. Thomas Ban chairman is important and indeed It is our contention that for a number crucial As we have noticed Dr Lipton of reasons Dr Ban was prejudiced made an unfavorable impression on the against the megavitamins from the start orthomolecular psychiatrists and others and that both the content and tone of his whom he addressed in California. He told publication and his public statements the California audience that he had never reflect this prejudice. In 1966 Dr. Ban used megavitamin therapy and did not was offered a comparatively small grant treat schizophrenics Nevertheless, on of money by the Canadian Mental Health the strength of having received his Ph D. Association to settle the matter of at the same university where Elvehjem "Hoffers megavitamin claims once and and Woolley discovered that nicotinic for all " There is no reason to suppose acid was the antipellagra vitamin, he that the Canadian Mental Health Assoc- launched into a poorly informed attack iation directorship was particularly keen on the megavitamin treatment and its for any positive affirmation of this work theoretical underpinning. Since he It happened that one of us (AH) was a seemed to be so antagonistic, dogmati- member of the CMHA Advisory cally self-assured and, in addition, Committee and was present when Dr. ignorant about the matter in which he Ban produced his final research protocol. was going to inquire, one of us (AH) At this meeting he outlined a simple requested the APA to remove him from experiment comparing nicotinic acid and the Task Force on vitamin therapy in tranquilizers against tranquilizers only. It psychiatry This request was rejected on was pointed out to him that he had not the grounds that the APA Council on included provisions for ECT in Phase II Research and Development would insure patients He gave assurances that this the objectivity of its subcommittee and would be done later on as his studies monitor its reports developed Another committee member Recently Leff (1975) confirmed our made the same point, but was reminded conclusion that Dr Lipton was the main of Dr Bans pledge Dr: Ban also stated author of the report when he stated," Id that no reports would be released until warn people of megadoses for mega- the entire study was completed Neither periods says Dr. Lipton, who wrote the of these pledges was kept APA Task Force Report." Lipton has, Since Dr Ban is a member of the since 1970, been the chief crusader committee responsible for the Task against orthomolecular psychiatry. Forces report stating "the credibility of Since this was the APAs official the megavitamin proponents is low," his position, it must bear full responsibility own credibility is open to similar for the errors and misrepresentations of questioning. He is well known for his tranquilizer studies and has published (Siegler and Osmond, 1974) At a many of them Some years ago he meeting in Washington arranged by informed one of us (AH) that much of his NIMH (1973) in response to pressure income derived from grants from from the American Schizophrenia Assoc- companies and other sources interested iation, Dr Mosher stated forcibly that if in selling tranquilizers He was thus every psychiatrist in the U S A believed inherently likely to be caught in a that megavitamin therapy helped conflict of interest He may well, in all schizophrenic patients, he would not sincerity, feel himself to be wholly believe it. He was being consistent For if unbiased, but one has only to ask what he considers that schizophrenia is not an would have happened to many of his illness, it follows then that no chemo- grants had he found niacin to be more therapy, particularly nutrient therapy, effective than tranquilizers He would can possibly work While Dr Moshers have faced a painful dilemma It was forthrightness may be admirable, he can unfair to expect him to view the hardly be considered unbiased for he has persistence of megavitamin claims with made his biases perfectly clear One anything but concern and suspicion Dr might, of course, wonder how the NIMH Bans eagerness to disseminate his find- bureaucracy could possibly justify his ings long before his final report appeared appointment to the schizophrenia was shown by his lecturing professional section. It would be just as appropriate groups and attacking orthomolecular for a well-known Christian Scientist to psychiatry He cannot be considered a head up a cancer program disinterested party to the dispute and Since the APA Task Force was pub- quite apart from the effect this may have lished Dr Mosher presented a report on had on his researches, the propriety of Soteria House, a special home for his being a member of the Task Force is schizophrenic patients for the provision questionable In any official inquiry he of Laingian-type milieu therapy In this would have been obliged to declare his report he shows an interesting difference position in attitude toward research data arising Psychiatrists who are supposedly from his own research and toward all the experts on subconscious motivation data originating from orthomolecular apparently do not interest themselves in psychiatry Toward his own data he the conscious motivation of those they displays a friendly cheerful optimism would have evaluate a new treatment concluding that Soteria milieu shows According to Lionel Penrose, who has great promise, even though at the end of studied these matters, two members of a the study period there is not even one committee of five are quite sufficient to index of improvement in which his group bias it in their direction should they was better than the control group The choose to collude With Doctors Lipton Soteria group required 167 days in and Ban on the committee, the odds residence compared to 21 days residence against a fair and detached report were in a psychiatric ward by the control small; however, there was a third group, a difference of 800 percent. This member, Dr. Loren E Mosher. Mosher truthfully describes as being significantly larger There was no dif- Dr. Loren E. Mother ference in global psychopathology after Dr Mosher was the head of the Center one year between the two groups But in for Studies of Schizophrenia of NIMH spite of the fact that in every index of This choice was a curious one since he change there was no difference Mosher has frequently stated that it is his concludes there is a trend favoring their personal belief that schizophrenia is not approach The difference, so slight it a clinical entity and it is not a disease or a does not appear in any of the tests, is series of diseases: He is a disciple of the maximized in his sanguine report. Scotsman, Dr R D Laing, and prefers to In striking contrast Mosher as a view schizophrenia as a way of life member of the Task Force adopts an

4 entirely different stance. Here he finds to us to have been grossly biased against no amount of data, no matter how great the treatment they were supposedly the difference, is persuasive. Here he investigating with complete impartiality. minimizes the difference Had Mosher In Lionel Penroses view, which we have remained a pure critic as he was as a Task already noted, this would make it almost Force member his position would have certain for the final outcome to reflect remained less assailable, but having the views of the majority. exposed himself to public scrutiny by The committee represented two in- publishing a report he has shown his stitutions: (a) the National Institute of undoubted bias against orthomolecular Mental Health which since 1967 has been therapy and toward milieu therapy This as antagonistic toward the megavitamin is consistent with his remark several years approach as it was against tranquilizers ago that he would not accept mega- in 1955—it had two representatives, Dr vitamin therapy as valid even if every J. Levine and Dr L R Mosher; (b) the psychiatrist in the U S A did North Carolina Department of Psychia- try, College of Medicine, with Dr M A. In April 1971 AH wrote to Chairman M. Lipton, Chairman of the Department and A Lipton requesting that he disqualify of this committee, and Dr F J. Kane, himself as chairman because of his un- one of his professors Dr Kane was co- doubted bias. He did not reply. June 8 author with Dr Lipton of the privately 1971 AH wrote to President R S. Garber, circulated attack on orthomolecular American Psychiatric Association, psychiatry in 1970 before the committee repeating this request These letters are completed its studies or published its reproduced in the appendix Since then report in 1973 It is unlikely Dr Kane the public activity of at least three could have differed significantly from his committee members, Ban, Lipton, and chief even had he wanted to do so. Mosher, have confirmed our suspicions The appearance of bias is so powerful that no prudent person or organization that even if there had been none the would have chosen them as unbiased committee was incapable of submitting investigators in an important public n objective and fair report issue. Recently Emanuel (1975) wrote; Dr R Wittenborn, Ph D., was a "Teachers and students alike delude consultant of the committee and pro- themselves as to the worth of what is bably one of its least biased sources. It is transmitted but because the teachers not certain, however, that NIMH was of often play a role in the subsequent career this opinion when he was given five of students and become prestigious hundred thousand dollars to conduct his centers attracting the most able, these study Several years earlier, we were told delusions become self-fulfilling pro- by a well-known U.S. psychiatrist from phecies In no branch of medicine is the midwest that he had been ap- there less to transmit than in my specialty proached by the NIMH to direct this —psychiatry—by supervision, correct- same study He agreed on condition that ness of approach and doctrinal conform- one of us (AH) was retained as a working ity to an extent sometimes more appro- consultant for the duration of the study priate to a theological seminary Pro- He was promptly dropped from further bably the best training for any psy- consideration Apparently Dr Witten- chiatrist and perhaps internist too would born did not make this demand; as a be a year or more in general practice psychologist he may have been less where exposure to a wide range of human aware of the high feelings generated suffering and human responses to it among psychiatrists by megavitamin would teach a sense of proportion." treatment. However, he was not a Emanuel s strictures against professors member of the committee and so cannot may just as aptly be applied against this be held responsible for its conclusions. committee It is not our opinion alone Of the five committee members, then, that committees can inhibit progress in three by their own words and deeds seem medicine Lasagna (1967) recently wrote, "Indeed, it is not impossible that a series shrug, the hardly expressed innuendo of of inaccurate opinions from a number of one or other of our brethren? Thus, we distinguished experts would snowball work not in the light of public opinion, into an overwhelming endorsement or but in the secrecy of the chamber condemnation of a drug "Jain (1975) in a serious discussion of ethics refers to the Did the Procedures Used Provide for a enormous power wielded by establish- Fair and Objective Examination of the ment committees He discusses the Data? relationship of physicians to physicians, but his views are just as applicable when The bureaucratically inclined some- one considers the relation of new to old ti mes hope that by proper procedures the ideas He lists four reasons why com- effects of personal peculiarities and mittees representing old ideas resist new shortcomings can be avoided These ideas These are: (1) human nature (i e , hopes are frequently disappointed. In interpersonal hostility); (2) territorial this case, however, inadequate pro- imperative (i e , the threat of the new cedures combined with a committee ideas against old, widely established three out of five of whose members were ideas); (3) financial factors; (4) the clearly prejudiced against megavitamins generation gap made an unbiased report most unlikely The resistance of well-established Because there was no orthomolecular ideas no matter how mistaken against psychiatrist on the committee and none new ones is probably the major reason was asked to attend its deliberations, for the committee bias Their tran- nobody checked to see whether the quilizer-only idea of treatment is coupled literature had been examined properly, firmly to establishment professors, summarized fairly, and presented intel- directors of research and administrators li gently The committees actions suggest There may be a feeling that giving up the that they relied upon the inertia of their old ideas will mean losing their place in colleagues to avoid criticism of their the hierarchy of the establishment So far report They appear to have assumed that not a single professor of psychiatry has their task was to prevent the public and given public support to orthomolecular the profession from worrying itself psychiatry even though a substantial unduly about orthomolecular psychiatry. number have given it private support In other words, the end was to encourage Jain then lists the difficulties facing the reader to adopt Dr Moshers avowed new physicians The same fate meets position, which as we have already noted new ideas We will repeat the difficulties was that even if every psychiatrist in the he lists, except that we are referring to United States believed in megavitamins, ideas "Doctors controlling the ethics he would still not do so The means by committees are usually from the which they set out to achieve this will be establishment and it is no use complain- examined in detail Unluckily, there are ing to them " "Most of the maneuvers by many errors in the Task Force Report the doctors in the establishment are done and we keep finding new ones, yet unless under the name of the university or these errors are exposed the casual reader hospital or a committee to which the unacquainted with the literature can doctor belongs The result is that on the easily be misled into supposing that a surface, decisions appear to be based on Report published with the approval of sound medical reasoning not on personal the American Psychiatric Association bias which can only be uncovered after must be accurate and truthful exhaustive legal investigations " He then It may seem unlikely that a responsible quotes Sir Clifford Allbutt, "Unfortunate- professional organization such as the ly, the same kind of medicine is played APA would give one of its sub- with the cards under the table in the committees such license and pay so little intimacies of medical counsels Who is attention to the composition of that there to note the significant glance, the committee, but at the time when these

6 matters came under the APAs scrutiny, the word "shift" is usually used as a Washington was heavily infected by the pejorative term implying that theory or Watergate atmosphere. Minority views practice is constantly changing so that were not respected; "dirty tricks" were an duplication of experiments and re- accepted necessity of political life; futation of theories is impossible This is authority, whether presidential or pro- not so In our original report (Hoffer et fessional, was looked upon as limitless It al., 1957) we listed a number of possible was assumed that the big battalions had mechanisms by which vitamin B3 could not only the right but also the duty to work These were: (1) Elimination of the trample upon those who disagreed with vitamin deficiency We did not think them, using any means available. Ortho- then nor do we think now that schizo- molecular psychiatry was a nuisance to phrenia is due to a vitamin deficiency both the APA and the NIMH, and some The concept of a vitamin dependency members of both these establishments had not been developed, but when it apparently believed that anything that came along it created the possibility that would damage it would be doing a public some schizophrenics might be vitamin service It should not strain credulity that B3 dependent (2) Cerebrovascular if the CIA or FBI can sometimes be effects (3) Mass action on cellular overzealous in the defence of what many metabolism (4) Placebo effect (5) conceive to be the public good, less Depletion of methyl groups (6) Restora- prestigious agencies should do likewise. tion of acetylcholine esterase activity. (7) The Title Inhibition of DPNase (now called The Task Force was appointed to study NADase) activity (8) Acceleration of vitamin therapy in psychiatry as the title destruction of a schizophrenic toxin (9) of the report suggests Instead, it Direct antagonism to a schizophrenic attempted to deal with the megadoses of toxin We, therefore, have put forward a vitamin B3 only, and entitled the report number of theoretical possibilities for erroneously "Megavitamin and Ortho- further inquiry molecular Therapy in Psychiatry "Ortho- As we gained more experience with our molecular therapy was not examined treatment, we improved it It would because the committee stated that they surely be unreasonable and unenter- knew of no way by which it could be prising to continue recommending an tested original pioneering effort and to use exactly the same dosage and exactly the The Report same substances decade after decade. If We have read the report carefully and the same rule were applied to tranquiliz- then compared it with the original ers, psychiatrists would still be using the sources When this was done, our early doses of chlorpromazine and reserpine impression that it was biased and hostile recommended in 1955 Treatments, if in tone was confirmed There are many they are any good, grow and evolve For errors and omissions, while its scholar- some reason the committee seemed to ship is of such low level that it cannot be expect us to stand with the original doses trusted In the following pages we will of the original vitamins as they were used show this by using a point by point in 1952, thus ignoring the entire his- examination of the examples of bias and torical development of the ortho- error and sometimes sheer muddlement, molecular treatment It must be a matter of opinion as to whether the committees Introduction expectations were naive, perverse, or (1) On Page 5 the report claims that both we "shifted" our position (The reader (2) Hormones are generally not used should have a copy of the Task Force by orthomolecular therapists unless there Report #7 before him, read the whole is a definite indication such as hypothy- booklet, then reread each page as we roidism, diabetes, etc continue with our discussion ) In science (3) Vitamin B3 was never considered a

7 competitor against tranquilizers This is the answers to these problems will come one of the notions developed by the with future research " committee Our original double-blind Cinader (1975), an immunologist, is experiments began before tranquilizers well aware of the importance of in- became available. They were, therefore, cliviclual variation in disease and therapy. not included in the design of these In discussing controlled comparison experiments and were not used for these clinical trials he writes, "A treatment studies They were used in conjunction selected by clinical trial may be in- with the program for other patients and appropriate for some patients who are still so employed using the standard cannot be identified in advance Such indications We have been continually treatment failure is due to the heter- surprised by the number of psychiatrists ogeneity of the disease or of the response who advise their patients that we never of individuals to the disease or the use tranquilizers When pressure from treatment or is due to both factors A their patients is great, they have fre- better definition, that is, identification of quently placed them on inadequate low homogeneous disease entities, is an age- closes of vitamins and promptly dis- old objective of clinical research " continued the tranquilizers This has, on We were aware of these factors many occasion, caused relapse for which the years ago and always described as vitamins were blamed We have always carefully as possible (within space limit- made it clear that even with correct ations of medical journals) the kind of closes the response can be slow patients we had treated The committee (4) On Page 6 they correctly refer to ignores this surely not out of ignorance the orthomolecular view that the schizo- (5) Page 6—The committee continual- phrenias are a group of illnesses with ly quibbles about terms. There is different biochemical aberrations, but, certainly nothing orthomolecular about thereafter, they ignore this basic view I:CT or about foreign molecules such as and do not distinguish between acute tranquilizers, but there is no reason why and chronic patients In 1957, Hoffer et a name designed to direct attention to al concluded, "although many chronic correction of metabolic disorders by ambulatory schizophrenic persons have nutrient therapy should be dropped responded to nicotinic acid therapy, because these other non-orthomolecular similar results have not been obtained methods are helpful adjuncts with chronic schizophrenic persons in (6) Page 7—The committee accuses us mental hospitals This suggests that of making categorical statements without either the chronic process is different systematic documentation This is not from the acute process, or that it is more so Orthomolecular therapists have malignant " provided large quantities of data based "Lack of response of nicotinic acid upon double-blind, clinically controlled, indicates that doses have been in- follow-up, and other studies The only adequate or that the biochemistry and li mitation has been the modern style of physiology of schizophrenic persons medical journals to reject papers they differ in some hitherto unsuspected deem too long Hawkins statement was a manner. The differences may be due to summary of a vast experience Not one of irreparable enzymatic damage as a result the committee had ever personally of a long inhibitory process, irreparable treated schizophrenics using the full functional destruction of vital cerebral treatment They are in no position to be centers, the presence of biochemical critical. Even if Dr David Hawkins had mechanisms not reversible by nicotinic given them 2,000 case histories, would acid, or an inability of the patient in they have been any more receptive? chronic stages of the disease to as- By quoting our statement on pre- si milate nicotinic acid adequately or to vention out of context, they deny readers utilize nicotinic acid in the same way as an opportunity to see how this hy- the patient in the acute stages Perhaps pothesis was derived Before flour in the

8 U S. A was enriched with small false So far, no one has repeated the quantities of nicotinamide, it was original double-blind experiments These thought that pellagra could not be used acute and subacute cases with a influenced in so simple a manner. but combination of vitamin B3 and ECT in enrichment of flour nearly eradicated comparison to placebo and ECT None of pellagra, a vitamin B3 deficiency The the reports listed in the Task Force Report use of larger doses might prevent followed these procedures development of vitamin B3 dependency. However, their statements on Page 8, Since we have already seen this in "The latter claim is probably correct children of some schizophrenic parents because it is virtually impossible to our suggestion is hardly fanciful. The replicate studies in which each patient committee may not agree, but since they receives a highly individualized thera- have never used vitamin B3 in this way peutic program with from one to seven their criticism is founded on their vitamins in huge doses, plus hormones, personal opinion and nothing else special diets, other drugs and ECT, which (7) Page 7—While attacking our sug- are added or subtracted not on the basis gestions for prevention they make such of proven biochemical abnormalities but unnecessary errors as referring to the rather on the basis of the clinicians Huxley Institute for Biosocial Research as individual judgment as to the patients the Huxley Society and to the Academy needs It is also impossible to replicate of Orthomolecular Psychiatry as the studies in which as many as five years of treatment may be needed before results Association of Orthomolecular Psy- " chiatrists There are many other similar begin to appear, are not correct either. examples of simple carelessness through- If this was their opinion one wonders why out this document which should make they continued to write a report It is readers wary Authors who cannot get possible to replicate far more comp- names, titles, and dates correct may be licated treatments than those which we even less reliable in more complex have described, and very few medical or matters surgical treatments are completely (8) Page 8—We have received a favor- stereotyped and without individual var- able press perhaps because we have been iation The studies must be published open and honest with reporters, but our and those who wish to replicate them discussion with writers did not occur must first examine what was in the until they sought us out and many years original work Where there is doubt, or if after publications in medical journals necessary details are lacking, the ethical We have never had the same access to investigator aiming at replication the media as the APA with its great approaches the original authors and resources and paid staff members seeks their advice and clarification This doing public relations So far the Task was not done, whether due to careless- Force Report has not been very warmly ness, incompetence, or lack of good will received This may be because many is a matter for the reader to decide science writers have done their own (10) Page 8—We have never claimed inquiries and have concluded, as we that vitamin B3 is the crucial variable It have, that this report is not worthy of an is one of several crucial variables As important subject which bears on the many of our studies show, ECT and other lives and well-being of thousands of chemotherapy can be crucial We cannot suffering people. be sure why the committee chose to (9) Page 8—(lines 16-19) When the imply that we claimed that B3 was the committee writes, "consequently when a crucial variable; perhaps they felt that serious scientific attempt is made to unwary readers, being persuaded of this, replicate the clinical experiments under would fail to notice that important the specific conditions for which the treatment components had been original claims were made, one finds that omitted. Whatever the committees the conditions have changed," this is motives its members overlooked the fact

9 that if they condemned a useful treat- referred to a Sugargate coverup, pointing ment unfairly the losers would not be out that the data could equally well be their professional opponents (us and our interpreted as showing that insulin and colleagues), but tens, perhaps hundreds glycemia control are more dangerous of thousands of patients. What in other than placebo But the UGDP scientists circumstances might be considered nowhere discuss this finding In other clever debating tricks becomes less words, double blinds do not guarantee clever and more irresponsible here that the results of an experiment will be (11) Page 8—Whenever the com- objective or accurate mittee refers to the negative double- Restak (1975) attacks most double blind experiments its Report employs blinds from another approach supporting such flattering terms as "the rigorous Hoffer and Osmonds (1961, 1963) earlier double-blind studies with vitamin B3" views Restak wrote, "one thing funda- and "the careful attempts at replication mentally wrong is the design of the deal with the explicit procedures." If typical experiment using human sub- an experiment which uses chronic jects All too often such experiments are patients rather than acute or subacute set up in a manner that almost guaran- ones, which ignores ECT as we originally tees emotional distance and alienation used it, and which uses entirely different between the experimenter and his sub- evaluative procedures can be called a jects. It is not unusual for many careful attempt at replication, then there contemporary researchers to have no is little hope in psychiatric research The personal knowledge of the identity of the committee adopts the rule that every participants in their own experiments experiment purporting to be double blind which are carried out via intermediaries which yields negative results is by All- too often scientific objectivity is definition "careful, rigorous " They do distorted to include callousness and lack not, however, apply the same rule to the of concern for the human aspects of original experiments done under our research " direction in Saskatchewan because Several of the psychiatrists who were presumably they consider that we were clinically involved with the patients in so biased that even the sacred double Wittenborns and Bans experiments later blind was not to be trusted became orthomolecular psychiatrists We doubt whether this committee was They saw improvement not visible to the so ill-informed as not to know that for all directors of the study because the s the faith placed in them, double-blind directors saw only paper and numbers, studies can be badly designed and not patients. Their clinical observations executed so that false conclusions result. were more meaningful than the APA For example, the University Group conjectures Diabetes Program (UGDP) concluded (12) Page 1—It would seem to us that biguanides (Phenformin) increased that one doctor experienced with a new cardiovascular mortality in diabetics. treatment would be much more trust- This was an expensive controlled experi- worthy than 1,000 who had never used it ment, but recently Biron (1975) wrote, If the committee wishes to play the 4 "There were so many flaws and biases in numbers game, they might explain why ; the design and execution of this trial, over 1,000 psychiatrists had the temerity " that experts in experimental design who to diagnose Senator Goldwater without meticulously appraised the methodology ever having examined him. and the results believe that there are few On Pages 1 and 2 the committee 4 6 reasons to ascribe the higher death rate extracted phrases or sentences from the i to the oral drugs, but many reasons to original reports in such a way as to bring; attribute them to differences in the out the worst possible interpretation of numerous pertinent risk factors that were what was said The only way to prove not measured at time of entry into the hostile bias is to examine the papers; study " In a satirical letter Biron (1975a) which have been published, to abstract them briefly, and to highlight the (13) Page 3, 4th paragraph—The com- conclusions therein We have, therefore, mittee seems to be, or wants to appear, referred to a large number of original naive when discussing the role of reports as well as to the corroborative pharmaceutical companies in the popu- papers which have been published larizing of drugs At the present time These are discussed in an appendix so as drugs hardly ever become popular unless not to burden the reader unduly But there are forces which keep bringing these reports should, be examined in them to the attention of the medical and detail and compared with the com- lay public When a pharmaceutical mittees interpretations and conclusions company has a use patent on a drug it is As will be seen, the committee review Ale to invest heavily in its advertising has been marred by errors of omission, of knowing that other companies are pre- distortion, by incorrect references to the vented from profiting from the original literature, by bias obtained by a careful companys efforts Advertising consists selection of the literature and of the data of spreads in medical journals, frequent presented in any one paper Thus, from visits from friendly, personable, well- about 26 original reports they were trained salesmen who leave samples and seemingly unaware of eight, but they had literature, and articles sponsored in access in the literature to 19 Out of medical journals Drugs which are not about 29 corroborative reports they patented are known in the pharmaceuti- should have known about 15, but cal jargon as "orphan drugs. " They are referred to three or less But they did owned by no one and therefore are not discuss any study which was negative no promoted by any particular companies matter how badly it had been done In The vitamins are orphan drugs This one case they were instrumental in means that there are no detail men, no having one such study published even massive skillful advertisements to keep though there had been no attempt by the the vitamins before physicians as thera- authors to publish until now It appeared peutic agents An example is the pro- in a free journal edited by one of the motion of atromid, a British drug used for committee and distributed by NIMH, towering cholesterol and triglycerides Washington Nicotinic acid, the orphan, is an even Because the committee ignored so better broad-spectrum hypolipidemic many reports favorable to orthomolecu- substance Nearly every physician knows lar therapy while paying attention to any about atromid which is constantly before negative report, however obscure, it physicians in their medical journals in becomes possible to give their bias a three- to four-page spreads There is no mathematical form by using a frequency advertising whatever for nicotinic acid, distribution and the null nypothesis This and very few physicians are aware of its shows: li pid-lowering properties Reports Reports The committee admits there is a grain Favorable Unfavorable of truth in our charge that orphan drugs are less impressive to psychiatrists than those that have been massively ad- vertised They doubt whether there is much to this: "If however they contained Chi so 10 00 n c 001 the full truth, psychiatry would indeed be NAD reports are not included since in a sorry state, gullible to the seduction NAD is neither nicotinic acid nor nicotin- of advertisement, pitiful in its naivete" amide Not every favorable report was and so on counted This shows that the betting odds that the committee surveyed the literature fairly is less than .001, or one in We have not counted any of the papers in Ortho- molecular Psychiatry edited by D R Hawkins and L. a thousand that such a bias occurred by Fouling (19731 since higher chi squares would be chance alone. meaningless

11 It is for our readers to judge whether able Thus, the resulting lack of com- the committee may not have been over- mercial sponsorship further clouded optimistic about psychiatrists capacity recognition of lithiums potential " to resist advertising If they are correct Parsons (1974), a pioneer in the then many drug companies are wasting a development of nicotinic acid as a 1 great deal of money buying up space in broad-spectrum hypolipidemic agent, in 4; the journal of American Psychiatric reply to a hypothetical question, "why is Association and the APAs many other niacin with its long and impressive record j: publications It is possible that these vast not used more widely by clinicians?" companies are so slipshod as not to know stated, "as a non-patentable drug it has the benefits they gain from advertising? not enjoyed the commercial promotion 4 Other psychiatrists are not quite as of other lipid-lowering drugs " Parsons naive as this committee for example, himself is employed by a pharmaceutical Samuel Gershon and Baron Shopsin house and is speaking from personal (1973) in their book on lithium write, knowledge on these matters "another important factor contributing to The committee winds up Section II by the delay in using lithium for psychiatric suggesting that megavitamin therapy has y purposes is undoubtedly that its ready little scientific support and that legiti- availability rendered it commercially mate empirical attempts at scientific p non-profitable; drug companies neither replication have failed There are two investigated nor promoted its use Rowell main classes of scientists: (a) those like of Laboratories, a small pharmaceutical Linus Pauling, Nolan D C Lewis, H house in Baudette, Minn , had the Kluver, Gyorgyi, and others who make foresight and the initiative to support the original contributions; (b) those who " necessary investigational work finally follow along and re-plough fields already leading to the commercial marketing of opened Of the committee members 1 : lithium in 1969 " So far no Baudette- none are in the first rank They may be I company has come forth for vitamins excellent representatives of then== and they still remain orphans However, psychiatric establishment, but are not i a large number of pharmaceutical noted for their scientific contributions companies, not listed among the giants, This may be why this entire APA report do provide the vitamin tablets necessary reads more like a polemic as one would I : for orthomolecular therapy find in Time Magazine, rather than like a 1 The same conclusion was reached by a learned discussion as might appear in4 report released by the National Institute Science. j• of Mental Health in 1970 (revised in The committee finally writes, "legiti- 1974) entitled "Lithium in the Treatment mate empirical attempts at scientific; - of Mood Disorders " This report is replication have failed " The term legit-= introduced by Bertram S Brown, imate is an unusual word in a scientific r: Director He obviously does not disagree document. Presumably, the committee;) with this as there is no disclaimer. considered all the positive studies illegiti- On Page 1: "In the United States, mate however, neither the first report in 1949 The statement that the empirical3 nor the impressive Danish work pub- attempts to replicate failed is untrue fora as we shall show none of the studies4i C lished in 1954 aroused any research i interest in lithium " extolled and praised by the committeef "This situation seems strange at first have made the slightest attempt too glance, for the discovery of the psycho- replicate active properties of lithium was of great (14) Page 5—The committee wrote ,E: significance " an alternative hypothesis proposed by"! On Page 2: "Lithium itself, moreover, Hoffer " They ignored Osmond and;( was of no interest to the drug companies Smythies in this reference perhaps: until quite recently, because it is a because they were then not aware that; natural product and therefore unpatent- Smythies had found evidence supporting"

12 the use of vitamin B3, Perhaps the intent those who sign them agree are untrue? was to dissociate Hoffer from Osmond Surely Lincolns warning has not been and Smythies They then state that the wholly forgotten in Washington where oxidation of adrenalin to adrenochrome the difficulties involved in fooling all of was demonstrated long before we refer- the people all the time have been shown red to it, but neglect to point out that we up vividly in the last few years discovered the psychotomimetic pro- (16) Page 6, second paragraph—"In perties of adrenochrome Oddly enough, their first experiments, started in 1952, the original work was completed at the they compared, in a double-blind study, University of Saskatchewan under the patients given nicotinic acid and nicotin- first professor of biochemistry, Dr Roger amide at doses of 3.0 g per day for 30 Manning, University of Saskatchewan at days with other treatments available at Saskatoon, in 1935 that time. The major tranquilizers were (15) Page 6—The committee refers to not yet available. ECT and sedation were only one out of nine possible explana- given to all patients as needed, but tions we gave for the action of vitamin insulin shock and autonomic drugs were B 3, i e , the methylation ideas. This, as avoided Assessment of results during the we have already shown, is one of many hospitalization was by clinical evaluation possibilities. They then state "not only is of symptom intensity At the end of the there no evidence for adrenochrome for- 33 days the patients were discharged mation in vivo, but the psychotomimetic home or, rarely, to a mental hospital. properties of adrenochrome have also Follow-ups after discharge from the not been replicated " Both these state- hospital were by contact every three ments are demonstrably false; there is a months with patients and relatives to substantial body of evidence that adren- assess adjustment to the community, job ochrome is made in vivo and this has and family. The follow-ups were made by been summarized in detail in our book social workers who did not know the The Hallucinogens (Hoffer and Osmond, treatment given, and occasionally by 1967) This evidence may not satisfy the letters and questionnaires Follow-up committee, but since they did not refer varied from about a year to somewhat to our book, we must assume that they more than three years Re-admission to were ignorant of it and so are in no hospital was used as a criterion of failure position to judge of treatment The results showed only The last part of their statement is small degrees of improvement on the simply untrue Double-blind experiments vitamin over placebo during the hospital- in Prague confirmed the hallucinogenic ization, but a decreased relapse rate in properties of adrenochrome It is listed in the first four years in the nicotinic add NIMH-sponsored literature as an hall- group related to use of drug either in ucinogen and is so recognized by Ban hospital or upon follow-up " (56, APA Task Force Report Reference) We were hoping to find one of our who wrote "after a considerable dispute, papers abstracted correctly But this was however, the psychotomimetic pro- not to be In this paragraph the perties of adrenochrome were con- committee confused two quite different firmed " Yet here is Doctor Ban, a co- reports, the original double-blind report signer to a report which states that its of 30 cases, and a second follow-up study psychotomimetic properties have not on a larger group most of whom had not been confirmed Several years ago he been treated in the double-blind experi- and one of us (AH) debated before a ment. group of psychiatrists in Newfoundland. (17) Page 6—The committee writes, When AH quizzed him about this "During a period of five years a total of statement he admitted that adreno- 82 patients were studied, 43 of whom chromes psychotomimetic properties received placebo and 39 of whom had been confirmed. What is the point of received nicotinic acid." They did not the APA publishing reports which even include the important fact that 21 of the placebo patients also received ECT and committee continues, "but little dif- 15 of the vitamin group received ECT ference in the relapse rate " This seems to us an attempt to neglect This is an astonishing distortion of ECT as an important variable Then they what we reported, equivalent to calling continue, "In this study, the nicotinic black, white. We pointed out that over acid group had significant improvement the 5½ years of follow-up (June 1953 to in the hospital " What they did not say December 1958) all patients from the was that 31 out of the 39 improved second double-blind controlled experi- compared to only 18 out of the 43 ment were given either 1 g of nicotinic placebo group We reported this was a acid or 1 g of placebo per day after highly significant difference They also discharge The two follow-up groups did not record that doctors not in the were randomized. We, therefore, had research group were allowed the option four groups: (a) placebo in hospital and of requesting the medication given to after discharge; (b) placebo in hospital their patients be decoded if they felt and 1 g of niacin after discharge; (c) there was insufficient progress This was niacin in hospital followed by placebo; requested 18 times from the placebo and finally, (d) niacin in hospital and group and once from the vitamin group after discharge We showed results as (chi sq = 19 p < 001) Then the follows:

Group Treatment Percent of group requiring No. of In After readmissions after dis- 5-year Hospital Discharge N charge, year after discharge Total cures

placebo placebo 20 placebo niacin 8 niacin placebo 29 niacin niacin 25

It is obvious that the best record was creasing merit of treatment was as achieved by the niacin-niacin group and follows: niacin-niacin.> placebo-niacin> the worst by the placebo-placebo group niacin-placebo > placebo-placebo There The other two groups were in between was, in fact, a very significant difference We also reported that out of 118 with those patients on niacin in and out ; patient-years in community on niacin of hospital doing much better. Three there were seven readmissions, while five-year cures out of 20 on placebo- = from 182 patient-years on placebo there placebo (15 percent) is surely different E were 60 readmissions (chi square=20, from 19 out of 62 or 30 percent in the p<0001) niacin groups What did the committee The 20 placebo-placebo group re- read? quired 16 readmissions totalling 9. 1 years Then they added, "The only patients ? while the 62 patients on niacin at one who had a significant improvement with time or another required 39 readmissions nicotinic acid continued after discharge; for a total of 11.2 years Had they from the hospital were seven acutely ill required the same number of days in females " hospital relative to the size of the group It seems more charitable to ascribe this) they would have required 28 2 years. statement to a deliberate attempt to b Finally, we concluded, based upon six confuse rather than to accuse the authors indices of improvement, : (1) condition in of being unable to read This is what AH community, (2) number readmitted, (3) wrote on page 54 of his book (1962): "A -r number of readmissions, (4) number total of 33 patients received nicotinic well, (5) number much improved, (6) acid after discharge Of the nineteen five-year cures, that the order of de- rated improved, only nine retained this!`l status, but out of fourteen rated un- only group which differs significantly i mproved on discharge, seven improved from all the other groups listed in Table This latter group, although small, is the 24 " This table showed the following:

Statusin community — Treatment in Discharge well and much community N evaluation improved

19 la) improved 14 Ibl not improved

other treatment 31 lal improved 18 lb) not improved

What this table showed then was that published studies, while ignoring a out of 14 patients discharged as un- number, and list four reports they had improved on 1 g of niacin per day, seven never read These were APA references became well or much improved after at #33, 36, 37, and 40 These were papers least one year treatment in the com- read at the Brunswick Hospital meeting, munity In contrast, out of 18 discharged but never published None of the as not improved not given niacin but committee members were present This is given other treatment, only one became an example of padding It is customary well or much improved On the other not to refer to unread papers unless this is hand, out of 19 discharged as improved noted in the text. and continued on 1 g of niacin, only nine (19) Page 8—The committee made the remained well or much improved while following criticisms of megavitamin out of 31 evaluated improved or dis- work: charged but not given niacin only 13 (1) Contamination of studies by frequent remained well or much improved. use of ECT We have always shown This shows that 1 g per day is enough to dearly that ECT was an essential com- produce improvement in some and not in ponent of treatment for Phase II patients others, which is not surprising It has It is odd to term an essential ingredient a always been clear there is an optimum contaminant The committee still treatment and follow-up dose. We find attempts to play down ECT, presumably the committees capacity to distort our to further their contention that vitamin findings incomprehensible and are at a B3 is the crucial variable loss to account for it It appears to be a (2) A nonrandom or biased selection of deliberate attempt to mislead unwary the small numbers in our studies com- readers in the hope that they would not pared with the total population at risk. compare the report with the original For the first two double-blind studies source If this was the intention then it every patient admitted who was schizo- was doubly deplorable for apart from the phrenic was taken into the study, falsification it underestimates the provided that his therapist allowed this to curiosity and zeal of some members of happen This is the way most studies are the public It suggests an arrogant and done We do not know of any studies supercilious approach to both the profes- where a random selection of all ad- sion and the public missions has been used All that is (18) Page 7—The committee stated, required by classical double-blind "Positive claims for the efficacy of methodology is that the allocation of nicotinic acid have been made by other patients into the treatment groups is workers " They then list a number of randomized The committee has created some new rules to suit their fancy: The ••• The difference between niacin and other treatment size of the groups treated was adequate in the community was statistically significant. Chi sq = 3.7 If <0.051. to test the null hypothesis and was somewhat larger than sample sizes used use until 1957 By then our first by Ban and Lehmann If our work is experiment was completed and our questioned on this count the same second one nearly completed Since then criticism should be levelled at Ban and we have published many reports compar- Lehmann Ban (1972) is uncertain ing vitamin B3 as a treatment component whether 15 to 30 patients in any group against tranquilizers alone. can yield any conclusion at any accept- (8) The final attack is a repetition of able level of thoroughness. earlier mistakes The committee wrote (3) The lack of clearly specified initial "In the first one the patients received the diagnostic groups or systematic rating of drugs only in hospital, did not improve patients This is false The reader must significantly in hospital but had a read our original papers where we lessened tendency to relapse for four described in detail diagnostic criteria and years after discharge." The committee evaluative methods used manages to be confused about even (4) The failure to specify chronicity. This elementary reports We concluded that is false as any examination of our the vitamin B3 patients were better off published data shows than placebo patients on discharge, but (5) Nicotinic acid was never the only that at the end of one year they had treatment given We have repeatedly reached a one-year recovery rate twice as emphasized that vitamin B3 was one of high as the placebo group. This the the main treatments in any series. committee terms "a lessened tendency." However, we have seen hundreds of As usual they play down the positive and patients recover on vitamin B3 alone We emphasize the negative more like hostile are prepared to demonstrate these to any attorneys than scientific inquirers Then physician who wishes to see our patients they say, "In the second study the reverse and their clinical records So far over 50 is true: there was an improvement in the physicians have done so and are now hospital, but the subsequent relapse rate practicing orthomolecular therapy was the same." As we showed earlier the 2 (6)"The number of patients in the follow- second half of this statement is false The up sample were small." This is a committee then remarks, "These dif- misleading criticism How many 10-year fering results are hard to explain." follow-up studies have been reported Perhaps so; if one cannot read almost with tranquilizers? We have recently seen anything must be perplexing Both one Perhaps the committee will bring studies showed that patients on vitamin others to our attention "Treatment and B3 therapy improved in hospital and had comparison groups were not matched as a significant decrease in relapse rates.;; to pre-treatment prognosis " This is But the committee falsely concluded another after-the-fact suggestion which white is black. makes it look as if the committee was We do not find any inconsistencies in searching desperately for every possible the statements in the last paragraph on criticism of our work They were much Page 8 It is true a few patients recover less critical of the Wittenborn and the very quickly on vitamin B3 therapy, but r Ban and Lehmann double blinds which that most patients recover more slowly 1 were not double blind Had they found This is also true of tranquilizers. We do such errors in our work there would have not understand why this is considered an been no end to their comments To be inconsistency It is a general phenom-z fair, in the original protocol Ban termed enon of all therapeutic drugs But with his study "semi-blind," but he conven- orthomolecular therapy a large pro-), iently ignores this in this report portion of patients recover fully to` (7) The committee is critical because in become doctors, lawyers, professors, our original double-blind studies we did farmers, white collar workers, and so on not compare vitamin B3 against tran- We have yet to see one schizophrenic: quilizers We would have done so, but physician become normal on tranquilizer tranquilizers did not come into general therapy only . " `

16 (20) Page 9—The committee finds (during pregnancy) to babies There is another inconsistency between a report evidence that it can protect babies by Saarma and Vasar (Ref 46) and their against the harmful effects of other reference to O Reilly (Ref 47) They say substances " Saarma et al cited negative finds for The New World Dictionary, Second nicotinic acid in acute schizophrenia College Edition defines broadside as This is what Saarma said, but the follows: "(1) The entire side of a ship committee knew the OReilly study was above the water line; (2) (a) all the guns on chronic patients only since they listed that can be fired from one side of a ship; the title of his paper accurately as (b) the simultaneous firing of these guns; "Nicotinic Acid Therapy and the Chronic (3) a vigorous or abusive attack in words Schizophrenic." (See Ref 47 ) It was also especially in a newspaper; (4) the broad so listed by Saarma and Vasar who surface of any large object; (5) (a) probably missed the word in their (originally) a large sheet of paper printed proofreading on one side as with a political message or (21) Page 9—In complaining about in 17th century England a popular ballad our original methodology the committee also broadsheet; (b) a large sheet of cited three examples The first one is paper printed on one or both sides as from Hoffer et al (1957) where they with advertising and often folded " extracted sentences from a paragraph: We have never mass circulated any "When the adjustment rating is not communication, but have as a policy available for a particular patient but his prepared printed information letters progress after discharge is adequately which are sent only to lay and profes- known, , an impressionistic score is sional people who have written to us for given, but the committee carefully information. Nowhere in the precise omitted the rest of the statement: "(for definition of broadside is there anything example, good adjustment or poor remotely resembling anything we have adjustment) These findings, however, done However, definition #3 fits closest are excluded from the mathematical of all the APA Task Force Report evaluation of progress," Surely this is a In our personal communications, most important statement to leave in, which these letters were, we did not refer but if the committee had done so they to literature references. For the com- would have removed one of their mittee to treat these private letters as if examples of questionable methodology they were documents published in a However, this evaluative method was medical journal is grossly unfair used for nine patients out of the 30 as We have been using niacin on several follows: (a) from the placebo group four thousand cases since 1952. A large had poor adjustments; (b) from the number of females have become preg- nicotinic acid group, two; (c) from the nant and had normal children while on nicotinamide group, two—both being niacin There has been not one infant then in mental hospital This exclusion of born to these patients with any con- a crucial qualifying sentence suggests genital defect that either deliberate falsification or massive subconscious bias was at work. The APA Research Committee should Safety, Side Effects, and Relative Lack of have been more diligent in monitoring its Toxicity of Nicotinic Acid and Nicotin- Task Force amide, A. Hoffer (19696) The second example of the committee In this paper, AH differentiated is an attack on Chinaglia (1965) and the between side effects which may he a third example is an attempt to smear us nuisance and toxic effects which are The committee writes, "Hoffer in a potentially harmful. Side effects include: broadside for public distribution pub- (1) Vasodilation of the anterior part of lished in 1965 says, It (nicotinic acid or the body with a sensation of heat and nicotinamide) does not cause any harm itching (2) Nausea occasionally followed by medically serious " vomiting. The committee writes, "Hoffer for (3) Rarely activation of peptic ulcer example, in his 1967 pamphlet (18) and (4) Rarely dry skin and very rarely in his 1971 paper (13) cites violent increased pigmentation of flexor sur- vasodilatation Here is what AH wrote, faces "Nicotinic acid produces a remarkable (5) Headaches vasodilatation " The committee manages They are not dangerous and are easily to transform remarkable into violent, controlled by lowering the dose or using evidence of bias which can hardly be lost other means. Possible toxic reactions of on students of psychopathology To nicotinic acid include liver toxicity which round off this example they omit a is rare, occurring about one-tenth of the description of how this flush recedes if frequency with which it appears with one continues to take niacin tranquilizers It may alter the sugar- In 1971 AH wrote, "It is still not tolerance curve and may cause insulin clear how many of the gastrointestinal requirements to go up or down It may effects are due to the vitamin and how increase uric acid blood levels, but has many to the vitamin filler " This is how not precipitated or aggravated gout. the committee summarized it, "The There have been no reports of toxic gastrointestinal symptoms are attributed effects on the embryo Female rabbits on to the inert filler used in preparation of nicotinic acid produced normal litters. the B3 tablets " In this section the A H referred to findings which showed committee continues to distort both form that vitamin B3 could protect embryos and substance of what we wrote, from toxic effects of other drugs. Sub- presumably secure in the belief that their stances which prevent vitamin B3 from psychiatrist readers will not refer to the being incorporated into NAD are terato- original publications So far events have gens such as 6 aminonicotinamide supported their belief However, since :FlI Nicotinic acid protects animals against they were entrusted by the APA to these compounds Mosher (1970) quoted make an honest and unbiased report these studies and had he found any others may now become curious to see a evidence whatever for any teratogenic how they carried out a duty to which effect he would have certainly produced they were pledged both to psychiatry and it He concluded, "at this time there is to the public This entire section on side t little evidence either positive or negative effects reads like one of the glib reports with regard to the possible teratogenic with which Parsons takes issue. Re- effects of nicotinic acid " As he was garding peptic ulcer Parsons wrote, "Although in 1960 I reported five patients unaware of the earlier report this is whom ulcers became active during understandable. He subsequently apolo- in gized for his neglect to properly report niacin therapy subsequent experience the literature. has failed to show any close correlation " In a recent review Parsons (1974) "I do not hesitate to prescribe niacin in a discussed the side effects of nicotinic hyperlipidemic patient with previous acid. He wrote, "Many clinicians are ulcer " unduly concerned about the cutaneous With respect to liver toxicity high- flushing which niacin produces, lighted by the committee, Parsons states, apparently not realizing that with large Some of the serum enzymes used to doses it subsides early in treatment Such assess hepatic function may be mildly to negative attitudes have probably been moderately elevated during therapy AA enhanced by glib review articles listing These changes are usually not pro- symptoms and biochemical changes gressive, often returning to normal while which occur during therapy, but failing treatment continues Light microscopy ;g to clarify which could be formidable " "It has frequently shown no abnormality in is also well to emphasize that the flush is at worst merely a nuisance which is not •• emphasis ours. not in the APA report

18 hepatic tissue even when enzyme levels subject who had also been taking LSD, have been considerably abnormal " hashish, and a curious form of psycho- "Similar liver enzyme changes occur with therapy The committee did not refer to a clofibrate therapy and appears to be letter of rebuttal, from Hoffer (1969) inherent in these drugs without signifying Here he wrote "This pharmacologically hepatic damage " Jaundice has been very naive report deserves little comment rare. except that it will certainly be quoted About hyperglycemia Parsons wrote, widely as evidence for niacin toxicity " the changes in carbohydrate tolerance We did not then realize that a committee have no clinical significance—unless the of the APA would be the first and only clinician incorrectly interprets them as group to prove this prediction correct evidence of diabetes " Discussing in- The committees concluding paragraph creased uric acid levels Parsons con- on Page 44 of their report might be cluded, "Hyperuricemia occurs some- ascribed to a serious concern for the what less frequently but has not been welfare of patients But since every accompanied by gouty arthritis or renal known tranquilizer is many times more calculi " toxic, one has to weigh the risks of: (1) Parsons found pigmentary changes in Remaining chronically tranquilized and the skin not significant This he des- more or less ill for life This as many cribed as a localized velvety thickening authorities have indicated is occurring to and tanning of the skin especially in the an increasing number of patients with all axillae This change, which resembles the increasing risks of irreversible con- acanthosis nigricans, is of cosmetic ditions such as tardive dyskinesia and importance only It does not require that akinetic mutism (2) Recovering on the drug be discontinued Wittenborn et the orthomolecular approach while using al (1973) did not report any cases of vitamins the rest of ones life We acanthosis nigricans They wrote, "A believe that given such a choice and not substantial portion of the sample misled by prejudicial comments most developed a pigmented hyperkeratosis people would choose the latter The risks which in some cases bore a disturbing are small We have still to see a single superficial resemblance to acanthosis patient harmed by megavitamin therapy nigricans " They referred to a report by although we have seen those not Parsons But it is obvious that Parsons benefited During the same time we have who has been studying nicotinic acid seen numbers of permanently impaired since 1956 is not disturbed It is not the patients on tranquilizers The costs in tanning of the skin which is disturbing, terms of their lives and to the community but the unfamiliarity of Wittenborn and have not yet been computed, but they his colleagues with this phenomenon must be immense which excited and disturbed them There (22) Page 10, Attempts at Replication are no reports that nicotinic acid causes —The committee continues to insist that acanthosis nigricans The committees vitamin B3 is the crucial variable for the statement was false when they wrote, entire orthomolecular program They use "and acanthosis nigricans have been this to justify their single-minded reported " From 853 patients treated with employment of vitamin B3 in their nicotinic acid for five years the Coronary experiments This sometimes seems to be Drug Project Research Group did not a deliberate attempt to confuse—one is report a single case They did not even unwilling to believe in such massive mention it as a side effect incompetence. Had Ban and Lehmann The committee referred to a case of seen fit (as they had originally agreed) to incipient psychosis produced by nico- repeat our original experiments using a tinic acid. They apparently read a letter combination of vitamin B3 and ECT, and to the editor by Heninger and Bowers had the results turned out negative, there (1968) who concluded that 1% g of is no doubt the committee would have nicotinic acid produced a psychosis in a dropped all reference to vitamin B3 as the crucial variable No matter how the studies not only for what Dr Wittenborn committee squirms about the issue, the reported, but the way this committee; fact still remains that no one has used his data It is not clear just what repeated the original two double-blind responsibility Wittenborn himself must) experiments Those who have employed bear for the committees report since hef the entire orthomolecular technique was the consultant As with Ban the= have become enthusiastic users committee seems to be expert at mud-ii (23) Page 11—The list of negative ref- dling roles in a deplorable manner We erences on this page is interesting -will not concern ourselves with Witten-) Nowhere is there any reference in the born the consultant body of their report to our first study We will list the Wittenborn con where we showed that nicotinic acid clusions and then the committees in- alone did not help chronic patients terpretation when they are different. (OReilly, 1955) OReilly was a colleague Wittenborn et al (1973) compared theI located at Saskatchewan Hospital, North effect of nicotinic acid, 3 g per day, Battleford At our request he ran a study plus tranquilizers against nicotinic acid) which was published in Diseases of the alone on an experimental group of 47 ill). Nervous System. This was the first on the average 4.8 years against a control published account of lack of response of group of 28 ill 3.0 years. They found: (1) chronics We have since then always 24 percent from the vitamin group were„ made this clear as is evident from the dropouts and uncooperative compared; review of our papers given earlier in this to 37 percent of the control This did not report OReilly (1955) is reference #47 in reach statistical significance, but sug- ; ±) the committee report Then they refer to gests a trend for more cooperation): Ashby et al., who confirmed our report, among the vitamin group (2) A slightly , and to Greenbaum who gave one-third larger proportion in the nicotinic acid= the active dose to schizophrenic child- group remained in hospital each month ? ren No information was given about the This difference was not statistically)) number who were cases of infantile significant. (3) There was no difference in autism the rate of readmission to hospital or inw The McGrath et al report discussed number of days spent in hospital. (4) 265 patients of whom 115 or 43 percent There was no significant difference in were ill five years or more, 91 (34 number of patients requiring tram))) percent) were ill one to five years, and of quilizers, or in the amount of tranquilizer whom only 59 (23 percent) were ill one required (dose) At the end of the first; year or less Thus, only one-quarter were month, 87 percent of the vitamin group ;+ acute This is then a study of the effect of and 96 percent of the control group were- nicotinamide on chronic schizophrenics receiving tranquilizers, while at the ends There is no breakdown anywhere in the of 12 months these values were 77 paper between acute and chronics and percent and 89 percent At the end of response to treatment There is no two years they were identical at 75 r;; evidence in this report to support the percent (5) There was no significant;: committee s statement "no improvement difference between the two groups" was noticeable either after 30 days of clinically (6) Home and community, treatment or after one year in either the adjustment was more favorable in the; acute or chronic patients " McGrath et control group than in the vitamin group. 4? al also confirmed OReilly (1955) (7) There were no cases of disturbedf The Wittenborn studies are reported in carbohydrate metabolism and gastro an interesting way And since Dr enteritis (8) A number of patients` Wittenborn is introduced "as an excep- developed a superficial pigmentation in tionally experienced researcher in the their skin area of drug effects on mental illness" it These findings were reported by the Yj is especially important to examine care- committee except for their first state-1r fully his "unusually comprehensive" ment (1) Subjects on niacin tended to

20 stay in the hospital longer, but the strong interpersonal commitments will statistical significance of this is un- respond well to niacin-supplemental certain What Wittenborn et al wrote therapy " This he proposed as a testable was that, "This difference continued hypothesis throughout the course of treatment, but The committee did not relish this did not meet the criterion for statistical second report and attempted to neutra- significance " There seems to be nothing lize and obscure these findings by writing uncertain about this last statement. in their conclusion, "the fact that he In a subsequent report (Wittenborn, finds no significant difference between 1973) first delivered in Washington and the total control group and the total later published Wittenborn (1974) re- vitamin group implies that a fraction of ported that he had examined a smaller his experimental population may have group of 24 patients selected on the basis had their progress impeded by the of certain predictor indices Half vitamin addition " There is no evidence received nicotinic acid Ten of the 12 whatever for this simplistic mathematical patients in the vitamin group had conclusion. Had there been any sub- outpatient adjustment scores of 0 60 or group identifiable in any way as a group higher at 24 months indicating a good made worse by vitamin B3, there can be outpatient adjustment score In the no doubt Wittenborn upon the urging of control group only five out of 12 the committee would have found it and achieved similar adjustment reported it Wittenbo n found "a high positive The committee referred to a possible predictor score was associated with a one-quarter of the group who did well on clinically important advantage for those vitamin B3 but neglected to refer to the patients whose treatment comprised 20 percent of the total group who were niacin supplementations " "For depres- made worse on tranquilizers alone Thus, sive retardation the percent of patients Wittenborn (1974) wrote, "one possible with substantial disorder at 24 months is explanation for the paradoxical per- approximately twice as great in the sistence of symptoms in these control selected control group as in the selected group patients with a good positive niacin supplementation group. For predictor score draws on observations schizophrenic excitement, the percent of that there are patients with a favorable patients with substantial disorder is more premorbid history who may possibly be than twice as great in the control group burdened by phenothiazine medication at 12 and 24 months as it is in the in their remission " He wondered if selected niacin supplementation group " niacin might be antitoxic to the pheno- Wittenborn (1973) stated, "There is a thiazines conceivable relationship between the But this is how the committee sum- fact that in the present sample patients marizes it: "although Wittenborn with a high predictive score responded considers his data to be consistent with tell to niacin and the fact that Hoffer the possibility that as many as one- and Osmond had claimed that niacin was quarter of his schizophrenic population more effective in relatively acute (those with good premorbid adjustment) patients than in chronic patients It is might be benefitted " We assume that probable that patients who, in the this figure is derived by multiplying present sample, had a high positive one-third (i e , the number of subjects predictor score would have been class- with good premorbid personality) by ified by Hoffer and Osmond as acute 10/12, i.e , the proportion who respond- schizophrenics. Perhaps in this way the ed to nicotinic acid plus phenothiazines. differential effect observed by them Note that the committee in criticizing could be in part explained " Wittenborn our work never talks about nicotinic acid further states, "those patients with and ECT in the same sentence, but here conditions diagnosed as schizophrenic they want to leave the suggestion it was who come to treatment with a history of the phenothiazine which should be r

emphasized. This may be how the of one-quarter based upon a mental committee arrives at the one-quarter hospital admission cohort, this is still 3. estimate. appreciable Having admitted that one- Wittenborn in his papers does not quarter might be benefited the com- make this sort of calculation In our mittee, by a form of convoluted reason- opinion Wittenborn had discovered un- ing which is very mysterious, states, "the usual and one might think unnecessary fact that he finds no significant dif- criteria for selecting Phase I patients The ference between the total control group proportion of Phase I patients, i e., acute and the total vitamin group implies a or less serious cases, varies with the fraction of his experimental population sample Thus, from a cohort of schizo- may have had their progress impeded by phrenics seen for the first time in the vitamin addition " One could just as outpatient clinics or by psychiatrists in well argue that had there been a simple private practice a much larger proportion placebo versus niacin study omitting are early, less serious, or Phase I. From a tranquilizers the results might have been cohort admitted to a mental hospital a even more significant in favor of vitamin Is much smaller proportion are Phase I Out B 3 of one practice in Saskatoon about 50 Wittenborn tried to save his study from = percent are early and AH is the first becoming too much in favor of niacin by 3 psychiatrist they have seen. The other suggesting that the 35 percent of his total half have been to one or more before and group were not really schizophrenic If : are more apt to be Phase II Since going this suggestion is accepted seriously, to a mental hospital very often means then the whole study must be in that there is no other facility willing or jeopardy For who would give a — able to take the patient they are more moments consideration to an investiga- : chronic, have already failed to respond tion in which the chief scientist reports to treatment, and are generally more that one-third of the patients did not intractable It is, therefore, not surprising have the illness being studied? ; to find only one-third of the Wittenborn The committee totally ignored DeLizs!3 group were Phase I But to be fair and (1973) charge that the Wittenborn study< objective the committee might have did not maintain its double-blind status 1_ abstracted Wittenborns paper more Although Wittenborn maintained it was carefully Even so, there is no evidence double blind, he presented no evidence.; from the Wittenborn studies that the two that it had remained so There were no=; main groups were suitably identical since questionnaires for either patient or staff: the placebo group were 1 8 years less to determine whether they thought they;;:. chronic (4 8 compared to 3 0) A were getting niacin or placebo DeLiz; substantial fraction of the poorer prog- stated that some patients were aware; nostic vitamin group could have res- they were on placebo and at least one ponded without any significant dif- purchased his own niacin This is not to ference appearing, and a substantial be construed as an attack on Wittenborn ` proportion of the better prognostic who is an able research worker, but ori placebo group might have responded had the methodology of theth e double-blind they been treated with nicotinic acid. technique It requires an al super ; Thus, the one-quarter estimate is so human effort to insure the double blind i crude as to be trivial not broken In other words, Wittenborns study In the Wittenborn studies it would confirms our claims that a substantial have been impossible to insure it- fraction of schizophrenics, i e , Phase I, remained double blind because of the will respond to nicotinic acid without vasodilation He attempted to cover this: ECT. But we must emphasize that this is by starting the entire group on 50Q; seldom our recommendation today The milligram tablets to give them all the committee quibbles on the proportion in flush and then changing the lacebo Phase I Even if we accept their estimate group over to placebo But anyonep with

22 any experience with long-term niacin use this will be followed by the committees knows that now and then throughout abstract treatment there will be random flushes, usually after the first dose in the Study No. 1 (58 in Task Force Biblio- morning We suspect that after a few graphy) Also published in Int. Zeit. Klin. months nearly every patient on niacin Pharm. Ther. and Tox., 54, 406-410, will know he has flushed and most of the 1972 group will know why In this study they treated 30 newly Furthermore, a number of patients admitted schizophrenics They do not who developed pigmentation had their describe them as acute or chronic, but as medication decoded and after a while newly admitted. This is an interesting were restarted on the niacin Thus, the term and suggests that the patients were double blind was not maintained through acute Anyone familiar with the Douglas no fault of the investigators (De Liz, Hospital in Montreal knows that newly 1975; Adams et al , 1975) admitted patients there include a large We now come to the Canadian Mental proportion of chronic cases, many of Health Associations studies begun with a whom had failed to respond to treatment grant given to Dr T Ban The reason the in a number of psychiatric wards in CMHA did this was that they became general hospitals The words newly disturbed by the claims that adding admitted have no meaning whatever and vitamin B3 to the treatment program the authors would have been more doubled the recovery rate They in- honest to have simply called them structed Dr Ban to disprove once and for admitted schizophrenics and to have all time our claims One of us (AH) that described their sample more carefully. year was on the Scientific Advisory Hoffer (1974) investigated these studies Council and was familiar with the back- carefully and wrote, "The patients were ground When Bans initial design was divided into three groups, one group seen it was obvious he was prepared to receiving nicotinic acid, one group use only Phase I treatment, i e , no ECT nicotinamide, and the third group place- When this was pointed out to him he bos Neuroleptic tranquilizers were responded with the reassuring statement administered to all the groups on a that after their first researches were restricted scale It was intended to completed they would continue with investigate the patients for two years, but Phases II and III He also added there only six patients completed the entire would be no release of any information period Nevertheless, 25 patients spent until the entire program (Phases I and II) the first three months in hospital and at could be completed It now appears that the end of this period their clinical status he had no intention whatever of going was assessed by means of the Brief beyond Phase I treatment for all patients Psychiatric Rating Scale (BPRS) and, as events showed, he rushed into "It was found that there were statist- print very soon after the first study was ically significant improvements in the completed He was supported by CMHA total BPRS scores for all three groups who circulated his first report to every However, Table 3 of the research paper psychiatrist in Canada They have since shows that out of 15 BPRS items, the refused to correct the misinformation patients receiving nicotinic acid im- distributed therein claiming they cannot proved in 11 items and the patients be involved in any treatment contro- receiving nicotinamide improved in 12 versy Examination of Table 1 of the items, while the patients receiving committee report shows no evidence placebos improved in only six items whatever of any study repeating any of Thus, both the B3-treated groups scored our original double-blind studies improvements in approximately twice as (vitamin B3 and ECT as required) many items of the BPRS as the placebo- For each of their published studies we treated group The published paper also will abstract what the authors wrote and includes clinical assessments of the

23 patients at the end of the two-year study reached about the study depends on There were improvements in 10 out of 15 whether one takes the average number of items in both the nicotinic acid and the days spent in hospital as the critical nicotinamide-treated groups, but variable, or whether one takes the improvement in only six items in the number of symptoms of mental illness placebo-treated group Because 80 per- alleviated in the course of the treatment cent of the patients dropped out of the as the critical variable The latter is by far study before its completion, these results the more reliable are much less reliable than the ones "The Task Force Report has interpreted j obtained at the end of the three-month this study as demonstrating that (page period in hospital, when few patients had 15): The overall therapeutic efficacy dropped out However, the same general of nicotinic acid as the sole medication picture is obtained as at the end of the in newly admitted schizophrenic patients three-month period; that is, both the is not superior to the overall therapeutic ? nicotinic acid and the nicotinamide- efficacy of an inactive placebo treated groups improved in many more "This conclusion is based on the I3PRS items than did the placebo group " insignificant differences in average dura- The committee reports, however, "the tion of hospital stays The evidence overall therapeutic efficacy of nicotinic derived from actual psychiatric evalua- acid as the sole medication in newly tion of the patients, which showed a ! admitted schizophrenic patients is not definite superiority of both the groups_ superior to the overall therapeutic receiving B3 over the control group, is." efficacy of an inactive placebo In fact, not even mentioned " the majority of newly admitted schizo- phrenic patients—in a placebo control- CMHA Study No. 3 (No 53 in biblio- led two-year study with 30 patients— graphy) from J Hoffer: could not be sufficiently controlled with "The Task Force Report summary of high dosages—3,000 to 8,000 mg per the CMHA Study No 3 by Ramsay et day—of nicotinic acid administration al (53) also gives a false representation Further analysis of data revealed that of the actual findings On Page 15 the. during the two-year investigational Task Force Report states: period—regardless of whether the " From Study No 3: the overall; patients were kept on the project or therapeutic efficacy of nicotinic acid as:: not—the average number of days spent an adjuvant medication in newly in hospital was lowest in the placebo (211 admitted schizophrenic patients is in- clays) and highest in the nicotinamide- ferior to the overall therapeutic efficacy;; treated group (353 days) However, the of an inactive placebo number of days spent in hospital was " In fact, the addition of nicotinic; only slightly higher—214 days—in the acid, in the dosage of 3,000 mg per day,;` nicotinic acid than in the placebo- to the regular phenothiazine treatment—1 treated patients (58) " in a placebo-controlled six-months study" J Hoffer then properly concluded, with 30 patients—prolonged the duration; "The summary of this study given in the of hospital stay and increased the= Task Force Report doesnt mention these amount of neuroleptic medication ref results Instead, it points out that the quired in treatment average number of days in hospital The results of this study," J Hoffer during the two-year period was 211 days concluded, "do not show that patientsl in the placebo-treated group, 214 days in receiving nicotinic acid were made worse; the nicotinic acid-treated group, and 353 because of it The difference in thee; , clays in the nicotinamide-treated group, average duration of hospital stays was;; showing that the length of time spent in not significant The difference in the;. hospital was not significantly different average amounts of neuroleptic tran4" for the B3-treated groups compared to quilizers administered to the different` the control group The conclusion to be groups is of doubtful significance. The s i drugs were prescribed for more than half been something there The fact that only the duration of the study on the basis of half were able to do the HOD suggests short, outpatient interviews by resident these newly admitted patients were a psychiatrists (psychiatrists in training) very chronic group In Saskatchewan Even among experienced psychiatrists, only chronic patients incarcerated for the dosages of these drugs given to acute many years had this low a completion schizophrenics are highly variable The record on the HOD test Acute and dosage of a tranquilizer drug prescribed subacute cases never had more than a 5 for a psychotic patient is a very crude percent rate of not being able to and very indirect indication of his complete the HOD clinical status, and it can be influenced by a multitude of extraneous factors CMHA Study No. 4 from J Hoffer: "The direct and obvious method of "The final CMHA collaborative study assessing the condition of patients is by was conducted on 30 chronic schizo- observing them If B3 had worsened the phrenic patients In this study one group patients, it would be detectable by a of patients was treated with 3 g of worsening of their symptoms In fact, it nicotinic acid, one group with 3 g of was found that the B3-treated groups nicotinamide, and the third group was improved significantly The research given placebos The Task Force Reports paper states: summary of the results of the study is as Of the three, the nicotinamide- follows: treated groups showed statistically sign- From Study No. 4: the overall ificant therapeutic improvement on more therapeutic efficacy of nicotinic acid— individual items (9) of the BPRS than in the dosage of 3,000 mg per day—as an either the nicotinic acid or the placebo adjuvant medication in chronically groups; the latter two groups showed hospitalized schizophrenic patients is significant improvement on six and eight inferior to the overall therapeutic items respectively (53). -efficacy of an inactive placebo In fact, One may conclude that the B3- in a one-year placebo-controlled study treated groups in this study did not, in with 30 patients, the active treatment the overall assessment, improve more groups fared worse than the placebo than the control groups This has little group by all measures of assessment The relevance to orthomolecular therapy, in least improvement and the greatest which 133 would not be used alone and in amount of deterioration was seen in the such small dosages There is no evidence nicotinic acid group Moreover, it was that 133 worsened the condition of the shown that patients in the placebo group patients who were treated with it " required less increase in their concomi- Contrary to the findings of an in- tant phenothiazine medication than creased need for tranquilizers, Witten- patients in the two active treatment born found no significant difference in groups tranquilizer requirements, nor did he find "The actual published data shows that any difference in the number of days in every statement in this summary is false. hospital Thus, Wittenborn demolishes In the study, three methods of clinical two of Bans main criteria of improve- evaluation were used: the Clinical Global ment Ramsay et al. did not report any I mpression Scale (CGI), the Nurses mean HOD scores, but did report mean Observation Scale for Inpatient Evalua- MMPI scores (only 11 out of 30 were able tion (NOSIE), and the Brief Psychiatric to complete MMPI) Half the group Rating Scale (BPRS) The patients were completed the HOD Had they given rated on these scales before the study HOD scores perhaps some differences began and after its conclusion, and the might have appeared Since as a rule they results are these: the changes in all three downgraded positive responses, one is evaluation scales before and after treat- left with the assumption there may have ment were insignificantly small for the patients in the two B3-treated groups and average dosages of the tranquilizers in the placebo group. There was no administered to the patients before and i mprovement and no deterioration in any after treatment were also insignificantly group small There was no evidence that the "It is clear that a treatment of 3 g of B3 patients in the placebo group required per day did not benefit these chronic less increase in their tranquilizer medica- patients This is a result to be expected tion than the B3-treated patients; the on the basis of the studies by Dr Hoffer statement to this effect in the Task Force and Dr Osmond and by Dr. OReilly, Report is wrong " who had already reported that chronic In APA Bibliography #56 Ban and patients, like the ones in this study, do Lehmann also reported on 10 newly not respond to 3 g of B3 alone At the admitted patients (acute and subacute is same time, contrary to the claims in the given as a descriptive term, but no data is Task Force Report, there is absolutely no given on their chronicity) Three were on evidence that the administration of B3 nicotinic acid, three on nicotinamide, worsened the condition of the patients and four on placebo In this study the who received it It can easily be shown nicotinic acid group required 164 mg that the numerical variations in the tranquilizers/day and the placebo group clinical scales which were observed are 259 mg per day However, they down- small, random fluctuations which are grade this by promptly pointing out the due to the inexactness of the evaluation placebo group had fewer days in methods For example, on the CGI scale, hospital Neither of the indices has any the nicotinic acid-treated group went value in judging response to treatment from a pretreatment score of 4 1 down to There are too many clinical variables In 3 9 after treatment, an improvement of our own studies we never used duration 0 2 points The placebo group went from of first treatment admission as a 4.2 down to 3 7—an-improvement of 0.5 criterion, but we did use duration of points The nicotinamide group also readmission as a measure. Ban and !)4 improved by 0.5 points (4 7 to 4 2) On Lehmann studiously avoided this latter the basis of this the Task Force Report statistic They can conclude, it would states that the nicotinic acid group be erroneous to amplify results of our had the least improvement and the clinical trials with other negative reports greatest amount of deterioration Yet the and to conclude that nicotinic acid has CGI scale in this experiment is inexact by no place in treatment of schizophrenic; a minimum of 0 6 points; any change less patients" This was one of their few: than that is equivalent to no change at correct statements, especially its first = all The nicotinic acid groups improve- part, based upon 10 patients in one study j ment by 0 2 points is not less than the and 30 in another Then they continue placebo and ni.cotinamide groups with the meaningless and trivial state- i mprovement of 0 5 points—all these ment, all one can say on the basis of changes are too small to have any these findings is that there is sufficient° significance evidence to suggest strongly that, "The Task Force Report states: the nicotinic acid or nicotinamide is not the; active treatment groups fared worse than treatment of choice for every schizo-;. the placebo group by all measures of phrenic patient under all possible; and without any furtherrl€€ assessment This is false for the nicotin- conditions :: amide group improved on the BPRS by consideration " Is there any drug used for 1 3 points (improving from a pretreat- any condition for which this statement,! merit 45 9 to 44 6 after treatment), while would be untrue? the placebo group deteriorated by 1 6 This statement was repeated by Dr J points (rising from 37.8 to 39 4). D Griffin, General Director, Canadian "As it happens, BPRS was imprecise by Mental Health Association (Progress at least 10 points, so these changes, too, Report 1) Since then and following his are not significant The differences in the retirement Mental Health Canada hasi

26 changed its position and no longer "And: officially wishes to be involved in the " On balance, these results suggest continuing controversy that the addition of pyridoxine may potentiate the actions of nicotinic acid. Study No. 7, from j Hoffer, page 26: Thus, pyridoxine seems to be a useful "Study No 7 of the CMHA studies adjunct to nicotinic acid therapy. " by Ananth, Ban, and Lehmann, 1973, is entitled Potentiation of Therapeutic Study No.12, from john Hoffer, pages 24 Effects of Nicotinic Acid by Pyridoxine in and 25: Chronic Schizophrenics It was intended "First, Study No 12, by Ananth, Ban, in this experiment to test the finding of Lehmann et al is entitled, Nicotinic orthomolecular psychiatrists that B3 and Acid in the Prevention and Treatment of 136 (pyridoxine), when combined, have Artificially Induced Psychopathology in an enhanced effect in the treatment of Schizophrenics (54) It consisted of a schizophrenia A 48-week double-blind study on chronic schizophrenics (Phase study was conducted in which one group Ill) in which half the patients were given of patients received nicotinic acid, one nicotinic acid in a dose of 3 g per day and group pyridoxine, and a third group half were given placebos, for two weeks. received a combination of nicotinic acid The neuroleptic tranquilizer therapy and pyridoxine. All the patients were which all the patients had been on was chronic schizophrenics The Task Force withdrawn As might be expected, the Report summarized the results of this patients receiving placebos deteriorated study as follows (page 15): significantly when the tranquil lizers were " From Study No 7: the overall withdrawn However, the patients therapeutic efficacy of combined receiving 3 g of B3 showed a marked administration of nicotinic acid and statistically significant improvement pyridoxine as an adjuvant medication in "All the patients were then given very chronically hospitalized schizophrenic large doses of methionine, 20 g per day, patients is inferior to the overall thera- along with their continued medication of peutic efficacy of the component drugs 3 g of B3 or placebos The hypothesis "This summary is a completely in- tested in this experiment was that accurate description of the actual find- methionine, which has been shown to ings in the study The results which were worsen the symptoms of schizophrenia, actually obtained and reported in the might exert this effect because it is a published research paper were the methyl group donor B3 , on the other following: hand, is a methyl group acceptor. It was " In this 48-week placebo-controlled hypothesized that the effectiveness of B3 study, the therapeutic effect of a in schizophrenia results from this combination of nicotinic acid and characteristic of the molecules of B3; pyridoxine was compared with that of that is, B3 might remove methyl groups treatment with either nicotinic acid or from some methylated compounds in the pyridoxine alone Of the three indices of body which could be causing the mental therapeutic effects, global improvement illness in psychopathology (BPRS and NOSIE) "After the administration of 20 g of scores was seen in all three groups; the methionine per day, all the patients number of days of hospitalization during showed a pronounced worsening of their the period of the clinical study was lower symptoms The Task Force Report has in both the nicotinic acid and the interpreted this as showing that nicotinic combined treatment group; and only in acid does not neutralize the methyl- the combined treatment group was the donating effect of methionine in daily average dosage of phenothiazine worsening schizophrenia This con- medication decreased. Thus, improve- clusion, however, is not justified, ment in all three indices was noted in the because there was a serious flaw jn the combined treatment group experiment The patients were given 20 g

27 of methionine per day, but only 3 g of not wish to continue the controversy. nicotinic acid Over 16 g of nicotinic acid Apparently the editorial board believed is required to accept the methyl groups they had already given too much space donated by 20 g of methionine. The to orthomolecular psychiatry. experiment was bound to fail "Sir: "This flaw was acknowledged in the "In a recent reply to my letter, Ban original published research report as well (1975) has retracted his earlier con- as in an official summary of it. The flaw is clusion Nicotinic acid failed to prevent not acknowledged or even mentioned in by prior administration or to relieve by `. the Task Force Report The only valid subsequent administration the methio- finding emer g ing from this study is that nine-tranylcypromine-induced exacerba- B3 not only forestalled the deterioration tion of psychopathology (Ananth et al., anticipated when tranquilizer medica- 1970, Canadian Psychiatric Association, tion was withdrawn, but it produced a 15, 15-20, 1970) He had in the body of ft significant improvement in the patients this paper recognized that 3 g of treated with it This finding is not nicotinic acid was totally inadequate to mentioned in the Task Force Report." counteract any methyl-depleting effect Methionine binds pyridoxine which is which could be ascribed to methionine. essential for the conversion of try- But having recognized this he should ptophan into coenzyme one, nicotin- have concluded that his experiment was amide adenine dinucleotide (NAD). The irrelevant and trivial and added nothing injurious effect of methionine is there- whatever one way or the other to any fore easily explainable It would be methylation hypothesis However, Ban almost a miracle if any quantity of finds it very hard to admit he has erred vitamin B3 could compensate for a and attacks the problem from another methionine-induced pyridoxine deficien- direction Although this recent idea of cy his does not appear anywhere in his w J. Hoffer therefore concluded (Page original paper, he now concludes that : 28): nicotinic acid had a negative therapeutic "In summary, three of the five CMHA effect on the two toxic drugs he had studies provide evidence to support the given his patients in large dosages findings of orthomolecular psychiatry. It is interesting to read again his The Task Force Reports description of original paper This I urge every reader to every study is biased and misleading It is do To help them follow the reasoning of ) remarkable that the authors of the report his earlier work I have subjected his make incorrect claims that B3 is worse paper to a critical scientific look than a placebo, putting the most In this paper, 20 chronic patients were ii negative possible interpretation to some divided into two groups of 10 each The: : equivocal research findings, while not 10 destined to receive nicotinic acid , even mentioning the research findings consisted of seven men and three that showed B3 was of clear definite women The control (placebo) group; benefit " consisted of three women and seven Recently, one of us (AH) criticized Ban men This immediately shows that his, (1975) for repeating his claim that randomizations had broken down and nicotinic acid did not protect patients that the experiment no longer met the against toxic doses of methionine. In his rules of double-blind methodology The reply he produced a new objection whole experiment should have been claiming that patients on a combination scrubbed, especially by a group so keen; of nicotinic acid plus methionine and the on methodology as Ban and his col -t amine oxidase inhibitor deteriorated leagues In effect the nicotinic acid; more The following letter was submitted group were male and the placebo group to the Journal of Psychosomatics, but female they did not want to publish it as they did In his introduction he ascribed to us-

28 incorrectly that we tested a hypothesis nicotinic acid) eight improved and two that nicotinamide would prevent excess deteriorated (P < 0 02) Out of the female methylation In fact, the hypothesis we group six deteriorated and two improved tested was that the addition of vitamin (There is however some confusion since B3 to the current treatment program these figures do not agree with Table 3 (then ECT and psychotherapy) would nor is it clear which scale is being used to improve the outcome, and it did We evaluate response) (P < 0 05) then described a large number of It is clear that in a group of mostly hypotheses to explain how it could work, male chronic schizophrenics who and the methylation idea was one of needed neuroleptic drugs all the time" them It was also one of our ideas (quotation from Ananth et al ) nicotinic (among a number of others) which led to acid not only prevented a relapse, but our first pilot trials in 1953 These produced an improvement They had not preceded our double-blind experiments reported for these patients on neuro- in 1953 to which Ban makes no leptics only The placebo group deter- reference He leads the unwary reader to iorated as one would expect believe we did not do double blinds We For the next two weeks the entire were the first psychiatrists ever to do group were placed on the amine oxidase them as is clear from our 1957 paper to inhibitor tranylcypromine, 30 mg per which Ban refers clay But there is nothing in the report to Then Ananth et al (1970) claim their indicate what happened to the patients experiment was double blind It was not For the next four weeks all the patients It is impossible to double blind any study were placed on 20 g of methionine per with nicotinic acid as any physician who clay has used it knows The initial dramatic But according to Ananth it was flush usually (but not always) recedes maintained for one week in six patients and is seldom troublesome, but nearly and for two weeks in another four That every patient on maintenance medica- is, half the group were dropped out tion even for many years will flush now before completing the four weeks This and then, especially in the morning with means (also not mentioned by Ananth) the first dose The flush is unmistakable that the same 10 were no longer on the by the flusher and anyone who sees it amine oxidase inhibitor Nowhere is Therefore, it cannot be double blind In there any indication which group, the our first experiment we used three nicotinic acid or placebo group, had the treatments, placebo, nicotinamide, and greatest number of dropouts. Therefore, nicotinic acid in conjunction with ECT if any meaningful evaluation is probably needed and with psychotherapy No one impossible in the unit knew that nicotinamide was The last period of four weeks the included and as it does not produce a original male nicotinic acid group were flush it was not detected This, then, was switched over to placebo while the a true double blind original placebo female group were l3an is well aware of the fact that you started on nicotinic acid cannot blind nicotinic acid because in In the female group (on nicotinic acid his first unpublished protocol he called it for the first time) the deterioration a semi-blind experiment No matter what started by placebo at the beginning of he called it, it was not blind, nor was any the study and intensified by toxic doses evidence published that it was It is of methionine was not reversed by strange that in studying the effect of nicotinic acid toxic quantities of methionine he did not Seven patients continued to deter- use a placebo comparison iorate and three improved From the After a two-week drug wash-out original male group (on nicotinic acid) period, the male group were placed on the original improvement caused by nicotinic acid and the female group on nicotinic acid and reversed by toxic placebo Out of the male group (on doses of methionine was not reversed by placebo These results are shown in the of methionine-homocysteine We have, following table taken from Ananths own therefore, two possible ways by which results: methionine is toxic Yet Ban continues to use his early study as an argument worse no change better against vitamin B3 as a therapeutic agent a Patients originally on for schizophrenia. vitamin B3 and finally 6 1 3 The only reasonable conclusion from an placebo his entire paper is that it was poorly conceived, badly executed, poorly b Patients originally on placebo and finally on 7 0 3 reported, and faulty in its conclusions. vitamin 03 As I have said earlier, it is irrelevant and trivial to the orthomolecular controversy It seems to me that these groups are not and serves only those who refuse to read significantly different in terms of their the original papers pro and con and who response to placebo and nicotinic acid prefer to be led by authority and not by However, Ban writes, "Furthermore, it scholarship was noted that after discontinuation of The table on page 31 details the both tranylcypromine and methionine treatment, patients, and indices of administration there was deterioration change used by Ban and Lehmann and with nicotinic acid and some improve- those we used ment with placebo within a two-week Yet the committee can write, "The period " "It is this negative therapeutic negative findings in these carefully effect of nicotinic acid and not the lack controlled studies are clearly at variance of prevention of methionine-induced with results claimed by megavitamin exacerbations in schizophrenic patients proponents " It would be surprising that we keep on stressing, something indeed if the Ban-Lehmann studies could which Dr Hoffer systematically and have come to any other conclusion since )? consistently chooses to ignore " they used chronic patients mostly (even In other words, Ban bases his entire if newly admitted) without ECT for those case on the fact that with nicotinic acid for whom it was indicated and did no „ (given to the original female placebo follow-up studies Had we done our group), seven were made worse while in original studies the way Ban-Lehmann the other group only six were made worse did we would have undoubtedly come to and one showed no change their conclusions Is there any reason why this finding It should also be made clear that even should not be ignored? Had the one though they claim their studies were i,i patient changed from none to deteriora- double blind (Ananth et at , 1973), it is tion the results would have been identi- impossible to keep a patient on nicotinic cal acid unaware of the fact he flushes now Finally, Ban ignores the fact that and then and equally impossible to methionine binds with pyridoxine and prevent nurses or other staff from seeing.; produces a pyridoxine deficiency This the flush when it does occur They ( would be worse the longer patients realize they are on weak ground and , remained on the amino acid. Why would most often refer to placebo-controlled`` anyone expect vitamin B3 to compensate studies, thus lulling the unwary reader for a vitamin B6 deficiency induced by into believing these studies were double;: methionine? blind In our first double blind we used; Beaton et at (Biol. Psychiatry 10, nicotinamide as a hidden control, i e,; 45-52, 1975) found that methionine no one knew it was being used. In our;,: decreased REM sleep in rats and mice second study we did not use it, but told which was not reversed by nicotinamide everyone we were including it Thus ourM Their experiment suggests that meth- placebo and nicotinamide groups were: ionine does not increase methyl groups, true double blinds and the second was; but that the effect is due to a metabolite also by inference No attempt was madet;

30 newly admitted mostly chronic

Study C3—30 Study 14—30 Study f1—30

psychiatric ward in general hospital

previous treatment reported

treatment vitamin B3 plus vitamin B3 and ECT as indicated tranquilizers

double blind with no hidden control. therefore hidden control not double blind; original plan used term semi-blind

criteria for improvement nl number times re- ttl duration of first treatment hospitalization hospitalization

121 duration of re- 121 improvement in scales hospitalization

131 clinical improvement 131 amount of tranquil izer used Per day

It

in these studies to make them really obesity, and other toxic changes pro- double blind Finally, they presented no duced by tranquilizers we are delighted evidence that the code had not been we have only to deal with a few cases of broken by patients or staff, something nausea, flushing, and so on produced by surely that no modern double-blind vitamin B3 . methodologist would fail to do Claude Bernard emphasized in clinical In a recent report Ban and Lehmann experiments activities likely to harm and (1975) caution physicians against the use unlikely to help are by definition of these dangerous vitamins invoking the excluded In the Canadian experiments Hippocratic oath, primum non nocere of Lehmann and Ban this simple This is rather surprising when one reads condition was omitted and the omission their report #12 wherein they showed was so flagrant as to throw doubt on the that schizophrenic patients who were good sense, the fairness, and even the improved by nicotinic acid were then humanity of the experimenters This given a combination of a monoamine occurred most obviously in the experi- oxidase inhibitor plus a toxic dose of ment where chlorpromazine was with- methionine, 20 g per day, and so made drawn and the patients were placed on worse One wonders about the ethics of niacin At the end of the period of this workers who in the name of science phase of the investigation those on allow patients to be made worse while niacin had improved and those on trying to frighten physicians away from a placebo had become worse. The ethical vitamin considered safer than any tran- experimenter would then have given quilizer presently available. When we those on placebo niacin which was recall the cases of tardive dyskinesia, exactly what we did in our second niacin jaundice, incapacity to function, double-blind study Failure to do this was scientifically unsound for more infor- There are several means by which mation would have been gained this way, methionine could make patients worse: and morally inept What Lehmann and (1) by binding pyridoxine and producing Ban actually did was scientifically idiotic a deficiency of this vitamin, (2) by and morally reprehensible. It is incon- increasing homocystine ceivable that their mentally ill patients Thus, Beaton et al (1975) found that would have agreed to their second stage methionine produced behavioral and had they been in their right minds We do sleep cycle disturbances in rats and mice not believe their relatives would have which were antagonized by I-serine but agreed and no legal guardian could not by I-histidine or nicotinamide possibly have consented If the Canadian Apparently an increase in methyl groups _`: Mental Health Association associates was not a factor In their experiments j. itself with such an experiment then nicotinamide increased rapid eye move- `; public support should be withdrawn. ment sleep in contrast to methionine What happened was this The patients which decreased it who had been improved by the minimal We still believe the transmethylation (3 g) doses of niacin even though their idea is worth examining although it is tranquilizers had been withdrawn were likely to be only one possible factor It , given 20 g a day of methionine There was first proposed by Osmond and was ample evidence that this amount of Smythies (1952) Kety (1967) was in- methionine made many schizophrenics terested in this hypothesis, but it always `; worse and there was none that any had seemed to bother him that no trans- been benefited by it Under Bernards methylation hypothesis can ignore rules it was a disallowed experiment vitamin B3 However, with a simple However, as Linus Pauling has stroke of the pen, Ban and Lehmann , emphasized even supposing one ignores (1975) have solved this problem for their;.; the ethics of the experiment and can colleague who is equally determined separate them from its scientific value never to allow additional adequate this was scientific nonsense The 3 g of clinical trials to be carried out by; niacin were substituting very successfully establishment centers Ban et al state, for the withdrawn chlorpromazine, but In 1967 Kety formulated the trans-f there was no reason to believe it could methylation hypothesis of schizophrenialja possibly cope with 20 g of methionine It by shifting the emphasis from the" says much for the ethical insensitivity psychotoxic compound produced byx and scientific obtuseness of the APA Task faulty transmethylation to the bio Force that this reprehensible experiment chemical process itself " By this they; seems to be well accepted by their hope to entrench Kety as the originator,; committee of the transmethylation hypothesis In their earlier reports Ban and However, to a biochemist, this statement!. Lehmann were convinced that the in- by Ban is meaningless The object of any ? ability of 3 g of niacin to reverse 20 g of biochemical reaction is the transforma-, methionine disproved a transmethylation tion of one molecule into another Only"; hypothesis and so removed a theoretical a molecule can be harmful, not the= rationale for the efficacy of vitamin B3. process of its formation They no longer follow this line of reasoning, but maintain that the niacin Pellagra, Schizophrenia, and the aggravated the toxicity of methionine Question of NAD compared to placebo An examination of The committee as usual finds that: ` their published data does not support speculations offered in 1957 for theme their conclusion There appears to be action of vitamin B3 are contradicted bya` little difference for methionine with other hypotheses considered 13 years tranylcypromine was toxic with or with- later In fact, no one knows why vitaminn out niacin [33 works and this will remain unknownf until research in this area is greatly attempts to replicate his findings have expanded resulted in a decrease of interest in the The argument that schizophrenia and nicotinamide adenine dinucleotide pellagra are not identical is spurious question " There is a wide overlap Many pellagrins The NAD problem was brought into a in southern mental hospitals were con- different light, however, by the system- fused with schizophrenia, and around atic studies of Pfeiffer and his collabora- the turn of the last century the dif- tors (1968) In combining the clinical ferential diagnosis included pellagra and with the electroencephalographic dementia praecox This is reviewed in a method, Pfeiffer and his group were able chapter in Orthomolecular Psychiatry to demonstrate that an enteric coated (1973) which the committee did not read NAD preparation does exhibit a thera- (at least they did not refer to it in their peutic action Pfeiffer et al s (1968) long polemic) See also Hoffer (1970) findings indicate that the claims about There is no doubt that pellagra produces the clinical effectiveness of NAD therapy a schizophrenic syndrome need to be further investigated with The committee then zeros in on our contemporary methods." nicotinamide adenine- dinucleotide Recently, Liebow and Rothman (1975) (NAD) studies First, they point out no reported that intact digestive enzymes studies have ever been published re- can be absorbed by the intestine and lating NAD blood levels to schizo- resecreted by the pancreas. They phrenia But they then fail to add that the specifically studied chymotrypsinogen, a relationship between blood NAD levels very large molecule, much larger than and pellagra is not good There are two NAD They further report that the main nucleotides: (1) the mononucleo- intestinal epithelium is permeable to a tides which are inactive as enzymes and variety of proteins and they list a number (2) the dinucleotide In pellagra even of references for this observation begin- though total nucleotides are in the ning in the year 1958 If such a large normal range, there is a significant molecule can pass through the intestinal increase in the mononucleotide fraction cell walls intact there is no reason why There are no studies showing how these NAD, a much smaller molecule, should substances are distributed in schizo- not pass through. And if it can pass phrenic red cells. Unpublished work by through into a cell there is every reason Philpott (1973) does show that schizo- to believe it can pass into other cells also phrenic erythrocytes in many patients are as needed The problem is to place NAD lower and that a vitamin B3 treatment far enough into the intestine to avoid the improvement coincided in time with enzymes of the stomach and the upper restoration of normal total nucleotide part of the small intestine This is why levels We would expect that schizo- special preparations must be used phrenic red cells contain too much Thirdly, they falsely state that the NAD mononucleotides and too little of the studies we published were thoroughly dinucleotide, NAD This has yet to be refuted by several groups We will now examined. show what we did and what these other Secondly, they state that NAD cannot investigators did penetrate into cells on a priori grounds Most scientists know that even the best a Our Studies priori reasons must give way before the We used a number of acute and facts Apparently, Ban was once aware of chronic schizophrenics, not chronic this since in 1970 he wrote, "In spite of patients only as the committee stated the challenging theoretical considera- Our exact words were, "In this study tions based on animal pharmacological NAD was given to a wide variety of studies and Hoffers (1966) positive schizophrenic patients who had been ill therapeutic results, the unsuccessful from six months to 30 years " This study was done at University authors tried to test out NAD. The first Hospital, Department of Psychiatry, one was a study by Kline et al (1967) Saskatoon, Saskatchewan in 1966 One Kline used a number of chronic patients patient had been transferred from a who had been in the hospital for many mental hospital, Miss A N., the rest were years The committee conveniently either inpatients or outpatients None leaves the word chronic out even though had been chronically incarcerated in Kline had it in the title of his report. Kline mental hospitals even though they had also used his own preparation of NAD been ill for a long time which was impure and which could The NAD was a specially prepared hardly have survived passage through the enteric tablet in an oily medium The stomach Although the committee contents were designed not to be referred to HOD tests, Kline, in fact, did released for two—three hours after they not accept the conclusions of the HOD were swallowed We found that out of 18 which showed that the four patients on patients of whom six were much NAD had marked decreases in HOD improved and two improved before paranoid, perception, and total scores receiving NAD, 11 became well in a few while four patients on placebo showed weeks (some in a few days), three much no decrease in HOD scores Pfeiffer improved, and four improved When we found that Klines preparation showed ran out of supplies of NAD within a few very slight activity on the quantitative weeks all the patients reverted to their EEG compared to our preparation earlier state Miss A N , as we reported, Gallant et al used the same NAD, but as was remarkably improved and this was he stated used a group of chronically witnessed by the psychiatrist who had incarcerated patients The other three if known her best, Dr M. Herjanic As long studies are irrelevant since we did not use as she was on NAD she remained well I V NAD Thus, it is clear that so far no } When we ran out she relapsed There was one has used the same two factors as we =` never any improvement thereafter even did, i.e , (1) a good preparation of NAD, (2) a group of acute and chronic cases for a day until she died in the mental i hospital a few years later who had not been chronic inmates of i We thus used a specially prepared mental hospitals They were typical NAD on a variety of acute to chronic psychiatric ward patients commonly cases of whom only one had been a admitted to general hospitals in 1966 chronic mental hospital schizophrenic The differences in the studies are There were a few studies where the shown in the following table:

Hoffer and Osmond Kline Gallant

Preparation a special commercial his own preparation same as Holler preparation

Patients acute and chronic. not chronic mental chronic mental chronically incarcerated hospital patients hospital patients in mental hospitals

In our report (1966) in reply to Kline we sulated in a heavy enteric coat, Canadian}:. wrote, "Because NAD is hydrolyzed Patent #670, 909—1963 It was released; readily by phosphatases in the digestive two to three hours after being swallowed tract, NAD given orally probably will be Earlier studies by Enzomedic Labora Thiiii inactive unless it is prepared in a special had shown that this preparationr form that will carry it into the intestine, was active in many patients when: where this destruction is minimized In unprotected NAD was not active the research reported in Enzymology of "Since Enzymology of Hallucinogensi Hallucinogens the material was sus- was written, we have given 1 g doses, pended in a special vehicle and encap - dissolved in water or placed in ordinary}

34 capsules, to a schizophrenic patient who is of little relevance to the pragmatic had responded dramatically to the question, does vitamin 133 work. It is of original NAD; there was no clinical immense theoretical significance, but response Then she was given 1 g per day not of practical value in the megavitamin of the original NAD; once more she B 3 debate NAD is not nicotinic acid or responded and remained very much nicotinamicle even though many psy- improved for nearly six weeks when, chiatrists are not aware they are dif- there being no more NAD, she quickly ferent relapsed and is still ill "This difference may explain the The Diagnosis of Schizophrenia findings of Kline and co-workers who It is not unusual for psychiatrists to found no response in 10 chronic schizo- play the diagnostic game if this will save phrenics They used NAD placed in their own hypothesis This is a problem si mple enteric capsules; in addition, it we have encountered since we began our was 70 percent pure and produced research. In 1953 one of the patients vasodilation (flush) in several cases, admitted into our double-blind control- indicating that free nicotinic acid was led experiment was screened in the usual present However, on the HOD test, way His psychiatrist diagnosed him to be completed by eight of their total group of paranoid schizophrenic and this was in 20 (four on placebo, four on NAD), there agreement with the clinical director AH was no change in scores with placebo, as Director of Research also concurred but the HOD scores decreased as follows: After two weeks on medica- tion he was nearly well whereupon his psychiatrist maintained that since Paranoid scores 575 to 3 25 schizophrenics cannot recover so quickly Perception scores 14 to 1.75 Total scores 63 to40 he was not schizophrenic As a result he did not follow medication at home and soon relapsed to be admitted in an "It is not possible, therefore, to acutely paranoid psychotic state re- determine whether their lack of clinical quiring a series of ECT plus nicotinic response was due to a form of NAD that acid On decoding we found he had been did not survive passage in the gut, or on nicotinic acid He remained well for whether they used too little, or whether it 13 years with no medication, relapsed was due to the chronicity of their and required two further admissions after subjects All of our series of 17 were a near-fatal suicide attempt On vitamin chronic, but only one had been severely f33 he recovered in 1966 and has injured by many years of continuous remained well ever since. Time sub- hospital treatment " sequently removed all doubt about The committee apparently did not read diagnosis. this addendum Recently a recovered schizophrenic on Finally, the committee finds it interest- vitamin therapy applied to an eastern Ivy ing no additional studies have been League medical school He honestly reported This is due to the fact we have described his illness and recovery fully been unable to obtain any more NAD expecting he would not be accepted To The Kline report effectively killed any his surprise he was. The admitting interest that drug companies might have committee told him that since schizo- had and none have been willing to invest phrenics never recover he could not have large sums of money in any further been schizophrenic This is the game—if studies If and when we obtain more you recover you obviously have not been supplies we will be the first to renew our schizophrenic The committee plays this studies We found it less interesting and game well Wittenborn had such a more annoying. careful screening system that a few However, whether or not NAD is patients believed to be schizophrenic finally established as a therapeutic agent were later rejected Later from this purified group he found 24 who as a Mahood (1963), but did not bother to group did respond well (half on placebo refer to a subsequent paper when thei ;f+ got worse on tranquilizers), but since errors and inconsistencies of this paper:; they did do well he assumes they could were discussed (Kelm et al , 1965) not be schizophrenic, following the As with so much of the committees ;I committee rule, "if you recover you are report there was a rigorous avoidance of not schizophrenic " a searching analysis of all the HOD At the bottom of Page 24 the reports The fact that they were able tos committee repeats its false assertion that find only one negative report compared 4 CMHA studies were negative We will not to over one dozen positive reports repeat the counter claims which have indicates that there has been a rather= already been discussed. widespread use of this simple test The second paragraph of Page 25 is a The mauve factor work is reported in z totally misleading account of our work an equally biased way In our first papers This would have been obvious to anyone we reported that the presence of mauve= who has consistently and accurately read factor cut across all diagnostic groups,;.=! our reports Our criteria for diagnosis but the committee tries to leave the::„ have consistently remained that used by impression we claimed it as a diagnostic; most psychiatrists The HOD test was test invariably related to schizophrenia always an adjunct, never primary We Thus, it is not surprising that "other have not run any more double blinds workers (90) (OReilly et al ) found the because having directed four of them mauve factor to appear across diagnostic;: there comes a point where further classes " OReilly was our colleague and repetition is wasteful of time and money under our direction set up the laboratory" and does not convince One properly run to run mauve factor assays at his;., double blind which truly reproduced our hospital original double blinds by Ban and The committees basic premise seems: Lehmann would have been more to be that none of the orthomolecular valuable than a dozen double blinds run research is of any value Therefore, they" by us We have never depended upon grasp at any research, no matter how; either HOD or mauve factor for any of badly done, which supports their our double-blind experiments In fact, and they call upon any theoretical idea?: our first two were completed before the no matter how wild which supports; mauve factor was discovered and the them This they have done with their HOD test developed brief examination of the mauve factor re-22 The committee then devotes Pages 25 search They ignored all the work; to 35 to discussing the HOD which is reported from Dr Carl Pfeiffers laborat gratifying as it may arouse interest in our tory relating mauve factor (kryptopyr test (as it has already done), but is a role) to loss of pyridoxine and zinc complete waste of space since we did not None of the early workers with mauve= do HOD testing in any of our double- factor had suggested that it was an=i blind experiments endogenous hallucinogen because it had There are, however, a number of false not been tested The committee antici ` assertions about the HOD test such as the pated such a conclusion and on a priorBi statement it has never been studied for grounds concluded it was quite unlikely`, validity and reliability Each test kit it had this kind of activity They also, contains a manual which carefully based this on Sohlers findings, that it, describes these aspects of the test. Over sedated rabbits This is another example; 3,000 test kits have been sold, but of the committee s propensity to seizey apparently not to any member of the upon observations to bolster their own,, committee Had they inquired from us preconceived conclusions Recentlyr we would have advised them of the Walker (1975) concluded that "kryptop- presence of this data They referred to yrrole decreased EEG voltage, disrupted`=.. one negative report by Stewart and synchronization and induced abnormal;

36 spiking at a variety of cortical and schizophrenia these are nonetheless used subcortical sites Intermittent periods along with unspecified clinical criteria and low frequency hypersynchronous for the diagnosis of this illness, the EEG activity were consistently elicited by initiation of treatment and the assess- kryptopyrrole These waves bear a ment of improvement " Each reader will resemblance to the hypersynchronous have to determine the accuracy of these EEG pattern associated with hallucina- conflicting views by reading the litera- tory agents such as LSD-25 Marked ture. There is no substitute for reading behavioral alterations were observed the literature oneself following the initial injection including On Page 36 there is another typical ataxia, hyperventilation, locomotor misstatement Before modified ECT came depression, and catalepsy Kryptopyrrofe into general use we did use ECT as did causes major central nervous system everyone else, unmodified, but when it dysfunction and these findings are came into general use it became part of discussed in the context of a drug- the entire orthomolecular program induced model of psychoses " In his final paragraph Walker con- Quantitative Aspects cluded, "Hoffer and Osmond have The arguments in the last paragraph proposed that mauve factor now Page 40 and in the first paragraph Page 41 believed to be kryptopyrrole represents have been effectively answered by a metabolic anomaly that is associated in Pauling (1974) an etiological fashion with certain Their discussion on toxicity is bizarre psychiatric conditions, particularly to say the least. If the committee had schizophrenia They maintain that the found real evidence for toxicity they disappearance of this biochemical would have shouted it to high heaven anomaly is statistically associated with Had they treated the toxicity of any psychiatric improvement The results of commonly used tranquilizer in the same the present study strengthen the Hoffer- way they would be ethically bound to try Osmond hypothesis by demonstrating and force it off the market j Hoffer has that the introduction of kryptopyrrole adequately replied to their biased into the mammalian body is behaviorally reporting It is important to remember and electrophysiologically disruptive. that as codiscoverers in 1954 of the The abnormal behavioral reactions and hypolipidemic properties of nicotinic EEG patterns associated with kryptopyr- acid we have had more experience than role provided evidence that this com- any other physician with the potential pound has a serious detrimental effect on side effects and toxic reactions The first normal brain function " reviews of these aspects were ours, This report by Walker effectively appearing long before any member of the demolishes the committees speculation committee was even aware of our that kryptopyrrole could not be an vitamin B3 work (see Hoffer, 1962) endogenous hallucinogen It has, so far, not been tested on humans, but in view Conclusions of Walkers report we doubt whether Our criticism of the committee and members of the committee will be their report is that: (1) The committee rushing out to try it out on themselves was in composition biased, failing to We trust that after digesting our ob- contain anyone who was familiar by jections to the methionine study they will personal experience with orthomolecular not be tempted to use it on unsuspecting therapy Not only was the composition patients incompatible with fairness, it could not This statement on Page 35 is a typical possibly even seem to be fair (2) The committee falsehood: "Although the procedure used by the committee failed evidence suggests that both mauve test to insure any objectivity or fairness for: as employed by Hoffer and the HOD test (i) they did not obtain any evidence from are not reliable for the diagnosis of anyone using orthomolecular therapy; (ii) they selectively examined the litera- amide when used as an adjunct to ture using the rule that any double-blind conventional therapies such as bar- study or allegedly double-blind study biturates and ECT as reported earlier by (even if it were not like the Witten- Hoffer may have a beneficial effect in the born and Ban studies) was evidence if it treatment of some patients suffering yielded negative results while conversely from acute early schizophrenia As far as no clinical study if positive was is known, no attempt has been made to scientific The four original double-blind duplicate these earlier studies (2) Mega- studies from Saskatchewan were suspect vitamin therapy has not been demon- since we did them, so were not evidence; strated to be generally efficacious in the (iii) the report is characterized by treatment of the vast majority of chronic falsehoods, direct and by inference, by schizophrenic patients. biased statements, by use of brief He concludes, "Orthomolecular psy- sentences taken out of context, by chiatrists should be invited to return to omissions which always favored the the forum of conventional psychiatry in committees view; (iv) the report was order that they might be given audience written in order to bolster the com- Their articles should be submitted to mittees negative conclusion conventional journals and should be received with the same enthusiasm and Unfortunately, the committee was cordiality as other submissions, provided correct in their assumption that most the general criteria of the journal are psychiatrists who read their report would met " accept it at face value and would not check their references The report has This is the first comment in any had a pernicious effect in dampening psychiatric journal where an attempt is interest in orthomolecular psychiatry made to be fair The editorial writer is not While this will not hurt any ortho- fully aware of the degree of misinforma- molecular psychiatrists it will condemn tion and bias in the committees report, hundreds of thousands of patients to a but he has achieved adequate awareness lifetime of tranquilized chronicity to reject the committees conclusions Fortunately, the number of ortho- Controversy is part of the history of molecular physicians is increasing medicine and is essential to it if medicine rapidly while the families of schizo- is to continue to advance There will phrenics become increasingly knowled- always be an establishment of ideas, geable about the illness and critical of some of which will eventually be proven the Establishments posture wrong Thus, there will always be a Community psychiatry, which is controversy affecting various parts of essentially an expensive system for medicine However, worthwhile though delivering tranquilizers to chronic it is, there would be a lot less emotional patients in various shelters, is coming controversy if physicians followed the1 more and more into disfavor Psychia- basic rule of science, i e , follow the trists are sinking lower and lower in both same procedures and conditions when: public esteem and in the esteem of their attempting to corroborate If this rule; nonpsychiatric medical colleagues The were rigorously followed it would not, printing and distribution by APA of a matter whether the scientist was positive report so bigoted and biased as the Task or negative about the study But since{ Force Report can serve only to drive the this rule is seldom followed it does: psychiatric profession lower in public matter a good deal If the investigator, esteem has a negative bias toward the original In a recent editorial in the Canadian work he will conduct his studies in such a>D Psychiatric Association journal W T B. way as to maximize the negative con- (1975) after summarizing the pros and clusions and will then discontinue them.t cons of orthomolecular therapy con- There are many examples of this from the cluded: (1) Nicotinic acid or nicotin- reports of hostile anti-orthomolecular

38 psychiatrists. If they had run their studies were twice as high in the treated group more scientifically and longer they would Twenty-five percent of the treated have run the risk of seeing positive group had abnormal ECG while only 4 conclusions. A scientist with a positive percent of the control group showed bias may make the same error But in similar abnormalities. general the error of the negatively biased To dramatize his objections Dr Moss psychiatrist is much more serious In our posed a number of questions: opinion the failure to use a treatment 1 How can one evaluate treatment in which is beneficial is much more serious patients who do not have the disease? to patients than the error of concluding 2 How can one evaluate a drug if only that a nonactive drug is active For in the 46 percent of the group have hyper- latter case it will soon be shown that the glycemia? treatment is ineffective, especially if it 3 How can one evaluate a drug if has to compete with other more useful one-half should not have been given it? treatments Destroying a useful treat- 4 How can one evaluate a drug when ment by sloppy hostile research may the wrong doses are given? prevent its reintroduction for several Our objections to the negative thera- decades This would insure that large peutic trials upon which the committee numbers of patients will have lost their leaned so heavily are the same How can chance and will be condemned to a one evaluate the benefits of a drug (or of lifetime of unnecessary ill health a treatment program) when only a small Moss recently (1975) was severely proportion of the groups used were of the critical of the UGDP studies on tolbut- kind that could respond, when the amide The results from these double- treatment program was not followed, and blind controlled studies indicated that when idiosyncratic criteria for improve- tolbutamide was more hazardous than ment were used such as milligrams of placebo for diabetic patients But Moss is tranquilizers required and number of in total disagreement with this con- days in hospital during which treatment clusion writing, "No amount of statistical was started manipulation can compensate for the Another controversy, this time in- erroneous conclusions that are drawn volving the drug propranol, aroused Dr. from a study in which one-quarter did Lasagna to write, "Some (speaking of the not have the disease, three-quarters FDA advisory committee) appear to should not have been given the drug, the have gotten hung up on the concept of wrong dose was used and the treated the totally satisfactory paper! The only group had twice as much pre-existing totally satisfactory papers are fraudulent.. cardiovascular diseases " "The value of Every experiment has deficiencies and any therapeutic agent should be judged the problem is to decide whether the by the benefits that are obtained when it deficiencies are so great as to render the is used properly and not by the harm that experiment totally useless " results when it is used indiscriminately " The committee has demanded that our Moss pointed out that 23 8 percent of experiments must be totally satisfactory, the treated sample did not have diabetes but have for obvious reasons not according to standard criteria, 54 percent followed the same impossible rule for had fasting glucose levels under 130 mg their own favorite papers percent and did not require tolbutamide, 50 percent were more than 33 percent They are unaware of Dr Samuel overweight and should have been treated Johnsons rule, "nothing will ever be by a lower calorie diet Only 27 percent attempted if all possible objections must of the entire group were proper can- first be overcome " They demand of us didates for tolbutamide treatment The that our first double-blind experiments dose was constant whereas it is generally started in 1953 should have anticipated accepted it should be increased with all the newer findings and complications time, and base line cardiac risk factors discovered many years later The last controversy concerns DMSO, done at Munroe Wing, (2) a group of recently discussed at the third DMSO studies undertaken at the University conference, New York Academy of Hospital, (3) Dr OReillys study done at Sciences, 1974 (see annals New York the mental hospital at North Battleford, Academy of Sciences, 1975) On the (4) Dr Densons study at North Battle- basis of flimsy evidence the FDA literally ford In addition to this, there is a great banned the use of DMSO Arthur L deal of clinical data from clinicians who Scherbel in his summary of the con- have used our approach for several tens ference stated, "This new policy resulted of thousands of patients This data is no in the abrupt discontinuation of clinical less important than the double-blind investigations of DMSO because of the studies on the grounds of sheer volume appearance of lens changes in certain alone The belief that double-blind " animals that were receiving high doses of studies alone are valuable is held by the DMSO This decision was made despite naive, whose knowledge of scientific the fact that no eye changes had been history and methodology is usually scientific method and were in otherwise competent people under- capable of evaluating published litera- taking experiments in a curious way ture The reader will judge whether Dr which they would condemn in their own 13usses evaluation and expectations were pupils, and would attack most vigorously correct We agree that the Task Force had orthomolecular psychiatrists been could have accomplished this task, but equally slack and heartless they did not do so Perhaps one day the In recent years political and scientific professionals involved in this debate will establishments have acted as if they ask themselves why this particular kind believed that they were above the law of mistake was made and how it can be and above scrutiny As regards politics, avoided in future. this is now becoming unacceptable and The bias of three members of the we must hope that the same will apply to committee was so open that one of us, AH, objected vigorously at the beginning his is the stance of an unbiased man of the survey The first evidence of this Why then did the American Psychiatric was Dr Morris Liptons lecture in Association show such faith in the lack of , California at a public meeting where he prejudice of those who had not con- openly stated his strong opposition and cealed their prejudice? bias against the orthomolecular ap- Where important matters are con- proach He also demanded that the cerned even the faintest suspicion of bias chairman, Dr. Ross MacLean, provide is usually sufficient to disqualify those him with more time than was allotted to charged with fair judgment We infer him or to anyone else, because he was from the absence of these customary; the only critic of orthomolecular safeguards that the main objective of the" psychiatry Task Force was to defend the establish- Since three of the five Task Force ment against our disturbing opinions A members made no attempt to hide their second and more respectable objective bias against orthomolecular psychiatry, was to protect the public against false: this raises serious questions about the hopes and mistaken expectations, for conduct of the American Psychiatric many members of the establishment had Association itself. How could a profes- become convinced from their deep sional and scientific body allow an knowledge of psychiatry that the ortho- inquiry, conducted under its aegis, to be molecular claims must be without merit.: undertaken in a manner which in any Any group with such good ends in mind> other circumstances it would have might behave much as the APA did, but, certainly condemned? Would the APA however praiseworthy their intentions,? countenance an investigation of psycho- actions of this kind have been a frequent analysis or community psychiatry using a source of error in medicine These good! task force the majority of whose intentions made the means to be used of members were openly prejudiced against lesser importance, so that the APA° these activities? Would the APA attach establishment became unable to adopt a `. any importance to the findings of such a judicial stance other than that of judge : committee, and would anybody be Lynch surprised if psychoanalysts and com- However honorable the goal the mean munity psychiatrists were unwilling to employed negated all favorable reports accept such a report? found in the orthomolecular literature: Why then did this Task Force and those and led the Task Force to ignore any who appointed it behave in a way which supporting evidence even when it was clearly open to criticism and even derived, as with Wittenborn, from experi censure? It would be poor taste to subject ments approved by the committee How our colleagues on the Task Force to that could this happen? In our opinion the;`: personal psychodynamic scrutiny which most economic explanation lies in the;, Senator Goldwater received about a atmosphere and ambiance of Washings; decade ago from some hundreds of APA ton during the early 1970 s = members However peculiar these It is now evident that at few times in activities may appear when set out in the history of the United States have print we do not ascribe them either to those in authority believed more sincere- personal psychopathology or to bad ly that this gave them license to use any faith There is no need to when three means to further ends self-evidently committee members have never denied good Bad habits in big governments] their bias spread to little governments The; Lipton did not reply to a letter American Psychiatric Association is the accusing him of being prejudiced and "little government " of psychiatry in the requesting that he remove himself from U S A In this matter the APA had the": his position of Chairman Mosher was support and cooperation of the National quite explicit about his point of view Institute of Mental Health, (1) a huge The reader can judge for himself whether bureaucratic organ of Big Government?

44 which has never disguised its dislike of chance to recover with orthomolecular orthomolecular psychiatry therapy Perhaps psychiatrists should ask them- The question of honesty in science has selves just how and why, in spite of their been discussed frequently in Science, a study of the mind and heart, they too publication of the American Association were seduced into a ruthless urge to for the Advancement of Science, and in employ massive authority against min- the public press Thus, Robert C Cowen ority opinion By yielding to this tempta- in the Christian Science Monitor for tion the American Psychiatric Associa- March 26, 1975, opened his report on tion became contaminated with that "Corruption in Science" with the follow- spirit of intolerance which was abroad in ing paragraph Washington at the time It is now often "Fear, fame and fortune seem to be called Watergate replacing the challenge of the unknown as the driving force of much that passes Appendix for scientific research " We have made a large number of There are two main types of corruption serious charges against the Task Force in science reporting Scientists may Report published by the American report data in such a way that it cannot Psychiatric Association Our main charge possibly be reproduced no matter how is that the committee had already arrived much one would wish to do so, or in very at their negative conclusions long rare cases the data may have been before they examined the literature entirely fabricated And in the second available to them and that they tailored way, the literature review around which the report in order to bolster their biased the report is built may be presented in a conclusions As science students we used manner calculated, not to provide a fair to talk about how some students cooked view of what has been done, but to prove the data, i e , manufactured the data a conclusion gained by other means necessary to support the conclusion they Cowens strictures against corruption in knew they would have to reach. This the science are supported by Marc Lappe in committee did by a selective examina- his report to Science Thus, Lappe wrote, tion of the literature, by avoiding ref- "Those who practice it know that the erences to most of the collaborative nature of the scientific enterprise itself reports, by downplaying or ignoring any hinges on the scrupulous integrity of its positive data in what they considered practitioners " reports favorable to their own point of In a memo to Hoffer dated March 27, view, and by so distorting and mis- 1975, Osmond wrote: interpreting data in our original work "Sometime ago I suggested in a memo as to turn our positive conclusions based that it was not fanciful to suspect that the upon our observations into their negative ethics which we saw at work during the conclusions These they based upon Watergate affair had not been confined tactics such as ripping statements out of to politics My particular concern was context, reporting from tables in a with the behavior of the APA Task Force misleading way, and generally con- and with its Canadian counterpart of Ban ducting themselves in such a way that no and Lehmann We know from our own matter how hard anyone familiar with the experience in Washington that high literature might try it would be im- federal officials have countenanced possible to have even the appearance of dubious behavior as regards our work scientific objectivity Scientific dis- We also know that the APA used its honesty is a serious matter, especially in house organ Psychiatric News to attack this case, to the hundreds of thousands our findings while refusing or being very of patients who will be deprived of a tardy about publishing our rebuttals. We also know from very unpleasant personal nl Two of the members of the Task Force were working for the National Institute of Mental Health. experiences that the APA ethics cam- mittee was used to attempt to dissuade is so unsound in one direction can you be us from discussing the megavitamin work sure of it in another? publicly. In the encounter that AH and I "The failure to report the breaking of had with that committee in the fall of the double blind at Marlboro was another 1970, it was evident that its members did error suggesting bias to even the most not know very much about our many well-disposed. Not being among the best published papers They seemed to disposed to the APA-NIMH junta I am believe that we had reported first to the inclined to take these signs at their face public, a habit only too frequent today value It would be a little improper in which, however, we did not do on psychiatry not to give one s adversaries principle Reporting first to the public is the full benefit and courtesy of psy- the scientific equivalent of the political chodynamic interpretations" leak and is used to steal a march on The grand strategy of the committee opponents It seems to have occurred in was to provide as much support as ` the notorious Sloan-Kettering affair possible for the conclusions they had "It is unlikely that so important an already arrived at before they began their activity as science can be apolitical: studies, namely, that orthomolecular apart from anything else its political psychiatry had no merit as a treatment consequences are so vast, but just and at its worst was a fraud Once that . because politics impinge upon it so strategy had been conceived the tactics heavily, that it is the duty of scientists to used followed logically, being based t insure that its morals and ethics are not upon the philosophy of the ends justify- eroded The politicians among scientists ing the means Their ends were to protect have always been there and some of the public from the evils, errors, and them have been magnificent scientists dangers they knew were inherent in Isaac Newton was a Member of Parlia- orthomolecular psychiatry Therefore, ment Benjamin Franklin was a marvel- any method, no matter how objection- ously adroit diplomat, while Benjamin able it might be in another context, Thompson, Count Rumford, was an would be permissible, even desirable extraordinary combination of soldier, Inherent in these tactics was then spy, traitor, gunmaker, and pure phy- assumption that they could get away={ sicist The important thing is that with it since very few members of the= although Newton and Rumford were American Psychiatric Association would`= difficult and cantankerous men they read the original reports with care and were not cheats and they were devoted diligence The committee naturally to science They strove to enlarge truth assumed that their own status and4 There is much evidence that the APA prestige as members of an APA sub-;" Task Force, far from wanting truth committee of a research committee` enlarged, much preferred that it be would satisfy the members of the APA::, suppressed Unfortunately, they were correct "Of the one-third of the patients who Several years ago at a press conference benefited significantly from niacin in the in New York City, arranged by the: Marlboro Study it seems a little bizarre to American Schizophrenia Association, Drat ti suggest that they were not really schizo- Linus Pauling was questioned about his

phrenic This suggests that those who views on ascorbic acid and the common;;) respond positively to niacin are thereby cold He was asked by a well-known" not schizophrenic However, if the science reporter, known for his advocacy NIMH study misdiagnosed one-third of of establishment medical views, why if their cases, why not the other two-thirds? ascorbic acid was so good in preventing "Bans use of large doses of methionine colds, was it uniformly rejected by most- comes in a similar category but worse physicians? Dr Pauling opened his reply= since it actively harmed people who were by stating, "I think I am the only person: improving on niacin If a mans judgment who has read my book " He then analyzed his conclusions that there was adequate evidence in the medical litera- ture to warrant research relating ascorbic acid to the cold and that he had made an attempt to draw this to the attention of medicine to encourage them to proceed with these studies We have often felt that we and other physicians practicing orthomolecular psychiatry must be the only ones who have read the ortho- molecular literature Our charges against the committees report are based upon what was written in the literature and how it was reviewed by the committee So that each reader can follow our argument in detail and check our conclusions we are attaching an appendix It contains the following information: (1) A brief abstract of all the reports which we have authored which deal with aspects of orthomolecular psychiatry. We also make a few comments with respect to the committees use of this information (2) A brief abstract of all the corrobora- tive reports mostly ignored by the committee (3) A reprinting of "On the Ortho- molecular Environment of the Mind: Orthomolecular Therapy" by Linus Pauling American journal of Psychiatry 131, 1251-1257, 1974 (with permission of the American journal of Psychiatry and at a cost of $100) (4) Dr Linus Paulings Comments on the Comments, American Journal of Psy- chiatry 131, 1405-1406, 1974 (5) Our comments on the comments by Wyatt, 1974, Klein, 1974, and Lipton, 1974 (6) Comments on Double-Blind (Place- bo) Methodology (7) Efficacy and Toxicity (8) Copies of letters to the American Psy- chiatric Association re Dr. M Liptons chairmanship of Task Force Report (9) Bibliography. (10) Reading list in Orthomolecular Psy- chiatry (11) Real attempts to corroborate with failure to confirm original studies. SECTION I— Brief Abstract of Orthomolecular Treatment by Saskatchewan Group

(1) Treatment of Schizophrenia with acid group It would be natural to assume ` Nicotinic Acid and Nicotinamide, A. that every patient who flushed would be Hoffer, H. Osmond, M. J. Callbeck, I. on nicotinic acid and every patient who Kahan (1957), did not would be on placebo, whereas: This was the first major report We one-half of the nonflushing patients were reported that a pilot study to determine on nicotinamide dosage, duration of treatment necessary, In our second double-blind controlled, side effects, and so on was positive and experiment we used only placebo and led to the double-blind controlled experi- nicotinic acid, but we had let it be known`..; ment on 30 schizophrenic patients This that this experiment would be run in was the second double-blind experiment exactly the same way as the first By this ever conducted in psychiatry We did the ti me we had uncoded the results of the` first on a yeast nucleotide preparation a first and reported them to the clinical; year before The groups receiving group vitamin B3 (some of whom received ECT) The rest of this paper summarized the? , fared much better than the placebo results of treatment on 73 other patients: group (an equal proportion receiving who were compared to 98 cases treated)) ECT) At the end of one year three out of in the same ward who had never receive nine placebo patients were well vitamin B3 From the 98 cases not given compared to eight out of 10 on nicotinic vitamins there were 49 readmissions toa acid and nine out of 11 on nicotinamideq hospital averaging 319 days per patient i. e , a one-year recovery rate of three out readmitted, and in 1956 seven were still of nine on placebo compared to 17 out of in hospital. From the 73 on vitamin B3, 21 on vitamin B3 Follow-up evaluations there were eight readmissions in they were conducted by a trained worker who same interval averaging 234 days per was not aware of the treatment code patient readmitted, and none were We were aware that it is impossible to hospital in 1956 i i t run double-blind experiments with We, therefore, concluded, when used nicotinic acid for the following reasons: in adequate dosages nicotinic acid and (1) It is impossible to prevent or disguise nicotinamide materially contribute to the the flush Even after patients become recovery of schizophrenic patients used to it they will now and then have a marked flush, especially in the morning, (2) The Adrenochrome Model and and will even more often have a pink Schizophrenia, A. Hoffer and H. Osmond glow. They are aware of these reactions (1959) and it is easily seen by any observer (2) It After discussing our hypothesis we tastes sour and no allowance can be wrote, "Nicotinic acid and its amide artl•, made for this For these reasons no claim methyl acceptors which when they are` for the blindness of any experiment using used in large doses may compete withj nicotinic acid can be accepted unless noradrenaline for methyl groups and sq there is proof these factors have been decrease adrenaline output This was oncr allowed for We, therefore, used a reason why nicotinic acid was tried for nicotinamide group This form of vitamin schizophrenia The results for early; B3 does not cause a flush in 99 percent of schizophrenia are good ; About 15 per the subjects But the staff were not told cent of our schizophrenic patients ` about this third hidden group They require daily administration of this expected that there would be only two vitamin and relapse a few weeks after groups, the placebo and the nicotinic stopping it It does not help chroniq-

48 schizophrenics even when such massive illnesses " The committee did not read doses as 25 g a day are given for three this paper months " The committee did not read this paper (4) Massive Niacin Treatment in Schizo- phrenia. Review of a Nine-year Study, H. (3) Schizophrenia: A New Approach, H. Osmond and A. Hoffer (1962) Osmond and A. Hoffer (1959) This was a general review paper In referring to our treatment we wrote, comparing results of adding vitamin B3 "This consisted of massive doses of to standard treatment before tranquiliz- niacin or its amide ranging from 3 to 25 g ers came into use ECT was the best daily " Table 1 from our recent paper treatment then and about half of the outlines our results. These are that while patients were so treated niacin seems beneficial in early schizo- The results of treating all schizo- phrenia and apparently reduces the rate phrenics treated at this ward (Munroe of relapse (one out of 37 vs six out of 36) Wing, General Hospital, Regina) when medication is continued, it is between 1952 and 1955 were given as usually ineffective in long-continued follows:

Number of Group N On ECT Number sent to Mental Hospital Suicides

Thus, out of 73 on niacin 66 were able readmitted (Chi Sq = P < 0 001) to remain in the community while out of We also showed the cumulative re- 98 on other treatment 51 were not admissions as follows:

Number of Readmissions . Group N 1952 55 1956. 57 195859

Between 1952 and 1955 the readmis- four out of 20 on other treatment (20 sions accumulated more quickly in the percent) From an earlier study, out of 58 non-niacin group, but thereafter the treated with niacin (many of whom also relapse rate was nearly the same We had ECT) 45 (78 percent) were five-year said, "It seems from this that niacin kept cures compared to 34 out of 90 on other the disease in check; but one can hardly treatment (many of whom had ECT), or expect such a protective action to 38 percent continue indefinitely " Most of the Finally, we compared treatment results original niacin group were not receiving on three groups treated by other any during follow-up We also reported physicians, none of whom had any that from our second double-blind study enthusiasm for vitamin therapy, and on vitamin B3, 34 out of 62 had achieved some of whom were actively hostile a five-year cure (55 percent) compared to

Days in hospital Discharge status N well on treatment. well and much last evaluation Group N admission I mproved in community On other treatment two out of 22 were Hoffer and H. Osmond (1964). well (10 percent), on ECT only 10 out of One of the few abstracts which is 26 were well (39 percent), while on the correct except the committee got the combination of niacin plus ECT 24 out of year of publication wrong, one of many 30 were well (80 percent) None of the editorial errors They dated it 1963 in the patients were seen by us, but we had body of the report and 1964 in their access to the hospital and follow-up references records We, therefore, concluded, "In our (7) Treatment of Organic Psychoses with view it is a useful adjunct in the Nicotinic Acid (a single case), A, Hoffer treatment of schizophrenia both for (1965) acute cases and to reduce the chance of A patient with an organic psychosis relapse; and we hope it will be tested on who had failed to respond to several a fairly large scale with a carefully medications recovered within 24 hours designed follow-up. For with niacin and after he was started on nicotinic acid and its amide, unlike the waters of Jordan, ascorbic acid The decision to begin this one can always try the Abanas and treatment was based on a chemical test Pharphars of the drug companies at the which showed he had mauve factor in his same time " urine In a further report, Hoffer (1970a) (5) Malvaria: A New Psychiatric Disease, reported this subject survived 34 months A. Hoffer and H. Osmond (1963) after his inoperable bronchiogenic In this paper we discussed the relation- cancer was established (diagnosed) The ship of the presence or absence of a last radiological examination before he mauve-staining factor in urine to diag- died showed no recurrence of the cancer nosis, treatment, and prognosis We The cause of death at age 76 was suggested the term malvaria for any probably coronary disease Unfort- person who excreted this factor Since unately, there was no autopsy The then it has been identified as kryptopyr- committee ignored the case role and can be measured quantitatively We also reported results of a brief (8) Malvaria and the Law, A. Hoffer; experiment on 24 retarded children All (1966b) were tested and then started on nicotin- One of us (AH) reported that out of 740 amide using 1 g per 50 pounds This dose, subjects tested for mauve factor in their we now realize, was too low The present urine, 14 had been charged with a variety recommended starting dose is 3 g per of crimes Of the group, 10 had mauve day We assumed that parents who saw factor in their urine This was a very high no improvement would not wish to proportion being similar to the pro- continue while those who did note portion of schizophrenics who test i mprovement would continue positive When the mauve-positive sub- The parents, of course, did not know jects were treated with orthomolecular the results of the urine test Out of 16 therapy most recovered and no longer mauve-negative children five remained were involved in further criminal on vitamins, whereas in the same interval activity Detailed case histories were out of eight children who were positive given The committee ignored this none were discontinued As a class report parents of mauve-positive retarded children were happier and more optim- (9) Biochemistry of Nicotinic Acid and istic about the results. Chi Square is 7 5, Nicotinamide, A. Hoffer (1967b). i e , P < 0 01, this is due to chance Here one of us (AH) presented a biochemical review of vitamin B3 in- (6) Treatment of Schizophrenia with cluding a discussion of side effects and Nicotinic Acid (a 10-year follow-up), A. toxicity There was little evidence it was hepatotoxic The fallacy of the abnormal Frequency and Duration of Re-Hospital- liver function tests was discussed. ization of Schizophrenic Patients: A "Nicotinic acid and nicotinamide are Controlled Comparison Study, A. Hoffer remarkably safe compared with the (1966) whole field of chemotherapy" was the In this paper one of us (AH) compared conclusion still valid today The com- the results of treatment by other psy- mittee ignored this paper chiatrists who sometimes used nicotinic acid against the results of their standard treatment on similar patients (10) The Effect of Nicotinic Acid on the Here were the results:

Treatment by N N Total Days in all Psychiatrists N Readmitted Readmissions Hospital Suicides

Nicotinic Acid 128 7.422 0

Other 346 54 491 6

1. The majority of chronic schizo- female patients" who had not responded phrenics were not benefited to any other treatment Tranquilizers had 2 The majority of acute patients given not come into use Mean duration of stay 133 responded much better to treatment in hospital was 16 years They were given when these vitamins were included than 3 g per day for eight weeks They were the comparison control group carefully examined and rated every week OReilly found that the patients (11) Nicotinic Acid Therapy and the improved significantly over an untreated Chronic Schizophrenic, P. OReilly control group of 43 patients (at 10 (1955) percent level) in the following areas: This is an important paper because it 1 Sleep improved in all patients has been used by opponents as an attack 2 Appetite increased in all patients on our work. Dr OReilly was then a 3 Directability was better in six. psychiatrist at the Saskatchewan Hospital 4 Initiative alone was better in five in North Battleford and was in charge of 5 Cooperation with routine was better research under our direction We en- in four couraged him to do this study and helped 6 Care of personal property was better him have it published It was important in three for it confirmed our observations that None of the control group showed any chronic patients such as those kept many significant improvement. years in the hospital did not respond We Three patients generally improved and hoped that publication of this report two histories were given to illustrate this. would protect us thereafter from the There was no improvement in delusions, recurrent attack on our work based upon hallucinations, and in other schizo- chronic patients; obviously it did not phrenic features. since even the committee persists in OReilly concluded, "While this trial confusing the reader does not show nicotinic acid to have any OReilly referred to three of the effect on the schizophrenic process per possible mechanisms of action of vitamin se, it is felt that nicotinic acid should be B3 including its role as a potential methyl further investigated in a larger trial acceptor He selected "eleven of the series " It is clear that we claimed no most refractory, regressed, deteriorated success in treating these cases even though their behavior was significantly any previous treatment They were better These are patients similar to those treated with our Phases I, II, and III given deteriorated, badly prepared NAD treatment procedures At the time this by Kline et al (1967). The committee report was compiled three were well or does not discuss this paper, but erron- much improved Today one of them, LR, eously refers to it among its ECT is still well, one, CS, refused to cooperate references with vitamin therapy and is today chronically tranquilized and ill. We have no report on the others (12) Some Schizophrenic Recoveries, A. We also reported the following results Hoffer and H. Osmond (1962) of treatment achieved by the research We described five chronic schizo- division on all patients treated between phrenics who had failed to respond to March 1, 1960, and March 1, 1961:

N Much Nsent to NSick I mproved Mental Hospital at Home

To mental hospital and their home

We wrote, "Well means that the patients are as healthy physically and mentally as they were before illness (13) Nicotinic Acid: An Adjunct in the struck them They are free of complaints Treatment of Schizophrenia, A. Hoffer and function normally at home and in (1963) the community Of 16 patients treated Here AH compared readmission data only with Phase I, a total of 14 are well or on all schizophrenic patients treated at much improved These patients were a University Hospital, Saskatoon, between better group prognostically than were the 1955 and 1962 They were all diagnosed other two groups From Phase I I a total of and treated by members of the staff not 16 patients are well or much improved connected with our research group All Two went to a mental hospital and one is standard treatments were also used still there From Phase III (i e , Phases I including ECT, tranquilizers, and and II failures) three are much improved psychotherapy Results are shown below: Thus 33 of 40 treated have to all intents

N N N Group N Suicides Readmitted Readmissions AH concluded, " Although many was used without any other component patients are so sick they will not recover of orthomolecular psychiatry on nicotinic acid alone, the majority of schizophrenic patients who have re- covered as a result of treatment with ECT (14) Nicotinamide in the Treatment of or tranquilizers will remain well if they Schizophrenia, R, Denson (1962) are maintained on nicotinic acid Denson selected from new or first "Since vitamin B3 is not toxic and is admissions and readmissions only those easy to administer I suggest that schizo- requiring ECT Out of 41 cases chosen, 36 phrenic patients (excluding those chron- were able to complete the study They ically ill in mental hospitals) are not represented about one-third of the total receiving the best treatment if this admissions vitamin is excluded from the therapeutic There were no side effects and the regimen " Earlier AH had said, "Chronic double-blind code remained unbroken. schizophrenic patients of the type found At the end of the year there was no in mental hospitals do not respond and significant difference, but eight months there is no point in giving them this later it was determined that group A had treatment " done markedly better than group B The The committee avoided this important code was then opened and it was found document, important since none of the that the treatment group had been the patients were under our care and at that group doing better time only nicotinic acid or nicotinamide Denson found the following:

Days in Hospital Hospital at 5th and 6th Months Group. ( Mean) In Out

Nicotinamide 1.064 1 16 Placebo 1.775 8 11

Significance 0 05 P c 0 01 005 P c 7001

The fifth and sixth months were on nicotinic acid would relapse if selected because one could not expect switched over to xanthine nicotinate. A five weeks on nicotinamide to exert its double-blind cross over design was used. effect forever as Denson put it Our conclusion was that the nicotinic acid derivative was just as effective in (15) Schizophrenia and Suicide, H. maintaining the patients Osmond and A. Hoffer (1967). As we have been accused of claiming In this report we discussed the high nicotinic acid was absolutely safe, we frequency of suicide among schizo- will quote here one of our sentences, "No phrenics which was about 25 times more medication is free of side effects and frequent than one would expect in any nicotinic acid and nicotinamide in mega- general population However, the suicide vitamin doses are not exceptional Most rate for patients treated with ortho- of the side effects are irritating and molecular methods was very much less inconvenient rather than toxic "

(16) Comparison of Xanthine Nicotinate (17) Childhood Schizophrenia: A Case and Nicotinic Acid as Treatment for treated with Nicotinic Acid and Nicotin- Schizophrenia, A. Hoffer (1969a). amide, A. Hoffer (1970) This was a study to determine if A single case is discussed patients already well or much improved

53 (18) Megavitamin B3 Therapy for California patients who recovered on Schizophrenia, A, Hoffer (19716) orthomolecular therapy They had not This is a general review article trying to responded to any previous treatment correct the many errors and biases then There was nothing unusual about this being promulgated by the CMHA studies report except that it set off a chain Apparently it had little effect since Ban reaction culminating in our appearance and Lehmann continue to publish as if before the committee on Ethics of the! they had not read this paper and recently American Psychiatric Association in Ban was given an award by the Canadian December, 1970 Apparently a psychiat- Psychiatric Association for his brilliant rist who was not willing to identify work in disproving our megavitamin himself complained before the com- claims mittee This is an example of retros- pective censorship (19) Vitamin B3 Dependent Child, A. The committee on Ethics have since:: Hoffer (1971) then not communicated with us andI The syndrome of the vitamin B3 apparently did not consider our action in `>? dependent child is characterized by publishing a scientific paper unethical (1) hyperactivity (2) deteriorating performance in school (25) Niacin Therapy in Psychiatry, A. (3) perceptual changes Hoffer (1962) (4) inability to acquire or maintain social In this monograph, the first ever` relationships published dealing with nicotinic acid and A few cases are given to illustrate the mental illness, AH described the results use of the orthomolecular approach of treatment as then known, giving histories of 64 patients treated so the)) (20) A Vitamin 83 Dependent Family, A. reader would know the diagnostic and;; Hoffer (1971a) treatment orientation A father and his three children, the This book contained a special section youngest from a second wife, were all on side effects and toxicity No refer-f vitamin B3 dependent and recovered on ence is made to this by the committee vitamin 83 therapy who referred only to the Mosher study, a member of the committee

(21) Orthomolecular Treatment of (26) How to Live With Schizophrenia, A. Schizophrenia, A. Hoffer (1972) Hoffer and H Osmond, final writing and- A review of the development of ortho- editing by F. H. Kahan (1966 and 1975) molecular psychiatry This is the first book written fo patients and their families consumed by (22) A Neurological Form of Schizo- schizophrenia phrenia, A, Hoffer (1973) It provided our perceptual theory of A young woman first ill with schizo- schizophrenia first elaborated in some phrenia at age 13 developed what was detail by John Conolly about 150 years diagnosed as a progressive degenerative ago The first edition treatment section cerebellar syndrome On nicotinic acid, was written in 1965 and represents our 3 g per day, she recovered treatment view then Since this book was written for lay people we made certain - (23) Nutrition and Schizophrenia, A.. we were very careful in our recommend Hoffer (1975). ations We stated, "If after this treatmen A general review article has been completed you do not improve, it is because you have been sick so long- (24) Five California Schizophrenics, A, that the disease has become chronic and Hoffer (1967a) treatment will have to continue for a long. This was a clinical report of five period of time, either in hospital or at

54 home As a rule patients who have been same dose level If and when the patient sick for many years will not be helped recovered the nicotinamide was replaced with nicotinic acid alone But if they can by identical appearing placebo tablets be improved in any way whatever it is The child was not aware this would be better to keep them on this treatment " done The parents were advised about We also pointed out the need for this before they agreed to place the child control of diet, control of infections, in the study If and when the patient control of smoking, adequate sleep, use relapsed the placebo was discontinued of medical psychotherapy and other and the nicotinamide resumed The psychosocial aids such as OT and RT parents kept records listing when they The treatment outline in our second placed the child back on the active edition contains the more compre- medication All the children were also hensive orthomolecular program We placed upon a sugar-free diet This have been accused by the committee of closely resembles Dr B Feingolds diet being shifty because our treatment has which excludes synthetic additives to i mproved Using their definition, every which many of these children react with modern psychiatrist is shifty since they hyperactivity Manufactured foods no longer use treatment available in which contain sugar also contain these 1965 The three phases of treatment are other undesirable additives discussed, but provision is made for Of the 37 children who started the junk-free and allergy-free diets, other program, 21 became normal and 14 were vitamins are discussed, and more better At the final evaluation 18 attention is given to children The remained normal, five much improved, concept of vitamin B3 dependency is and the rest were ill or their condition introduced as a cause of schizophrenic was unknown and they were assumed to syndromes and as a cause of some of the be ill That is, 24 out of 37 are well or learning and behavioral disorders in much improved Most of the failures did children not follow the program consistently This book is not a best seller, but has chiefly because the parents could not sold over 20,000 copies and continues to persuade or force the children to take the sell well medication The vitamin tablets were We have thousands of letters from rather large for children and capsules grateful parents, spouses, and patients, were then not available Only 19 were some of whom wrote that it literally placed on placebo because some were saved their sanity since it gave them an lost from the study and others had alternative view They no longer were improved so slowly that we did not wish forced to accept the popular psychiatric to expose them to the hazards of a view that they, especially parents, had relapse Early in this study it became made their relative ill They were for the apparent that many children who re- first ti me introduced to the medical lapsed on placebo were set so far back model of schizophrenia that it took much longer and higher doses of vitamins to return them to good health (27) Controlled Study of Orthomolecular again All the patients on placebo Therapy on Children with Learning and relapsed within four weeks, some within Behavioral Disorders (1967-1974) two For example, one child had re- This was the final report submitted to covered to the point that he was Mental Health Saskatchewan in 1975 It promoted one grade in school. At the is the study reported in paper (19) same time he was switched over to Thirty-seven children under age 14 (with placebo No one at the school was aware a mean age of 8 3) with a variety of of the study, but in a few weeks the learning and behavioral disorders were teacher called the parents to inform them treated They were given nicotinamide, that they had made a mistake in 1-3 g per day, and ascorbic acid at the promoting him and that they were forced

55 to revert him to his previous status When the parents were convinced of his relapse he was placed back on the nicotinamide, recovered, and thereafter had no further problem in class It was clear that the ascorbic acid did not prevent relapse

56 SECTION II—Brief Abstracts of Corroborative Reports

It is important to describe briefly all had been helped In a later study on the corroborative reports The committee tranquilizers, Borda (1973) found that referred to a small number of reports in only 21 percent of the patients felt they addition to those we have already had been helped compared with 66 discussed (#15, 17, 34, 35, 38, 39); listed percent of their doctors who concluded a number it could not have seen since they had been helped There is a better they were never published (#33, 36, 37, consensus for orthomolecular treatment 40) and they were not present at the Ward confirmed our work that non- meeting schizophrenic patients who scored high on the HOD test also responded well to (1) Cyproheptadine: An Excellent Anti- the therapy He concluded that "massive dote for Niacin-Induced Hyperthermia, dose niacinamide or niacin is of benefit T. R. Robie (1967). in schizophrenia and in various Dr Robie was the first psychiatrist to nonschizophrenic states " As regards report his corroboration of our work He neurotics the committee suggests that all described six cases Since then he has neurotics, not just those who score high remained an enthusiastic proponent of on the HOD, do equally well on the orthomolecular therapy Lehmanns first orthomolecular megavitamin treatment tranquilizer study was conducted on only an equally small number of cases He (3) Treatment of Schizophrenia with also remains an enthusiastic proponent Nicotinic Acid, M. Herjanic, B. L. Moss- of tranquilizer therapy Dr Robie, with Herjanic and W. K. Paul (1967). over 40 years of experience, observed This paper is ignored by the com- that on vitamin B3 therapy his patients mittee became his friends Never before had he Four groups were studied: experienced this with schizophrenics (a) All outpatient schizophrenics seen at one clinic were given nicotinic acid and ascorbic acid, 3 g per day of each for six (2) Treatment of Neurotics and Schizo- months, plus any other medication phrenics Using Clinical and HOD required Criteria, f• L, Ward (1967) (b) One-third of the patients from one Fifty-nine schizophrenics were treated chronic ward with orthomolecular methods. One (c) A control for group (a) matched for patient was worse, five unchanged, and age, sex, diagnosis, duration of illness, 43 (88 percent) were improved and much and duration of previous hospitaliza- improved This improvement was asses- tions 11 sed by clinical and HOD score criteria (d) Control for group (b). The same number of patients felt they All other patients on the same ward

Much Mean per N I mproved Admissions Mean days Total Group

Grout) a 21 8 6 Ss for dads 510 195

Groupc 21 1 10 Ss for 16 ads 776 591 These results are statistically sign- After describing in clinical detail the ificant. On the other hand, groups (b) diagnostic criteria and treatment pro- and (d) did not differ That is, acute and gram, Dr Cott presented six detailed subacute cases benefited while the case histories of children he had treated mental hospital chronics did not As a pioneer in the treatment of children Dr Cotts views must be taken very (4) Treatment of Schizophrenia Based on seriously. He concluded, "The response the Medical Model, D. R. Hawkins to the nicotinic acid treatment is slow (1968) and in my experience three to six months The committee ignored this paper Dr is the minimum time during which Hawkins reported treatment results on significant changes become manifest 315 consecutive patients who applied for Most parents have reported that the first treatment at an outpatient clinic Very noticeable change is a slowing of the strict diagnostic criteria were used The hyperactivity and attendant on this majority were chronic Eighty-nine per- slowing, a willingness to learn." cent had previous treatment Many had "Although much work and research multiple and lengthy periods in hospital will be required to fill the gaps remaining of up to 12 years Almost all had had in our knowledge of schizophrenia, we phenothiazine and other drug treatment can be encouraged with the accomplish- often for prolonged periods Some had ments achieved in less than two decades over 100 ECT, previous psychotherapy, or in treating this dread illness We can psychoanalysis for up to 20 years A few offer hope to those who suffer its ravages families had spent $150,000 (by 1968) on and to the parents of children whose ineffectual care potential is destroyed so early " Hawkins concluded, "The majority of patients i mproved significantly and (6) Schizophrenia: Responsive to In- progressively Those in whom the illness tensive Hospital Treatment as Monitored began during adulthood showed the most by the HOD and OIT tests, F. Chiossone, dramatic response If the onset of the D. R. Hawkins, F. Furfaro, and R. P, illness was before age 17 the response to Runyon (1969) treatment was slower and most treatment Over a 10-month period 140 patients failure occurred in this group of grown- were admitted into the psychiatric up childhood schizophrenics. Patients division of Brunswick Hospital Center: who were either too regressed or ill to ECT was given to 85 patients This group cooperate on an outpatient basis were responded as follows: treated in hospital for an average of six unimproved 2 weeks with a short series of ECT improved 118 I mprovement was rated by: much improved 12 (a) Patients subjective statements very much improved 6 (b) Family observations recovered 2 (c) Psychiatric evaluation The authors concluded, "Intensive (d) Decrease in HOD scores short-term hospital treatment for schizo- Of the group 71 percent improved The phrenia proved to be highly effective in greatest response was made by the 70 bringing about substantial improvement patients who were both alcoholic and in the great majority of patients and this schizophrenic i mprovement was substantiated by. objective testing " The committee ignored this report (5) Treatment of Schizophrenic Child- ren, A, A, Cott (1969). (7) Subclinical Pellagra: Its Diagnosis Dr Cotts article ran between pages 44 and Treatment, R. G. Green (1970) and 60, not 44 to 49 as the committee A discussion and presentation of a few erroneously wrote cases to demonstrate the response of these patients with learning and be- since, according to the hospital staff, havioral disorders to vitamin 133 The vitamin therapy "has already been committee ignored this report proven not to work " Of the six, three were in almost constant restraints or (8) How One Psychiatrist began Using seclusion of one kind or another Five Niacin, H. L. Newbold (1970). had been in hospital one month and the This is an excellent account, ignored sixth for seven They had as a group been by the committee, in which a skillful in hospital _ 18 times, averaging 8Y it psychiatrist describes his history which months per patient The mean HOD total led to him becoming an orthomolecular score was 144 5 indicating very severe psychiatrist Most psychiatrists would be psychosis The average for all schizo- unwilling to expose themselves to such phrenics is around 70 Each patient pressure from their antivitamin col- responded They became more manage- leagues able, less agitated, less hostile, less aggressive They began to talk and (9) The Use of Megavitamin Therapy in became more sociable Hallucinations Regulating Severe Behavior Disorders, and delusions diminished These obser- Drug Abuses and Frank Psychoses, G. vations by patient, family, and staff were Von Hilsheimer, S. D. Klotz, G. McFall, confirmed by a decrease in the HOD It Lerner, A. Van West, and D. Quirk scores to a mean of 4 8 in 2 months (1971) ( Normal scores range from 0 to 15) Four These investigators treated 32 patients were discharged with no tranquilizers between September 1967 and September and two on tranquilizers, but the doses 1969 in acute psychotic episodes or in were much smaller. After six months only the aftermath of acute crises which did one was still on tranquilizers Five not appear to be psychotic in nature, not remained well after discharge The sixth related to drug abuse The patients were discontinued his vitamins and was re- given up to 24 g of niacin per day hospitalized three times in 10 months "All these patients have responded As each patient was discharged, with reduced dysphoria, subjective another was placed on the same pro- reports of improved feeling states, gram Eventually another 24 were treated i mproved perception, control of be- with similar results havior and general improvement in Another 14 were started, but could not tonus, orientation and appearance of be continued because one was dis- health " covered to have a medical problem, six "Several severe psychotic patients were transferred to another hospital, and seem to have recovered as a direct one was discharged by the court, two function of niacin therapy " The com- were transferred to a private hospital, in mittee ignored this report three patients new physicians would not permit vitamins to be continued, and in (10) A Report on the Use of Ortho- one emesis of niacin and niacinamide molecular Therapy in a California State was unavoidable While on vitamins for a Hospital, E. R. LeClair (1972) brief period, 11 of the 14 showed some E R LeClair described results of improvement Ten are still in hospital treating 30 male schizophrenics in a state mental hospital She was permitted to do Summary of Results: so after she was able to demonstrate the Hospital experience before vitamins-- effect of orthomolecular therapy on six 3 43 times for 10 47 months calculated psychotic patients They were too dis- for all 30 (per person) orientated and agitated to participate in Excluding seven never in hospital psychotherapy and had failed to respond values were 4 48 for 13 65 months to the comm i ttees favorite therapy- Discharge—19 to themselves; seven to tranquilizers o iy This was a test project parents; four to board and care facility. Follow-up—When the paper was pre- They concluded, "In any event, the pared 28 were evaluated. Twenty re- fact that megavitamin treatment was mained on megavitamin therapy Of the associated with significant results in this eight not on vitamins six had been re- study justifies further research into this hospitalized one to five times in the type of therapy " This paper was ignored following 10 months One committed by the committee suicide and one maintained himself on phenothiazines Three were ordered by (12) Clinical Observations on the Treat- their physicians to discontinue vitamins. ment of Schizophrenia and Hyperactive Of the 28, 19 were gainfully employed, Children with Megavitamins, E. L.. Rees five were in board and care facilities, two (1973) retired, and one was dead Five were on This is a general outline of treatment welfare assistance compared to 18 before including treatment of children allergic treatment started to foods The author noted, "A discouraging aspect of the project was the poor (13) Psychiatric Syndromes Produced by reception by many of the hospital Allergies: Ecologic Mental Illness, H. L. personnel The security and com- Newbold, W. FL Philpott, and M placence in tradition were apparent The Mandell (1973). program director, who gave permission This is one of the first accounts of the for the project, experienced many un- role of allergies in producing mental complimentary comments from his illness An explanation for schizophre- fellow psychiatrists Several physicians nics failure to respond to megavitamins also placed patients on 100 mg to 300 mg is now available Why should a patient of niacin and ascorbic acid. When no who is psychotic because he is con- improvement was noted within two to suming milk to which he is allergic, four weeks, they boastfully made it respond to vitamins? known that the vitamins did not work for them " Had they done it double blind (14) Pyridoxine and Trace Element using these totally inadequate doses we therapy in Selected Clinical Cases, P. are certain the committee would have Cutler (1974) given them ample space in their report. The use of trace elements is rapidly The committee ignored this study expanding

(11) A Study of Neurological Organiza- (15) Orthomolecular Approach to the tion Procedures and Megavitamin Treat- Treatment of Learning Disabilities, A. ment for Children with Brain Dys- Cott (1971) function, S. Krippner and S. Fischer This is a general review paper of (1972) orthomolecular treatment based upon Subjects were 100 children diagnosed treatment of 500 children between 1966 as suffering from brain dysfunction They and 1971. were divided into four groups: (a) 41 Ss (28 boys, 13 girls) who received (16) An Integrated Community System neurological organization (NO) only for the Effecitve Treatment of Schizo- (b) 14 Ss (6 boys, 8 girls.) NO only phrenia, D. It Hawkins (1971) (c) 14 Ss (10 boys, 4 girls) NO and Using a comprehensive treatment megavitamin therapy MV approach under the medical model, Dr. (d) 24 Ss (18 boys, 6 girls) NO and MV Hawkins Clinic treated over 4,000 For groups (a) and (b) there was no patients At this Long Island Clinic they significant gain in the neurological carry a case load of 1,500 patients for quotient (NQ), but for groups (c) and (d) $300,000 per year Many are chronic there was a significant improvement in schizophrenics with repeated admissions NQ to hospital. Their results were superior to

60 any they had seen with standard psy- ing Vessels and Sanity? C. C, Pfeiffer chiatric treatment and cost averaged to (1975) $200 per year per patient. This is a good paper to illustrate the One family agency, the Council for importance of minerals in orthomolecul- Youth Services of the Episcopal Diocese ar psychiatry of Long Island, had become bogged down with long waiting lists and shortage (20) Relationship of Kryptopyrrole, Zinc, of staff When they converted to the new and Pyridoxine in Schizophrenics, J, system, they soon eliminated a waiting Ward (1975) list, doubled their case load, and solved This good paper confirms that krypto- their financial problems The committee pyrrole (KP) is found primarily in patients ignored this paper who have serious mental disease. It cuts across all diagnostic groups and can be (17) A First Evaluation, M. Williams used to indicate when pyridoxine and (1971) zinc are required "I was trained in orthodox analytical treatment methods and applied these in (21) Orthomolecular Treatment in my practice for 15 years " Disturbances Involving Brain Function, "I discovered that results of strictly L. B, Silverman (1975) psychoanalytical therapy with or without On the basis of 400 cases (mostly combined chemical (tranquilizer) children with learning and behavioral therapy produced poor recovery and disorders) treated between July 1972 and remission percentages in schizophrenic April 1974, Dr Silverman, an ortho- patients " molecular pediatrician, concluded, "On "After three years of using these the basis of a rather concentrated diagnostic and treatment procedures experience it certainly suggests to me (orthomolecular—our note) I have com- that whenever medical treatment is piled sufficient case histories upon which indicated, the orthomolecular method is to base my own conclusions My first the first and safest treatment of choice in impression was the number of un- children with perceptive and behavioral recognized schizophrenics Almost 50 problems associated with minimal neuro- percent of previously diagnosed neuro- logical difficulties " Several illustrative tics were actually suffering from schizo- cases were given phrenia History usually indicated life- long problems, and early recognition and (22) The Schizophrenias: Yours and orthomolecular treatment, in some cases Mine, C. C. Pfeiffer, J, Ward, M. El- accompanied by supportive psycho- Meligi, and A. Cott (1970) therapy, brought about rapid response " The committee completely ignored "Chronic (long-standing) schizo- this i mportant work as they have phrenic patients do not respond as continued to ignore every paper put out quickly or as well However, I have noted by Pfeiffer and his colleagues They marked improvement in even the most obviously believe that in so doing chronic cases " This report was ignored Pfeiffers work will go away and they will by the committee not need to deal with it The book contains a comprehensive outline of (18) Clinical Impressions in Early and schizophrenia and its treatment A Chronic Schizophrenia and Diagnostic number of new findings have been made Procedures, M. Williams (1972) relating histamine levels, kryptopyrrole Dr Williams presented three cases to levels, and zinc to various schizophrenic illustrate the response to treatment This syndromes report was ignored by the committee (23) A Study of Zinc Deficiency and (19) Does Acid Well Water Erode Plumb - Copper Excess in the Schizophrenias, C. C. Pfeiffer, U. Iliev (1972) See also 27 graduates, 17 were schizophrenic and Pfeiffer, Iliev, and Goldstein (1973) 22 were on megadose vitamins He Both papers are ignored by the concluded, "in this 14-month program, committee low-dose methadone is enough for maintenance, that the immediate flush (24) Treatment of Drug Addicts in of nicotinic acid successfully replaces Private Practice, A. Vajay (1973) the heroin high and is a useful tool to Dr Vajay treated 89 outpatients in maintain motivation and keep the private practice between October 1970 patient free from craving for heroin " and December 31, 1971 By then 23 had The committee ignored this paper "graduated" away from drugs and four months later the number increased to 27 (25) Nicotinic Acid Therapy in Chronic This was a chronic group, the most Schizophrenia, Sehden and Olson (1974) frequent ages being 19, 20, and 21 These authors treated 14 chronic Duration of addiction varied from six to schizophrenic patients with 3 g per day 84 months Only 17 used one drug The of nicotinic acid for 90 days and rest were primarily on heroin, but compared their progress with 13 untreat- combined it with three or more other ed patients Every patient had been on a drugs None had ever been treated with plateau at their current level for six methadone, 14 had been treated once, months Of the nicotinic acid group two seven, twice, 20, three times, and 34, were much improved and four made four times, and five had been in and out minimal to moderate improvement Out five to 10 times of the placebo group one was much There was a very high rate of physical improved and one moderately improved illness, 68 had orthostatic hypotension, For this distribution, Chi Sq = 2 5 The 50 chronic bronchitis and nasopharyngi- probability this is due to chance is about tis, 52 had pustular acne, 48 acute 12 percent However, it is a very small thrombophlebitis of anecubital or dorsal sample Had the sample been twice as veins of hands, 23 had chronic prostatitis large with the same distribution Chi Sq. (nine due to gonorrhea), 11 women had would have been over five which would pelvic inflammatory disease (10 had reduce the probability to 2 percent gonorrhea) Twenty developed hepatitis However, these authors were so con- during treatment Eight had ulcerative vinced nicotinic acid could not work colitis, one duodenal ulcer, and one they muddled around in their con- chronic asthma clusion Surely the improvement of six All were also suffering from a variety of out of 14 chronic patients who had psychiatric illnesses One was manic shown no change in six months should depressive, one epileptic with psychosis have alerted them that there might be following brain trauma, two were organic something there They could as easily brain syndromes, and 35 were schizo- have expanded their series This is the phrenic borderline or pseudoneu- reason why the motivation of an experi- rotic menter is important An investigator Twenty-six were given 5 g buffered wishing to negate findings will run his nicotinic acid, 1 g of ascorbic acid, and 1 experiments in such a way as to mg of vitamin B12 plus 15 mg of vitamin maximize the negative effect while an B6 by injection every four days. They experimenter hoping to corroborate will were all started on methadone 40 mg per run his experiments longer and may then day for 30 days This was then gradually find the positive results The first reduced until they graduated off it They investigator will always quit when he is also received individual psychotherapy ahead because he minimizes the danger Group therapy was quickly rejected of being proven wrong by his own data For such a severely sick group the The corroborator may also be dis- results were very encouraging Out of the appointed, but by perserveting heat least greatly increases the probability he will mittees favorite treatments including be a party to the introduction of counseling,. milieu therapy (three something useful and novel The com- months) in a general hospital psychiatric mittee were all hoping to destroy the unit, three weeks of day therapy, the megavitamin claims They, therefore, usual gamut of major tranquilizers, and a conducted their literature review in a series of 6 ECT, a rehabilitation program, way designed to maximize this hoped-for and frequent visits to a social worker. event This was followed by six additional weeks in a psychiatric ward from which he was (26) Pfeiffer, Sohler, Jenney, and Iliev almost forcibly discharged and admission (1974) confirmed our original des- soon after to a mental hospital It is clear cription of malvaria (Hoffer and that this. unfortunate patient had not Osmond, 1963) A more appropriate term responded and was doomed to the usual in our opinion is pyrroluria, the term pattern of the chronically tranquilized coined by Pfeiffer The patient who patient—the usual revolving door excretes too much kryptopyrrole (here- between community and hospital or after KP), i e., has too much in his body, hospital surrogate has the following characteristics: (1) But the parents had read our book, white spots in the nails; (2) failure to How To Live With Schizophrenia, took remember dreams; (3) sweetish breath their son out against medical advice and odor; (4) left upper quadrant abdominal had him sent to an orthomolecular pain; (5) dysperceptive schizophrenia psychiatrist far from home. On discharge and neurological metabolic symptoms from this latest treatment he was greatly KP combines with pyridoxine and zinc to improved produce symptoms of pyridoxine and One would think that most reasonably zinc deficiency Adequate doses of curious psychiatrists would become in- pyridoxine, up to 3 g per day, and zinc terested Dr Mickelson, who carefully will relieve the symptoms reported how the most persuasive techniques known including milieu (27) Pfieffer (1974) In this report therapy and the other psychotherapies Pfeiffer summarized his work leading to a had failed to do anthing, now falls back division of schizophrenics into several on the old, never established notion that biochemical types, i e , histapenics, the patient improved because of the histadelics, and pyrroluriacs The parents faith in the biochemical specific biochemical treatment for each approach That is, the recovery arose group is outlined from a powerful placebo effect operating from a distance of several hundred miles (28) Cott (1973) Here Dr Cott reported his conclusions based upon a series of (30) Rimland, Dreyfus, and Callaway 500 children tested over a seven-year (1976) completed a double-blind control- period He concluded that a large led experiment on 16 autistic type child- number of disturbed children and child- ren who had shown noticeable behavior- ren with learning disabilities can be al improvement when given pyridoxine helped by orthomolecular treatment (up to 3 g per day) The patients were This paper came out after the APA Task also taking other nutrient supplements. Force Report, but they would undoubt- The pyridoxine supplement was replaced edly have ignored it since it did not during two separate experimental trial follow the fad double-blind metho- periods; first by substance A, then by B. dology The first two authors assigned behavioral ratings to the experimental trials after (29) Mickelson (1975) reported the case which the third author revealed which of a 21-year-old male schizophrenic who substance was pyridoxine. It was ident- did not respond to any of the com - ified correctly in 11 out of 15 children

63 For the 16th child the judges could see no difference It was then learned that pyridoxine had been given for both A and B periods This is one of the best types of double blinds for a group homogeneous with respect to their response to pyridoxine was used Secondly pyridoxine, contrary to nicotinic acid, does not give itself away by producing a flush In the spring of 1974 the Canadian SchizophreniaJoundation held its third annual meeting It was entirely devoted to orthomolecular treatment and was published in the journal of Ortho- molecular Psychiatry, 1974, December issue It is available from the Canadian Schizophrenia Foundation, Regina, Saskatchewan, as a "Primer on Ortho- molecular Treatment "

64 SECTION III—Pauling Paper

OPINION AND COMMENT studies of vitamins in relation to mental On the Orthomolecular Environment of disease by Cleckley and Sydenstricker the Mind: Orthomolecular Theory (5-6) and others. In the course of time I By Linus Pauling, Phi), formulated a general theory of the dependence of function on molecular The author defines orthomolecular psy- structure of the brain and other parts of chiatry as the achievement and preservation the body and coined the adjective of good mental health by the provision of the "orthomolecular" to describe it (1) optimum molecular environment for the There is no doubt that the mind is mind, especially the optimum concentrations affected by its molecular environment. of substances normally present in the human The presence in the brain of molecules of body, such as the vitamins. He states that LSD, mescaline, or some other schizo- there is sound evidence for the theory that phrenogenic substance is associated with increased intake of ,such vitamins as ascorbic profound psychic effects Mental mani- acid, niacin, pyridoxine, and cyanocobala- festations of min is useful in treating schizophrenia The avitaminosis have been reported for several vitamins A cor- negative conclusions of APA Task Force relation of behavior of schoolchildren Report 7, Megavitamin and Orthomolecular with concentration of ascorbic acid in Therapy in Psychiatry, he says, result not only the blood (increase in "alertness" or from faulty arguments and from a bias against "sharpness" with increase in concentra- megavitamin therapy but also from a failure tion) has been reported by Kubala and to deal fully with orthomolecular therapy in Katz (7) A striking abnormality in the psychiatry. Three psychiatrists comment on urinary excretion of ascorbic acid after Or Paulings presentation an oral loading dose was reported for Orthomolecular Psychiatry is the chronic schizophrenics by VanderKamp achievement and preservation of mental (8) and by Herjanic and Moss-Herjanic health by varying the concentrations in (9) My associates and I (10) carried out the human body of substances that are loading tests for three vitamins on normally present, such as the vitamins It schizophrenic patients who had recently is part of a broader subject, ortho- been hospitalized and on control sub- molecular medicine, an important part jects The percentage of schizophrenic because the functioning of the brain is patients who showed low urinary probably more sensitively dependent in excretion of each vitamin was about its molecular composition and structure twice as great as that of the controls: for than is the functioning of other organs ascorbic acid, 74 percent of the schizo- (1) phrenic patients showed low urinary After having worked for a decade on excretion versus 32 percent of the the hereditary hemolytic anemias, I controls; for niacinamide, 81 percent decided in 1954 to work on the molecular versus 46 percent; and for pyridoxine, 52 basis of mental disease. I read the papers percent versus 24 percent The possibility and books dealing with megavitamin that the low values in urinary excretion of therapy of schizophrenia by Hoffer and these vitamins for schizophrenic patients Osmond (2-4) as well as the reports on resulted from poor nutrition is made Based on a lecture given at a meeting of the American unlikely by the observation that the College of Neuropsychopharmacology. Palm Springs. numbers of subjects low in one, two, or California. December 4-7. 1973 all three vitamins corresponded well with Dr. Pauling is Director, Linus Pauling Institute of Science and Medicine. 2700 Sand Hill Rd . Menlo Park. the numbers calculated for independent California 94025 incidence. Reprinted by permission of the American Journal of There are a number of plausible Psychiatry, Vol 131, pp. 1251-1257. 1974 (plus a charge of $100) . Copyright 1974, the American Psychiatric mechanisms by which the concentration Association of a vitamin may affect the functioning r

of the brain One mechanism, effective few of the abnormal human hemo- for vitamins that serve as coenzymes, is globins, most of which involve only the that of shifting the equilibrium for the substitution of one amino-acid residue reaction of apoenzyme and coenzyme to for another in either the alpha chain or give the active enzyme An example is the beta chain of the molecule, differ the effectiveness of cyanocobalamin greatly in properties from normal adult (vitamin B12) given in amounts 1,000 hemoglobin, leading to serious mani- times greater than normal to control the festations of disease disease methylmalonic aciduria (11-14) It was in the course of the study of one About half of the patients with this of these diseases, sickle cell anemia, that disease are successfully treated with the first abnormal hemoglobin was discovered (16) Most of the abnormal megadoses of vitamin B12 In these patients a genetic mutation has occurred human hemoglobins, however, differ and an altered apoenzyme that has a from normal hemoglobin in their proper- greatly reduced affinity for the coenzyme ties to only a small extent, so that there is has been produced. Increase in concent- no overt manifestation of disease There ration of the coenzyme can counteract is, nevertheless, the possibility that even the effect of the decrease in the value of the small changes in properties of an the combining constant and lead to the abnormal hemoglobin associated with a formation of enough of the active mild hemoglobinopathy will have del- enzyme to catalyze effectively the eterious consequences An example is reaction of conversion of methylmalonic the intolerance to sulfa drugs associated acid to succinic acid with the substitution of arginine for In the human population there may be histidine in the locus 58 in the alpha several alleles of the gene controlling the chain or 63 in the beta chain It is likely manufacture of each apoenzyme; in that individual differences in enzyme consequence the concentration of co- activity will in the course of time be enzyme needed to produce the amount shown to be the result of differences in of active enzyme required for optimum the amino-acid sequences of the poly- health may well be somewhat different peptide chains of the apoenzymes for different individuals In particular More than 100 abnormal human many individuals may require a consider- hemoglobins are now known, and the ably higher concentration of one or more human population may be expected to coenzymes than other people do for be similarly complex with respect to optimum health, especially for optimum many enzymes, including those involved mental health It is difficult to obtain in the functioning of the brain A experimental evidence for gene tendency to schizophrenia is probably mutations that lead to only small polygenic in origin I have suggested (1) changes in the properties of enzymes. that the genes primarily involved in this The fact that genes that lead to large and tendency may well be those which more easily detectable changes in the regulate the metabolism of vital sub- properties of enzymes occur, as in stances such as the vitamins individuals with methylmalonic aciduria, Some vitamins are known to serve as for example, suggests that mutations that coenzymes for several enzyme systems. lead to small changes also occur We might ask if the high concentration of Significant differences in enzyme coenzyme required to produce the activity in different individuals have optimum amount of one active enzyme been reported by many investigators, might not lead to the production of far especially by Williams (15) who has too great an amount of another active made many studies of biochemical enzyme The answer to this question is individuality It is likely that thorough that the danger is not very great. For studies of enzymes would show them to most enzymes the concentration of be similar to the human hemoglobins. A coenzyme and the value of the comb

66 ination constant are such that most (90 percent of schizophrenics hospitalized percent or more) of the protein is for the first time are treated successfully converted to active enzyme Accord- by conventional methods in that they are ingly, a great increase in concentration released and not hospitalized a second would increase the amount of most time. The conventional treatment fails active enzymes by only a few percentage for about 60 percent in that the patient is points, whereas it might cause a great not released or is hospitalized again increase for a mutated enzyme. Conventional treatment includes a decision about vitamin intake Usually it is decided that the vitamins in the food The Orthomolecular Treatment of will suffice or that a multivitamin tablet Schizophrenia will also be given. The amounts of ascorbic acid, niacin, pyridoxine, and In the book Orthomolecular Psychia- vitamin E may be approximately the daily try: Treatment of Schizophrenia (17) my allowances recommended by the Food colleagues and I pointed out that the and Nutrition Board of the U S. National orthomolecular treatment of schizo- Academy of Sciences-National Research phrenia involves the use of vitamins Council: 60 mg of ascorbic acid, 20 mg of (megavitamin therapy) and minerals; the niacin, 2 mg of pyridoxine, and 15 I U of control of diet, especially the intake of vitamin E Is this amount of vitamins sucrose; and, during the initial acute correct? Would many schizophrenic phase, the use of conventional methods patients respond to their treatment better of controlling the crises, such as the if the decision were made that they phenothiazines The phenothiazines are should receive 10 or 100 or 500 times as not, of course, normally present in the much of some vitamins? What is the human body and are not orthomolecular optimum intake for these patients? I However, they are so valuable in believe there is much evidence that the controlling the crisis that their use is optimum intake for schizophrenic justified in spite of their undesirable side patients is much larger than the recom- effects. mended daily allowances By the use of Hawkins (18, p 640) stated that his orthomolecular methods in addition to initial combination of vitamins for the the conventional treatment of schizo- treatment of schizophrenia was 1 gm of phrenia, the fraction of patients hospital- ascorbic acid, 1 gm of niacinamide, 50 ized for the first time in whom the mg of pyridoxine, and 400 1. U of vitamin disease is controlled may be increased E four times a day Other vitamins may from about 40 percent to about 80 also be given A larger intake, especially percent (19) of niacinamide or niacin, may be prescribed; the usual amount seems to be about 8 gm a day after an initial period of Ascorbic Acid 4 gm a day. The vitamins, as nutrients or medica- It was reported by Horwitt in 1942 (20) ments, pose an interesting question. The and by later investigators that schizo- question is not, Do we need them? We phrenic patients receiving the usual know that we do need them, in small dietary amounts of ascorbic acid had amounts to stay alive The real question lower concentrations of ascorbic acid in is, What daily amounts of the various the blood than people in good health. vitamins will lead to the best of health, The loading-test results of VanderKamp both physical and mental? This question (8), Herjanic and Moss-Herjanic (9), and has been largely ignored by medical and Pauling and associates (10) have been nutritional authorities. mentioned above In his discussion of Let us consider schizophrenia. ascorbic acid and schizophrenia Herjanic Osmond (19, p 200) stated that about 40 . (21) concluded: The individual variation of the need for administration of ascorbic acid. ascorbic acid may turn out to be one of the We found (10) that of 106 of the contributing factors in the development of schizophrenic patients we studied who the illness Ascorbic acid is an important had recently been hospitalized in a substance necessary for optimum functioning private hospital, a county-university of many organs If we desire, in the treatment hospital, or a state hospital, 81 (76 of mental illness, to provide the "optimum percent) were deficient in ascorbic acid, molecular environment," especially the as shown by the six-hour excretion of less optimum concentration of substances than 17 percent of an orally administered normally present in the human body dose Only 27 of 89 control subjects (30 (Pauling, 1968 (1]), ascorbic acid should percent) showed this deficiency Great certainly be included (21, p 314) deficiency (less than 4 percent excreted) There is, moreover, a special reason was shown by 24 (22 percent) of the for an increased intake of ascorbic acid schizophrenic subjects and by only 1 (1 by patients with schizophrenia or any percent) of the controls I have no doubt other disease for which there is only that many schizophrenic patients would partial control About 60 mg of ascorbic benefit from an increased intake of acid a day is enough to prevent overt ascorbic acid. My estimate is that 4 gm of manifestations of avitaminosis C (scurvy) ascorbic acid a day, in addition to the in most people. However, there are conventional treatment, would increase several significant arguments to support the fraction of acute schizophrenics in the thesis that the optimum intake for whom the disease is permanently con- most people is 10 to 100 times more than trolled by about 25 percent Except for 60 mg These arguments are summarized that of Milner (25), no controlled trial of in the papers and books of Irwin Stone ascorbic acid in relation to schizophrenia (22) and myself (23, 24) They constitute has been made, so far as I know the theoretical basis for the customary use of about 4 gm of ascorbic acid a day in the orthomolecular therapeutic and prophylactic treatment of schizophrenia. A significant controlled trial of The requirement of niacin (nicotinic ascorbic acid in chronic psychiatric acid) for proper functioning of the brain patients was reported in 1963 by Milner is well known The psychosis of pellagra, (25) The study, which was double-blind, as well as the other manifestations of this was made with 40 chronic male patients: deficiency disease, is prevented by the 34 had schizophrenia, 4 had manic- intake of a small amount of niacin, about depressive psychosis, and 2 had general 20 mg a day. In 1939 Cleckley, Syden- paresis. Twenty of the patients, selected stricker, and Geeslin (5) reported the at random, received 1 gm of ascorbic successful treatment of 19 patients with acid a day for three weeks; the rest severe psychiatric symptoms with niacin, received a placebo. The patients were and in 1941 Sydenstricker and Cleckley checked with the Minnesota Multiphasic (6) reported similarly successful treat- Personality Inventory (MMPI) and the ment of 29 patients with niacin. In both Wittenborn Psychiatric Rating Scales studies, moderately large doses of niacin, ( WPRS) before and after the trial Milner 0 3 to 1 5 gm a day, were given. None of concluded that "statistically significant the patients in these studies had physical improvement in the depressive, manic, symptoms of pellagra or any other and paranoid symptom-complexes, to- avitaminosis A decade later, Hoffer and gether with an improvement in overall Osmond (2, 3) initiated two double- personality functioning, was obtained blind studies of niacin or niacinamide in following saturation with ascorbic acid" the treatment of schizophrenia Another (25) He suggested that chronic psy- double-blind study was reported by chiatric patients would benefit from the Denson in 1962 (26) In 1964 Hoffer and

68 Osmond (4) reported that a 10-year nicotinic acid group, nine improved and follow-up evaluation of the patients in one deteriorated in both the combined their initial studies showed that 75 treatment group and in the pyridoxine percent had not required hospitalization, group" (27) They also stated: compared with 36 percent of the Of the three indices of therapeutic effects, comparison group, who had not received global improvement in psychopathology niacin Similar estimates have been made (Brief Psychiatric Rating Scale and Nurses by Hawkins (18, p 585) There are, Observation Scale for Inpatient Evaluation) however, contradictory statements by scores was seen in all three groups; the other investigators The question of the number of days of hospitalization during the weight of the evidence is discussed period of the clinical study was lower in both below in the section on the APA task the nicotinic acid and the combined treat- force report ment group; and only in the combined treatment group was the daily average dosage Pyridoxine of phenothiazine medication decreased Thus, improvement in all three indices was Pyridoxine, vitamin B6, is used in the noted in the combined treatment group treatment of schizophrenia in amounts of However, several side effects were ob- 200 to 800 mg a day by many ortho- served during the therapeutic trials, indicat- molecular psychiatrists Derivatives of ing that the vitamins used are not completely this vitamin are known to be the safe (27, p 381) coenzymes for over 50 enzymes, and the The investigators reached the con- chance of a genotype with need for a clusion that "on balance, these results large intake of the vitamin is accordingly suggest that the addition of pyridoxine great There is evidence that pyridoxine may potentiate the action of nicotinic is involved in tryptophan-niacin meta- acid Thus pyridoxine seems to be a bolism useful adjunct to nicotinic acid therapy" A double-blind placebo-controlled (27, p 381) Hawkins (18) commented on study had been made of pyridoxine and this work in the following way: niacin by Ananth, Ban, and Lehmann The therapeutic effect was demonstrable (27) Their experimental population con- even though the patients had been hospital- sisted of 30 schizophrenic patients: 15 ized for an average of 10 9 years, were not on were men, 15 were women, their mean hypoglycemic diets, and the doses of both age was 41 7 years, and their mean pyridoxine (75 mg daily) and vitamin B3 (3 duration of hospitalization was 10 9 gm a day) were considerably below the years They were randomly assigned to dosages we routinely prescribe (18, p 638). three treatment groups: 1) the combined treatment group, which received 3 gm of nicotinic acid a day for 48 weeks and 75 Cyanocobalamin mg of pyridoxine a day during three 4-week periods; 2) the nicotinic acid A deficiency in cyanocobalamin group, which received 3 gm of nicotinic (vitamin B12), whatever its cause, leads acid a day for 48 weeks and a pyridoxine to mental illness as well as to such placebo; and 3) the pyridoxine group, physical manifestations as anemia The which received 75 mg of pyridoxine a day anemia can be controlled by a large during three 4-week periods and a intake of folic acid, but the mental illness nicotinic acid placebo. In addition, and neurological damage cannot A neuroleptic preparations were administ- pathologically low concentration of ered according to clinical requirements cyanocobalamin in the blood serum has for the control of psychopathology The been reported to occur in a much larger investigators reported that "of the ten percentage of patients with mental patients in each treatment group, seven illness than in the general population: improved and three deteriorated in the Edwin and associates (28) determined the

69 amount of vitamin B12 in the serum of Some Errors in the Report every patient over 30 years old admitted to a mental hospital in Norway during a It is mentioned in the report that in the period of one year Of the 396 patients, treatment program of the orthomolecular 61 (15.4 percent) had a subnormal or psychiatrists "each patient may receive pathologically low concentration of as many as six vitamins in large doses vitamin B12, less than 150 pg per ml individually determined by the treating (the normal range is 150 to 1,300 pg per physician as well as other psychotropic ml ) This incidence is 30 times as great as drugs and hormones whose doses are also that estimated for the population as a individually determined for each patient" whole. Other investigators have reported (p. 46) The assumption is made by the similar results and have suggested that a task force that the optimum intake of low serum concentration of vitamin B12, vitamins for mental health is the conven- whatever its origin, may cause mental tional average daily nutritional require- illness In addition, of course, mental ment, with growth and development as illness may accompany some genetic the criteria: "In schizophrenia there is diseases, such as methylmalonic acid- apparently an adequate vitamin intake aria, which can be controlled only by for growth and development until the achieving a serum concentration of illness becomes manifest in the teens or cyanocobalamin far greater than normal early adult life" (p 40) Mention is made in the report of the well-known genetic diseases with both psychic and somatic manifestations that can be controlled by an intake of a vitamin 100 or 1,000 times Minerals and Other Vitamins the usually recommended daily allow- ance, but the possibility that less obvious There is some evidence that mental genetic differences could result in an illness may result from deprivation of or increased individual need for a larger abnormal need for minerals and other intake of vitamins in order to achieve vitamins (See, for example, Pfeiffer, good mental health, as discussed in my 111ev, and Goldstein [29]) Further work in 1968 publication (1) and in the earlier this field by psychiatrists and bio- sections of this paper, is rejected on the chemists is needed basis of arguments that have little value or pertinence One such argument is the following: The two theoretical bases adduced by THE APA TASK FORCE REPORT megavitamin proponents for the effective- ness of NA therapy (nicotinic acid as a methyl In July 1973 an APA task force of five acceptor and NAD deficiency) are in fact physicians and one consultant issued a generally incompatible, because NAA 54-page report titled Megavitamin and [nicotinamide), when functioning as a vita- Orthomolecular Therapy in Psychiatry min, is bound to the remainder of the (30) In this report the Task Force on coenzyme molecule by the nitrogen of its Vitamin Therapy in Psychiatry purports pyridine ring and hence can no longer accept to present both theoretical and empirical methyl groups reasons for completely rejecting the Essentially, then, the two views of NA as a basic concept of orthomolecular psy- vitamin precursor of NAD and as a methyl chiatry, which is the achievement and acceptor are incompatible, except for the preservation of good mental health by possibility that there is in schizophrenia the provision of the optimum molecular double deficitboth a vitamin deficiency environment for the mind, especially the and a transmethylation defect and that optimum concentrations of substances nicotinic acid has the happy fortune to serve normally present in the human body two purposes simultaneously (pp 40-42)

70 There is an obvious error in this task proper equimolar amounts of nicotinic force argument There is no incompati- acid and methionine. bility between two functions of nicotinic acid; some molecules may engage in one function and others in the other A defect The Failure to Discuss Ascorbic Acid and in either function might be controlled by Pyridoxine increasing the intake of the vital sub- stance A "double deficit" is not needed In several places the AM task force The authors of the report would have report mentions the use of 1 to 30 gm of seen the fallacy in their argument if they ascorbic acid a day by orthomolecular had set up some equilibrium and reaction psychiatrists There are, however, no rate equations, as was done in my 1968 references to the literature. Milners paper (1). double-blind study (25) is not mention- The task force expresses an interesting ed, nor is there any discussion of the misunderstanding of the nature of vita- many papers in which a low level of mins, in the following words: "By ascorbic acid in the blood of schizo- common definition a vitamin is not only phrenics was reported. Neither the an essential nutrient, but it is essential general theory of orthomolecular psy- because it is transformed into a co- chiatry, as presented in my 1968 paper enzyme vital for metabolic reactions" (p. (1), nor any of the special arguments 41) In fact, this is not the common about the value of ascorbic acid is definition of a vitamin; it is wrong Some presented or discussed in any significant vitamins, including vitamin C, are not way. There is, moreover, no discussion in known to be transformed into a co- the report of pyridoxine and no reference enzyme This misunderstanding by the to the 1973 work by Ananth, Ban, and task force may have contributed to the Lehmann (27) on the potentiation by misinterpretation of the evidence for and pyridoxine of the effectiveness of niacin the theoretical basis of orthomolecular in controlling chronic schizophrenia The psychiatry title of the report, Megavitamin and Nicotinic acid as a methyl acceptor is Orthomolecular Therapy in Psychiatry, is referred to in the report: "From Study No completely inappropriate, and the gen- 12: nicotinic acid in the dosage of 3000 eral condemnation of megavitamin and mg per day can neither prevent nor orthomolecular therapy is unjustified. counteract the psychopathology induced by the combined administration of a monoamine oxidase inhibitor (tran- Niacin ylcypromine) and methionine" (p 16) In fact, the molecular weights of nicotinic The report does say that it is possible acid and methionine (a methyl donor) that the other water-soluble vitamins will are nearly the same, 123 and 149, prove to be more effective than niacin, respectively Instead of 3 gm, 16 5 gm of but it adds: nicotinic acid would have had. to be Nonetheless, the massive use of niacin has given each day to accept the methyl always been the cornerstone of the theory groups donated by the 20 gm of and practice of megavitamin advocates methionine that was given each day The Since this has proved to have no value when study referred to as number 12 (31), it is employed as the sole variable along with which resulted in an exacerbation of the conventional treatments of schizophrenia, illness of 30 schizophrenic patients who the burden of proof for the complex and participated in it, has no value as a test of highly individualized programs now advo- the methyl acceptor theory of nicotinic cated would appear to be on the proponents acid Consideration of ethical principles of such treatment (p 46) may have kept the investigators from I shall point out below that the repeating the study with use of the principles of medical ethics prevent orthomolecular psychiatrists from with- the score of the 17 children receiving holding from half of their patients a niacinamide was 4 0 units and that of the treatment that they consider to be 24 controls was 2 6 units (there was a valuable Controlled tests can be carried third group of 16 children who were out only by skeptics I now ask whether given a tranquilizer and niacinamide) the task force is justified in saying that The children who were given niacin- the massive use of niacin has been amide showed a 54-percent greater proved to have no value when it is improvement than the children who were employed as the sole variable along with given placebo The groups were too conventional treatments of schizo- small, however, for the difference to be phrenia My answer to this question, significant at the 95-percent level of from a study of the evidence quoted in confidence This study does not prove the report, is that it is not justified that niacinamide has no value Rather it The evidence that niacin has no value indicates that niacinamide has greater is far from conclusive. A beneficial effect value than the placebo, even though it of niacin or niacinamide was reported for fails to show this at the customary level three double-blind studies (two by Hoffer of statistical significance and Osmond and their collaborators [2, 3, 32] and one by Denson [26]) and in 12 open clinical trials by other investigators The Hoffer-Osmond Diagnostic Test referred to in the report On the other hand, the report mentions 7 double-blind Two-thirds of the report relates to studies in which a statistically significant niacin, and one-third to the Hoffer- difference between the niacinamide Osmond Diagnostic Test (HOD) (34), subjects and the controls was not which has no special connection with observed megavitamin or orthomolecular psy- A failure to reject with statistical chiatry except that it was devised by the significance the null hypothesis that the originators of niacin therapy The report treatment and the placebo have equal should have been given the title Niacin value is not proof that the treatment has Therapy and the HOD Test, or published no value. The explicit statistical analysis as two reports, one on niacin and one on of an alternative hypothesis should be the HOD test It would have been still carried out: for example, the hypothesis better for the task force to have discussed that there is a 10-percent or 20-percent megavitamin and orthomolecular greater improvement in the treated therapy in psychiatry fully subjects than in the placebo subjects No such analysis has been published In fact, some of the " negative " studies The Question of Controlled Experiments indicate that the treatment has value. The report states that "Greenbaum [33] The report refers to the low credibility reported a double-blind study of 57 of the megavitamin proponents, whose schizophrenic children who received published results were not duplicated in nicotinamide 1 gm per 50 lbs of body studies carried out by one of the task weight or placebo for six months No force members (p 48) The penultimate statistically significant differences were sentence of the report is, "Their cred- seen in the two groups as a result of the ibility is further diminished by the treatment " (p 11) It is true that no consistent refusal over the past decade to statistically significant differences were perform controlled experiments and to seen, but that is not the whole truth The report their new results in a scientifically principal criterion of improvement in this acceptable fashion" (p 48) study was the increase in the score on a I have talked with the leading ortho- clinical scale of observable behavior molecular psychiatrists and have found categories The average improvement in that they feel the principles of medical

72

I. ethics prevent them from carrying out here) is a pejorative word, and "catch controlled clinical tests, with half of their phrases " is a pejorative expression I do patients receiving orthomolecular not understand why megavitamin therapy in addition to the conventional therapy and orthomolecular treatment treatment and the other half receiving should be called misnomers This con- only the conventional treatment It is the cluding sentence, like many others in the duty of the physician to give to every one book, seems to me to have been written of his patients the treatment that in his in order to exert an unjustifiably unfavor- best judgment will be of the greatest able influence on the readers of the value. Some psychiatrists, including report. Hoffer and Osmond, carried out control- I have written two popular books, No led trials 20 years ago. They became More War! (35) and Vitamin C and the convinced that orthomolecular therapy, Common Cold (24) I feel that each of along with conventional treatment, was them was worthwhile and that neither beneficial to almost every patient From would have been easily replaced by a that time on their ethical principles have more technical book. The second book required that they give this treatment and (24) was written because I had dis- not withhold it from half of their covered in reading the medical literature patients The task force is wrong in that there was much evidence there criticizing the orthomolecular psychiat- about the value of ascorbic acid in rists for not having carried out controlled decreasing both the incidence and the clinical trials during the last few years severity of the common cold and that Instead, it is the critics, who doubt the this evidence had been suppressed or value of orthomolecular methods, who misrepresented by the medical and are at fault in not having carried out well nutritional authorities Since publication designed clinical tests of the book, eight new studies have been It is also the duty of a physician to give reported Every one of these has verified to a patient a treatment that may benefit the value of ascorbic acid The APA him and is known not to be harmful The report shows the same sort of negative incidences of toxicity and other serious attitude as that shown by the authorities side effects of the doses of vitamins used toward ascorbic acid in relation to the in orthomolecular medicine are low. common cold There seems to be a sort There is significant evidence that an of professional inertia that hinders increased intake of certain vitamins may progress benefit the patient It is accordingly the duty of the psychiatrist to prescribe these vitamins for him CONCLUSIONS

Orthomolecular psychiatry is the The Bias of the Task Force achievement and preservation of good mental health by the provision of the The last sentence of the report reads as optimum molecular environment for the follows: mind, especially the optimum concentra- Under these circumstances this Task Force tions of substances normally present in considers the massive publicity which they the human body, such as the vitamins. promulgate via radio, the lay press and There is evidence that an increased popular books, using catch phrases which are intake of some vitamins, including really misnomers like "megavitamin therapy" ascorbic acid, niacin, pyridoxine, and and "orthomolecular treatment," to be cyanocobalamin, is useful in treating deplorable (p 48) schizophrenia, and this treatment has a This sentence, like others in the report sound theoretical basis The APA task shows the presumably unconscious bias force report Megavitamin and Ortho- of the task force "Promulgate" (misused molecular Therapy in Psychiatry dis- cuss vitamins in a very limited way 18 HAWKINS, D : Orthomolecular psychiatry: treatment of (niacin only) and deals with only one or schizophrenia Ibid. pp 631673 19 OSMOND. H.: The background to the niacin treatment two aspects of the theory Its arguments Ibid. pp 194 . 201 are in part faulty and its conclusions are 20 HORWITT. M.K.: Ascorbic acid requirements of in- unjustified dividuals in a large institution Proc Sec Exp Blot Med 49:248-250. 1942 21 HERJANIC, M : Ascorbic acid and schizophrenia. in Orthomolecular Psychiatry: Treatment of Schizophrenia REFERENCES Edited by Hawkins. D., Pauling, L.. San Francisco. W H Freeman and Co 1973 pp 303-315 1 PAULING, L : Orthomolecular psychiatry Science 160:265271. 1968 22 STONE. I: The Healing Factor: Vitamin C Against Disease New York. Grosser and Dunlap 1972 2 HOFFER. A : Niacin Therapy in Schizophrenia Spring- field. Ill Charles C Thomas. 1962 23 PAULING L : Evolution and the need for ascorbic acid Proc Nall Acad Sci U S A 67:16434648. 1970 3 OSMOND. H , HOFFER. A : Massive niacin treatment in schizophrenia: review of a nine-year study Lancet 24 PAULING. L : Vitamin C and the Common Cold San 1:316 . 319. 1962 Francisco W H Freeman and Co . 1970 HOFFER, A., OSMOND, H : Treatment of schizophrenia 25 MILNER. G.: Ascorbic acid in chronic psychiatric with nicotinic acidi a ten-year follow-up Acta Psychiatr patients: a controlled trial Br J Psychiatry 109:294-299. Scand 40:171 . 189. 1964 1963 CLECKLEY, H M., SYDENSTRICKER. V.P., GEESLIN, 26 DENSON, R ; Nicotinamide in the treatment of schizo- L.E : Nicotinic acid in treatment of atypical psychotic phrenia Dis New Syst 23:167172. 1962 states associated with malnutrition JAMA 112:2107- 2110. 1939 27 ANANTH. J.V., BAN. T A., LEHMANN, H.E : Potentia- tion of therapeutic effects of nicotinic acid by pyridoxine SYDENSTRICKER, V.P., CLECKLEY. H.M : The effect in chronic schizophrenics Can Psychiatr Assoc 1 . of nicotinic acid in stupor, lethargy and various other 18:377 382. 1973 psychiatric disorders Am 1 Psychiatry 98:83 .92. 1941 28 EDWIN, E , HOLTEN. K . NORUM, K R , et at : Vitamin KUBALA, A L., KATZ, M M : Nutritional factors in B12 mental diseases Acta Med psychological test behavior .1 Genet Psvchol 96: Scandhy p77689 inoss in 343-352. 1960 29 PFEIFFER. C.C., ILIEV. F . GOLDSTEIN, L.: Blood 8 VANDERKAMP, H.: A biochemical abnormality in histamine, basophil counts and trace elements in the schizophrenia involving ascorbic acid Int J Newer schizophrenias, in Orthomolecular Psychiatry: Treatment Psychiatry 2:204-206. 1966 of Schizophrenia Edited by Hawkins, D.; Pauling. L.. San Francisco W H Freeman and Co 1973. pp 463- 9 HERJANIC, M„ MOSS-HERJANIC, B L : Ascorbic acid 510 test in psychiatric patients J Schizophrenia 1:257-260. 1967 30 Task Force Report 7: Megavitamin and Orthomolecular Therapy in Psychiatry Washington. DC. American 10 PAULING. L., ROBINSON. A.B., OXLEY. S S., et al.: Psychiatric Association. 1973 Results of a loading test of ascorbic acid. niacinamide, and pyridoxine in schizophrenic subjects and controls, in 31 ANANTH, .1.V., BAN, T.A . LEHMANN, H E . et al : Orthomolecutar Psychiatry: Treatment of Schizophrenia Nicotinic acid in the prevention and treatment of meth- Edited by Hawkins. 0.. Pauling, L.. San Francisco. W H ionine . induced exacerbation of psychopathology in Freeman and Co . 1973. pp 18-34 schizophrenics Can Psychiatr Assoc J 15:15-20. 1970 it ROSENBERG, L.E.. LILLJEOVIST, A-C, HSIA. Y.E: 32 IdOFFER. A . OSMOND, H., CALLBECK. M J., and Methyimalonic aciduria: metabolic block localization and KAHAN, I : Treatment of schizophrenia with nicotinic vitamin 812 dependency Science 162:805 . 807. 1968 acid and nicotinamide J Clin Exp Psychopathol 18: 131158. 1957 12 LINDBLAD, 8., OLIN P.. SVANBER G. B.. et al : Methy- Imalonic acidemia Acta Paediatr Scand 57:417-424. 33 GREENBAUM, G H C.: An evaluation of niacinamide in 1968 the treatment of childhood schizophrenia Am J Psychiatry 127:89-93. 1970 13 WALKER, F.A , AGARWAL. A B., SINGH. R : Methyl- malonic aciduria: response to oral 0 12 therapy J 34 KELM, H.: The Hoffer-Osmond Diagnostic Test IHODIi Pediatr 75:344. 1969 in Orthomolecular Psychiatry: Treatment of Schizo- phrenia. Edited by Hawkins. D Pauling. L. San 14 ROSENBERG, L. E.. LILLJEOVIST, A-C, HSIA, Y E , Francisco. W H Freeman and Co . 1973. pp 327.341 et al.: Vitamin 8 1 2 dependent methylmalonicaciduria: defective 812 metabolism in i cultured fibroblasts. 35 PAULING, L.: No More War! New York. Dodd. Mead Biochem Biophys Res Commun 37:607-614. 1969 and Co .1958 15 WILLIAMS. R.J.: Biochemical Individuality Npw York. John Wiley B Sons. 1957 16 PAULING, L , ITANO. H A.. SINGER. S.J et al.: Sickle cell anemia. a molecular disease Science 110:543 .548. 1949 17 HAWKINS. D PAULING, L. lads.): Orthomolecular Psychiatry: Treatment of Schizophrenia San Francisco. W H Freeman and Co 1973

74 SECTION IV— Letter To The Editor

Dr. Pauling Comments on the Comments

Sir: I believe that the comments made In the task force report it is stated that by Drs Wyatt, Klein, and Lipton on my the massive use of niacin "has proved to paper "On the Orthomolecular Environ- have no value when it is employed as the ment of the Mind: Orthomolecular sole variable along with - conventional Theory" (November 1974 issue) help to treatments of schizophrenia " (1, p 46). clarify the question, and I thank the three One of my criticisms of the task force authors for their illuminating discussions. report is that this statement cannot be In my article I concluded that the supported general condemnation of megavitamin Klein stated that "one cannot prove a and orthomolecular therapy by the APA negative assertion, i e , that a drug is no Task • Force on Vitamin Therapy in different from placebo." I gave the Psychiatry (1) is unjustified Wyatt following brief discussion of the concluded that the principles of the question: orthomolecular hypothesis are reason- A failure to reject with statistical signifi- able and might be testable, but that there cance the null hypothesis that the treatment is no good scientific evidence as yet that and the placebo have equal value is not proof megavitamin therapy is beneficial Klein that the treatment has no value The explicit pointed out that society needs to know statistical analysis of an alternative hypo- whether a treatment is effective or thesis should be carried out: for example, the deleterious and that there is an un- hypothesis that there is a 10-percent or pleasant likelihood that orthomolecular 20-percent greater improvement in the methods will continue -to be used in treated subjects than in the placebo subjects psychiatry without adequate scientific No such analysis has been published assessment He mentioned his belief that My statement was so brief that Dr. only programmatic centers can develop Klein misunderstood it. His discussion of the large-scale, adequate, and timely this point began as follows: comparative factorial treatment studies Insofar as I understand his exposition, necessary to answer the many complex Pauling seems to be saying the following: questions in the field of psychiatric care. Consider an experiment that finds that a drug Lipton discussed some of my criticisms of is 30 percent more effective than placebo in the task force report He mentioned the the samples studied, but that the 30-percent need for further evidence only incident- difference could easily have arisen from ally, but I think that he would agree with sampling fluctuations One has no way of Wyatt, Klein, and me that further studies telling this 30-percent sample difference from should be made a true zero-percent population difference Much of Kleins comment dealt with Therefore, the null hypothesis of no dif- the question of scientific inference My ference in the sample populations cannot be conclusion, derived from the published invalidated Pauling says one should also studies, is that there is evidence (al- make a test against the possibility that there though it is far from overwhelming) that is a true 10-percent or a true 20-percent an increased intake of some vitamins, population difference including ascorbic acid, niacin, pyri- That is not what I said Let us consider doxine, and cyanocobalamin, is useful in a study in which niacin is given to a treating schizophrenia and that this sample of 20 subjects taken at random treatment has a sound theoretical basis from a given population and placebo is given to a sample of 20 from the same Reprinted by permission from. the American Journal of population Let us assume that 10 Psychiatry, Vol. 131, pp 1405 1406, 1974. Copyright 1974, the American Psychiatric Association subjects in each sample improve The conclusion might be drawn that niacin are not supported by the evidence I do has no greater value than placebo It is not think that my paper contains any on the basis of studies such as this incorrect or unduly strong statements hypothetical one that the task force In this connection, Klein stated that he reported that niacin has proved to have was baffled by my having appraised a no value. My question was whether a study (2) which both he and I consider to study such as this has shown, at a certain be a poor one that contains methodo- level of confidence (e g , the customary logical errors A main reason for my 95-percent level), that there was less than inclusion of this study was that one of its 10-percent or less than 20-percent greater authors was a member of the task force improvement in the niacin sample than Another reason for mentioning it was in the placebo sample that it is pertinent to orthomolecular Reference to statistical tables shows therapy in psychiatry but was not that, because of possible sampling errors, mentioned in the task force report It was this hypothetical experiment does not a double-blind study and deserved to be eliminate at the 95-percent confidence mentioned both in the task force report level the hypothesis that, relative to and in my article placebo, niacin increases by as much as I pointed out that derivatives of 50 percent the fraction of subjects who pyridoxine are known to be coenzymes improve If niacin and placebo were in for over 50 enzymes and that the chance fact equivalent, studies of much larger of a genotype with need for a large intake samples would be needed before it could of the vitamin is accordingly great. I also be proved with statistical significance stated that there is evidence that that niacin has little value. As I pointed pyridoxine is involved in tryptophan- out, no such analysis has been made to niacin metabolism I described the study justify the statement made by the task (2) and quoted the statements made by force about niacin I have not made a the investigators about their results as thorough statistical analysis of the niacin well as a comment by Hawkins I did not studies that are described as giving appraise the study myself; Klein errs in negative results, but the rough cal- saying that I did I quoted the statement, culations that I have made indicate that "On balance, these results suggest that they do not reject at the 95-percent the addition of pyridoxine may potenti- confidence level an effectiveness of ate the action of nicotinic acid Thus niacin as great as that claimed by the pyridoxine seems to be a useful adjunct proponents of megavitamin therapy to nicotinic acid therapy" (2), which was Klein wrote that "one further problem made in an article that was coauthored is Paulings incomprehensible accept- by a member of the task force but was ance of very minimum differences that omitted from the task force report. lack statistical significance as solid Both Klein and Wyatt discussed my evidence of therapeutic efficacy " I feel reference to the work of Greenbaum (3), that this remark distorts the facts I have who reported no statistically significant said that there is evidence that mega- differences in a double-blind study of vitamin therapy has value It is not schizophrenic children receiving niacin- necessary that the results of a study be amide or placebo Klein stated that I significant at the customary level of pointed out that the children given p 05 (which is quite arbitrary) in order niacinamide showed greater positive to constitute evidence There are recog- gains on a critical scale than the control nized methods for combining the results subjects, although not at a significant of several independent but similar level He also pointed out my statement studies with low statistical significance that the study "indicates that niacin- into a result with higher statistical amide has greater value than the significance I have criticized the task placebo, even though it fails to show this force for making strong statements that at the customary level of statistical

76 significance " Klein responded to this statements about the ethical questions with the following statement: associated with experiments on human This seems utterly incorrect The mere beings I see no reason to change my fact that one sample had a bigger effect than opinion on this matter another sample does not justify the statement that "niacinamide has greater value than REFERENCES placebo," since this is a statement that 1 Task Force Report 7: Megavitamin and Orthomolecular generalizes to the population relationship Therapy in Psychiatry Washington. DC. American Psychiatric Association. 1973 Klein is wrong in suggesting that my 2 ANANTH, J.V , BAN, T.A., LEHMANN, H.E : Potentia- statement or argument is incorrect, tion of therapeutic effects of nicotinic acid by pyridoxine although of course it may have seemed in chronic schizophrenics Can Psychiatr Assoc .1 18. utterly incorrect to him. First, I did not 377-382. 1973 state that niacinamide has greater value 3 GREENBAUM, G H C.: An evaluation of niacinamide in the treatment of childhood schizophrenia Am J than placebo; what I said was that the Psychiatry. 127:89.93. 1970 Greenbaum study indicated that niacin- Linos Pawling, Ph.0 amide has greater value than placebo, Menlo Park. Calif even though it failed to show this at the customary level of statistical signifi- cance Even if the study had indicated a greater value for niacinamide at the p < 05, p <01, or p < .001 level, I could not have said simply that the study proved niacinamide has greater value. I could state only that it indicated this at a certain level of statistical significance. There is nothing holy about the 95- percent level of confidence. A study may provide evidence whether or not it reaches this conventional level Greenbaum s paper (3) permitted only a rough estimate to be made of the p value for this comparison of his niacin- amide and placebo subjects. The value of 37 given by Wyatt (obtained from Greenbaum) corresponds to p < 18 by a one-tailed test The value of p (one- tailed) is pertinent to the question of whether the samples showing higher scores for niacinamide ; than for placebo subjects correctly represent the popula- tion from which they were drawn or whether they represent a statistical fluctuation associated with the selection of the samples from the population. There is an 18-percent chance that such a fluctuation would occur; that is, accord- ing to this calculation, it is five times as likely that niacinamide would give better results than placebo in the whole population than that the two are equiva- lent Greenbaums observation. might si mply be the result of a sampling error.. Both Wyatt and Klein criticized my

77 SECTION V—Hoffer and Osmonds Comments on R. J. Wyatts Comment (1974) on L. Paulings report:

On The Orthomolecular Environment of carefully calculated decision not to do the Mind: Orthomolecular Theory any more If psychiatrists are going to We wonder why Wyatt bothered to disbelieve our four double blinds, why write his comments since they are merely should they believe another hundred if opinions lifted holus bolus from the Task we were disposed to present them? Force Report Since he makes exactly the His economic argument is totally same errors it suggests he did not bother fallacious since it is comprised of: to read the original reports His criticisms (1) the number of visits to a psychiatrist are these: which are required much less frequently (1) That H Osmond in a brief back- with orthomolecular therapy; (2) fewer ground paper on orthomolecular psych- admissions to hospitals; (3) recovery to iatry did not reprint the massive data we the point they are able to pay substantial have published in a large number of income tax as lawyers, doctors, and so papers since 1957 on We challenge Wyatt to show us a (2) That we did not again repeat all this series of schizophrenics who have re- data in our suicide paper where we covered to this degree on tranquilizers restricted it to show how orthomolecular alone treatment markedly decreased the Wyatt reports that three studies on suicide rate acute cases failed to show significant (3) That we exaggerated the safety of i mprovement with niacin or niacin- vitamin B3. He referred to a report by amide An examination of the three Chinaglia that five out of 14 patients references showed the following One of were taken off vitamin B3. He referred to them was a paper by Meltzer et al , who the Ban-Lehmann studies showing the used NAD (which is not the same as need for phenothiazines was apparently either niacin or niacinamide and which increased and to Wittenborns pigment has different dose requirements). The studies Nowhere does he refer to the second paper is a study by Ananth et al. massive evidence available in the litera- on chronic patients only In the title of ture showing that vitamin B3 is much this paper it is clearly shown that this was freer of toxic reactions than any tran- a study on chronic patients The last quilizer He does not refer to the huge reference is to a nonpublished report. In coronary study where out of several a brief communication by McGrath a thousand cardiovascular cases on nicot- large number of acute and chronic inic acid no cases of acanthosis nigricans patients were treated with niacinamide were reported, nor that in no one elses only, but only one-third of this group series has such a large proportion of the were acute Thus, on close examination series had these innocuous skin changes of Wyatts statement one finds that his He does not refer to Wittenborns group statement "there are three studies (12, who found no increased need for pheno- 16, 21) in which acute schizophrenics thiazines, thus refuting Ban and Leh- were given niacin or niacinamide" is mann totally wrong. He is also contradicted by Wyatt thinks the fact we have reported a recent editorial in the Canadian no further double blinds in 10 years is Psychiatric Association Journal 20, 97- data against the efficacy of ortho- 100, 1975 molecular therapy He is unaware that we (1961, 1963) have been very critical of Comment on D. F. Klein (1974) double blinds from a theoretical and We totally disagree with Kleins thrust practical point of view We made a which seems to be that only when the scientific community has accepted an dyskinesia, thought blocking, and at- idea is it a useful fact He ignores the tempted suicide (many successful), sex- history of medicine which shows that a ual impotency, and a variety of neuro- large number of very useful treatments logical disorders in patients referred to us currently acceptable were exposed to as who have already been on tranquilizers much criticism for as long as is ortho- for many years Every year we have to molecular psychiatry There have been deal with intelligent patients immobili- gaps of 40 years and more in medicine zed by their constant tranquilizer medi- between a discovery and its application cation, oral or parenteral, who are totally In addition, he presents no evidence the unproductive We would rather deal with psychiatric and scientific establishment the occasional case of nausea and are the same Very few psychiatrists are vomiting, with the ubiquitous initial scientists, nor do they claim to be so vasodilatation produced by nicotinic Very few bother to read original material, acid, with the occasional allergy to the being content to read erroneous reviews tablets, and with the infrequent benign such as the one produced by the APA case of hyperpigmentation The undesir- Task Force committee able side effects of vitamins are minor Since the first double-blind compari- irritants and have never caused death son experiments in psychiatry were The undesirable side effects of the conducted under our direction using a phenothiazines and their toxic reactions design which is still considered the way would require a volume to report and to one does these experiments, we find it describe There can be no comparison hard to understand how Klein can fail to between the undoubtedly toxic tran- accept conclusions from our first double quilizers which the committee accepts as blinds while accepting the so-called the best that modern psychiatry can offer double blinds of Wittenborn and Ban and for schizophrenia and the minor side Lehmann The studies he favors were at effects of vitamins Perhaps this is why best semi-blind, but it would be Lipton does not present any comparable thoroughly dishonest to consider them data for toxicity as he does so frequently double blind when patients were so for efficacy easily identified by the flush His concluding statement is mistaken. If Klein were motivated to use his There is, on the contrary, increasing position as Director of Research to repeat evidence that vitamin therapy now used our work as described, i e , similar over 20 years for some patients has not patients, the same treatment, and the only not caused any harm to the patient, same method of evaluation, he would do but has instead so sharply reduced the much to settle the controversy Action, dose of tranquilizer required that even not good advice, is required these toxic drugs can be used with safety The final result of many years of Comment on Lipton (1974) tranquilizer medication has been the Liptons arguments are what one would production of the perfect human con- expect from one of the most violent and sumer, of welfare, of nursing support, bitter opponents of orthomolecular treat- medical support, community psychiatry, ment His arguments are, as they have and with no hope of ever being any always been, irrelevant and trivial, better Has Lipton ever studied the especially his views on toxicity As fantastic costs to patient and community clinicians who have used megadoses of of perpetually chemically produced vitamins since 1952, we are in a stronger tranquility—of the perfect chemical position to judge their relative toxicity straight jacket? than Lipton who has not yet given any megavitamin treatment to patients Every year we are confronted with cases of jaundice, blood dyscrasias, tardive SECTION VIComments on the Double- Blind (Placebo) Methodology

We will summarize the ideas of those deduction they succeed in building a who are not enamoured with double- system which is logical but which has no blind techniques as the only ones avail- sort of scientific reality Superficial able to physicians This we do to persons often let themselves be dazzled illustrate that there is a good deal of by this appearance of logic; and dis- opposition toward accepting placebo cussions worthy of ancient scholasticism experiments (all double-blind experi- are thus sometimes renewed in our day " ments must eventually begin with one "Men who have excessive faith in their containing a placebo) as the only valid theories or ideas are not only ill prepared method for judging the efficacy of for making discoveries but they also treatment or of drugs Since the com- make very poor observations " mittee accepted only experiments they But it happens further quite naturally considered to be double blind, even that men who believe too firmly in their when they were not, these ideas sum- theories do not believe enough in the marized here provide an attack upon the theories of others So the dominant idea committees basic notion. It was this of these despisers of their fellows is to erroneous premise that permitted them find others theories faulty and to try to to ignore a vast amount of clinical data contradict them The difficulty for corroborating orthomolecular therapy science is the same They make experi- The onus remains with them to present ments only to destroy a theory, instead of data proving that the double-blind to seek the truth At the same time they experiment really is an effective method make poor observations because they for sorting efficacious from noneffective choose among the results of their treatments We will begin with a few experiments only what suits their object quotations from Claude Bernard, the By these two opposite roads men are pioneer in the development of clinical thus led to the same result, that is, to controlled experiments falsify science and the facts " Bernard, Claude. An introduction to the "It is said that coincidence may play so study of experimental medicine. Trans- large a part in causes of statistical errors lated by H. C. Greene, first published that we should base conclusions only on 1865. Available from the MacMillan Co., large numbers What a physician needs 1927, New York. to know is whether his patient will "It is therefore clear to all unpre- recover and only the search for scientific judiced minds that medicine is turning determinism can lead to this knowledge toward the permanent scientific path By But when determinism increases, statis- the very nature of its evolutionary tics can no longer grasp and confine it advance, it is little by little abandoning with a limit of variations There we leave the region of systems, to assume a more science for we are forced to invoke and more analytic form and thus chance or an occult cause to regulate gradually to join in the method of phenomena. I therefore refuse to investigation common to the experiment- acknowledge that science has a place for al sciences " men who make criticism their specialty, "These men (talking about system- as in letters and in the arts To be really atizers) start in fact from an idea which is useful criticism in every science must be based more or less on observation and done by men of science themselves and which they regard as an absolute truth. by the most eminent masters." They then reason logically and without "Pure contradiction would amount to experimenting and from deduction to an accusation of lying and we should so avoid it because happily scientific falsi- trial Editors refuse new and promising fiers are rare As such cases moreover work unless accompanied by an adequ- have no connection with science, I need ate series of normal controls, except an not offer any precept on the subject I occasional article from the right source, wish merely to point out here that if in fine with what is accepted by the science does not consist in proving that authorities One editor stated over his others are mistaken; it can be a profitable signature that case reports would not be work for science only insofar as we show considered as evidence! how he was mistaken." "An American when told about a new "Physicians often pride themselves on idea usually asks, What is it? but the curing all their patients with a remedy Canadian asks, Who is doing it? that they use. But the first thing to ask However, one American editor said his them is whether they have tried doing magazine never reported clinical nothing, i e , not treating other patients; material not accompanied by suitable for how can they otherwise know controls Concerning a disease known to whether the remedy or nature cured be always fatal within five years, would them From all this I conclude that he not report 10 cases who lived 10 years comparative observation and experiment with a certain treatment, but would are the only solid foundation for experi- publish five cases if the other five had mental medicine " been allowed to die in the accepted manner? Absurd, you say! Control- worshiPpers are a bit absurd! But there are signs of rebellion against their retarding progress any longer Atkins, A. Conduct of a controlled "In science a controlled experiment clinical trial, British Medical journal 2, means every variable is held steady 377-379, 1966. except that being studied This is "If there are problems—ethical, impossible in clinical medicine! In the scientific and even mathematical— average controlled clinical observations associated with controlled trials it never- are the following equally balanced? theless remains the case that this Nutrition, smoking, drinking, sexual or technique holds out greater promise for marital adjustments, pregnancy, pre- advance in therapy than any yet devised vious medication or treatment, desensit- More important, however, is it that ization or immunization, differences in recognition of the scientific basis upon social classes (affecting precautions, which such trials are constituted will exposures, cleanliness, natural vac- insure so far as is possible that the cination from exposure, plumbing), undesirable state of affairs prevailing in blondness, or brunetteness, size, body medicine during the first half of this build, mental type, inheritance, etc century will never be repeated to the How controlled is an experiment which extent of producing so many false trails assumes none of these affects the result? and so many unnecessary and unworthy "The value of the so-called double- modes of therapy " blind study is much questioned today by many thinking writers, who suggest the following: It is not a foolproof mechani- cal means of insuring a correct interpret- Baird, K, A. Medicines Domination by ation of result It may mislead as well as the Control Worshippers. Canadian lead The objectivity of the double-blind Doctor, page 27, 1968. study is a medical illusion It is time that "The Establishment in Canadian the double-blind approach be prevented Medicine insists on the method of from developing into a triple-blind controls, especially what Gilder called disaster The use of the double-blind one of the fetishes of experimental technique does not guarantee the medicine the double-blind clinical sanctity of the trial " 81 Baird, K. A, Assessment of Reports of of placebos in the clinical evaluation of Drug Trials. Canad. Med. Ass. ). 90, psychotropic drugs in a number of 1279, 1964. instances a source of error He argues "The insistence in recent years on that unless the placebo is administered in blindness or double blindness in eval- such a fashion that an observed emergent uating the effect of therapy is an insult to can be clearly linked either to the the intelligence of the average clinician. placebo, the test substance, or both, Most new drugs today provide sympto - then obviously administration of the matic relief and are not curative. The placebo has been fruitless and any ultimate observation is made by the consideration of the validity of the given patient, who alone knows whether or not result merely because placebo was given he is relieved of his subjective symptoms. is unwarranted. Moreover, he claims Relief due to psychotherapy and sug- another pitfall arises from the necessity gestion is nonetheless relief that the placebo itself has to be rigidly "Use of a placebo is based on the controlled. If orally given it must have assumption that the placebo has no physical characteristics analogous to the effect or that its psychotherapeutic effect active medication and it has to be will equal that of the drug being tested. administered in the same fashion with Neither assumption is necessarily true In identical procedures as the real drug. the Proceedings of the Royal Society of "From a theoretical point of view, in Medicine (The Placebo and the Clinical human beings where transaction of Trial, 57: 67, January, 1964) James processes are present, a double-blind Parkhouse points out that the physician controlled study seems to be essential to himself cannot escape being a placebo to eliminate the bias that might be intro- some extent: but that in any case, One duced through feedback mechanisms of the first things to be realized, between the observed and the observer therefore, before embarking lightheart- (11) However, in Batterman and Gross- edly upon the use of a placebo is that far mans experiment the double-blind from clarifying the issue it may merely method for some unknown reason add confusion " obscured the presence of an actually existing pharmacotherapeutic property Ban, Thomas, A. Methodology and of the drug which arose when they Pitfalls in Clinical Testing of Psycho- switched to a single-blind placebo trial. pharmacological Drugs, Chemotherapia Furthermore in Uhlenhuths experiment 9, 223-230, 1964. the therapists attitude broke through the "The asylum clinician has such great double-blind experiment and Hoffer and advantages in regard to the observation Osmond (8) argue that the double- of the action of these medicaments that blind method, when the group under it is a neglect of opportunity if he fails to study is not homogeneous, may obscure lead and instruct the whole medical the presence of significant differences profession in this respect In private or "It is really unfortunate that the out-patient practice, and even in statistical method also has its own pitfalls ordinary hospitals and sanataria, the (5) Some of these were expressed by results of any mode of treatment are Huntsman by the following: the prestige liable to be vitiated by variations of diets of mathematics is so great that many and habits of life, which are entirely persons forget that even in mathematical beyond the ken of the physician In the hands, probability, chance and random hospital for the insane, on the contrary, mean ignorance They come to think that the diet and habits are under almost in the alembic of mathematics chance in absolute control, and observation on the some way becomes certainty They take results of treatment should be much great care to select random samples more reliable " without realizing that insofar as a sample "Bigelow considers the administration has been random, they dont know how it

82 was selected (9) A more severe criticism of the study and must be followed was launched in the Lancet by Wiener meticulously to the end It would quite recently (1962) (14) According to obviously be absurd if these types of him, many clinical investigators because studies should become the law of the they are unduly sensitive or insecure land " regarding their lack of mathematic training and knowledge habitually hand Cromie, B. W. The Feet of Clay of the over all their data to biometricians for Double-Blind Trial. Lancet 2, 944-997, analysis in order that their papers may 1968. include the appropriate tests, standard "After generations of doctors have errors and so on In that way they have accepted without question the opinion of come to depend more and more on the great names in medicine, a change mathematicians who have no knowledge has come about so that little or no or understanding of the subject to credence is now given to clinical interpret their findings, instead of relying observations even by experienced in- on their own experiences and common vestigators. This change in official at- sense Wiener concludes that mathe- titude is probably a step in the right matics is a poor substitute for accurate direction, but one wonders whether the observations, reliable experimentation, pendulum has not swung a little too far, and common sense " allowing a blind acceptance of double- blind trials without a critical evaluation Bellak, L, and Chassan, J, B. An of their shortcomings and their ability to Approach to the Evaluation of Drug mislead as well as to lead " Effect During Psychotherapy: A Double- Blind Study of a Single Case. J. Merv. Dinnerstein, A. J., Lowenthal, M., and Ment. Dis. 139, 20-30, 1964. Blitz, B. The Interaction of Drugs with "There has long been abroad in the Placebo in the Control of Pain and land of clinical research the notion that Anxiety, Perspectives in Biology and comparisons between groups of patients Medicine, 10, 103-117, 1966, is the sine qua non of statistically valid "For scientists attempting to under- scientific clinical research, and that the stand the action of analgesic and study of the individual case must be psychoactive drugs, it is suggested that relegated at best to a status of intuition the simple double-blind study is not an and the clinical hunch, not capable of adequate experimental design. A given statistical testing and validation For drug may produce opposite directions of reasons that have been discussed in some effect on pain or anxiety in different detail (5, 6) this view is seen to lack emotional and instructional contexts. It validity in its own right It has unfortun- may produce opposite directions of ately tended to perpetuate a basically effect in different subjects within the superficial methodology as a unique same objective context. The simple prototype for science in clinical research double-blind study, employing a single with mental patients " set of instructions and subjects treated as a random variable, is thus inadequate in Cotzias, G, C. New Eng. J. Med. that it provides no hint concerning the Limitations of Controlled Double-blind degree to which the observed drug effect Studies of Drugs. New Eng. J. Med, 287, is dependent on contextual, instruction- 937, 1972. al, and subject variables." "In double-blind evaluations of drugs neither the patient nor the physician can know what is being administered; such Feinstein, A. R. Clinical Biostatistics IX. studies are also called controlled when How do we measure "safety and ef- the patients are randomly assigned to a ficacy?" Clin. Pharmacol, and Therap, placebo and a drug-receiving group. The 12, 544-558, 1971. protocol is formulated at the beginning "My purpose in this essay is to show that our act of faith is a delusion The the complex, crucial data that distinguish methods do not exist There are no a person from a dog or a field of wheat. satisfactory standard procedures for "The treatment of patients requires assessing the safety and efficacy of attention to at least three issues that drugs Despite general acceptance, the become paramount in experiments where existing techniques are oversimplified, the material is a person: (1) of the naive, and grossly inadequate for the many things that can happen when a needs of clinical medicine person is treated, which will be chosen as "These intellectual maladies of clinical the indexes of accomplishment; (2) from therapy cannot be cured merely by the the many changes observed in these further application of inappropriate indexes, how do we rate each change for statistical theories, by crash programs its desirability as good or bad; (3) how do and bureaucratic fiats, or by recom- we combine these multiple individual mendations from scientists who have had ratings of desirability into a single rating little or no personal responsibility for the that represents the final decision? The continuing care of patients The pro- controlled, statistical randomised pro- blems arise in clinical activities, and can cedures do not currently provide data to be best perceived and solved by con- answer these questions noisseurs of those activities "There are many scientists in academic "The public will continue to demand or government advisory positions today regulations that assure the safety and who seem to prefer a 5 percent efficacy of pharmaceutical therapy and improvement rate which seems scientifi- regulations will inevitably be created in cally pure to a scientifically impure response to this demand Without modif- rate of 68 percent ication of current procedures, however, "Fortunately, of course, aspirin had the regulations will succeed in replacing been used for decades before develop- clinical experience that is scientifically ment of our current scientific doctrines unspecified by scientific statistics that Millions of people already knew about are clinically worthless If academic and aspirins many benefits and recognised its practicing clinicians want these regula- hazards as relatively infrequent and tions to be both scientifically meaningful slight Aspirin has been appraised and and clinically sensible, the clinicians deemed beneficial by an empiric but cannot continue to evade their own balanced scheme of assessment that is paramount responsibilities while com- sometimes called common sense plaining about the work done by the Aspirin might never be approved if statisticians, pharmaceutical companies, subjected to the unbalanced assessments and federal personnel to whom the used in modern therapeutic science. responsibilities have become allocated "A different problem in balance relates by default " to evaluations performed by experts usually chosen from the ranks of Feinstein, A. R. The Need for Humanised academic scientists and clinicians work- Science in Evaluating Medication. The ing full-time at a university or other Lancet 2, 421-423, 1972. research institute An academician "These principles of biometric science seldom sees the patient or the patients have proved suitable for the experiment- family at home, and seldom follows a al goals and data encountered with the patient for an extended period The total animals or agricultural crops for which picture of human therapy—with all its they were developed However, they do effects on performance, convenience, not deal with scientific problems in anticipation, family, and economics— selecting the type of information that is will not be regularly seen by an academic to be appraised in the therapy of sick specialist. people In particular, biometric methods "The evaluation of all the humanistic do not contain provision for evaluating data associated with therapy will there-

84 fore require additional judgments from ly higher clinical improvement rates than sources outside the academic or govern- did short-term studies, demonstrating ment enclaves These sources will in- that duration of therapy, as well as clude full-time practising doctors, degree of blindness, may be a very patients, and others who are familiar meaningful variable in determining with the total picture These consultants clinical outcome may not be connoisseurs of current "Duration of therapy was significantly doctrines in science, and may not speak related to degree of blindness in that the magisterial language of statistics, but only one of 11 double-blind studies was they can often provide experience, long term and only four of 16 single- wisdom, and common sense in a blind studies were short term situation for which contemporary "Long-term, single-blind studies science is inadequate This type of showed appreciably higher clinical consultative judgment will be especially improvement rates than did short-term, necessary in evaluating over-the-counter double-blind studies The very meager medications in which doctors do not number of long-term, double-blind participate and for which all of the studies (1 only) and, to a lesser extent, of anticipation effects occur in the patient short-term single-blind studies prevented "Until the methods of science are us from differentiating between degree of made satisfactory for all the important blindness and duration of therapy distinctions of human phenomena, our regarding their relative impact on best approach to many problems in improvement rates Thus, no clear-cut therapy will be to rely on the judgments certain evidence could be adduced either of thoughtful people who are familiar to support or nullify the contention that with the total realities of human ail- the double-blind, placebo-controlled ments Human testimony and human method is, per se, a necessity for the judgments are not objective; they may accurate clinical evaluation of a drug. not be precise; and they are often "We were unable to demonstrate a fallible At this stage in the development general decline in improvement rates of human science, however, our primary with the passage of time Thus we could challenge is to assemble information that not validate the commonly held belief of is meaningfully human, even if scientifi- a progression from an initial over- cally imperfect We shall advance the enthusiasm to a later realism in the progress of neither science nor humanity subjective evaluation of a drug " by obsequious adherence to scientific doctrines that provide quantitative glitter Lasagna, L. The Impact of Scientific and statistical significance, while de- Models on Clinical Psychopharmacol- humanising our data, confusing our ogy: A Pharmacologists View. Seminars sensibility, and diverting our attention in Psychiatry 4, 271-282, 1972. from the people who are the only proper "A third general area is the worship of subjects for the study of mankind " the controlled trial. Having spent a lot of time in my life arguing on behalf of the controlled trial, I think I know its values Glick, B. S., and Margolis, R. A study of as well as its limitations I am sorry that the influence of experimental design on so many people have overbought the clinical outcome in drug research. The concept of the controlled trial and that Amer. J. Psychiat. 118, 1087-1096, 1962. other valid ways of acquiring evidence "Those studies which included within have been neglected L-dopa is an their structure the double-blind, example of how a drug can be rated as placebo-controlled technique showed ineffective on the basis of poor double- significantly lower clinical improvement blind controlled trials, several of which rates than those which did not. were done early in its history. Because "Long-term studies showed significant- inadequate dosages were used for in- adequate periods of time, there was no ference exists between treatments be- significant effect. It was on the basis of cause the population has been chosen in uncontrolled trials of L-dopa (as well as the wrong way, because the numbers are on all the beautiful logic and experiment- too small, because the observations were al data that preceded it) that one came to too sloppy, or because the patients failed the conclusions, and rightly so, that this to take their medication If a new drug drug was a dramatic therapeutic ad- has been compared against placebo, one vance We have only to remind ourselves may erroneously conclude that the drug that all sorts of highly important psycho- is inefficacious, since the errors sug- active agents such as barbiturates, gested above will tend to prove the null meprobamate, chlorpromazine, imipra- hypothesis mine, etc , were discovered by ways "(h) Professional judgment and the other than the formally controlled trial " marketplace. Popularity among the public or among physicians is not tantamount to worth On the other hand, Lasagna, L. The nature of evidence. there are interesting examples of drugs Triangle 11, 145-152, 1972. that have sold well despite an absence of "(a) Anecdotal or uncontrolled advertising, or compounds that have observations. Usually these phrases are failed despite a good deal of advertising, used in a pejorative sense, despite the and suggest that the physician or the fact that such observations constitute the patient is not completely devoid of oldest method for studying drug actions discriminatory ability It is generally and remain a mainstay even today The assumed that expert anecdotal judg- point too readily forgotten is that they ments are better than non-expert are in fact not uncontrolled The control anecdotal judgments, despite the fact consists of what the observer believes that there are some compelling instances would have occurred in the absence of where the practising doctor has discover- the drug ed truths that the experts failed to "(d) The comparative randomized recognize. trial. This approach is relatively new. The "Schneller has recently suggested that so-called trial in the Book of Daniel in experts in the science of clinical investi- the Bible or the famous trial by James gation are not the same as experts in the Lind on H. M.S Salisbury on citrus fruits art and science of treating patients He and scurvy are really not modern trials in states: For the one kind of expert to the strict sense! For example, Linds dominate the drug usage of the other is experiment would be criticized today like a Sebring race driver setting the because of a difference in baseline operating regulations for New York City variables in his therapeutic groups He taxicab drivers took two patients very sick with scurvy "It is my contention that three or four and purposely assigned them to the citrus well-done trials by people who are expert fruit diet, which he suspected would be in a field, with conclusions that are beneficial The therapeutic results were similar, is enough to demonstrate that a dramatic, but the supersceptic could drug has effectiveness. The accumula- have accused him of using a population tion of thousands of patients often that was destined to irnprove because serves, I believe, merely to provide they had nowhere to go but up! (They psychological comfort. could have chosen to die, of course, but "Weiner has suggested that for drugs such trivial points have been known to be used for a long time with apparent completely ignored by a supersceptic success and without evidence of signifi- with blood in his eye ) cant toxicity, the burden of proof should "There are many ways in which be on those who claim that such drugs do controlled trials can go wrong One can not work 3 come to the conclusion that no dif- "It is quite possible that the new

86 developments in regard to substantial be criticized in the future The double- evidence are carrying us farther and blind technique is most cherished by farther away from the real-life situations those professional people who have in which drugs are ultimately to be the least contact with patients It is rare applied. Certainly most drugs are not to find clinicians who enjoy doing double given under the circumstances of double- blinds, believe the results of double blind technique, obtaining informed blinds published by others, or defend consent, hospitalization, the avoidance them in any public debate of other simultaneous therapies, the It is unlikely that double-blind experi- application of drugs by experts, etc " ments really are double blind for even what appears to be a simple task of Plutchik, R,, Platman, S, R., and Fieve, preparing placebo tablets, similar in R. R. Three Alternatives to the Double- every respect to tablets containing the Blind. Arch, Gen, Psychiat, 20, 428-432, active medication, may be extraordinar- 1969. ily difficult Joyce (1968) remarked that "This double-blind method has been in none of the 20 clinical trials he had criticized on several grounds. First, in been involved in had the first attempts of many cases drugs produce side effects the manufacturer at identical formula- which are easily noticed by the evaluat- tion been successful Hill et al (1976) ing psychiatrist These effects immedi- studied 22 pairs of agents used in ately eliminate his blind condition and published double-blind controlled enable his expectations to begin to affect experiments A panel of four observers his judgment Since differential side found only five pairs so closely matched effects are an almost universal con- they were indistinguishable, but in seven comitant of any therapeutically pairs all four observers detected obvious efficacious drug, it is practically impos- differences This is not very encouraging, sible to keep an observant psychiatrist but even worse is the fact that the really blind to the medication being medication may cause changes in the used person which are easily distinguishable "A second argument against the Some agents discolour the urine (rif- double-blind technique is that it creates ampin or riboflavin), stain the linen a highly artificial situation which has (p-aminosalicylic acid), or produce phy- little relevance to the clinical setting in siological reactions such as the flush which any drug would actually be used. (vasodilation) of nicotinic acid The cold, impersonal evaluation of Hill et al concluded, "it may be very changes is not typical of clinical contact difficult to produce indistinguishable In the language of stimulus sampling preparations for use in double-blind theory, such evaluation has little trials and that as a consequence such ecological validity 5" studies are often not double blind at all " They add, "The facts that stand out are that, unless the organization of the study is appropriate, the interpretation of the results may remain in doubt and that the Clearly there is a growing recognition double-blind study is an idol which may that the double-blind technology is only and often does have feet of clay " one of a number of methods for testing We have presented our views in several drugs and that it has so many errors and published papers Our conclusions arose biases that it ought to be used sparingly from our experience with double-blind and with scepticism It will never replace experiments which we began in 1952, clinical judgment although it may con- long before most psychiatrists had the tinue to serve to allay the anxiety of slightest idea what the method was We editors and government officials who have not been able to find any double- need reassurance their decisions will not blind study in psychiatry which preceded ours Dr. A Shapiro in his extensive equivalent to Flemings discovery of search of the placebo literature has not penicillin.2 This statement by a surgeon, been able to find any one either, at least who freely admitted that the double- he has not been able to support by any blind method had no place in surgical reference to the literature his thoughtless research, indicates how convinced some statement made in a letter to JAMA that physicians are that this method will we were not the first We are still waiting prevent serious errors in the development for his statement admitting his error of new treatments, and will lead us to which he seems reluctant to make new heights in therapeutic discovery Rather than prepare a new discus- According to Atkins, every therapeutic sion we will reprint a major portion of our discovery made before 1945 was made by paper, "Some problems of stochastic researchers of Nobel calibre such as Lind, psychiatry," J Neuropsychiatry 5, 97- who discovered that oranges and lemons 111, 1963, as well as the paper, "A could cure scurvy Since we have double- Theoretical Examination of Double- blinds, we need no longer depend upon Blind Design" by A Hoffer, Can Med. these sporadic occurrences of geniuses to Ass. 1 97, 123-127, 1967 discover even better therapies We need The reader should note that our papers no longer breed Harveys, Pasteurs, were written and published long before Ehrlichs and Flemings the APA Task Force Report 7 on mega- I wish I could agree with this optimistic vitamin therapy was published It does view It is my thesis that controlled not appear that in their inadequate experiments are not new, that they go examination of the megavitamin litera- back certainly to Lind, that our Nobel ture they recognized the importance of laureate colleagues have always used our objection to the methodology by controlled experiments, that the only which they came to set such store thing new is the "double-blind", and that However we need not be surprised by this this double-blind addition has created so omission for as we have noted here, Dr many new difficulties and errors that it Thomas Ban, one of the Task Force should be re-examined carefully and members, apparently shares our sceptic- rigorously. ism when not engaged in his Task Force A surprising number of younger duties scientists are convinced that controlled experiments are new in medicine. This may be a reflection of our ignorance of medical history and the rapid adoption A Theoretical Examination of Double- by governments, grants and editorial Blind Design committees of the false idea that only A Hoffer, MD,Ph D,F.APA, double-blind clinical experiments are CRCP.[C], controlled experiments A double-blind Saskatoon, Sask experiment is one in which neither the people evaluating the results of treat- Recently an eminent surgeon wrote ment nor the subjects being evaluated that A Bradford Hills contribution to the know whether they have been given an design of controlled experiments was inert substance or a substance shown in previous pilot experiments to be active Director, Psychiatric Research. Psychiatric Services One may compare two active sub- Branch, Department of Public Health, located at stances, but, in the end, reference must University Hospital. Saskatoon. Saskatchewan be made to the placebo for base-line Supported by the Psychiatric Services Branch, Depart- ment of Public Health. Saskatchewan, and by the activity Department of National Health and Welfare. Ottawa To equate double-blinds with a con- Mental Health grant ) ( trolled experiment leads many to assume Reprint requests to: Or. A Hoffer. BOO Spadina Crescent East. Saskatoon. Saskatchewan. that once an experiment is "blinded" no Reprinted by permission of the editor of the Canadian other controls are required. It is more Medical Association Journal accurate to talk about comparison

88 experiments since one treatment is There are, of course, ethical and practi- compared to another Comparison cal difficulties as well experiments may be open, single-blind, double-blind, or if you like, multiple- 1. Role of Probability Theory blind. Probability theory was invoked as a Comparisons between treatments have way not only of randomizing groups, but been made by physicians for centuries of determining the significance of a The history of discovery in medicine is finding; that is, a statistical test was the history of trial and error, and made to see if the results observed could recognition of error indicates that com- have by chance occurred with an parisons have been made. A controlled inactive drug. But no clinical trial experiment was reported by Pare in the satisfies two of the basic theorems upon seventeenth century when he compared which probability theory is based This the effect of crushed onions on burns by matter was recently discussed by Hog- applying them to only half the body Lind ben.15 Probability theory was developed in 1747 compared the effect of two partly as an aid to English noblemen, oranges and one lemon per day on two who wished to win at the gaming tables scorbutic patients against the effect of in Monte Carlo According to Hogben, " a standard treatment in 10 cases. Only the calculus of probability is relevant to the two recovered Claude Bernard frequent- real world (a) only in so far as it specifies ly discussed the need for controlled frequencies of observable occurrences in experiments and, of course, men like an indefinitely protracted sequence of Pasteur and Ehrlich performed only trials, (b) only if also such occurrences comparison experiments Claude Bernard collect a sequence wholly devoid of pointed out that a comparison group (his order " Neither one of these essential word) should provide an estimate of the conditions is present in clinical trials natural remission rate Any treatment When one gambles with dice, it is must do better than this if it is to have possible to use dice manufactured to any value in medicine precise standards One can assume that a Theoretically the double-blind method man one thousand years from today who is designed to test the efficacy of a drug throws these dice by carefully prescribed free of the influence of bias in the techniques will come up with the same observer and faith in the patient It is probabilities, i e the dice have been assumed that bias and faith confound the made invariant; but every biological results of other kinds of comparison phenomenon is subject to minor and experiments. major cyclical changes Since human Since, as far as I know, no experiments observation beyond one life span is have been recorded which prove or difficult, it is hard to measure changes suggest that the double-blind does over decades or centuries, but it is pretty compensate for these variables, it is clear we do not live in the same world as possible to examine it only theoretically, did our grandparents Biological pheno- as we are in the presence of a standard mena are subject to remarkable evolu- clinical method which has never been tionary and geophysical drifts It is, calibrated or subjected to the hard test of therefore, possible to specify phenomena experiment Since what were probably rigorously, but not to ensure an in- the first two double-blind experiments in definitely protracted sequence of trials. psychiatry were conducted under my Nor are our sequences wholly devoid of direction, we have had nearly 14 years of order Perhaps these considerations continuous experience with it I am, worried Sir Ronald Fisher, because, therefore, to some degree responsible for before his death, he expressed to his the present popularity of the double- students great concern about the blind method. direction clinical trials were taking 13 There are several theoretical ob- One of the assumptions in probability jections to the use of the double-blind theory is that the population from which

89 the sample is drawn is homogeneous But faith will encourage his patient to in psychiatry, where diagnosis is highly persevere, he will hold out the promise of subjective and, therefore, imprecise, it is recovery or improvement, he will mini- impossible to have homogeneous groups. mize nontoxic side effects, he will not Double-blind studies have been reported produce many iatrogenic side effects and using antidepressants for treating depres- he will remain interested and enthusias- sion The matched groups contained tic If he has no faith in a medication he endogenous depressions, schizophrenics will be more apt to discourage the who were depressed and neurotic depres- patient, to use improper dosage sche- sives When heterogeneous groups are dules, to maximize side effects and to used, the therapeutic response is so discontinue treatment too early Both variable that the response of the treated these forms of faith, positive or negative, and control group depends too much on influence the therapeutic result, but the random distribution of different since in office practice physicians do not classes of patients in them No provision use therapies of which they disapprove, is made for this in the double-blind the negative factors are seldom controlled design operative The double-blind technique makes it 2, Control of Bias difficult to sustain these two variables at It has been assumed that not knowing their optimum level It is hardly likely whether a patient is receiving drug or that a doctor will have as much faith in a placebo will reduce or eliminate bias If new drug as he does in drugs with which the code remains unbroken and the he is familiar, and when he is forced to experiment remains truly blind, this is work in a double-blind way his faith and probably true But the double-blind enthusiasm are reduced to a very low introduces serious new biases of its own, level. It has been our tradition for which may be even more misleading. centuries to abhor the use of placebo or There are at least three major variables trickery For centuries doctors have in any therapeutic program. The first is condemned quacks. In the Middle Ages that feeling of trust or faith the patient the only difference between quacks and has in his doctor and, therefore, in his doctors was that while the doctors were therapy The second factor is the faith or more honest, the quacks were more confidence the physician has in himself intelligent Quacks knew their remedies and in the line of therapy he proposes to were no good and so sold atmosphere, use. The third factor is the therapy. The displays, catharsis and other trappings of best results are obtained when all three nonmedical faith Doctors used similar variables are set at their optimum level. remedies which were no more thera- If he has little faith in the doctor, the peutic, but they did have faith in their patient may or may not follow the efficacy In the end the doctors won recommended treatment This may ex- because therapies in which we can justly plain why a large proportion of patients have great faith developed tear up the prescription very soon after Serious ethical problems are raised by they leave the doctors office. The double-blind techniques which further patients faith must sustain him until the reduce faith If severe toxicities should treatment begins to work It can be extra- develop, one may have to break the code ordinarily great I know several patients (and ruin the experiment) or run the whose faith in their doctors remains grave risk of harming the patient intact even after 10 years of therapy with Conversely in order to ensure that side no improvement. effects are not missed, the physician may The doctors faith in his medication search for side effects in all his subjects must also be maximum. This does not too diligently and markedly increase mean that he need be deluded about the iatrogenic side effects. response to therapy. The doctor with If the doctor is unenthusiastic about

90 the therapy, it is certain the patient will glutamic acid on intellectual perform- know it and his faith and enthusiasm will ance These authors were so convinced be dampened Thus two of the basic that only double-blinds should be used ingredients of the therapeutic process are that in their survey they ignored 25 set at very low levels clinical studies By their selection of There are undoubtedly drugs which in papers they were able to prove that their natural setting, i e combined with positive results were obtained with optimum faith and hope, are very good, clinical non-blind studies, whereas con- but which without these human factors trolled studies usually showed glutamic are nearly inert The double-blind is acid to be inert In fact, when all studies bound to destroy these compounds and were included and errors in reading the so deprive us of valuable safe medica- original papers were corrected, it turned tions To survive these serious limitations out that both non-blind and blind studies of the double-blind, the drug must be yielded similar positive results powerful and nonspecific It may be said that the double-blind works best for compounds where it is least needed, e.g. Do Double-Blinds Establish Good or nicotinic acid for Therapies and Destroy Bad Ones? for penicillin 2 pellagra If Atkins is correct, our present era of When a biochemist wishes to test the double-blind methodology should be rate of reaction of an enzyme which has characterized by a substantial increase in an optimum temperature of 370 C., he good (i.e effective) therapies and by a will not get very far by putting his massive reduction in poor or ineffective reacting vessel in a deep freeze. By treatments Perhaps this is true in some running a double-blind we are, in effect, of the other branches of mediGine, but placing the therapeutic process in a deep unfortunately it seems not to have freeze happened in psychiatry. Apparently the To confound double-blinds even more, double-blind has not replaced our need it is doubtful if more than a small for the Pasteurs, Bantings and Flemings proportion of these experiments are Not only should our era be remarkably really blind Hardly ever does the design successful in developing new therapies, of the study ensure that at no time will but one should be able to ascribe these the code be broken by doctor or nurse changes to the double-blind method. observers In many psychiatric wards there is a tradition among nurses which TABLE 1 ensures that every attempt will be made to break the code. Nurses are no worse The Relationship of Clinical Trials and the than doctors and, like doctors, they also Introduction of New Therapies into Psychiatry have ethical problems about giving their A "Good" patients a placebo They will chew, taste, therapies swallow the tablets, suspend them in Double-blind Not blind water, pound them with a hammer, 1 Acceptable None Tranquilizers throw them against the wall and stamp Anti-tension on them They will study the fluid agents characteristics of the coded liquid in Antidepression syringes and see how it mixes with blood agents Modified ECT which may flow back into the barrel. It Penicillin for GPI seems the double-blind not only reduces Nicotinic acid for faith to an undesirable low level, but the psychosis of pellagra brings out petty larceny in all of us " 2 Not acceptable Mega -nicotinic An example of severe bias in medical acid for reporting was recently described by schizophrenia Vogel et al.10 In 1960 Astin and Rossi Mega-thyroid for reviewed the literature on the effect of schizophrenia B Poor proved to be nil, i e the initial flush of therapies enthusiasm will have waned If true, a 1 Acceptable None Psychotherapy drug company could become wealthy by Group therapy si mply putting out a new placebo with a Family therapy new name every year backed by enthus- 2 Not acceptable None None iasm-creating factors Apparently drug companies have not considered this Mega—this refers to doses which are much above method This myth was examined by the usual range required to control deficiencies These Glick and Margolis,14 who reported that are 3-250 per day for nicotinic acid or nicotinamide and it was false They examined reported 200 mc0 or over of tri-iodothyronine or its equivalent recovery rates of the same drug over a five-year period and found no evidence I have listed in Table 1 the treatments of a decline in therapeutic efficacy most frequently used in psychiatry It Therapies replace each other if there are would be useful if specialists in other real advantages, one over the other Thus branches of medicine would perform a insulin coma therapy was replaced by si milar exercise. tranquilizers because tranquilizers work- Not all new therapy in psychiatry has ed more quickly, were cheaper and been developed as a result of double- required less skill in their administration blind methodology On the other hand, It is still debatable whether the long- we have a large number of very effective term effects are any better, and I suspect treatments including tranquilizers, anti- that the use of insulin coma may well tension chemicals, antidepressant drugs, come back Similarly, chlorpromazine modified electroconvulsive therapy displaced reserpine The rule is not that (ECT), penicillin for general paresis of the drugs are forsaken because they lose insane (GPI) and nicotinic acid for their efficacy, but that they are replaced eradicating pellagra psychosis by other more effective or less toxic Chlorpromazine, first introduced by therapies Delay and Deniker,12 was found by Two good therapies for schizophrenia Lehmann and Hanrahanl7 to reduce were developed by double-blind techni- markedly psychomotor excitement The que which are not yet accepted One is hundreds of double-blind studies on nicotinic acid therapy that we have been chlorpromazine have added hardly any- using since 1952 We have completed thing to our knowledge of chlorproma- three double-blind controlled studies zine. In fact, only a couple of years ago with follow-ups going back 14 years. Our nearly one million dollars was spent in a 10-year cure rate is 75 percent compared well-designed double-blind study which to our comparison control rate of 35 suggested that chlorpromazine was a bit percent The other is high-dose thyroid more active in controlling overactivity therapy developed by Danzigerll and than starch This study was appropriately Lochner, Scheving and Flach.l8 Finally, reported as "the million-dollar fizzle " there is one good therapy for alcoholism, Reserpine was introduced into LSD, which will never be double-blinded American psychiatry about the same All the "poor" therapies were develop- time Kline16 in the.first study showed ed by non-blind studies, but are accept- that it improved 22 percent of 200 able to most psychiatrists Thus it is clear patients with chronic psychosis to the that therapies in psychiatry have been point where they could be discharged. It developed by clinical studies and have was subsequently found that 86 percent received little help from double-blind were improved.3 At this point it may be studies Non-blind studies have develop- useful to lay at rest another myth about ed treatment methods which are poor, clinical testing It has become a cliche in i e can be improved, but they have also psychiatry that any new tranquilizer must given us excellent therapies which have be used very quickly because with time revolutionized the treatment of psychia- the real value of the drug will have been tric patients Double-blind studies have

92 not led to the development of a single data—i e double-blind data In fact, useful psychiatric therapy, and even many drug companies are now deluded when this method has been used as with into thinking double-blinds are not so nicotinic acid, the results have not been bad after all; but then they do not have accepted to run them They merely have to find Double-blinds are considered essential others who will for clinical testing for many reasons A beautiful example of circular logic First, we have been confronted with a was used to bolster the double-blind large number of new treatments and technique. It is common knowledge that naturally it is important to know which drugs, said to be effective when tested ones are best for certain classes of single-blind, turned out to be no better patients The clinical trials common than placebo when double-blinded It before 1945 did lead to many polemics was, therefore, assumed that since the between originators and their detractors double-blind was infallible this proved It appeared to many scientists, especial- that these chemicals really were inactive ly those having no responsibility for It seems not to have occurred to these treating patients, that the double-blind workers that since the double-blind had would settle these issues Over and over I not been validated, or calibrated, it have observed that the most enthusiastic might be a dud method In other words, supporters of double-blinds are some one could just as logically assume that statisticians, psychologists and others any method which could not demon- who never have done, nor will do, strate efficacy in drugs known to be clinical experiments themselves, and active must be of little value physicians like deans and chairmen who This view was supported by Glick and order their junior men to perform them Margolis,14 who discovered that double- Uniformly the physicians who are res- blind experiments are of short duration, ponsible for evaluation and treatment are while single-blind experiments are of much less enthusiastic about the long duration The double-blind is so method. difficult to operate that it must be a A second reason is that men given the short-term experiment If it ran for a long responsibility of receiving and vetting time, all the difficulties would be greatly research grants believed that this method increased Since most psychiatric illness- or design would help in deciding who es are chronic, it seems inappropriate to should receive a grant. The National run short-term experiments Health Grant application forms all con- In 1865 Claude Bernard wrote, "These tained a question concerning the statis- men [talking about systematizers] start, tical design to be used. It soon became in fact, from an idea which is based more clear that no one could hope to receive a or less on observation and which they grant unless the double-blind method regard as absolute truth They then was described Whether it was eventually reason logically and without experi- used is a different matter In any event, menting and from deduction to deduc- research workers are intelligent and tion they succeed in building a system easily conditioned, especially when the which is logical, but which has no sort of carrot of grant support is dangling before scientific reality Superficial persons them. often let themselves be dazzled by this When the work was done, journals appearance of logic; and discussions refused to accept papers unless they worthy of ancient scholasticism are thus described double-blind experiments, and sometimes renewed in our day " soon the journals blossomed forth with self-congratulatory titles such as "a CONCLUSIONS controlled study of Drug X," etc And finally, drug houses discovered that I suggest that since the double- when government agencies wanted data blind method for testing drugs has never they wanted only a certain kind of been rigorously tested in the laboratory,

93 i e. has never been validated or cali- therapeutique quelconque (la confiance brated; is not based upon mathematical mise, et par le malade et par le medecin, theory acceptable even to mathematic- clans le traitement Iuimeme); elles sont ians; sets two important therapeutic discutables sur le plan de Iethique variables at unreasonably minimum professionnelle; elles ne sont daucune levels; is ethically questionable; cannot utilite pour comparer de petits groupes be used for comparing small hetero- heterogenes et, enfin, elles nont jamais geneous groups; and has not led to the permis de mettre au point une thera- development of any useful new thera- peutique utile, du moms en psychiatrie pies, at least in psychiatry, it should be re-examined seriously to see if these important flaws can be corrected REFERENCES Other studies critical of double-blind 1 ASTIN_ A W . and ROSS. S : Psycho) Gull 57:429. controlled experiments are given in the 1960 list of references 4-10, 19 2 ATKINS. H : Brit Med 1 , 2:377. 1966 3 BARSA..1 A . and KLINE. N S JAMA. 158. 110. Summary 1955 Controlled experiments may be con- 4 BELLAK, L.. and CHASSAN..I B New Ment Dis ducted without the use of double-blind 139: 20. 1964 techniques, which themselves induce new difficulties and errors In view of 5 CHASSAN..1 B : Psychiatry. 20: 163. 1957 their wide acceptance as an indispen- 6 Idem Biometrics. 15: 396. 1959 able tool in therapeutic trials, double- 7 Idem: Psychiatry 23: 173. 1960 blind techniques should be critically re- 8 Idem: Behavr Sci 6: 42. 1961 examined because their value has never been rigorously tested in the laboratory, 9 Idem: Psychopharmacologia (Berlin). 4: 78. 1963 they are based upon unacceptable 10 (dem: Intensive or single-case design in drug evacuation: some preliminary experience Paper presented at the mathematical theory, they diminish the Second Annual Meeting of the American College of effectiveness of two important variables Neuropsychopharmacology. January. 1964 in any therapeutic situation (the faith of 11 DANZIGER. L : Dis Nery Syst 19: 373, 1958 the patient and the doctor in the 12 DELAY, J , and DENIKER. P : Thirty-eight cases of therapy), they are ethically questionable, psychoses under prolonged and continuous chlorpro- mazine treatment Paper presented at Congres des they cannot be used for comparing small medicins alienistes et neurologistes de France et des pays heterogeneous groups, and they have not de langue lrancaise. 50e session. Luxembourg. July led to the development of any useful new 21-27. 1952 therapies, at least in psychiatry 13 FISHER. R : Personal communication. 1964 14 GLICK, B S., and MARGOLIS, R : Amer .1 Psychiat 118: 1087. 1962 Resume 15 HOGBEN, L : Statistical theory: The relationship of pro- Des experiences controlees peuvent bability, credibility and error Allen El Unwin Ltd . etre effectuees sans recourir aux me- London 1957 thodes a double iconnu, lesquelles font 16 KLINE. N S : Ann N Y Acad . Sci , 59: 107. 1954 naitre de nouvelles difficultes et intro- 17 LEHMANN. H. E . . and HANRAHAN G E : A M A duisent de nouvelles erreurs. Etant donne Arch Neural Psvchiat 71: 227 1954 leur emploi generalise, comme outil 18 LOCHNER. K H., SCHEVING. M R_ and FLACH. F F : indispensable Bans les essais therapeuti- Acta Psvchiat Scand . 39 413 1953 ques, it serait bon de reexaminer dans un 19 McLAUGHLIN, B E . CHASSAN. 1 B and RYAN. F esprit critique les methodes A double Comer Psvchiat 6 128 1965 inconnu. Leur valeur na jamais ete 20 VOGEL W et al : Psycho) Bull . 65: 367. 1966 rigoureusement mise A 1epreuve en laboratoire; elles sont basks sur une theorie mathematique inacceptable; elles reduissent Iefficacite de deux variables importantes dans une situation

94 SOME PROBLEMS OF STOCHASTIC have us use more helpful than misleading PSYCHIATRY on balance? A. Hoffer and H. Osmond It is hardly surprising that clinicians have joined in the general fashion and Hogben (1957) reminds us that probab- psychiatrists too now cherish these ility theory was developed to benefit mathematical devices. Only a few years noble English gamblers who hoped to ago those authors of medical papers who increase their winnings at the tables used statistics would explain such terms These early statisticians were dealing as "standard deviation" or "X degrees of with man-made objects (dice, wheels, freedom" for the uninitiated Today, cards, etc.) built to certain exact authors sometimes present statistics specifications of size, symmetry, density, only, no longer bothering to include the hardness, etc Hogben writes "a calculus data from which they were derived. This of probability is relevant to the real world increasing interest in statistical methods (a) only insofar as it specifies frequencies has undoubtedly been fostered by the of observable occurrences in an in- rediscovery of what has long been definitely protracted sequence of trials, known, and has indeed been the stock in (b) only if also such occurrences collect- trade of quacks since time immemorial ively constitute a sequence wholely This is that the simple act of giving devoid- of order " The calculus of something or doing something no matter probability was first used in physics and what it is often produces astonishing chemistry and later adopted by scientists effects on patients Some procedures who work with plants, animals and may be started or some drug prescribed humans One of its earlier applications to and the patient improves When this human affairs was in insurance where occurs without any consensus that the large numbers of individuals or incidents procedure produces its benefits or the were involved. drug its effects by some means under- Psychologists who develop tests for stood by the profession at large, this intelligence personality and aptitude benefit is often called the placebo effect. also applied a variety of forms of This refers to reactions which may be statistical analysis, and they seem to beneficial or harmful by chemicals have been useful here, but they have not "believed" to be inert We use "believed" always found statistical methods to be because the inertness of a substance can more effective than clinical methods, only be established empirically There is Meehl (1954), Sydiaha (1959) Hogbens no reason why the purest starch should sharp criticism and the fact the statistical not be harmful to some people and analyses are not always very enlightening beneficial to others These reactions may when applied to clinical matters raises an be termed positive or negative placebo important question To what extent is the reactions. In a recent paper, Hoffer and real world in which we live, work, Osmond (1961), we have noted that become ill and die of a kind that can be some people do not respond with analyzed accurately and objectively by appropriate- physiological or psycho- methods which some statisticians believe logical changes to compounds long can do just this? In other words, are the known to be active, and half jesting we measuring devices which they would have termed these obecalp reactions, (placebo in:.reverse) The possibility that We are indebted to Professor Hogben for this useful, human subjects can react positively or accurate and inclusive term. stochastic for those who are not conversant with it, the shorter O.E.O. defines adversely to drugs raises serious issues. Stochastic (now rare or obsolete) from Greek to aim at The chief of these is whether the "blind" a mark. guess Pertaining to conjecture studies of a classical kind are applicable • Director, Psychiatric Research Unit, Department of Public Health, located at University Hospital, Saska- to drug effects After many years of toon, Saskatchewan. relatively uncritical acceptance by •• Onet Cottage, Milford (near Godalming) England. Received for publication: May 17, 1962 scientists but private resistance from

95 clinicians, statisticians themselves and which are known to be active in most clinicians have raised these questions 4, people 15 We will therefore see what 5, 11, 13, 18, 19, 20 This problem happens to his sort of experimental requires urgent and immediate examina- design which is so highly recommended tion by all scientists working with human by theorists today when one does take subjects Unless this is done, research in this into account. these matters may be seriously hampered Treloar (1939) describes two classes of because scientists are being encouraged erroneous inference (A) where insignifi- to use inappropriate methods which cance is found when there is in fact a real nevertheless have received general difference, (B) where significance is assent. It is already apparent that some claimed when none in fact exists Class A granting agencies make this new fashion errors lead to valuable procedures or a necessary preliminary for getting active pharmacological substances being money for research, yet as we shall show, either ignored or improperly discarded, it is at least possible that double-blind thus increasing or prolonging human studies will as often indicate that an suffering unnecessarily Class B errors active compound is inactive as the lead to the use of ineffective treatments converse when better may be already available or Grayson (1961) has given an admirably could perhaps be devised In addition, clear account of the views of those who they may result in wasteful and expensive use double-blind techniques to test new investigations in the future Treloar drugs in psychiatric practice At a believes that Class B errors are more symposium on Chlordiazepoxide he harmful to the progress of science criticized severely papers given there and Treloar states that the price for elsewhere According to him, no study avoiding one sort of error must be to can be termed confirmatory unless it increase the chance of the other sort It is includes: (1) a controlled group of a matter of debate which class of error patients; (2) an objective evaluation has the graver consequence for procedure; (3) compliance with statis- medicine It is by no means certain that tical requirements Treloars verdict holds equally in every Dr S Cohen voiced a different sort of scientific situation, for sometimes errors dissent saying, "I would rather see a dirty of the second sort (mistaking a positive study by Fritz Freyhan than a clean result for a negative) may be by far the double-blind study by many other in- more serious The great blood-letting dividuals " He added that dirty studies epidemic of the eighteenth century had shown certain chemicals to be certainly shows that harm results when effective many years ago and that significance is claimed where none classical double-blind studies in Veterans exists Generally speaking, unless the Administration Hospitals had merely treatment itself is dangerous little confirmed what was already well-known. damage is done; even if a particular The clinician and the statistician were medicine does no good it at least gives at logger-heads, the statistician stating patients, their relatives and doctors, a bluntly that he alone was correct, and feeling that something is being done the clinicians expressing a dour un- which may tide them all over a difficult willingness to give up their ways which time If, however, insignificance is they believe have worked Although alleged when in truth the treatment or Grayson did not actually say that all substance is effective, then we run a errors could be resolved by using the certain risk of not discovering an insulin classical double-blind experiment which or penicillin That this is no idle notion he had described, he clearly implied this, can be shown by the fact that it actually but in company with most other theorists happened with penicillin itself Ernest in experimental design, he had neglected Augustin Clement Duchesne in 1897 patients failure to react to chemicals wrote his doctoral thesis on antagonisms between microbes and moulds. (See inferred that it was pointless to use M.D of Canada, January 1961). He con- insulin as a treatment for schizophrenia. cluded "Furthermore, it seems from some Clinicians, however, seem to have paid of our experiments, unfortunately too no attention to their advice for if few in number and which ought to be anything, more deep insulin was given repeated again and checked, that certain after their paper than before it. Insulin moulds (penicillium glaucum) inoculated was not discarded until safer and simpler into an animal simultaneously with treatments such as the phenothiazones extremely virulent cultures of certain became available The clinicians re- pathogenic microbes (8. coli and Ebar- luctance to relinquish insulin is some- thella typhosa) are able to attenuate the ti mes used as an example of obstinate virulence of such bacterial cultures to a and supercilious behavior, but it might remarkable degree It is to be hoped also mean that those who work closely therefore that in pursuing the study of with patients were better able to assess the facts of biological competition what had happened than statisticians between moulds and microbes—merely working with data outlined by ourselves and to which we In our particular example, the clinic- have no claim other than rendering here ians may have been well advised to a very modest contribution—the dis- continue to use insulin, for we believe covery of further facts directly useful and that the statisticians made a serious applicable to prophylactic hygiene and mistake which has gone unnoticed for therapy may be attained " Duchesnes nearly 18 years They did not ask work passed completely unnoticed at the themselves relevant questions about the time and was soon forgotten kind of illness which they were exam- It is therefore particularly important ining In other words, they used the not to jump to hasty negative con- wrong sort of model with which to clusions, because it frequently happens determine whether treatment was that an initial substance which either has successful or not. There are at least three side effects or is not notably potent can kinds of models which are useful for be a stepping stone to something both thinking about diseases and their treat- safe and potent What has saved useful ment The first is that of a single attack substances and procedures in the past Pneumonia is such a disease. Often in has often been simply the faith of a few these cases, the body is overwhelmed by committed people There is a real danger the intrusion of the foreign organism but, that the rash pontifications of dedicated having thrown off the assault, it seems to methodologists may be enough to be resistant to any recurrence of the destroy the faith at a crucial moment same disease A second class of disease is one in Model Error which there is a phasic course of the There is another kind of error which illness with exacerbations and remis- has crept into psychiatry in evaluating sions. Such a disease is, for example, the results of therapy from a long-term arthritis. point of view. This kind of error has been A third kind of model is where the directed against the evaluation of the disease is continuously present and shock treatments, especially ECT and unless adequately treated, may lead to insulin shock therapy Penrose and Marr quick death For example, pernicious (1943) evaluated insulin shock then being anemia or diabetes mellitus In assessing given in the Province of Ontario, and the response to treatment, one must concluded that the outcome of this know which model is most appropriate treatment, as measured by the number of for a particular disease Schizophrenia, patients in hospital at the end of four and being a very variable disease, may follow five years, was no different from those any one of these three models and who had not received it They therefore therefore the type of evaluation must be quite different for each case. If schizo- been. given ECT and nicotinic acid show a phrenia were like pneumonia and were very small number of readmissions produced by a massive attack from a during the first few years after discharge single organism, then one would expect a compared with those who have not had specific treatment to quickly vanquish this vitamin, but the protective action the organism, and if four or five years only seems to last for about two to three later another attack produced a relapse, years. After this, those patients who have one would not state that the original benefited greatly from nicotinic acid treatment had been ineffective. One slowly begin to relapse. An account of would merely be disappointed that the this in which the data is given in detail disease had recurred and would give the has been published by C. C Thomas in a same treatment again. If schizophrenia book entitled Niacin Therapy in Psychia- were an illness like arthritis, even when try A similar group of schizophrenic there was a good response to treatment, patients given ECT but no nicotinic acid one could never be quite sure that this had a remission rate of 50 to 60 percent was not one of those natural remissions within the first one to two year periods which do occur after discharge, but over the next four, The third model, the chronic disease, five or six years this did not greatly is the easiest to work with, especially increase Those not receiving nicotinic when one has a treatment which is quite acid had a downward concave curve specific This is because here treatment is followed quickly by remission and ceas- FIGURE1 ing treatment results in recrudescence of the illness and this can be repeated until the investigator is certain that a relation- 90- ship exists between treatment and re- mission It is clearly possible to treat a large 0 00 " COMPARISON group of patients, to have a good 4- GROUP remission of symptoms and to find after W 4O- C NICOTINIC some months or years have passed that ACID GROUP all or many of them have relapsed And zI- since with the control group of patients, u :0 there would also be remissions and exacerbations, it is likely that in an illness of this kind, regardless of treatment 1950 1954 1950 given, the same proportion of patients YEAR would suffer relapse four or five years Number of schizophrenic patients readmitted at least later without further treatment once during a follow-up period If schizophrenia is a chronic disease and most people think it is, then it would be unreasonable to expect any treat- while those who had it show an upward ment, however successful at first, to concave curve This data is shown continue to exert a beneficial effect for graphically in Figure 1 an indefinite time after that treatment Curve A represents the proportion of had been stopped If schizophrenia is a 98 patients who required readmission to chemical disease, then one would expect hospital over a follow-up period of about a response to treatment resembling that nine years At no time did any of these of other biochemical diseases patients have nicotinic acid or its amide For the last nine years we have studied The 73 patients shown in curve B were the effects of massive nicotinic acid and treated with nicotinic acid as well as the its amide on schizophrenic patients. We other treatments used in curve A. The have found that those patients who have significance of the difference between

98 these groups depends upon which year is of inference of the second sort are more selected after discharge As it happens, likely to occur unless proper follow-up with these patients the differences are assessments are used significant for all years, but if curve B One of us (H 0 ) has been involved continues to follow its trend and curve A recently in an interesting example of an remains stable, then in a few years time error of the second sort in connection the same proportion of patients will have with a study of ololiuqui Osmond25 been readmitted from each group One made the first psychiatric study of the could perhaps select a ten-year follow-up psychotomimetic properties of ololiuqui, and show no difference whatever then long known as the chief narcotic of the Suppose we had known nothing about Aztecs 28 After a series of self experi- our patients progress during this decade, ments with increasing doses of ololiuqui and had undertaken our follow-up at the (Rivea Corymbosa) seeds, he reported end of it, we might have well concluded, definite and an unexpected kind of quite erroneously, that niacin was use- activity, i.e , psychological changes and less. Our statistical conclusions would be apathy followed by a marked feeling of correct but wholly misleading In these well-being This report was received with patients, nicotinic acid was given for at some excitement and studies of its least one, and sometimes for several psychological properties and attempts to years It exerted a protective effect isolate the active fraction began against recurrence of schizophrenia Investigators at Lexington 2l ran a which was sustained long after it had classical double blind study, and Kinross- ceased to be given Other substances Wright22 conducted a single blind might work in much the same Way, but experiment. Neither found any con- be of a kind which could only be given in vincing evidence that ololiuqui was a a hospital. Insulin coma treatment seems psychotomimetic agent It now appeared to be of this type. We have still to be that Osmond had made a serious error convinced that the many able clinicians due to his somewhat subjective method. who reported on the successful use of The chemical studies were more pro- insulin were all self-deluded. As we have ductive In 1960, Hofmann (discoverer of already noted, psychiatrists using insulin LSD-25 and psilocybin) reported at a in the treatment of severe schizophrenia symposium in Australia that he had discontinued its use only upon the isolated an indole alkaloid, lysergic acid development of other treatments which amide from Rivea Corymbosa (ololiuqui). were almost as effective as ECT, re- Further, he had consumed a small serpine and tranquilizers, and which quantity of this alkaloid and had experi- were simpler, safer and easier to ad- enced a reaction similar in many respects minister Some mental hospitals still use to one Osmond had experienced in 1954 insulin and report upon it favourably Hofmanns report was received with great Since it is possible that this misunder- skepticism by some chemists who stated standing originated in Penrose and Marrs that they had been unable to find these paper, it should perhaps be carefully re- alkaloids in ololiuqui and assumed that examined for it has had great influence this meant that no one else could find and not determining what had happened any Lysergic acid alkaloids had until historically is important Their error lay now been found only in some fungi and in the first, second and third years after not in higher plants, so this claim of treatment It is quite possible that there Hofmanns was doubly exciting. Taber were significant differences here which and Heacock30 corroborated Hofmanns escaped them The selection of the claim and have isolated lysergic acid fourth and fifth years was quite arbitrary, amide (L A ) as well as other substances indeed Penrose and Marr give no Since L.A. is known to be a weak adequate reason for choosing this time psychotomimetic, the original work of rather than some other Statistical errors Osmond is now verified It seems clear

99 from this that even very competent and attitude seems to be not uncommon in experienced investigators are not psychiatric research where the discoverer guaranteed success by using methods is often assumed to be foolish, brash, which are often discussed as if they alone crack-potted and even a little crooked at can guard against error ti mes There is another matter, not illustrated Some behave as if they believed that by the ololiuqui example but which is, the best attitude towards their fellow we think, important. This concerns the researchers was one of suspicion or even way in which scientists perceive each hostility They do not act as if they were other Is it better for science if scientists attempting to corroborate or confirm try to corroborate each other or try to anothers work, but to disprove it or destroy other scientists work? Although expose some trick or stupidity This one might suppose that either method attitude is common among certain kinds would yield much the same results, there of inspectors whose function is to find are great practical differences It may be evidence for misdeeds and here it is that in psychiatric research a number of doubtless proper, but is this an attitude those ostensibly engaged in it do not which we can afford to foster in the know that the effort of corroborating scientific community of psychiatric re- anothers work is frequently as onerous as searchers? For with a negative and that of original discovery It is indeed for inspectorial attitude the scientist, sup- this very reason that men who do this are posedly trying to confirm original work, so highly regarded by their fellow may be tempted to publish findings as a scientists It seems proper to ask our- refutation of that work without the selves what motives are likely to be the infinite patience, care and zeal exerted best for undertaking a task which is of the by the original discoverer In effect, a highest importance, calls for great lack of trust in the integrity of a fellow- exertion and yet which lacks the special scientist may lead to one giving up the spice and excitement of original dis- search far too soon. In this way, science covery Much must surely depend upon can be done great disservice and patients the attitude which one scientist has damaged Readers of psychiatric journals towards another. It has long been our will come across many examples of this tradition, rarely broken, for scientists to kind of study in the literature of the last accept their peers as being men of decade Indeed, some researchers seem honesty and integrity although always to make an occupation of " inspecting" being ready to disagree with their other peoples claims and failing to inferences and their conclusions unspar- validate them after cursory efforts, ingly Polemic has been the life blood of thereby establish for themselves a reput- science, but generally speaking, ation for "soundness." At times one character assassination has been less well wonders if this is not becoming a more regarded. Attempts to corroborate must acceptable way of being recognized as a be persistent, cautious, sustained and psychiatric researcher than by attempt- only after determined attempts to cor- ing the onerous task of new discovery. roborate would a negative report be We think it may be important for made. No such report should ever be researchers to enquire whether they are made unless the procedure originally conforming to those customs which have described had been used with exactness been found useful and productive in This still seems to be the best method to other branches of science In contrast to us We believe that one should have faith Engel, 6 we hold that one of the scientists in the resourcefulness, skill and honesty main tasks is to question the ideas and of other research men combined with a inferences of other scientists 14, 15, 27 rigorous and prolonged investigation of Discussion, polemic, satire are entirely their claims and readiness to disagree proper here Let us have the strongest when necessary. Unfortunately another disagreements, but no ad hominem attacks, character assassinations, im- Kind of Study Therapeutic Claims putations of dishonesty or incompet- ence, and above all no inspector complexes Eminence in science is Acceptable conferred by ones peers, it does not Not Acceptable descend on a man simply because he is the head of an institute, a department, a section or a laboratory It inheres in men Chi Square = 8.54, i e , the null and women, not in the position which hypothesis was disproven In other they chance to hold in an organization words, there was a significant difference in the conclusion of the two kinds of Research does not require superscientists papers to decide what is and what is not; the But Glick and Margolisl0 found that scientific method and the passage of the duration of clinical studies con- time will do that soon enough There is founded these results Although double the even greater danger that the in- blind studies showed significant dif- spectors will insinuate themselves into ferences less frequently they were more the councils of fund-granting bodies and often brief studies. Only one out of with their passion for neat, clean and tidy eleven double-blind studies was of experiments do psychiatric research un- long duration. But 12 out of 16 single told harm Indeed, they may already blind studies were long clinical studies have done some. What has happened is (Chi Square = 8 ca ) Long-term studies that a confusion of function has arisen. It more often reported clinical improve- is far easier to be a capable inspector ment than short-term double blind than to be a good judge of what is likely studies They stated "there is no valid to be a valuable research and to increase theoretical or scientific reason why our knowledge It happens that it is this double blind studies must be short-term more difficult function that is needed or even placebo controlled or why single most blind studies must be long-term or non- placebo controlled " Finally from their The Relationship of the Experiment to the extensive review of the literature, these Investigator authors could find no support for the common belief that initial enthusiasm for Foulds8 surveyed the literature on a particular drug is always followed by a double blind studies He found that later realism and a more sober evalua- significantly more double blind studies tion showed drugs to be ineffective Fox,9 Why, then, do people who carry out surveying a different set of studies, came orthodox clinical studies seem to get to the same conclusion Fox collected better results than investigators who run many reports on treatment, and by double blind studies? selection reduced them to a series of (1) Fox considers that authors may be papers which he divided into those he reluctant to write and editors even more considered had used acceptable methods reluctant to publish negative results This and those which had not Each classifica- may have once been true, but Foxs own tion was further sub-divided into two collection of papers hardly suggests that sub-groups In one, the results suggest this is so now We have found few signs that a therapeutic drug was significantly that authors are unduly sensitive or better than chance (or faith). In the anguished by negative results, rather the other, negative results were found reverse Indeed, one sometimes has the Papers with adequate controls (compari- feeling the investigators have become so son groups) in which adequate statistical interested in method that the success or analyses had been used were classified as failure of a research is equated with a acceptable This is what Fox found nicety of design rather than with new discovery For faith can be made constant at a (2) We believe that double-blind low level or a high level, yet the double studies may prove drugs ineffective, i e , blind technique usually sets it at a have large errors of the second kind constant low level But faith is an (3) What has usually been much important ingredient in any therapeutic neglected is the impact upon the process, and if this is so, why not set it at investigator and thus on his staff and the most effective level? Indeed as patients of the particular design fol- doctors, we are ethically bound to do just lowed Barber in a witty study has dealt this, particularly when so far as the with this in a general way 2 statisticians are concerned the results are In any therapeutic study a variety of the same so long as the faith level is controls are required It is not, of course, constant The investigator then wishes to true that a controlled study is always one show that faith plus a drug is significantly where a comparison group is used better for a patient than faith plus a Controlled studies are used in all the placebo As Hogben and Wrighton aptly sciences In biochemistry, a controlled point out, this is not usually done experiment is one in which major because "The reason is that cookery book variables such as temperature, pressure, recipes will commonly prescribe as the concentration, pH are set at steady levels appropriate null hypothesis the one while other variables are allowed to which commends itself to the math- fluctuate But in clinical practice ematician for reasons which have no- thing to do with the operational intention "controlled" has come18 to mean the use of a comparison group It would be more of the scientific worker "20 accurate to call these studies comparison The mathematician little interested in studies for such studies with two or more faith except to exclude it, cannot know groups may ignore important variables that human nature being what it is, such as drug dosage, its relationship to doctors prefer to know what their maximum need, etc In fact, comparison patients are getting and that there is studies may be nearly uncontrolled and some therapeutic benefit And this is those without a comparison may be very where we run into a major problem, meticulously controlled because it is so difficult to ensure One of the main variables which maximum but equal faith for both groups psychiatric investigators have tried to with double blind studies This difficulty control has been called faith, suggestion, is readily explained on operant con- placebo effects, etc Mathematicians ditioning theory have implied that the classical double- One important ingredient for main- blind study will in fact do this The taining a satisfactory relationship mathematician may be correct, but he between doctor and patient is what does not concern himself with the level amounts to positive reinforcement of the at which faith is "controlled " A chemist, doctor himself by what appears to be for instance, can control temperature at successful treatment When a doctor freezing or at boiling point It makes gives medicine to a patient and the little difference statistically unless one is patient seems to benefit, this reinforces interested in temperature as a variable (encourages) the doctor who heartens and not as a constant The chemist will and supports the patient to continue therefore select that temperature which taking the medicine Such encourage- is most efficient for obtaining his ment may in itself minimize side effects particular objective. Being reinforced by his success with one One may perhaps excuse the statist- patient, the doctor will use the treatment ician for his lack of understanding about on others with even greater confidence, faith as a variable, but we can hardly and so a fruitful combination of medi- excuse those investigators who follow his cine and faith develops On the other recipes so blindly hand, if many patients fail to respond, or if there are side effects which disturb remarked for so long? It has, of course, both patients and doctor, then the been discussed repeatedly in the past, doctors habit of giving that particular but possibly in recent years clinicians treatment will be extinguished quickly; have become intimidated and muddled indeed, it is something of a joke among by the formidable mathematics and the those who often use new drugs that if one i mposing words which methodologists so of them is to be successful, it is essential often use Kluver (1931) warned elo- for the first few patients to do well, for quently almost one-third of a century ago this produces enough reinforcement to against applying refined mathematics ensure continuing trials It is obvious that inappropriately Like a great brandy, his the reverse can occur A clinician may papers read even better after a few have negative reactions to an active drug decades We can only urge the stoch- and his faith in the drug can be as quickly astically inclined to meditate upon his extinguished Originators of newer treat- ideas, but we cannot resist whetting their ments are often sustained by their appetites with a few lines from his paper hypotheses But the fact remains that "We must start from the facts and clinicians have introduced many treat- somehow find the tools adequate for ments which work their investigation If we find in psycho- This suggests strongly that in clinical logy that certain dynamic systems, studies without control groups, due to certain behavior units, exist to which we reinforcement, active drugs will be used cannot do justice by pointing out the few until replaced by something proven mathematical relationships known at better; while the giving of inactive drugs present; if, at the same time, there seems will be quickly discontinued It follows to be no hope whatever for increasing from this that clinical studies are those in our knowledge of these relations or of which the doctors habit of giving the relations found by other exact methods; drug has been reinforced Studies of then even the description of these short duration are those in which the behavior units by means of these exact habit has been extinguished The fact methods (not to mention a thorough that studies are long suggests then that scientific treatment) is inexact since the there has indeed been therapeutic bene- tools are totally inadequate In such fit Long studies may indeed be an index cases a type may be far more exact of therapeutic benefit One could argue than an equation Only one who thinks that non-specific remedies have been about method as something divorced used for centuries However, such from the facts and from the material at remedies are not altered until better ones hand will doubt this statement In come along and many "non-specific closing we would like to call attention to remedies" have been found to contain the fact that physicists inform us that greater or less quantities of active drugs there are scientific procedures which The finding by Fox and Foulds may be enable us to test the validity of a due to this 8, 9 It is at least possible that proposition by reference to a single the use of drugs or treatments for long observation " periods of time is a better index of their It may be that our old and discredited therapeutic efficiency than any measures medical standby, the single case, will yet available, for were this not so, their one day become respectable again use might have been discontinued long Others preceded Kluver with sensible ago in the manner which we have warnings, none more eloquently than described This should at least be Claude Bernard whom Hogben quotes as considered by those planning clinical writing almost a century ago, "By trials destroying the biological character of phenomena, the use of averages in Epicrisis From Methods in Social Science. Page 184 Analysis If this is as obvious as we have and typological method Rice Ed 1931 University of suggested, why then has it gone un- Chicago Press physiology and medicine usually gives and said: The law is that anterior roots only apparent accuracy to the results If, are sensitive, for instance, 25 times out for instance, we observe the number of of a 100? Or should we have admitted, pulsations and the degree of blood according to the theory called the law of pressure by means of the oscillations ofa large numbers, that in an immense manometer throughout one day, and if number of experiments we should find we take the average of all our figures to the roots equally often sensitive and get the true or average number of insensitive? Such statistics would be pulsations, we shall simply have wrong ridiculous, for there is a reason for the numbers In fact, the pulse decreases in roots being insensitive and another number and intensity when we are reason for their being sensitive; this fasting and increases during digestion or reason had to be defined; I looked for it, under different influences of movement and I found it; so that we can now say: and rest; all the..biological characteristics The spinal roots are always sensitive in of the phenomena disappear in the given conditions, and always insensitive average If we collect a mans urine to in other equally definite conditions" analyze the average, we get an analysis Hogben comments, "Against this back- of a urine which simply does not exist; ground of lucid exposition (1865), it is at for urine when fasting is different from first difficult to understand why it should urine during digestion A startling in- now (1954) be necessary to challenge the stance of this kind was invented by a claim of the statistician to prescribe the physiologist who took urine from a design of experiments in general and of railroad station urinal where people of all the clinical trial in particular In my view, nations passed, and who believed he such claims are acceptable only if we could thus present an analysis of average relinquish the standards of intellectual European urine! Aside from physical and rectitude of an earlier generation "18 chemical, there are physiological And again, " In short, statistical theory is averages, or what we might call average temporarily, at least, in the quicksands. description of phenomena, which are Nothing less than a transvaluation of all even more false Let me assume that a values is in process For my part, I have physician collects a great many in- reluctantly come to the conclusion that dividual observations of a disease and the statistician will emerge in the end that he makes an average description of with a very much chastened view of what symptoms observed in the individual traditional methods can accomplish If cases; he will thus have a description that there proves to be any enduring basis for will never be matched in nature So in a stochastic calculus of judgments, we physiology, we must never make average shall be able to define its proper terms of descriptions of experiments, because the reference clearly only after we have true relations of phenomena disappear in cleared the site from an overgrowth of the average I acknowledge my prescriptions which can certainly no inability to understand why results taken longer claim the universal assent of from statistics are called laws Certain professional mathematicians " And, "If experimenters, as we shall later see, have we then concede every claim put forward published experiments by which they for such devices as the Chi Square test found that the anterior spinal roots are and others of its kind till recently insensitive; other experimenters have prescribed by most professional statisti- published experiments by which they cians without misgivings, we may still found that the same roots were sensitive entertain misgivings about how far the These cases seemed as comparable as questions for which they claim to possible; here was the same operation prescribe the method prerequisite to a done by the same method on the same correct answer tally with what the spinal roots Should we therefore have clinician and the biological research counted the positive and negative cases worker do want or should most want to

104 know in the context of the clinical trial warded) by the elegance or cleverness of In stating my own view about this, I the design rather than by any real or approach the topic with the admitted supposed benefit to patients Such preoccupations of my main professional studies as Foxs scholarly enquiries lifework as an experimental biologist In showed that they are their own reward, that capacity, I see the assessment of but in our present climate they reap in remedies as the disclosure of a specific addition a harvest of praise from critics, stimulus-response nexus; and I mean by like Dr Grayson, who admire the new controlled experiment no less exacting an mode and scorn the old If learning undertaking than as stated in my opening theory is any guide, these self-rewarding paragraph." Hogben and Wrighton2O studies will continue until there is a summarize their point of view in this marked change of medical opinion way:" (1) Hitherto it has been customary regarding their worth. to assess the claims of therapeutic and Some other test than this is needed prophylactic measures in statistical terms We could enquire for instance how often by recourse to tests which invoke a elaborate statistical manipulation and unique and so-called null hypothesis, the methodological refinements now namely that the procedures compared considered essential for good psychiatric are equally efficacious (2) This pro- research, have played a large part in cedure has no bearing on the operational those developments of the biological intention of the trial, viz to find out how sciences which have done so much to much advantage accrues from sub- improve the human condition in the last stituting one treatment for another. (3) century Few would disagree that Nobel Within its more restricted domain, the prize winners are a fair sample of those credentials of any significance test which who have made great discoveries. takes within its scope only one hypo- According to Stevensons (1953) survey thesis have now to meet the criticism fifty-eight Nobel prizes were given for that it takes into account only one sort of discoveries in the biological sciences error, viz that of rejecting the hypothesis. between 1900 and 1950. Table 1 shows when it is true (4) A procedure which how they were distributed. justifies assertions of so limited and conditional a scope may be a useful self-disciplinary convention; but its TABLE 1 claims to rank as an instrument of Distribution of Nobel Winners statistical inference are no longer accept- by Discipline 1900-1950 able " It may be however that there is Discipline Number something about statistical experiments Immunology and Bacleriologv 10 which Bernard, Kluver and Hogben have Physiology 12 all failed to appreciate. We shall attempt Anatomy and Pathology 4 some sort of empirical test One of our Biochemistry 18 earlier arguments could perhaps be Genetics and Embryology 3 turned against us—in the form that since Surgery Opthalmology and Otolaryngology 2 many people use and are enthusiastic Therapeutics 8 about the statistical methods they must Total 58 be effective We noted that doctors use certain medicines and procedures for long periods of time because these result It appears from Stevenson that only in their being reinforced by their patients one (Muller) made any extensive use of betterment and tend to relinquish those statistics, and this was in genetics None which do not result in improvement In of them referred to statistics in their main double blind studies, those who under- work None of the eight prize winners in take them seem to be reinforced (re- therapeutics used the double blind method now thought to be so indispens- 8 FOULDS. G : 1 Ment Sc : 104:259. 1958 able This can hardly be because 9 FOX B : J Ment Sc 107:493. 1961 statistics are new; Calton and Pearson 10 GLICK, B S., and MARGOLIS. R : Am .1 Psychiatry. did much of their valuable work in the 118:1087. 1962 last quarter of the nineteenth century, 11 GOLDMAN. D : in Biological Psychiatry Ed. J H Fisher (1925) in the first quarter of the Masserman Grune Stratton. New York. 1959 twentieth Statistics of this kind are as GRAYSON, H : Dis New Syst 22:52. 1961 old as bacteriology and immunology and 12 13 Group for the Advancement of Psychiatry Report 42. far older than biochemistry founded by May. 1959 104 East 25th Street. New York 10. N V Gowland Hopkins about 1912 In spite of its recent origin biochemistry in which 14 HOFFER. A : Perspectives in Biol 6 Med . 4:492, 1961 statistics play a very small part heads the 15 HOFFER, A and OSMOND. H : J Neuropsychiatry. list with eighteen prize winners, almost 2:221. 1961 one-third of the whole It seems from this 16 HOFMANN, A ; International Symposium on the Chemistry of Natural Products Abstract of Papers. empirical test that statistical expertise Australia. 1960 has little to do with original discovery. 17 HOFMANN. A . and TSCHERT ER. H Experentia 16: Those who put their faith in it should 414. 1960 consider these findings before becoming 18 HOGBEN. L : The Medical Press. 232. October 13, 1954 too over-bearing and insistent that theirs 19 HOGBEN, L.: Statistical Theory: The Relationship of is the only path to truth Probability, Credibility and Error George Allen and Unwin Let there be no misunderstanding We Ltd London. 1957 do not imply that stochastic theory 20 HOGBEN. L., and WRIGHTON R : Brit J Soc Med should dispense with statistics or that 689 . 117 1952 scientific methodology should be neg- 21 ISBELL. H Personal Communications to H Osmond. lected It is and must continue to be a 1957 valuable aid which can ease the burden 22 KINROSS-WRIGHT, V J.: Neuropsychopharmacologv of discovery and speed its confirmation Proc 1st Int Congress. Amsterdam. 1959. p 453 and acceptance. But sometimes it has 23 LUCY J CLANCY, J.. HOFFER, A., OSMOND, H.. SMYTI-IIES, J . and STEFANIUK. B . Bull Menn Clinic. become a straight-jacket, even a coffin, 18 147. 1954 imposing harmful and fatal limitations on 24 MEEHL, P E.: Clinical Vs Statistical Prediction U of those delicate tendrils of enquiry which Minn Press. Minneapolis. 1954 are among the most precious growths of 25 OSMOND H : J Ment Sc 101:526. 1955 science Clinical trials should be done 26 PENROSE. L S and MARK. W B. .1 Ment Sc. 89: cautiously and with modest expecta- 374. 1943 tions We should not be too keen to POLANYI. M The Lancet. 1:921. 1956 discard or deride substances or treat- 27 28 SCHULTES. R. E : A Contribution to our knowledge of ments which experienced clinicians say Rivea Corvmbosa Botanical Museum of Harvard help their patients They may, after all, University- 1941 be right 29 SYDIAHA. D : J Applied Psychology 43:395. 1959 30 TABER. W A., and HEACOCK. R A : Can J Micro- biol B.137. 1962 REFERENCES 31 TRELOAR, A E.: Elements of Statistical Reasoning John Wiley 6 Sons. Inc New York 1939 1 ABRAMSON. H A. The use of LSD in psychotherapy 32 STEVENSON, L G.: Nobel Prize Winners in Medicine 2 BARBER B : Science. 134:596. 1961 and Psychology. 19014950. Henry Schuman. New York. 1953 3 CAFFEY, E. M . and KLETT C ..l : Dis Nery Syst 22:370 1961 4 CHASSAN. 1 B : Psychiatry. 23:173. 1960 5 CHASSAN. 1 B : Behavioral Science. 6:42. 1961 6 ENGEL. G L Perspectives in Biol 6 Med 4:386. 1961 7 FISHER, R. A.: Statistical Methods for Research Workers. Oliver Boyd. Edinbourgh. 1925

106 SECTION VII—Efficacy and Toxicity

The double-blind controlled method intensity of undesirable side effects and for testing efficacy is only one of a reactions which would be very toxic and number of possible tests In spite of its even lethal if allowed to continue overwhelming popularity, especially among professors, editors, and civil Children, Drugs, and Vitamins—A Matter servants; there is a large and growing of Ethics, A. Hoffer, M.D., Ph.D. body of scientific opinion that it has When Dr H Osmond read Dr B many inherent errors and should be used Rimlands megavitamin study on a large with great scepticism and its limited series of sick children, it occurred to him conclusions accepted with extreme re- that it lent itself to an examination of luctance When it comes to a matter of efficacy as against toxicity. Efficacy toxicity no double blinds are recom- would be the improvement due to the mended. This is too serious a matter to drug while toxicity would be the term be left in the hands of double-blind applied to any worsening of the con- methodologists We do not know of a dition Relative efficacy would be the single drug taken off the market because ratio of one to the other Thus if drug A of double-blind human trials We believe helped 50 percent of a sick population this double standard tells us much about and made 10 percent worse, its relative the validity of the double blind For group efficacy would be 5 If it helped 25 serious matters such as toxicity it is percent and deteriorated 25 percent, its ignored For efficacy, obviously con- relative group efficacy would be 1 sidered much less serious, it is recom- Obviously the drug with highest relative mended efficacy would be the one best used for How then are we to judge the relative most sick children. toxicity of drugs? We cannot demand Rimland (1972) reported results which animal type toxicity trials where the make it possible to rate a large number of lethal dose is determined by finding out compounds. His Table 2 is here re- how much will kill half the subjects We produced: are forced to fall back on the number and

TABLE 2

No Possibly Some Made a Made Definite Helped a I mpr Def. Little Much Efficacy Drug Name Total Effect little Total Helped Total worse Worse Total Index

Dexedrine 172 30 18 48 25 19 44 27 53 80 0 5 Aventyl 35 16 5 21 3 3 6 5 3 8 08 Benedryl 151 47 45 92 13 21 34 12 13 25 1 3 Compazine 49 15 16 31 5 2 7 4 7 11 06 Deana) 73 30 16 46 10 7 17 8 2 10 1 7 Dilantin 204 69 36 105 18 39 57 21 21 42 1 3 Mellaril 277 60 61 121 57 44 101 31 24 55 1 8 Stelazine 120 25 27 52 20 20 40 16 12 2B 1 4 Thorazine 225 49 50 99 25 33 58 39 29 68 0.8 Valium 106 28 16 44 9 22 31 17 14 31 1 0 Ritalin 66 7 10 17 10 12 22 9 18 27 0 8 Phenobarbital 52 11 10 21 3 7 10 7 14 21 0 5 Ataraz/Vistaril 51 15 12 27 3 6 9 11 4 15 0.6 Mysoline 10 0 2 2 1 3 4 2 2 4 1 0

107 Rimland wrote, "Table 2 shows for the design of the study. The study made use total group of children that certain of the of an unusual design in which clusters of drugs (e g , Dexedrine) seem to impair children, grouped by a computer in terms behavior more than they help, while of their similarity on Form E-2, were other drugs (e.g., Mellaril) are more compared on their response to treat- often beneficial than harmful. Half of the ment. The computer grouped the child- drugs appear to have harmed more than ren with no information on their response helped, and even Mellaril was reported to the vitamins. The criticism was that to have helped only about one-third of our positive results might stem from the the 277 children on whom it was tried." fact that many parents would be inclined We have added the relative efficacy to overrate the vitamins because they numbers calculated by dividing the want so badly to see their child improve. number of children who were definitely This criticism is not valid, but if it were helped or showed improvement by the valid, the same spurious effect should be number of children made a little worse or seen in the parents assessment of the made much worse drugs It is not. Since there is clearly Rimland states: "It is interesting to much more improvement reported for compare the drug results in Table 2 with the vitamins than for the drugs, the the results of our so-called megavitamin argument must be rejected that our study The megavitamin study involved vitamin findings reflect only wishful several hundred children who were given thinking by the parents (As indicated in large amounts of vitamin C and certain our primary report on the megavitamin of the B vitamins, especially niacin, B6, study, the finding of significant between- and pantothenic acid The vitamins were cluster differences in response to the given for a three-month period, followed vitamins leads to the same conclusion by a one-month no-treatment period. [Rimland, 6]). Evaluations of change were made by "I predict that in a few years the use of each childs parents and his physician high dosages of vitamins will be a "Table 3 shows that the vitamins are common-place method of treating—and not only far more likely to help than the preventing—various disorders, including drugs—they are also far less likely to especially the so-called mental dis- cause any kind of harm—behavioral or orders. There is a very common mis- physical. conception to the effect that anyone who "The findings in Table 3 are of special eats a normal diet will not require interest in view of the criticism of our additional vitamins That may (or may vitamin study commonly made by people not) be true in most cases, but it is who do not understand the experimental certainly not true in all cases."

TABLE 3

Comparison of Parent Ratings of Effectiveness of All Drugs, Best Drug (Mallard), and Vitamins

No Possibly Made a Made Def Helped a Some Def Little Much Efficacy Treatment Total Effect Little Total I mpr Helped Total Worse Worse Total Index

All drugs 1591 402 324 726 202 238 440 209 216 425 1 0 (Avg Drug) 100% 253 20 3 45 6 12 7 14 9 27 7 13 1 13 6 26 7 Best Drug 277 60 61 121 57 44 101 31 24 55 1 8 I Mellari8 100% 21 7 22 0 43 7 206 158 364 112 87 199

High dosage 191 20 37 57 41 86 127 4 3 7 18 0 Vitamins 100% 104 19 4 298 215 450 665 21 1 6 37

108 Thus it is clear that the megavitamin helped are three times that of Mellaril approach not only helped more children while the chances of being made much than the best single drug, Mellaril, but worse are less than 1:25 If one also had an efficacy index 10 times as concentrates on the definitely helped- high, chiefly because it produced so few much worse figures and compares Mell- side effects aril and vitamins and uses the product of This then is the background for one of these two categories, on my reckoning Dr Osmonds memos entitled "Children, the vitamins are 12 times as effective as Drugs, and Vitamins—A Matter of Mellaril, because they are (roughly) three Ethics," which follows: ti mes more likely to produce definite "You will see that Bernie R has now help and four times less likely to do done this piece of computation with very harm interesting results What I hope we shall "I do not know that medicines have be able to do is to underscore the facts ever been assessed in this way before, which this very simple approach has but it seems to me that an examination of made so very clear. All drugs may do this and other medical procedures in nothing much, some good or some harm these terms would be possible and might The clinician aims at getting as much throw a very different light on drug and benefit as possible and as little harm. other treatment effectiveness. My math- One would suppose that a rational ematical knowledge is so poor that I may approach would be to start with the best have made some gross blunder here, but bet which would clearly be that which I am inclined to think that I have not did most good and least harm Because a done so There are times when lack of substantial proportion of all these sub- sophistication allows one to recognize . stances came into the nothing much issues which would otherwise be ob- category, we need only study the worse scure and improvement categories There is no "As far as the patient and his/her reason why a drug should not have a 50 family, what they are concerned with is a percent much worse or a 50 percent cost or risk-benefit which can be assessed much better split, but none of these did. fairly simply To make that reasonable Clearly when this is likely to happen one assessment, which NIH urges upon us as must be very alert to deterioration and a right for all patients, one has to have wherever possible discriminate between some way of assessing and presenting the those who are likely to be benefited and information available I do not doubt those who are likely to be harmed that there are more elegant and efficient "Bernies figures allow us to construct ways than those which I have suggested a sort of rough cost-benefit approach. I here, but since at this moment, so far as I shall exclude the no-change cases al- know, no method of this kind is in though they too could be examined and general use, mine can stand until should be examined in a longer article. superceded It has much bearing when it "Where change occurs, Mellaril and comes to measuring the nature and the vitamins apart, it is as likely to be for extent of improvements in medicine, the worse as for the better. This applies surgery, etc over the years to both categories of improvement and "My own eye operations are examples worsening. With Mellaril the chances are of this (cataracts); 25 years ago or so the 2:1 in favor of improvement I am a poor odds were not very much better than say statistician but go by Sir Ronald Fishers 50 percent definite improvement against rule, as told me by Leonide Goldstein, 50 percent complete loss of vision The that in medicine the kind of statistics you operation itself was frightening, some- need are those that dont require ti mes very painful, psychotic episodes statistics Mellaril looks better to me than were not infrequent, and occasionally the assembled drugs operation on one eye might result in "However, when we come to the complete blindness in both. Today the vitamins, the chances of being definitely odds in favor of restoring vision are about

109 99:1, and the odds on losing ones vision patients already were afflicted and by a have become miniscular In other words, report that tranquilizers bind manganese the benefits have increased greatly and firmly (this is called "chelation") and the risks have been as greatly reduced could cause a manganese deficiency "There have been many similar situa- Manganese is found in high concentra- tions, but in my experience medical tion in the extrapyramidal system It matters are rarely presented in this appeared likely that, by leaching mang- manner Were this done it might make it anese out of these parts of the brain, easier for us to discriminate among the tranquilizers caused tardive dyskinesia various treatments available and allow Very soon after, Kunin was consulted by doctors, patients, and their families to a young man who complained of gauge realistically where the best course dyskinesia due to fluphenazine enanth- lay This approach would also draw our ate. This condition had not cleared with attention to those illnesses in which the previous medication. However mangan- current natural history has been insuf- ese chelate 10 mg three times per day ficiently investigated for us to be able to cleared it in two days In his report he make a reasoned and reasonable decision gave details of 15 cases These are regarding the chances that treatment will Kunins conclusions: help rather than hinder " (B Rimland, 1 Fifteen cases of withdrawal and "Recent Research in Infantile Autism," ). tardive dyskinesia were treated with Operational Psychiatry 3, 35-39, 1972 ) manganese chelate, and 10 of these with One of the most dangerous side effects niacin or niacinamide also of tranquilizer therapy is a condition 2 Review of frequency of occurrence until now considered irreversible, tardive and mechanisms of cause and treatment dyskinesia. Kunin (1976) referred to it as in drug-induced dyskinesia are discussed. a prolonged and sometimes permanent 3 There are four cases (27 percent) of extrapyramidal syndrome present in up dramatic and almost immediate cure, to 50 percent of patients older that 50 after manganese treatment In nine other who have been on tranquilizers over cases (60 percent) definite improvement three years Over 2,000 cases have been occurred in two to five days. Only one reported in the world literature by case was unresponsive to manganese mid-1973 An FDA bulletin in May 1973 treatment advised caution in the use of tran- 4 In one case unresponsive to mangan- quilizers It acknowledged that the ese, niacin therapy was dramatically symptoms appear to be irreversible in successful, associated with almost some patients and that there is no known complete cure in a matter of hours treatment 5 In eight of nine other cases in which Modern psychiatry would collapse niacin was used it was associated with without tranquilizers It is the main base significant elevation of mood and clear- for so-called "community psychiatry " ing of sensorium In seven of seven cases Tranquilizers are very helpful when used that also were treated with niacinamide in moderation wisely and as an adjunct similar clearing of sensorium was noted to orthomolecular psychiatry It is desir- and, in two cases, significant improve- able to prevent the toxic side effects of ment in extrapyramidal symptoms which tardive dyskinesia is one of the 6 It is concluded that manganese worst appears to be of value in many cases of Ironically the solution may have come tardive and withdrawal dyskinesia from orthomolecular principles Kunin 7. It also appears that manganese may (1976) was spurred to investigate the be of value in preventing the occurrence cause of tardive dyskinesia by finding of tardive and withdrawal dyskinesia that 10 percent of his schizophrenic 8 It is likely that niacin and niacinamide are of some value in many cases of Reprinted from the Huxley Institute . CSF Newsletter. drug-induced extrapyramidal syndrome. April. 1974. Vol 1. No 2 9 More extensive and better controlled studies are needed to evaluate all of these observations and impressions One of us (AH) observed similar responses It is now (AH) policy to use manganese in combination with zinc for any patient where there is any evidence of dyskinesia developing or present. It is likely Kunins work will be confirmed when it is done by competent orthomolecular psychiatrists His work suggests that tranquilizer preparations should contain enough manganese to prevent the production of manganese deficiencies

to SECTION VIIILetters

April 14, 1971 June 8, 1971

Dr M A Lipton Dr R S. Garber, President Department of Psychiatry American Psychiatric Association University of North Carolina Carrier Clinic CHAPEL HILL, North Carolina BELLE MEAD, New Jersey 08502

Dear Dr Lipton: Dear Bob:

I recently noticed with some surprise Sometime ago I wrote a letter to Dr. that you were Chairman of an APA Morris Lipton, the Chairman of a special committee given the mission of looking committee to investigate the mega- into the megavitamin B3 claims You vitamin claims, and I sent a copy to your have clearly established yourself as a vig- office. So far I have not received any orous and unrelenting opponent of the reply from Dr Lipton who seems to be a use of this approach as is witnessed by man who refuses to answer his mail. your address to the symposium in I now write to you directly to protest California, by your press conference with his appointment as Chairman of a APA Newsletter, and in your letters to committee to investigate the mega- Mr. J De Silva which you circulated vitamin claims since he has already widely expressed himself publicly over the past In view of your known and evident bias year as being very much against the against the use of vitamins I now ask you position of those of us who are using to disqualify yourself as Chairman For these treatments I do not see how any any report coming from your committee Commission with such a Chairman at its with you as Chairman would properly be head can possibly come up with a as suspect as a favorable report coming neutral and objective assessment. from a committee whose Chairman is a For this reason, I therefore request you rabid enthusiast as President of the American Psychiatric If you decline to accede to my request Association to take action in connection I will make this an official request to the with my request. President of APA, Dr R Garber In order You realize, of course, that if you do to acquaint him with my intention, I am not do so any report that comes out from sending him a copy of this letter. this Committee will obviously be very To give him a complete record of your biased and I, of course, will make it views, I also ask you to send him a copy widely known that this is the case of your letter to Mr. J De Silva in which I was slandered and a copy of my letter to Sincerely, you which you did not acknowledge If A Hoffer, M D , Ph D you feel reluctant to do so, I will be pleased to send him copies AH:afm

Yours truly, A Hoffer, M D , Ph D

AH:afm cc: Dr R Garber cc: Dr. H. Osmond

112 A Hoffer, M D , Ph D 1201 CN Towers, First Avenue South Saskatoon, Saskatchewan Canada

Several weeks ago I received your letter from Dr. Garber In your letter of June 8, you expressed some concern regarding the APA Task Force on Vitamin Therapy and the Chairman, who is Dr Morris Lipton The Task Force members are Dr. Morris A Lipton, Chairman; and Drs Thomas Ban, Francis Kane, Jerome Levine, Loren Mosher, and Richard Wittenborn (consultant) The Task Force is responsible to the Council on Research and Development. The Council is presently composed of Dr. Sidney Malitz, Chairman; Drs. Monroe, Blueck, Hamburg, Schwab, and Shervington. Any reports that the Task Force prepares are first submitted to the Council for review. If the Council approves, the report is considered by the Reference Committee and finally by the Board of Trustees I believe it is obvious that a very excellent review mechanism exists and that the Task Force, as well as the Council, is composed of highly qualified psychiat- rists who are thoroughly familiar with the scientific method and are capable of evaluating published literature. I hope this information is of value to you

Sincerely yours, Ewald W Busse, M D President

EWB:bsk cc: Drs Garber and Barton

113 SECTION IXReferences

ADAMS, A 113 other authors) and WITTENBORN, J. R : A COTT. A A : Orthomolecular Approach to the Treatment of Corrective Response to the Note of Criticism Concerning the Children with Behavioral Disorders and Learning Dis- Double-Blind Study of Niacin Supplement in the Treatment abilities J Applied Nutrition 25. 1524. 1973 of Schizophrenia J Orthomolecular Psychiatry 4. 283285. 1975 COTZIAS. G. C.: Limitations of Controlled Double-Blind Studies of Drugs New Eng .1 Med 287. 937. 1972 ANANTH, J V . BAN, T A , LEHMANN, H. E and BENNETT -1.: Nicotinic Acid in the Prevention and CROMIE, B. W : The Feet of Clay of the Double-Blind Treatment of Methionine Induced Exacerbation of Psycho- Trial Lancet 2 994-997. 1968 pathology in Schizophrenics Can Psychiat Ass 1 15. 15-20. 1970 CUTLER, P Pyridoxine and Trace Element Therapy in Selected Clinical Cases J Orthomolecular Psychiatry 3. ANANTH, J V , BAN. T A„ and LEHMANN. H E : 89-95 1974 Potentiation of Therapeutic Effects of Nicotinic Acid by Pyridoxine in Chronic Schizophrenics Can Psychiat. Ass De LIZ. A. J.: A Note of Criticism Concerning Wittenborn - s Ann Meeting 119721 Can Psychiat Ass .1 18 377-382. Paper on an Experimental Double-Blind Research Design 1973 Dealing with the Action of Nicotinic Acid on Schizophrenia 1 Or thomolecular Psychiatry 2 115-117. 1973 BAIRD, K A : Medicines Domination by the Control Wor- shippers Canadian Doctor 27 March. 1968 De LIZ. A. J : Dr. De Lizs Rebuttal J Orthomolecular Psychiatry 4 285-287. 1975 BAIRD. K. A, Assessment of Reports of Drug Trials Can Med Ass J 90. 1279. 1964 DENSON R Nicotinamide in the Treatment of Schizo- phrenia Dis New System 23 167172. 1962 BAN, T A,: Methodology and Pitfalls in Clinical Testing of Psychopharmacological drugs Chemotherapia 9 223-230. DINNERSTEIN. A. 1., LOWENTHAL, M, and BLITZ, B.: 1964.. The Interaction of Drugs with Placebos in the Control of Pain and Anxiety Perspectives in Biol and Med 10. BAN, T A Schizophrenia: a Psychopharmacological 103117 1966 Approach C C Thomas. Springfield III 1972 (Editorial) W T 8 Megavitamin and Orthomolecular BAN. T Letter to Editor Psychosomatics 16 54 1975 Therapy of Schizophrenia Ed Can Psychiat Assoc J 20. 97-100. 1975 BAN, T A . and LEHMANN, H. E : Nicotinic Acid in the Treatment of Schizophrenias Can Psychiat Ass J 20. EMANUEL. E A half life of 5 years Can Med Ass J 112 103-112. 1975 573 1975

BEATON, J. M.. SMYTHIES, J. R , and BRADLEY, R. J.. FEINSTEIN, A R. Clinical Biostatistics IX How do we The Behavioral Effect of L-Methionine and Related Com- Measure Safety and Efficacy? Clin Pharm and Thera- pounds in Rats and Mice Biol Psychiatry 10. 4552. 1975 peutics 12. 544-558. 1971 BELLAK. L , and CHASSAN, J B : An Approach to the FEINSTEIN. A. R : The need for humanised science in Evaluation of Drug Effect during Psychotherapy: a Double- evaluating medication The Lancet 2 421-423. 1972 Blind Study of a Single Case J New and Merit Dis 139. 20 .30. 1964 GERSHON, S., and SHOPSIN, B : Lithium. Its Role in Psychiatric Research and Treatment Plenum Press New BLUMENTHAL, D S.. BURKE, R , and SHAPIRO, A. K York. 1973 The Validity of Identical Matching Placebos Arch Gen Psychiatry 31. 214-216 1974 GREEN, R G Protein poor diet means pellagra Can Family Physician 16. 88. 1970 BIRON. P Diabetic Hearts and Biguanides Can Med Ass J 113. 175-176. 1975 GREEN, R G Letter entitled - Pellagra article Can Family Physician July Page 17 81RON, P . The Sugargate Coverup Can Med Ass 1 113 179-180 1975a GREEN. R. G Subclinical Pellagra Its Diagnosis and Treat- ment Schiz 2. Pp 70. 79. 1970 BORDA. I. T : Physicians. Patients Differ on Effects of Tranquilizers JAMA. Vol 224. p 7584. 1973 HAWKINS, D R Treatment of Schizophrenia based on the Medical Model J Schizophrenia 2. 3 . 10. 1968 CHINAGLIA, L : Sul Irattamento delta schizofrenia con amide nicotinica Folia Psychiatrica 8. 123130. 1965 HAWKINS D. R.: An Integrated Community System for the Effective Treatment of Schizophrenia Schizophrenia 3 CHIOSSONE, F, HAWKINS. D. R.. FURFARO, F., and 94. 1971 RUNYON. R. P : Response to Intensive Hospital Treatment as Monitored by the HOD and OIT Test Schizophrenia 1 HAWKINS, D R , and PAULING. L.: Orthomolecular 233242. 1969 Psychiatry W H Freeman and Co . San Francisco. Calif 1973 CINADBR, B : Individuality in Disease and Therapy Can Med Ass J 113 11-13 1975 HENINGER, G. R., and BOWERS. M B.: Adverse effects of COTT, A. A.: Treatment of Schizophrenic Children Schizo- niacin in emergent psychosis 1AMA 204. 1010-1011. 1968 phrenia 1 44 . 59 1969 HERJANIC. M.. MOSS-HERJANIC, B . and PAUL, W K.: COTT, A A.: Orthomolecular Approach to the Treatment of Treatment of Schizophrenia with Nicotinic Acid J learning Disabilities Schizophrenia 3 95-105. 1971 Schizophrenia 1 197-199 1967 Von HILSHEIMER. G KLOTZ.S D McFALL G., LERNER, HOFFER, A.: Nutrition and Schizophrenia The Can Family H. Van WEST, A.. and QUIRK, D. The Use of Mega Physician 21 7881. 1975 Vitamin Therapy Regulating Severe Behavior Disorders Drug Abuses and Frank. Psychoses Schizophrenia 3. 67. HOFFER A : Report to Can Mental Health Ass Sask 73. 1971 Division. 1975 HILL, L E . NUNN, A J and ._FOX. W.. Matching HOFFER, A , and OSMOND H : The Adlenochrome Model quality of agents employed in double blind" controlled and Schizophrenia J New Menl Dis 128. 18-35 1959 , clinical trials The Lancet 1. 352356. 1976 HOFFER, A , and OSMOND. H : Double-Blind Clinical HOFFER. A Niacin Therapy in Psychiatry C C Thomas. Trials J Neuropsychiat 2. 221-227. 1961 Springfield. III 1962 HOFFER. A , and OSMOND, H Some Schizophrenic Re- HOFFER. A . Nicotinic Acid: an Adjunct in the Treatment of coveries Ois Nery Svsl 23.204210. 1962 Schizophrenia Amer J Psychiat 120. 171 . 173. 1963 HOFFER. A and OSMOND, H Some Problems of Stoch- HOFFER. A : Treatment of Organic Psychosis with Nicotinic astic Psychiatry J Neuropsychiary 5 97 . 111 1963 Acid Dis Nery Syst 26 358 . 360 1965 HOFFER A , and OS MONO. H Malvaria: a New Psychiatric HOFFER, A.: The El loot of Nicotinic Acid on the Frequency Disease Acta Psychiatrica Scand 39. 335366. 1963 and Duration of Re-hospitalization of Schizophrenic Patients: a Controlled Comparison Study Inc 1 Neuro- . HOFFER. A , and OS MOND. H. Treatment of Schizophrenia psychiatry 2. 236 240 1966 with Nicotinic Acid Acta Psychiat Scand 40. 171-189. 1964 HOFFER, A.: Enzymdogy of hallucinogens Proc. Carl Neuberg Society Meeting J B Lippincott. Philadelphia HOFFER A , and OSMOND, H.: Nicotinamide Adenine Dine . Penn 1966a cleotide INADI as a Treatment for Schizophrenia .1 Psy chopharmacotogy 1 7995 1966 HOFFER. A : Malvaria and the Law Psychosomatics 7 303-310 1966b HOFFER, A , and OSMOND. H.. The Hallucinogens Academic Press. New York N Y 1967 HOFFER, A : A program for treating schizophrenic and other conditions using megavitamin therapy Available from A HOFFER A , and OSMOND H How to Live with Schizo . Holler 1967 Revised 1974 ohrenia University Books New Hyde Park. New York 1966 1975 HOFFER. A.: A Theoretical Examination of Double-Blind Design Can Med Ass J 97. 123-127. 1967 HOFFER. A . OSMOND. H CALLBECK. M J. and KAHAN, I.: Treatment of Schizophrenia with Nicotinic acid HOFFER A.: Five California Schizophrenics J Schizo- and Nicotinamide J Clin Exper Psychopath 18.131-158. ohrenia 1 209-220 1967a 1957 HOFFER, A.. Biochemistry of Nicotinic Acid and Nicotine . HOFFER, J The Controversy over Orlhomolecular Therapy amide Psychosomatics 8. 95 100. 1967b 1 Or thomolecular Psychiatry 3. 167185. 1974 HOFFER. A . Adverse El feels of Niacin in Emergent Psycho- JAIN. K K.. Are your peers what they appear Canadian sis J AMA 207. 1355. 1969 Doctor August. 58.60. 1975 HOFFER, A. Comparison of Xanthine Nicotinate and JOYCE, C R 8 Psvchopharmacology Dimensions and Nicotinic Acid as Treatment for Schizophrenia Schizo- Perspectives 1 B Lippincott Co Philadelphia. Penn phrenia 1 2437 1969a 1968

HOFFER. A. Safety Side Effects and Relative Lack of KELM, H , GRUNBERG, F., and HALL, R. W.: A Re- Toxicity of Nicotinic Acid and Nicotinamide Schizophrenia Examination of the Hoff er . Osmond Diagnostic Test Int 1 1 7887 1969b Neuropsychiatry 1. 307-312. 1965 HOFFER, A Childhood schizophrenia: A Case Treated with KETY, S S. Current Biochemical Approaches to Schizo- Nicotinic Acid and Nicotinamide Schizophrenia 2 43-53. phrenia New England J Med 276. 325331. 1967 1970 KLEIN. D F Comment Amer J Psychiatry 131. 1263 . 1265. HOFFER. A The Psychophysiology of Cancer J Asthma 1974 Research 8 6176 1970a KLINE, N. S BARCLAY. C. L., COLE, J 0 ESSER, A. H HOFFER A.. Vitamin 83 Dependent Child Schizophrenia 3 LEHMANN, H , and WITTENBORN, J R : Controlled 107-113 1971 Evacuation of Nicotinamide Adenine Dinucleotide Brit J Psychiatry 113. 731-742 1967 HOFFER, A. A Vitamin 83 Dependent Family Schizophrenia 3 41.46 1971a KRIPPNER, S . and FISCHER, S.: A Study of Neurological Organization Procedures and Megavitamin Treatment for HOFFER, A Megavitamin B3 Therapy for Schizophrenia Children with Brain Dysfunction J Orlhomolecular Psy- Can Psychiatric Assoc if 16. 499504 1971b chiatry 1. 121-132. 1972 HOFFER, A : Orlhomolecular Treatment of Schizophrenia J KUNIN. R A : Manganese and Niacin in the Treatment of Orthomolecular Psychiatry 1 4655. 1972 Drug-Induced Dyskinesias 1 Orlhomolecular Psych 5. 4.27. 1976 HOFFER, A Mechanism of Action of Nicotinic Acid and Nicotinamide in the Treatment of Schizophrenia —in Ortho- LAPPE M Accountability in Science Science 187. 696. molecular Psychiatry, Hawkins. D R and Pawling. L W H 1975 Freeman and Co San Francisco. Calif 1973 LASAGNA, L : The Clinical Pharmacologist as a Servant of HOFFER, A : A Neurological Form of Schizophrenia Can Society Can Med Ass J 97. 609613. 1967 Med Ass J 108. 186-188. 1973 LASAGNA. L The Nature 61 Evidence Triangle 11 145-152 HOFFER. A. Letter to Editor Psychosomatics 16 54. 1975 1972

115 LASAGNA, L : The Impact of Scientific Models on Clinical PFEIFFER, C C , and ILIEV, U : A Study of Zinc Deficiency Psychopharmacology: a Pharmacologists View Seminars and Copper Excess in the Schizophrenias Int Rev Neuro- in Psychiatry 4. 271-282. 1972 biol Supp 1 141 1972

LEHMANN, H : Options for Treatment of the Schizophrenic PFEIFFER, C. C.. ILIEV, U.. and GOLDSTEIN, I.: Blood Patient Canadas Mental Health. 24. 3 . 9. 1976 Histamine, Basophil Counts. and Trace Elements in the Schizophrenias Orthomolecular Psychiatry. Ed.: Hawkins. GLICK, B. S , and MARGOLIS, R : A Study of the In- D.. and Pawling. L W H Freeman and Co San Francisco. fluence of Experimental Design on Clinical Outcome in Drug Calif . 1973 Research Amer J Psychiatry 118. 10871096. 1962 PFEIFFER, C. C , SOHLER, A.. JENNEY, M S., and ILIEV, LeCLAIR. E R : A Report on the Use of Orthomolecular V.: Treatment of Pyroluric Schizophrenia IMalvanal with Therapy in a California State Hospital Orthomolecular Large Doses of Pyridoxine and a Dietary Supplement of Psychiatry 1. 104-108. 1972 Zinc J Applied Nutrition 26. 21 .28. 1974 LEFF, D N.: Megavitamins and mental disease Med World PFEIFFER, C. C., WARD. J , EL-MELIGI, M , and COTT, A News 16. 7182. 1975 A.: The Schizophrenias. yours and mine Pyramid Books. New York. N Y 1970 LIEBOW. C , and ROTHMAN, S S.: Enteropancreatic Circulation of Digestive Enzymes Science 189. 472-474. PHILPOTT. W H : Personal communication 1967 1975 PHILPOTT. W H : Private Communication 1973 LIPTON. M A : Comment Amer 1 Psychiatry 131. 1266- 1267.1974 PLOTCHIK, R , PLATMAN. S. R . and FIEVE. R. R.: Three Alternatives to the Double Blind Arch Gen Psychiatry 20. MICKELSON. C H.: Megavitamin Spinoff Canadas Mental 428-432. 1969 Health 23 11-13. 1975 REES, E. L.: Clinical Observations on the Treatment of MOSHER. L R : Nicotinic Acid Side Effects and Toxicity: Schizophrenic and Hyperactive Children with Megavitamins a Review Amer 1 Psychiatry 126. 1290-1296. 1970 J Orthomolecular Psychiatry 2. 93-103. 1973 MOSS, J M.: The UGDP scandal and cover up JAMA 232. RESTAK. R M : New York Times. Sunday. July 20. 1975 806808. 1975 RIMLAND, B.: Recent Research in Infantile Autism 1 NEWBOLD, H. L : How One Psychiatrist Began Using Niacin Operational Psychiatry 3. 35-39. 1972 Schizophrenia 2. 150-160 1970 RIMLAND. B, DREYFUS. P., and CALLAWAY, E: A NEWBOLD, H L., PHILPOTT, W. H., and MANDELL, M Double-blind Cross Over Evaluation of Higher Doses of Psychiatric Syndromes Produced by Allergies: Ecologic Vitamin Be on Autistic Children Sac. Biel Psychiatry. 31st Mental Illness J. Orthomolecular Psychiatry 2, 84-92, 1973. Annual Meeting. San Francisco. 1976 N I M H Workshop on onhomolecutar treatment approach in schizophrenia Holiday Inn. Bethesda. Maryland. April 18. ROBIE, T R.: Cyproheptadine; an Excellent Antidote for and 19. 1973 Niacin-induced Hypothermia 1 Schizophrenia 1. 133 . 139. 1967 OREILLY, P 0 : Nicotinic Acid Therapy and the Chronic Schizophrenic Dis New System 16. 67-72. 1955 SEHDEN, H S., and OLSON, J. L : Nicotinic Acid Therapy in Chronic Schizophrenia Comp Psychiatry 15. 611-617- OREILLY, P. 0, ERNEST, M and HUGHES. G.: The 1974 Incidence of Malvaria Brit J Psychiatry 111. 741-744. 1965 SIEGLER, M., and OSMOND, H : Models of Madness. Models of Medicine Macmillan Pub Co Inc New York. OSMOND, H and HOFFER, A.: Schizophrenia: a New N Y .1974 Approach III J Ment Sci 105. 653673. 1959 SILVERMAN. L. B.: Orthomotecular Treatment in Distur- OSMOND. H , and HOFFER, A : Massive Niacin Treatment bances Involving Brain Function 1 Orthomotecular Psychia- in Schizophrenia Review of a Nine-Year Sudv Lancet 1. try 4. 7184. 1975 316-320. 1962 STEWART, C. N., and MAHOOD, M C.: A Multiple Group OS MOND, H., and HOFFER, A.: Schizophrenia and Suicide Comparison of Scores on the HOD Can Psychiat Assoc 1 Schizophrenia 1. 5464. 1967 J 8. 133-137. 1963 OSMOND, H and SMYTHIES, J.: Schizophrenia: a New VAJAY. A.: Treatment of drug addicts in private practice Approach J Ment Sci 98.309315. 1952 Medical Times 101. 5462. 1973

PARSONS, W. B.: Nicotinic Acid in Hyperlipidemia: WALKER, J L : Neurological and behavioral toxicity of kry- Clinical Guidelines in the Use of a Broad-Spectrum Lipid ptopyrrole in the rat. Pharmacology. Biochemistry and Reducing Agent Internal Med 9.13-24 1974 Behavior 3 243250 1975

PAULING, L.: Comments on the Comments Amer J WARD. J L t Relationship of Kryptopyrrole, Zinc and Psychiatry 131, 1405 . 1406. 1974 Pyridoxine in Schizophrenics 1 Orthomolecular Psychiatry 4. 27-31. 1975 PAULING, L.: On the Orthomolecular Environment of the Mind: Orthomolecular Theory Amer J Psychiatry 131. WARD. J L.: Treatment of Neurotics and Schizophrenics 1251-1257.1974 using Clinical and HOD Criteria J Schiz 1. 140-149. 1967 PFEIFFER. C C.: Observations on the therapy of the Schizo- phrenias J Applied Nutrition 26. 29-36. 1974 WILLIAMS, M W : A First Evaluation Schizophrenia 3. 114. 115. 1971 PFEIFFER, C. C.: Does Acid Well Water Erode Plumbing. Vessels. and Sanity? .J Orthomolecular Psychiatry 4. 9 . 16. WILLIAMS, M. W : Clinical Impressions on Early arid Chronic 1975 Schizophrenia and Diagnostic Procedures Orthomolecular Psychiatry t. 5659. 1972

116 WIT TEN BO RN. J. R.: The Selective Efficacy of Niacin in the Treatment of Schizophrenia N I M H Conference Washington. 1973 WITTENBORN, J R.. A Search for Responders to Niacin Supplementation Arch Gen Psychiatry 31. 547552. 1974 WITTENBORN. 1 R., WEBER, E S. P.. and BROWN, M.: Niacin in the Long-Term Treatment of Schizophrenia Arch Gen Psychiatry 28. 308315. 1973 WYATT, R J Comment Amer J Psychiatry 131 1258- 1262 1974 SECTION X Reading List in Orthomolecular Psychiatry

New advances in medicine are fol- HILSHEIMER, G. Von: How to live with your special child Acropolis Books. Washington. D C . 1970 lowed by a gathering of the information HOFFER. A , and OSMOND, H The Chemical Basis of in scientific journals and books The new Clinical Psychiatry C C Thomas. Springfield. III . 1960 journals arise because standard medical HOFFER. A Niacin Therapy in Psychiatry C C Thomas. journals refuse to accept papers which Springfield. III . 1962 appear critical of the standard approach. HOFFER, A : A program for treating schizophrenic and other The new books arise in response to public conditions using megavitamin therapy Available from A demand The presence of the new Hoffer. 1967 Revised. 1974 literature stimulates interest among HOFFER, A., and OSMOND. H.: The Hallucinogens physicians and other professional Academic Press New York. N Y . 1967 workers who in turn contribute to it This HOFFER, A„ and OSMOND, H.: New Hope for Alcoholics is happening in the field of ortho- University Books. Secaucus. N J 1968 molecular psychiatry. There is a large HOFFER. A., KELM. H., and OSMOND, H : The Holler . Osmond Diagnostic Test R A Krieger Pub Co.. Hunting . body of literature available. Most of it is ton, N.Y., 1975. HOD test kit available from Behavior listed here for the convenience of Science Press. Box AG. University. Alabama 35486 everyone, lay person and professional HOGBEN, L.: Statistical theory: the relationship of probabil- Every book contributes directly or in- ity, credibility, and error George Allen and Unwin Ltd directly to the theory or practice of London. England. 1957 orthomolecular psychiatry KAUFMANN, W : Common Form of Niacinamide Deficiency Disease. aniacinamidosis Yale University Press. New Haven. Conn . 1943 KAUFMANN, W.: The Common form of Joint Dysfunction: ADAMS, R , and MURRAY. F : Body. Mind and the B its incidence and treatment E L Ftildreth and Co . Brattle- Vitamins Larchmont Books. New York. N Y 1972 boro. Vermont, 1949 ADAMS, R , and MURRAY. Fr, Megavitamin Therapy LILLISTON, L.: Megavitamins - a new key to health Larchmont Books. New York. N Y . 1973 Fawcett Publications. Inc . Greenwich. Conn 1975 ALTSCHUL, R.: Niacin in vascular disorders and hyper- NEWBOLD. H L The psychiatric programming of people tipemia C C Thomas. Springfield. III 1964 Pergamon Press Inc Elmsford. N Y . 1972 CHERASKIN, E., RINGSDORF, W. M., and CLARK, J. W r NEWBOLD, H L.: Meganutrienls for Your Nerves Peter H Diet and Disease Rodale Books. Emmaus. Penn . 1968 Wyden. New York. N Y . 1975 CHERASKIN. E. RINGSDORF. W. M , and BRECHER, A : PASSWATER. R : Supernutrition Dial Press. New York. Psychodietetics Stein and Day. New York N Y 1974 N Y . 1975 CLEAVE, T. L.: The Saccharine Disease Keats Publishing PAULING L.: Vitamin C and the Common Cold W H Free . Inc . New Canaan. Conn . 1975 man and Co San Francisco. Calif . 1970 CLEAVE. T. L., CAMPBELL, G. D , and PAINTER, N.S.. PFEIFFER, C C.: Mental and Elemental Nutrients Keats Diabetes, coronary thrombosis and the saccharine disease Publishing Co New Canaan Conn 1975 John Wright and Sons Ltd Bristol. England. 1969 PFEIFFER. C. C , WARD, J EL-MELIGI, M., and COTT, A : COTT. A : Fasting: the ultimate diet Bantam Books. New The Schizophrenias: yours and mine Pyramid Books. New York. N Y . 1975 York N Y . 1970 ELMELIGI, A. M., and OSMOND, H : EWt. manual for the ROSENBERG, G H., and FELDZAMEN, A N.: The Doctors clinical use of the experiential world inventory Mens Sena Book of Vitamin Therapy Putnams Sons. New York. N Y Publishing Co . New York. N Y 1970 1974 FOY, J G : Gone is Shadows Child Watching Book Sales. ROSS, H : Fighting Depression Keats Publishing Inc . New Watching N .J 07061. 1970 Canaan Conn 1975 FREDERICKS. C.: Psychonutrition Grosser and Dunlap. New SCHROEDER. H. A.: The Trace Elements and Man Devin- York N Y . 1976 Adair Co Old Greenwich. Conn . 1973 HALL, R H : Food for Nought - the Decline in Nutrition SCHROEDER, H A : The Poisons Around Us Indiana Harper and Row. New York. N Y 1974 University Press. Bloomington. Ind . 1974 HAWKINS, D R., and PAULING. L : Orthomolecular Psy- SHUTE, W. E : Vitamin E Book Keats Publishing. Inc . chiatry W H Freeman and Co . San Francisco, Calif 1973 New Canaan. Conn .1975

118 SIEGLER. M., and OSMOND, H : Models of Madness. Models of Medicine Macmillan Pub Co Inc . New York. N Y 1974

STEFAN, G : In Search of Sanity University Books. New Hyde Park. N Y 1966 STONE, I. The Healing Factor, Vitamin C against Disease Grosser and Dunlap. New York. N Y 1972 VONNEGUT, M : The Eden Express Praeger N 1 . 1975 WATSON, G : Nutrition and Your Mind Harper and Row, New York N Y . 1972 WILLIAMS. R J : Biochemical individuality .John Wiley and Sons. Inc . New York. N Y . 1956 WILLIAMS. R. J : You are extraordinary Random House Inc New York. N Y 1967 WILLIAMS. R. J Nutrition against Disease Pitman Pub Corp . New York N Y . 1971

WILLIAMS, R J.: Physicians Handbook of Nutritional Science C C Thomas. Springfield. III . 1975 YUDKIN, .1 : Sweet and Dangerous Peter H Wyden. Inc New York N Y . 1972

119 SUMMARY insignificant, were exaggerated 2 By the use of adjectives designed to We have examined critically and support the preconceived bias of the carefully the APA Task Force Report on committee megavitamins and orthomolecular psy- 3 By distorting our conclusions: chiatry We concluded that the report (a) by ripping phrases out of was biased, unfair, and contained a large sentences which changed the number of major and minor errors A meaning, and study of the composition of the com- (b) by misreading simple tables and mittee and the way it behaved explained statistical data why it carried out its mandate the way it Support for these charges is provided did by a careful examination of all the The chairman clearly voiced his bias published reports with the way the and antagonism in a public presentation committee abstracted them Our reports given several years before It is likely he are listed and briefly summarized in the was influential in selecting other mem- appendix This is followed by a brief bers of his committee This included one abstract of all the corroborative reports, of his junior professors who would most of them missed by the committee unlikely see things differently from his We would have given equal emphasis to chairman, two from NIMH then well any negative report where a serious known for its antagonism toward our attempt was made to repeat any of our work, and one man just preparing himself work We have not been able to find one. to launch a series of critical assaults Finally we have reprinted Dr L based upon experiments we consider Paulings critique of the APA Task Force inadequate He made no attempt to Report and his rebuttal of the three repeat in any scientific way any of our letters attacking his position early controlled experiments Since the committee accepted only Not only was the committee clearly evidence from double blinds (even if biased, it conducted its affairs in such a they were not) completed by others, we way as to avoid that degree of objectivity have presented a discussion of the essential for any proper investigations theoretical and practical aspects of the The committee not only should have double blind methodology We were the been fair, it should have appeared to first psychiatrists to use the double blind have been fair Objectivity could have and among the first to realize its serious been insured by having orthomolecular limitations as a method for testing representatives on the board and by efficacy of treatment inviting orthomolecular psychiatrists to Double-blind methodology is under present their data This was not done, nor attack by cancer research scientists. did the committee conduct any clinical Recently Dr C Freireich, Director of research Developmental Therapeutics at M D The report is characterized by the Anderson Hospital and Tumor Center in following: Houston concluded that the limitations (a) Pronounced bias against ortho- of such trials are so serious that there are molecular psychiatry few, if any, indications for using the 1 By a selective examination of the classical clinical trial strategy for evaluat- published reports In any corroborating ing and discovering new treatments for paper the positive conclusions were cancer Other types of controlled studies played down and minimized and possible in clinical research are superior, he side effects and toxicity were exagger- concluded National study groups foster ated In every negative paper the positive consensus-type research which stifles the or beneficial effects in these reports were creative individual with the capacity for minimized, played down, or ignored innovative work It is obvious that while negative findings, no matter how scientists are beginning to question

120 seriously double-blind experiments We finally concluded that the actions of the American Psychiatric Association and its subcommittee are explainable only if one took into account the spirit of Watergate then rampant in Washington, among some of the government agencies and the American Psychiatric Associa- tion, headquartered in Washington

121 SECTION XI—REAL Attempts to Corroborate with Failure to Confirm Original Studies

We have been unable to find a single were negative If then we had argued that published study The negative studies we had now changed (improved) the referred to by the APA Task Force made treatment procedure so that the attempt no attempt to replicate any of the to corroborate was invalid, then we original double-blind studies They made could have been accused of slipping out no attempt to use comparable patients, of the debate But this has never to use the same treatment protocol, or to happened Lehmanns argument really use the same criteria of improvement in cannot be taken very seriously until our hospital or after discharge Lehmann original experiments are repeated We (1976) admits this, but then complains cannot analyze why no attempts to that the treatment has changed Not duplicate have been made It is as Joyce even our first two double-blind experi- has written - ments were replicated His argument "To explore the reasons why some people would be much more persuasive if he, or choose a design for their experiments that is anyone else, had duplicated our first almost bound to lead to negative results is a controlled experiments little outside our brief " Suppose our first double blinds were There is no bibliography of negative duplicated with careful attention to our reports with respect to orthomolecular published procedures, but the results psychiatry

122 ADDENDUM pate I presume that the Task Force will or have already interviewed him so that A Memo Received from H, Osmond After here he was exercising a watching brief Completion of This Report After this six-hour free-for-all the Task Force is still open to comments from APA Psychiatric News, July 2, 1976, carried members It gives them an open invita- a report of an open meeting held by an tion to address their further suggestions APA Task Force on Electroconvulsive and views to the chairman, Dr Frankel Therapy. It was called to hear the views Had the Megavitamin Task Force of APA members in order to guide the conducted its business in such an open Task Force in drafting a report to APA and straightforward manner, it would Dozens of members spoke in a total of six have been far more difficult for us to hours of hearings The Task Force also criticize its conclusions invited comments from APA members In a public session of this kind it would who did not appear at the meeting doubtless come to light fairly quickly if It appears from this that the APA can the chairperson was known to be possess no general instructions for the flagrantly biased against ECT, or for that conduct of its Task Forces Nothing matter a keen proponent One may could be less alike than the behavior of assume that this may have excluded Dr those running the ECT Task Force and Kalinowsky from being a Task Force those examining megavitamins Just why Member There is no reason why he this should be is anyones guess, but it is should have been excluded, provided an a striking bit of evidence that the Mega- anti-ECT representative was included vitamin Task Force was conducted It looks as if the composition of the differently from at least one other Task Task Force and the method which it has Force The procedure, that of an open adopted is totally different from that hearing at which those who support and employed by the Megavitamin Task those who oppose the particular treat- Force under Dr Morris Lipton These are ment give their views and can be several explanations for this: questioned, seems a considerable (1) The APA may have learned from its improvement upon the practices of that earlier error, which seems unlikely since other Task Force As it turned out the it does not admit to error opponents of ECT either did not turn up, (2) The Megavitamin Task Force did or there are far fewer of them than we not follow Standard Operating Procedure have been led to believe and was not corrected, even though the It is interesting that the discussants APA pledged itself to give proper dealt with two problems which pre- supervision occupied the Task Force: (3) Too many APA members have an (1) No one knows why ECT works interest in ECT to permit any hanky (2) The data base for ECT, after nearly panky 40 years, is not all that it might be (4) By sheer good luck they picked a This is one of the well-known dif- fair unbiased chairperson ferences between Clinidok and the combination of Superdok and Megadok It is also of interest that the question of the efficacy of psychotherapy comes up once again It seems that the evidence in favor of megavitamins is a great deal more than for psychotherapy and appar- ently ECT if this account is correct Oddly enough Lothar Kalinowsky, who was present for most of the session, which lasted six hours, did not partici-

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