This review (1998) looks at the history of LSD as a possible treatment for alcoholism (AUD). It highlights the research that had been done and how psychedelics were subsequently relabelled as drugs of abuse.
Following Albert Hofmann's discovery of LSD's psychoactive properties in 1943, and previous to their scheduling as controlled substances, the psychedelic drugs were widely studied - six international conferences and hundreds of papers discussed their potential therapeutic usefulness. The observation that the frightening experience of delirium tremens sometimes led alcoholics to moderate their alcohol intake suggested to early psychedelic researchers that the psychotomimetic experience thought to be produced by LSD could be used to treat alcoholism. A number of hypothesis-generating studies employing a variety of research designs to examine this premise were completed, but relatively few controlled trials attempted hypothesis testing. After twenty-five years of study, a combination of flawed methodology, uneven results and social reprehension led to the abandonment of research on the therapeutic use of psychedelic drugs, leaving many avenues of inquiry unexplored and many questions unanswered. Today, after a thirty-year hiatus, this research is gradually being resumed, and there is renewed interest in the findings of previous studies. This article explores the history of one branch of psychedelic research, the therapeutic use of LSD in the treatment of alcoholism, and of the events that led to the relabeling of the hallucinogens as drugs of abuse.
Since Albert Hofmann discovered LSD's psychoactive properties in 1943, clinicians and researchers explored its therapeutic potential, producing more than 1,000 reports over the next quarter century. Early investigators proposed that LSD and related compounds might model psychosis, facilitate psychotherapy, or provoke powerful conversion-like experiences that could help people with refractory psychiatric problems, including alcoholism. By the mid-1960s, however, methodological weaknesses in many studies, inconsistent results, growing unsupervised recreational use, adverse-event reports and sensational media coverage combined with changing regulation to halt much clinical research. Mangini sets out to review the historical program of research that examined LSD (and related psychedelics) as a treatment for alcoholism. The paper traces early theoretical frameworks and therapeutic styles, summarises major uncontrolled and controlled clinical studies and adverse-event surveillance, recounts the regulatory and social responses that curtailed research, and identifies unresolved scientific questions and recommendations for future investigation.
Papers cited by this study that are also in Blossom
Ludwig, A., Levine, J., Stark, L. et al. · American Journal of Psychiatry (1969)
Osmond, H. · Annals of the New York Academy of Sciences (2010)
Strassman, R. J. · Journal of Nervous and Mental Disease (1995)
Strassman, R. J. · Journal of Nervous and Mental Disease (1984)
Papers in Blossom that reference this study
The paper is a narrative, historical review rather than a systematic review or meta-analysis. The extracted text does not report a formal search strategy, inclusion/exclusion criteria, databases searched, date limits, or a risk-of-bias assessment. Instead, Mangini surveys published reports, conference proceedings, institutional studies, government hearings and contemporaneous critiques to reconstruct the program of LSD research in alcoholism from the 1950s through the late 1960s and early 1970s. Coverage emphasises three strands: (1) early exploratory clinical programmes (for example, Saskatchewan Hospital and Hollywood/Hubbard approaches) that developed psycholytic and psychedelic therapeutic models and treatment manuals; (2) attempts at controlled clinical evaluation in multiple centres (including York County, Addiction Research Foundation [ARF], Spring Grove, Mendota and others); and (3) adverse-event surveillance, genetic/teratology studies and regulatory responses (FDA, congressional hearings, Sandoz withdrawal, and subsequent legal scheduling). Where trial methods are described in the source text, Mangini reports on design elements such as randomisation, control conditions, blinding, dose regimens, preparation/integration procedures and follow-up timing, and highlights recurring methodological shortcomings noted by contemporaneous critics.
Early exploratory work: The Saskatchewan Hospital programme (Osmond, Hoffer, Smith and colleagues) began treating refractory alcoholics in the 1950s, initially motivated by comparisons between LSD experiences and delirium tremens. Treatment evolved into a ‘‘psychedelic therapy’’ model emphasising a single high-dose, conversion-like experience (typically 200–400 µg LSD) in a carefully arranged setting, supplemented by preparatory and integration work. In an initial report of 24 very difficult cases, 12 were reportedly abstinent or drinking only minimally at follow-up (average one year), six reduced intake substantially and six were unchanged. Therapeutic models and setting: Two principal approaches emerged. ‘‘Psychedelic’’ therapy emphasised a profound, often transpersonal or conversion-like high-dose experience; ‘‘psycholytic’’ therapy (European) used repeated low-to-moderate doses (<150 µg) to facilitate psychoanalytic work. Investigators increasingly emphasised the importance of ‘‘set and setting’’ (patient expectations, therapist attitude, environment) in shaping outcomes. Uncontrolled series with favourable short-term outcomes: Several clinic reports described notable short-term improvements. MacLean et al. (Hollywood Hospital) reported 61 alcoholics treated with large initial doses (400 µg) and found 49% ‘‘much improved’’ at a median 9.09 months, 26% ‘‘improved’’ and 25% unchanged. York County reported better improvement rates in LSD-treated milieu programmes versus contemporaneous controls in some reports, though with substantial methodological caveats. Controlled trials: As stronger trials were attempted, results were generally less favourable or showed short-lived benefits. - Addiction Research Foundation (ARF): Thirty patients were randomised to three groups of 10 (LSD 800 µg IM, ephedrine 60 mg IM as active placebo, and nondrug control). Therapists usually guessed correctly which drug had been given (19 of 20), and post-treatment independent ratings found no significant outcome differences among groups at six-month follow-up. The ARF investigators concluded that, as used in their protocol, LSD failed as an effective adjunct. - Spring Grove: A randomised, placebo‑controlled study compared 90 patients given 450 µg LSD with 45 given 50 µg (active placebo). Intensive preparation (≈12 hours) and post-session integration were provided. At six months 53% of high‑dose patients versus 33% of low‑dose patients were rated ‘‘essentially rehabilitated’’ (differences statistically significant at six months, p<0.05) but advantages diminished and were not statistically significant at 12–18 months. - Mendota State Hospital (Ludwig and colleagues): The largest, most methodologically elaborate trial randomised 195 alcoholics to four groups (three LSD techniques versus a standard 30‑day milieu control), obtained extensive baseline batteries, used manual‑guided procedures and objective independent raters, and achieved <10% loss to follow-up at 12 months. All groups improved on personality and adjustment measures versus baseline, but there were no consistent differential benefits attributable to LSD treatment, and drinking relapse rates converged by a few months post-treatment. - Other controlled trials (VanDusen, Johnson, Hollister et al.) generally found initial or short‑term advantages for LSD-treated patients that faded over time; some reported small early benefits but no sustained advantage over standard care or active comparators by 6–12 months. Adverse events and safety surveillance: Sidney Cohen's 1960 investigator survey (44 respondents) estimated severe psychiatric reactions lasting >48 hours at about 0.8 per 1,000 in normal volunteers and 1.8 per 1,000 in patients; suicide was <0.4 per 1,000. Reports of emergency psychiatric admissions after unsupervised use increased in the mid‑1960s; Bellevue reported 27 LSD‑related admissions over a short period in 1965 and described three syndromes—acute panic, prolonged psychoses and later ‘‘flashbacks’’. Later concerns about chromosomal damage and teratogenicity followed Maimon Cohen's in vitro findings of increased chromosomal breaks; subsequent epidemiological and review work in the early 1970s generally concluded that pure LSD in moderate doses did not produce reproducible in vivo chromosomal damage or clear teratogenic/carcinogenic risk. Regulatory and social effects on research: Widespread recreational use, adverse publicity, political pressure and safety concerns produced stepped-up regulation. The Drug Abuse Control Amendment (PL 89‑74) in 1965 and later scheduling culminated in LSD becoming placed under strict control and, by the late 1960s, most manufacturers and sponsors (notably Sandoz) withdrew supplies; Sandoz formally stopped sponsorship and recalled supplies in 1966 after high-profile incidents. These developments, together with negative media narratives, discouraged investigators and reduced the number of human clinical studies dramatically. Synthesis: Across the reviewed literature, many uncontrolled studies reported dramatic, sometimes lasting improvements after psychedelic therapy, but controlled trials with better methodology tended to show either no sustained advantage for LSD over intensive psychosocial treatment or only short‑term benefits. Methodological variability—heterogeneous samples, inconsistent outcome definitions, inadequate controls or blinding, small sample sizes and poorly described ‘‘set and setting’’—limits comparability across studies and prevents definitive conclusions about efficacy.
Mangini interprets the historical record as one of early enthusiasm undermined by methodological shortcomings and by social, legal and safety controversies that effectively stopped progress. The author emphasises that many early positive reports were hypothesis‑generating, often uncontrolled and variably documented, and that better‑designed trials completed later (notably Mendota and Spring Grove) produced predominantly negative or transient results. At the same time, Mangini notes that those trials were themselves criticised for departing from elements of ‘‘classic’’ psychedelic therapy, particularly the attention to set and setting and intensive therapist commitment, so critics argued they may not have tested the same therapeutic model. The review situates the decline of research in a broader social context: widespread unsupervised recreational use, sensational media coverage, rising reports of adverse events, politically charged hearings and the withdrawal of industrial sponsorship combined to create regulatory barriers and a climate that discouraged investigators. The chromosomal‑damage controversy and high‑profile criminal cases amplified calls for restriction, even though later reviews largely failed to confirm robust in vivo genetic or teratogenic effects of LSD when used in controlled settings. Mangini reports that adverse psychiatric reactions were relatively rare in supervised research settings but increased with unsupervised community use. Key limitations acknowledged in the literature include heterogeneous patient populations, inconsistent and often crude outcome measures (frequently focusing solely on abstinence), small sample sizes, failures of randomisation or blinding in some trials, inadequate documentation of therapeutic procedures and therapist effects, and variable follow‑up schedules. The author stresses that these limitations leave important questions unanswered rather than conclusively disproving therapeutic potential. Implications and recommendations emphasised by Mangini are pragmatic: modern research tools and outcome measures could address historic flaws. Proposed priorities include using standardised diagnostic criteria and validated instruments (for example the Addiction Severity Index), predefining outcome domains beyond drinking (social, occupational, legal, medical functioning), ensuring high follow‑up rates, operationalising and documenting set and setting and therapist training with manuals and supervision, exploring which patient subtypes might benefit most, studying repeated/maintenance dosing strategies, and examining interactions with other treatments (for example pharmacotherapies like naltrexone). The author concludes that existing evidence neither proves efficacy nor rules out potential benefit, and that renewed, carefully controlled research could be justified to resolve outstanding questions.
Mangini concludes that the therapeutic potential of LSD for alcoholism remains unresolved. Historic research produced suggestive but methodologically limited findings and some short‑term clinical gains, yet later rigorous trials generally failed to demonstrate sustained advantages over intensive psychosocial care. Social controversy, adverse‑event reports and regulatory actions curtailed research before many important questions could be addressed. Renewed investigation, employing contemporary research designs, standardised measures, careful attention to set and setting, and rigorous safety oversight, is recommended if the field is to determine whether LSD has a role in treating alcohol use disorders.
Since Albert Hofmann's discovery of lysergic acid diethylamide's (LSD) psychoactive properties in 1943, the therapeutic potential of this drug has been the subject of speculation, study and controversy. Its exceptionally high potency, corresponding to that of endogenous trace sub stances that are thought to affect mental states, suggested the possibility of psychotherapeutic use to its earliest re searchers. Hofmann's reports of his self-experiments with LSD and Stoll's original systematic description of LSD induced mental states in healthy volunteers and in schizophrenic patients were fo llowed in the next three decades by more than 1,000 reports of therapeutic experimentation with LSD and related substances. After 25 years of study, a combination of flawed meth odology, uneven results and social reprehension led to the abandonment of this program of research, leaving many avenues of inquiry unexplored and many questions unanswered. To day, after a 30-year hiatus, research on the therapeutic potential of the psychedelic drugs is gradually being re sumed, and there is renewed interest in the findings of previous studies. This article will explore the history of one branch of psychedelic research: the therapeutic use of LSD in the treatment of alcoholism.
In 1953, Humphry Osmond and other researchers in Saskatchewan in western Canada were engaged in a series of studies on schizophrenia involving the use of mescaline and lysergic acid diethylamide. Their aim was to "start with the signs and symptoms and natural history of schizophre nia, and ask how these could be produced". Compounds that were thought to produce mental disturbances similar to schizophrenia were admin istered to volunteers in order to construct biochemical and psychological models of psychoses. In an early report of this research, Humphry Osmond stated that it had "been known for fifty years that mescaline ... produces symp toms almost identical with schizophrenia". At that time three divergent theories were held by re searchers concerning the effects of mescaline and LSD-25. They were variously described as "deliriants" which pro voked a toxic delirium, "psychotomimetics" which caused an artificial psychosis which was similar to the experience of a psychotic break, or "psycholytics" which produced psychic states in which the subject recalled repressed memories and other unconscious material in a setting of clear consciousness., another early researcher in this area, had noted the differences between schizophrenia and the effects of mescaline in 1951: "The symptoms of mescaline intoxication have been compared to those of schizo phrenia, but it is much more the strangeness experienced by the patient suffe ring from schizophrenia and the diffi culties of describing what is happening in the two conditions which is similar. Many typical schizophrenic symptoms are never seen in mescaline intoxication." In a search for a naturally occurring trace substance which could induce a schizophrenic-like reaction, Osmond and Abram Hoffer had studied the "schizogenic" proper ties of a group of materials, and had coined for them the name "hallucinogens": they included mescaline, lysergic acid diethylamide, harmine, ibogaine, and hashish. Based upon speculation that the LSD experience could be akin to that of de lirium tremens, a disorder involving visual and auditory hallucinations fo und in habitual and excessive users of alcoholic beverages, they began a series of studies of lysergide in the treatment of alcoholism at Saskatchewan Hospital in Weyburn, Saskatchewan, where the first two alcoholic patients were treated in 1953.
The experience of delirium tremens is unpredictable, overwhelming and frightening. First described in 1813, it is sometimes referred to as "the horrors," and may be accom panied by "rum fits" or seizures. It is the last in a continuum of alcohol withdrawal symptoms which may begin soon after the cessation of drinking as the blood level of alcohol begins to drop. It progresses erratically from agitation and autonomic hyperactivity, to mental con fusion, disorientation, delusions and vivid hallucinations of colored shapes, snakes, dragons, and other fantastic objects. The patient may be amnestic for the experience.. Delirium tremens occurs in about 4% to 5% of patients withdrawing from alcohol; in the early 1950s, it was fatal in about I 0% to 15% of patients. Advances in treatment have reduced mor tality today to less than 5%. Hoffer and Osmond were familiar with the testimo nies about "rapid abolition of ancient impulses and propensities"collected by William James from the reformed drunkards of the Jerry McAuley Water Street Temperance Mission in 1902, and with James' observation that the only radical remedy known to medi cine " ... for dipsomania is religiomania". They were aware that "a very remarkable experience" of some kind had been the cause of Bill W's beginning to build Alcoholics Anonymous (AA). They knew that some kind of "hitting bottom" experience was at the heart of the Wesleyan Methodist sect's success in converting alcoholics and helping them to stop drinking by catching them in the remorseful time after a drinking bout, scaring them thoroughly with the potential conse quences of continued drinking, and then offering hope for improvement in a program of abstinence. Because of these accounts concerning alcoholics who had experienced delirium tremens and sometimes were noted to "hit bottom" (an experience of surrender that is often considered to be the key to beginning recovery from alcoholism), Hoffer and Osmond wondered if a similar experience, therapeutically induced, would help alcohol ics stay sober. They understood the LSD reaction to be similar in character to de lirium tremens, but capable of being initiated at a time and place that could be directed and controlled. Hoffe r and Osmond speculated that one could inspire an alcoholic patient to "mend his ways•• by inducing such an experience. Hoffer and Osmond soon noted, however, that sub stances such as LSD and mescaline, which they had understood to produce hallucinations, could also produce "a particularly vivid and intense awareness of personality problems" which seemed to make the alcoholic more ame nable to psychotherapy. For many patients. this was also an "admonitory" experience, in which they were profoundly shocked and frightened by their vision of themselves and how alcohol was affecting them. Hoffer and Osmond abandoned the idea of provoking a simulacrum of the delirium tremens in fa vor of encouraging patients' self examination of personality problems, and the devel opment of insight into their "dismal present and appalling fu ture". They made no deliberate attempt to produce fear in their patients, since they had noted early in their investigations that making alcoholics afraid "often produces a desperate resolution to go on drinking", and seemed to lead to severe anxiety and poor com munication. In 1956 Humphry Osmond presented a paper at the New York Academy of Sciences conference entitled: "The Pharmacology of Psychotomimetic and Psychotherapeutic Drugs." In this paper, which was "a review of the clinical effects of psychotomimetic agents," Osmond described the major uses of this class of drugs. Some of these uses were the subject of ongoing research: the study of psychopa thology through the production of "model psychoses," the experiential training and education of psychiatrists and psychologists, and use as an adjunct to conventional psy chotherapy. Two of the potential uses that he proposed were less well known: exploration of the normal mind under unusual conditions, and discoveries with social, philosophi cal and religious implications made while using LSD and other drugs of this class. Osmond pointed out that to continue to consider these agents to be prima rily "psychotomimetic" begged the question of their other potential uses. To prevent this, he proposed a new name for the class of drugs that would include their capacity to enrich the mind and enlarge the vision: psychedelic, a term coined from Greek roots indicating "manifesting the mind." Research on the potential therapeutic benefits of psychedelic drugs in the treatment of the alcoholic continued for the next 12 years, producing innumerable areas of controversy.
The focus of the Saskatchewan Hospital program changed as the researchers came to believe that, although their patients benefited from their treatments, it was not the psychotomimetic effect that was beneficial to them. The literature on alcohol treatment acknowledges that "clients who make successful recoveries often attribute their suc cess to a spiritual experience or enlightenment".has sug gested that "one of the significant fa ctors in the etiology of alcoholism is the vain attempt of the person to satisfy deep re ligious needs by means of alcohol." Included among these needs are experiences of the transcendent and numinous; a sense of meaning, purpose and value in one's life; and a fe eling of unity, trust and relatedness.
The Saskatchewan Hospital program found that LSD and mescaline could address such needs in the alcoholic patient by inducing an experience "so profound and impres sive that his life experience in the months and years to fo llow becomes a continuing growth process". This emphasis on a transcen dent, overwhelming, conversion-like experience evoked by a high dose (200 or more micrograms) came to character ize "psychedelic" therapy as one of the two approaches to the therapeutic use of LSD.
In the other major therapeutic approach, psycholytic therapy, LSD is viewed as a facilitator of psychotherapy, and is used to produce insight, recall, reliving and abreac tion. Psycholytic therapy has been primarily practiced in Europe. The term psycholytic was coined in 1960 at a small European symposium on the use of LSD in psychotherapy in Gottingen, Germany; it was intended to suggest dissolving or releasing of tensions and conflicts in the human mind. In this form of therapy the remembering and reliving of child hood experiences are particularly prominent. The goal is to solve present neurotic com plexes in order to allow restructuring and maturation of the entire personality. Low to moderate doses (usually less than 150 micrograms) are repeated at inter vals of at least one week to facilitate conventional psychoanalytically-oriented psychotherapy for neuroses and psychosomatic disorders. By the mid-1 960s, the European Medical Society for Psycholytic Therapy included eighteen affiliated treatment centers in Holland, Denmark, Great Britain, Germany and Czechoslovakia.
The First Report of Studies at Saskatchewan Hospital According to, early in the Saskatchewan Hospital research " ... no special effort was made to con trol the environment of the patient undergoing therapy. Hospital rooms or psychiatrists' offices were used and there were many environmental distractions which interfered with the patient's experience." By 1957, when Hoffer and Osmond turned the Saskatchewan Hospital treatment pro gram over to Colin Smith in order to continue their research on schizophrenia, the researchers had recognized that the environment, and especially the attitudes of the people around the LSD subject, influenced his experience pro fo undly. Reports of volunteers and patients also suggested that the drugs produced a "marked loosening of repression and greater facility in recognizing conflicts". "Attitudes of love, faith and optimism" were desirable, as it appeared that the more intensely the patient experienced self-surrender and self-acceptance, the better the results. The fi rst report of this treatment, which was published in 1958, discussed 24 of "the most difficult alcoholics obtainable, those who had already failed to respond to other treatments and who, in the opinion of their own therapists, had a very bad prognosis". There was no attempt to use a control group receiving an alternative treatment or a placebo because, asdescribed it, ... "it would have been a trivial procedure to use pla cebo since both subject and therapist with any experience with LSD would know the difference." After an initial two-to four-week course of inpatient therapy which included attempts to develop therapeutic rap port, patients were given either a single dose of 200 to 400Jlg. of LSD or 500 mg. of mescaline. The patients were interviewed while under the influence of the drug, and strong suggestions to discontinue the use of alcohol were made. The content of this interview was then discussed during a further few days of inpatient therapy, and the patients were discharged. The average duration of follow-up was one year (range two months to three years). Twelve of the patients were abstinent or drinking only very small amounts at fol low-up, and an additional six had substantially reduced their alcohol intake. Six were unchanged). Smith's report (published in 1958 in the Quarterly Jour nal of Studies on Alcohol) emphasized that the effect of the drugs used was not separable from the treatment program as a whole. In addition, he pointed out that "exhortation, persuasion and suggestion" provided by the therapist dur ing the drug session would be likely to enhance the effect of the technique, although this practice did not come easily to him personally. The Influence of A. M. Hubbard In 1957 the Saskatchewan Hospital research group became aware of the work of A. M. Hubbard, "the unpublicized father of the American psychedelic therapy movement"). Osmond traveled to British Columbia to examine some of the alcoholics who had been treated with LSD using Hubbard's techniques, which were said to be particularly effective. Hubbard, who had accumulated a large series of unpublished cases while working with "gravely ill alcoholics", used music, flowers, and evocative symbols and pictures to enhance and direct the drug experience. The goal was to promote increased self-acceptance and spontaneity by encouraging alcoholics to reflect on themselves and their lives. In addition, Hubbard favored the "single overwhelm ing experience that produces drastic and permanent change". This format came to be iden tified as psychedelic therapy. The research group accepted the idea that an exact adherence to Hubbard's techniques was needed to prop erly evaluate his claims and the accounts of successful treatment that Osmond had obtained from Hubbard 's patients in Vancouver. Hubbard was invited to conduct demonstrations of his methods for the Saskatchewan Hos pital research group during a two-week visit to Saskatoon. Three therapists from Saskatchewan Hospital, Hoffe r, Smith and N. Chwelos, observed Hubbard's sessions; they were favorably impressed by Hubbard's skill and sensitiv ity and, beginning in January 1958, they began to modify their treatment techniques on the basis of Hubbard's methods. A Further Report from Saskatchewan Hospitalwrote a follow-up article to his earlier report of the Saskatchewan Hospital pilot study entitled "Some Reflections on the Possible Thera peutic Effects of the Hallucinogens, with Special Reference to Alcohol." It introduced some interesting topics that other researchers would later elaborate upon: he offered a thoughtful appraisal of some of the deficiencies in the existing research on LSD and mescaline and of their "puta tive therapeutic effects"; and he attempted to address how the psychological effects of these drugs were understood in differing ways by different researchers. The article outlined the technique then being used by the Saskatchewan Hospital group. Patients were first asked to freely give consent after a full discussion of the nature of the drug. After receiving their doses of LSD they were " ... encouraged to relax by listening to music and by examining paintings." According to Smith, "It was hoped by this method to make the experience a thought-provoking one rather than a frightening one. At present, I avoid the use of suggestion during the experience, with one excep tion: I do suggest strongly to the patient that he discontinue drinking"). Patients frequently were not asked to describe their experiences until the following day, and the overall tone produced was one of psychological safety and helpful friendliness. Treatment had been described in the original report of the pilot study as "LSD and mescaline used as adjuncts to treatment consisting of superficial psychotherapy supple mented by occupational and recreational therapy"). In the follow-up article, Smith noted the well-known difficulty of estimating the effect of treatment in psychia try. He recognized the way in which personal fac tors such as the style, training, and orientation of the therapist influ ence the psychological situation created in LSD therapy. In an attempt to standardize the "dose" of therapy, the Saskatchewan Hospital research group duplicated as exactly as possible the techniques that they had learned from Hubbard, and developed a treatment manual of indi vidual and group procedures for the use of LSD. No objective measures of the therapeu tic alliance of patient and therapist nor of primary patterns of the therapeutic relationship were used (as they would not be developed for almost 20 years). As described by Smith, the group selected for LSD or mescaline treatment consisted of "particularly refractory alcoholics". The original report of the pilot study had attempted to provide some measure of the severity of their alcoholism by assessing the number of years of uncontrolled drinking, previous occurrence of delirium tremens, and the existence of other complications of alcoholism (including blackouts, hepatitis, and periph eral neuropathy). Specific diagnoses of the study participants were provided, but did not delimit a homoge neous group. Subgroups of patients had clinical diagnoses of character disorder, psychopathy, borderline or actual psychoses and concomitant use of drugs other than alco hol. These diagnoses were assigned by the patients' own therapists, who were not involved in the LSD and mesca line treatment. Smith addressed the importance of follow-up in esti mating the effectiveness of new treatment, and pointed out that it is not unusual for a new treatment to enjoy a "hon eymoon" period of great enthusiasm for the method, followed by disillusionment and skepticism as patients who were judged to have been helped or even cured by the treat ment begin to relapse. In his original report of the results of the pilot study, Smith had concluded that in view of the refractory nature of the patient group, the results appear sufficiently encour aging to merit more extensive and preferably controlled trials. In his follow-up to the publication of the results of the pilot study, he reiterated that "initial results seem encouraging enough to justify further care fully controlled clinical trials".
The characteristics of an adequate study of psycho therapeutic use of LSD or similar drugs were delineated by 0in their presentation at the Swiss Academy of Medical Sciences symposium celebrating the 50th anniversary of the discovery of the psychotropic action of LSD. They pointed out that clearly defined objectives and an adequate sample size should be present in a hypothesis testing study, and that research should be influenced neither by the enthusiasm, nor by the skepti cism, of the researcher toward the treatment being evaluated. In addition, they described eight essential fea tures of an adequate study of treatment effectiveness: • Sp ecific diagnosis of patients before treatment • Random assignment of patients to treatment options • Use of severity measures to assess patients
Of these requirements, the Saskatchewan Hospital pilot study made no provision for random assignment, and evidently dismissed placebo control as an impossibility. Severity measures were employed, but were unsophisticated by comparison with today 's assessments. The pilot study did not methodically use blind ra ters to assess diagnostic category or patient improvement, but did employ diagnoses determined by the patients' own therapists, who were not members of the research team. The patient population was not homogeneous, nor was treatment directed at patients with a sp ecific diagnosis. Although all were designated as refractory alcoholics, the treated group also contained sub groups with other psychiatric diagnoses and abusers of other drugs. No attempt was made to conceal the nature of the drug from the patients, and informed consent was obtained. Although the duration of follow-up varied widely from patient to patient, confirmation of the patients' estimates of their posttreatment drinking was sought from other observers, and the use of AA to obtain follow-up data sug gests that the importance of fo llow-up was understood by the researchers . Standardized psychotherapy was attempted for the technique used in LSD sessions, and a treatment manual was developed, but no description of the content of this manual nor of therapist supervision was provided. Smith recognized the methodologic imperfections of the pilot study, and called for carefully controlled clinical trials to further investigate encouraging preliminary results.
There is a well-documented tendency for proponents of various psychotherapeutic theoretical orientations to fi nd their concepts of the psyche confirmed in psychedelic drug. Hoffer and Osmond were influenced by James' sto ries of conversion as a turning point in the alcoholic career, and by Tiebout's formulation of the conversion experience. According to Tie bout, conversion is a psy chological event in which a person who is governed by a set of hostile, negative attitudes shifts to predominantly positive and affirmative ones. This is cata lyzed by whatdescribes as an act of surrender: We can now be more precise in our definition of an act of surrender. It is to be viewed as a moment when the unconscious fo rces of defiance and grandiosity actually cease to function Vo lume 30 (4), October -December 1998 Mangini effectively. When that happens the individual is wide open to reality; he can listen and learn without conflict and fighting back. He is receptive to life, not antagonistic. He senses relatedness and an at-oneness which become the sources of an inner peace and serenity, the possession of which frees the individual fro m his compulsion to drink. In other words, an act of surrender is an occasion when the individual no longer fights life but accepts it. This moment arrives when the "force of circumstance or real ity"renders the alcoholic completely powerless. It was this force of circumstance that Osmond and Hoffer speculated might be found in the experience of de lirium tremens. Contrary to their expectations, the high doses used for their presumably refractory alcoholic sub jects propelled many of them, not into a frightening and aversive delirium, but into an experience of transcendence and conversion.
In May of 1958, Ditman and Whittelsey presented their report of a card sort test designed to compare de lirium tre mens and the LSD experience. They concluded that: "The delirium tremens experience was predominantly character ized by hallucinations that seemed real, anxiety, horror, depression, irritation, and paranoid thoughts. The LSD expe rience, in contrast, was typified by euphoria, humor, relaxation, and a nebulous sense of wonderment". Smith was aware of the varying and contradictory descriptions of the phenomena produced by drugs with sup posed hallucinogenic properties even before he began to work with them in therapy. In his follow-up article to the Saskatchewan Hospital pilot study, he reported three dif ferent kinds of observed effects of LSD and mescaline: experiences similar to those of delirium tremens; enhance ment of access to previously repressed material for psychoanalysis; and effects resembling religious conver sion experiences. Other investigators would subsequently describe these phenomena as stages in a con tinuum of experience. Smith had noted that the patients who had an intense reaction to LSD had improved more than those having a mild one). Ditman's work and his own experience convinced Smith that the similarity between the effects of LSD and delirium tremens was superficial. In September 1959, the Saskatchewan Hospital research group published a further follow-up to Smith's two previ ous reports, including results of the treatment of an additional 16 patients using the modifications in technique that had been implemented after the group's contact with A. M. Hubbard. This report pointed out that the experience obtained resulted from a combination of the patient's attitude, the effect of the drug on the individual, and the surroundings of the patient during the drug experience; and that it was "impossible to state categorically what the ef fect of the drug alone [might be]").
The Saskatchewan researchers attempted to list the most common changes in perceptions, emotions and un derstanding reported by patients and volunteers who had LSD sessions . These effects were then grouped into six types or levels of experience: this represented a continuum determined by the degree to which the subject experienced surrender of his usual patterns of emotions and percep tions, and changed his self-concept in favor of complete self-acceptance. They concluded that the therapeutic impor tance of the LSD experience lay in its ability to disrupt habitual patterns of thinking and feeling to create an opportunity for this change in self-concept to occur. The differences in the phenomena reported by diffe r ent researchers to be caused by psychedelic drugs were understood to be the product of patients' differing levels of experienced self-surrender. This level in tum was influ enced by the extent to which the therapeutic atmosphere reflected complete acceptance ofthe patient. The research ers proposed that psychotic manifestations seen in the drug experience were produced by the person's trying to main tain his usual perceptions and self-concept. Confrontation with repressed unconscious material was understood as a preliminary stage in the process of gaining complete self understanding and self-acceptance. Given this understanding of the importance of surren der in psychedelic therapy, the Saskatchewan research group emphasized the need for a safe and supportive envi ronment and empathetic staff. They pointed out that "unsympathetic, hostile, and unfeeling personnel bring about fear and hostility with a marked increase in the psy chotic aspect of the experience"). These views reflected the influence of A. M. Hubbard on the Saskatchewan Hospital research group.
This shared perspective was described by the first report of the research group at Hollywood Hospital in Vancouver, where Hubbard was the Director of Psycho logical). Hubbard's work, which "has never been widely reported in the scholarly and professional journals," influenced many of the earli est researchers, self-experimenters and therapists to use psychedelic drugs. The Hollywood Hospital report is the only one that bears his name; how ever, his practice of arranging the emotional and physical surroundings of the drug experience to encourage a pro found experience of ego-transcendence became a crucial ingredient of successful psychedelic therapy. The Hollywood Hospital group provided an articulate description of the effects of LSD as they were understood by these two groups of researchers: The ingestion of a therapeutic dose of LSD-25 produces profound alterations in perception, e.g., visually colors become brighter and patterns become more clearly defined. These changes occur within an hour and become more marked during the ensuing two or three hours. All perceptual modalities show parallel changes. Because an individual's concept of reality is based upon his sense experience it fo llows that if these sense experi ences be altered, his reality ties are lost to him. This includes his self-concept. A state is induced in which the unifying aspects of the individual's personality cease to function. In an uncontrolled setting, this reduction of self-concept to the point of depersonalization often results in confusion and panic. This is why LSD-25 was initially classed as an hallu cinogenic or psychotomimetic (psychosis mimicking) agent. But if the same process can be controlled, an experience can be developed in which the usual screen of rationalization is much reduced and may even be almost eliminated. The therapeutically controlled situation permits and helps the person to find meaning, reality and structure in the unusual experience. When the unhabitual perceptions are organized the individual undergoes what Osmond has referred to as a psychedelic (mind-manifesting) experience. It is this experi ence with its increased insight, its expanded awareness, and its altered frames of reference, that is the therapeutic vehicle. LSD-25 is not a medication in the usual sense. It is simply a triggering mechanism that initiates an experience lasting 12 hours or more .... Since it is, therefore, the experience and not the medication that is therapeutic, the treatment situation or milieu becomes the overwhelmingly important factor. It must permit the person to find new reference points, and it becomes the function of the therapist to provide these in such a way that they will be understandable to the patient and conducive to his emotional growth .... In guiding such an experience the therapist must refrai n from projecting his own solutions to problems upon his patient. On the other hand, if he is to help the patient find any structure in the experience he must in some way assist in the provision of a new frame of reference. A way of accomplishing this with out projection, developed by one of our group, is to provide universal symbols to which the subject may attach his own meaning. Through these symbols he may become aware of those archetypal or universal meanings which underlie all human fe eling and thinking. The symbols provide intermediate points of reference, creating a bridge between the habitual self-concept and a new concept based on self understanding and self-acceptance .... As this new self-concept develops, the need for habitual inappropriate defense mechanisms is reduced and the patient can now relate to another person more directly, with less defensive screening. MacLean and his colleagues used a large initial dose of 400Jlg. They reported on a total of 61 alcoholics (50 men and 11 women), with an average period of uncontrolled drinking of 14.36 years. Pretreatment status was assessed using an autobiography, psychiatric history, and therapists' notes from preparatory sessions. These cases were consid ered to have an unfavorable prognosis because of failure in AA, numerous previous hospital admissions, and a history of delirium tremens. Follow-up data were collected using interviews and questionnaires; patients were scored on interpersonal relationships, work habits, self-appraisal and the appraisal of close associates. Drinking patterns and signs and symptoms of psychosis were scored if applicable. A composite score was obtained by combining these data. We ighting given to the various measures was not speci fied. After a median of9.09 months of follow-up, 30 patients (49%) were "much improved." This was defined as com plete abstinence or a "marked improvement" in drinking pattern compared to the 12 months preceding therapy, as well as marked improvement in interpersonal relationships, work habits, self-acceptance and family relations. The cri teria for improvement in these areas were not specified. Sixteen patients (26%) were "improved" in the rated areas, including a "definite reduction in alcohol intake"; 15 (25%) were unchanged] . The research ers concluded that "LSD-25, used with the described treatment method [italics added]. is effective in the treat ment of alcoholism .... ".
Many of the criteria for an adequate study described by O'Brien and Jones were not met by this report. Sp ecific diagnoses were established only to the extent of grouping the patients into four diagnostic categories based on coex isting problems. Ye ars of uncontrolled drinking and history of alcohol complications were the only assessments used to determine severity. Only four of the total of 61 patients were "uncomplicated alcoholics". Info rmed consent was not mentioned, but patients were counseled about what might occur during their LSD ses sions during the preparatory period. Placebo control was not attempted, and patients were not randomly selected, instead being targeted for selection as particularly difficult cases with an unfavorable prognosis. The treatment envi ronment, and the composition, experience and attitude of the treatment group were identified as significant factors, and were specified in detail; and a treatment manual was developed, but was not described in the report). Objective raters were not used. The period of fo llow-up varied from three to 18 months (median 9.09 months). The Hollywood Hospital research group planned this study as a large-scale follow-up to the exploratory work of the Saskatechewan Hospital group, but no hypothesis was specified for testing in their studyIn their report, which was submitted for publication in early April of 1960, the Hollywood Hospital research group took note that fears of "cultism, fa naticism or thrill seeking" were developing around the use of psychedelic drugs, but deemed such fe ars overrated (MacLean et a!. 1961: 44). In January of 1960, a day-long symposium on LSD was held at Napa State Hospital, and subsequently broadcast on radio station KPFA. The symposium attracted considerable attention, in part by presenting a "new view" that LSD was more than a facilitator of therapy; it was an entirely new experience. Some of the papers from this sym posium, which were later published in the Journal of Nervous and Mental Disease, cited the Canadian research groups as the developers of this new view. Although an increasing number of persons out side the research environment were becoming interested in LSD, MacLean and his colleagues took the position that even though the LSD experience might be attractive because of its ability to "amaze and even overwhelm the individual through changes in perception ... [the] extreme physical and psychological discomfort" that this new experience could produce would act as a built-in control for potential misuse.
The first research group to attempt a controlled study of the use of psychedelic therapy for alcoholism was the York County Mental Health Clinic in Newmarket, Ontario, Canada. Their treat ment was based upon an attempt to instill the motivation to get well in chronic alcoholics who were assumed to be ambivalent about admission to a program of milieu therapy. In their pilot study, published in June 1962, patients were divided into three groups: 58 patients received the full inpatient treatment program, including LSD therapy; 35 received the researchers' standard therapy but no LSD; and 45 others were admitted to the hospital for treatment by other psychiatrists during the same period. The group receiving standard therapy without LSD was composed of patients who were judged to be unfit for LSD therapy, left the hospital early, or refused the LSD treatment. Thirty-eight patients, or 70% of the LSD treatment group, were judged to be improved at six to eight months post-discharge, compared to 47% and 45% of the two control groups. Based on these preliminary findings, further research was conducted using a modification of this design, and a subsequent report was published in June 1963. This report covered a total of 70 patients receiving the full program of milieu therapy, AA group meetings and LSD treatment, and 55 controls who were assigned to psychiatrists not using LSD when no beds were available to them in the experi mental unit at the time of their admission. No attempt was made to include those who refused to take LSD, who left the hospital before their LSD session or who were "consid ered unfit for LSD therapy" in the evaluation. Eight of the treatment group and 26 of the controls were not available at follow-up. Of the remainder, 74% ( 46) of the treatment group, and 41% ( 12) of the controls were improved at six to 18 months post-discharge. Although Jensen and his colleagues attempted to pro vide a control or comparison group, the many methodological difficulties of these studies severely limited their useful ness. In particular, the large number of the controls not fo und at fo llow-up creates great difficulty in comparing the results in the two groups. Additional problems with the studies include the variability in the period of fo llow up, the lack of a specific diagnosis or severity measure, and uncertainty about how the posttreatment rating was determi ned.. A total of 68 patients were treated with a 200JJ.g. dose of LSD. Fifteen of the patients had more than one LSD session. Patients were consecutive admissions to the psychiatric department, and all were chronic alcoholics who had not responded to other forms of treatment. Interna tional Classification of Diseases (lCD) diagnoses were assigned for a variety of additional problems. A special nurse was assigned to each patient to explain and discuss all aspects of the LSD treatment. Patients were monitored for two to 34 months, and collateral information on drink ing status was obtained from relatives and agencies in addition to patient self-reports. The immediate response to therapy was assessed after two months, and the last two months of the follow-up period were used to indicate recent trends. Thirty-eight percent of the patients were com pletely abstinent during the two months preceding fo llow-up. Abstinence was not found to be related to patient demographics, concurrent diagnoses, social circum stances, drinking history, nor to which of eight psychiatrists administered the patients' LSD sessions. Only "the nature of the LSD experience" was independently correlated with future abstinence. What the researchers defined as a "transcendental" experience, "a new way of looking at one's life, with a loss of previous defensive meanings or perceptions of oneself' was the only factor found to be related to sobriety. The Union Hospital studies share many of the meth odological flaws that were present in other self-described exploratory studies of this period. The patients vary in diagnosis and severity, there is no control group, the period of follow-up is not standardized, and the pre-and posttreatment data obtained are not clearly specified. The second report, by O'Reilly and Funk, which appeared in June of 1964, noted that controversy was arising over the use of LSD-25 in psychiatry. The authors may have been referri ng to numerous stories that appeared in 1963 and 1964 in the popular press, and to efforts to limit the accessibility of psychedelic drugs by U.S. and Canadian authorities. The potential impact of such publicity on the willingness of patients to participate in LSD therapy and on the interpretation of reported success rates was men tioned briefly, but deemed to be "outside the scope of this study". In any case, the future of LSD treatment for alcoholism seemed assured in Saskatchewan. In December 1962, the Saskatchewan Bureau on Alcoholism had reported that "such excellent results have been noted by the bureau staff in individual cases, usually with resistance to other forms of therapy, that LSD treatment, which was originally regarded by the bureau as experimental, became a standard form of treat ment to be used where indicated" (Bureau on Alcoholism 1962).
The Growth of LSD Experimentation Beside using LSD in the treatment of alcoholism, U. S. researchers had begun to explore the possibility that it might be used to enhance creativity, or to facilitate psy chotherapy. In their enthusiasm, some researchers had begun to share LSD with friends in their homes, and as publicity about the effects of LSD increased, so did the demand for LSD experiences. Many prominent persons, includ ing the founder of Alcoholics Anonymous, Bill Wilson, and Chuck Dederich, the founder of Synanon, were having LSD sessions. Te levision and newspaper coverage depicted LSD as a new wonder drug. A 1958 report in the Journal of Nervous and Mental Disease included "LSD-25 social parties" in a list of ways that LSD might be used).
The first attempt to systematically assess the potential side effects and complications of psychedelic therapy was Sidney Cohen's 1960 survey of 62 investigators using psilo cybin or LSD in therapy. The 44 researchers who replied to his questionnaire had administered psychedelics to almost 5,000 individuals on more than 25,000 occasions. Based on the data they supplied, Cohen estimated that psy chotic breaks, panic attacks and other psychiatric reactions lasting over 48 hours occurred in 0.8 per 1000 normal vol unteers, and 1.8 per 1000 patients undergoing therapy. Suicide was a less frequent complication, occurring in less than 0.4 per 1000 patients. No suicides or suicide attempts were reported in volunteers. Cohen concluded that untoward events were infre quent, and that the psychedelics were "safe when given to a selected healthy group" if used with proper precautions. Recommended precautions included constant supervision, hospitalization if doses greater than I J.lg. per kg of body weight were used, provision of trained and experienced support personnel during the experience, and the availability of consultation in the event of post treatment symptom development. Despite the relatively benign picture painted by Cohen 's survey, by the end of 1961 a "climate of criticism" was developing around psychedelic research. Psychopharmacologist Jonathan 0. Cole expressed "very mixed feelings" about research with psychedelics, particularly the possibility that they might be used to "establish long-term control over minds" by "altering loy alties or changing moral attitudes or political beliefs". Sensational accounts of the LSD experiences of celebrities, the influence of LSD on creativity, and the superiority of LSD treatment to conventional psychotherapy spurred popular demand, and college students began experimenting with psychedelics; Subcom mittee on Executive Reorganization 1966).
In October 1961, the Harvard Psilocybin Research Proj ect run by Timothy Leary and Richard Alpert had been criticized by its sponsor, the Center for Research in Per sonality, for failure to adhere to guidelines similar to Cohen's. At a special faculty meeting, David MacClelland, director of the Center, enumerated fo ur "symptoms" he had noticed in the Project's participants, both researchers and experimental subjects. Disassociation and detachment, interpersonal insensitivity, religious and philosophical nai'vete, and impulsivity seemed to distinguish those who had taken LSD. MacCielland saw these characteristics as evidence that the chief effects of psilocybin and similar substances were to encourage withdrawal from social real ity and concentration on one's inner life. The Project was required to surrender its official supply of psilocybin to Dr. Dana Farnsworth, head of the University Health Service, to be released only for experiments approved by an ad hoc faculty committee. Reports of the disciplinary action were carried by the Harvard Crimson and then picked up by national news wire services. In the Spring of 1962, when the committee refused to provide psilocybin for Wal ter Pahnke's (a doctoral student in the History of Philosophy and Religion) carefully designed Marsh Chapel experiment on the ability of psilocybin to provoke mystical experience, supplies that had not been surrendered by Leary and Alpert were used instead. University authorities protested that this was not the only occasion on which Leary and Alpert had failed to follow the newly agreed-upon pro cedure. Psychedelic researchers defended their action, pointing out that Pahnke's faculty-appointed doctoral com mittee had approved the experimental protocol, and that Farnsworth was "in no way equipped as an expert" on the use of psychedelic drugs. Soon afterward, Ti mothy Leary left Harvard without notice, and Richard Alpert became the only Harvard fac ulty member to be fired in this century. This highly controversial episode was discussed in a special issue of the Harvard Alumni Bulletin on the university 's professors and their work. Henry K. Beecher, the Dorr Professor of Research in Anaesthesia, refuted the accusation that University opposition was driving research underground, and maintained that, to the contrary, there was "an abundance of support in this field for the able, respon sible investigator, at present more than ever before".
By July of 1962, Sidney Cohen and Keith Ditman had encountered the rapidly growing illicit use of LSD, and had published an article describing "an increasing number of untoward events in connection with LSD-25 administra tion". Although they continued to support the investigational use of LSD for its potential to aid in the study of the mind, they pointed out that the unsu pervised use of the drug increased its potential for producing serious consequences. The consequences mentioned included antisocial acting-out behaviors, misuse of LSD as part of a larger pattern of multidrug use and "abuse of [the] euphoriant property" of LSD by marketing it as an item of underworld traffic. This was followed by a second report on adverse reac tions to LSD, in which Cohen and Ditman foresaw that the problems that could occur after inexpert or casual experimen tation could further complicate the research environment. They reported on nine cases illus trating several types of untoward effects: prolonged psychotic decompensation, depressive reactions, release of preexisting psychopathic antisocial trends, abandonment of social responsibilities, and paranoid reactions in which the transcendental aspects of the LSD experience confirmed latent ideas of grandiosity. They still held that such reac tions were infrequent, however, as long as the drug was employed with "carefully screened, maximally supervised patients, given the drug by responsible, experienced inves tigators". With considerable prescience, they noted that: "When undesirable reactions and sensational publicity become associated with a drug, competent investigators are inclined to avoid participating in the careful, thoughtful studies that are necessary to evalu ate it properly". By December of 1962, when this article was submitted, new legislation had already been passed by the U.S. Congress that would restrict availability of LSD solely to researchers engaged in fe derally-approved studies.
The discovery of the teratogenic properties of thalido mide had focused attention on the need for better regulation 1938, created a class of "investigational new drugs," i.e., drugs that had not yet been marketed, but were undergo ing testing to demonstrate their safety and efficacy. These "new drugs" could not be distributed commercially with out approval from the Food and Drug Administration (FDA). Despite the fact that they had been studied for almost two decades and had been the subject of more than one thousand English-language articles (Cohen 1968), sev eral of the psychedelics fe ll under this classification, as the FDA was not satisfied that their safety and efficacy had been established (Subcommittee on Executive Reor ganization 1966: 61). A special investigational new drug (IND) application form for permission to use drugs classified as investiga tional was instituted in 1963; before that time anyone could order LSD, psilocybin or mescaline by submitting to Sandoz a signed statement that the person ordering had the training and facilities to conduct drug investigations, and that the supplies of the experimental drug obtained would be used only for research purposes (Subcommittee on Executive Reorganization 1966: 60). Researchers and other interested users obtained LSD and psilocybin from Sandoz's branch office in New Jersey. LSD was supplied under the trade name Delysid ® , in the form of small, blue 25J,J.g. tablets or 100J,J.g./cc ampoules for parenteral use). Mescaline could be ordered from several chemical supply firms for about $20 per gram. These sources had provided material with which therapists in Los Angeles, Vancouver, and the San Francisco Bay Area were providing LSD sessions to paying clients eager for the experience. Under the new IND regulations, Sandoz technically became the "sponsor" for all investigations of LSD and psilocybin. James Goddard of the FDA testified in 1966 that Sandoz had in 1963 filed a basic investigational plan for testing LSD that indicated that a reasonably safe and rationally conducted program of experimentation would be required of researchers (Subcommittee on Executive Reorganization 1966: 61 ). There was, as yet, no direct relationship between investigators and the FDA). Sandoz's role in relation to psychedelic researchers was more that of distributor of LSD than as the sponsor of research, and researchers were using LSD from Sandoz in studies that were not designed by Sandoz). Sandoz's patent on LSD-25 expired in 1963, and manu facturers in Czechoslovakia and Italy soon began commercial production of the drug. Sandoz was becom ing uneasy about its ability to continue to control the distribution of LSD.
A flurry of articles about LSD appeared in popular periodicals during 1963, until, as Abram Hoffer suggested, it was "hardly likely that any literate citizen has not heard something about it". The Ladies' Home Jour nal quoted Jonathan Cole of the National Institute of Mental Health on LSD in an article on "Instant Happiness": "[LSD] can produce an unstable state varying-within five min utes-from horror to ecstasy". Ti me described spiritual experiences reported by users of psilo cybin, LSD and peyote as "instant mysticism "). Cosmopolitan reported that: "Suddenly LSD has become the sophisticated 'fun thing' to try around the smart set, the fast set and the beat set, and if you haven't got a buddy who can run down to his friendly neighborhood LSD bootlegger and buy an ampoule of those little blue pills, you are simply not in, my friend". As the drug's official sponsor, Sandoz began in 1963 to restrict the U.S. distribution of LSD to National Insti tute of Mental Health-funded programs, Ve teran's Administration-sanctioned programs in VA hospitals, gov ernment agencies, and programs in state universities that had approval from state mental health commissioners). In Canada, transportation and sale of LSD were forbidden, and possession was permitted only by re searchers with university appointments who were listed with the Ministry of Health. Private therapists without institutional affiliations were not included in the list of approved researchers for whom Sandoz would act as the IND application sponsor. Unlike the "neighborhood bootlegger," most therapists and clinics were unable to obtain the psychedelics, as they could not afford the time and expense the new regulations required them to invest. Some therapists continued to do LSD work with their patients, but the patients had to obtain their own drugs on the black market. Other thera pists were fo rced to discontinue their work because of problems with fu nding. The International Foundation for Advanced Study in Menlo Park, California, operated by Robert Mogar, Willis Harmon, Myron Stolaroff and others, closed in 1964 because the fee of $650 per person per session was not enough to cover costs, and hoped-for fe deral financial support was not forthcoming (Editor 1964).
As it was quite difficult to synthesize pure LSD-25, controls on importation and use were originally thought to be adequate for restricting the illicit supply. In the early 1960s, however, a new process for culturing the ergot fun gus made the precursor chemicals much more readily available. The 1963 White House Confer ence on Narcotics and Drug Abuse considered the psychedelics to be of only minor importance as drugs of abuse, largely because of their limited availability and high cost (White House Conference on Narcotics and Drug Abuse 1963). Others foresaw that the publicity that they had received and the possibility of profit would be likely to increase their distribution. Theoretical and philosophical speculation about LSD was beginning to appear in the journal literature. Joel Elkes, who had been among the first to call attention to the poten tial for untoward reactions to LSD, reiterated concerns about the side effects, complications, and dangers of abuse of the psychedelics that had been noted earlier in Cohen 's survey of research. In a short editorial, Roy Grinker (the editor of Archives of General Psychiatry) claimed that "latent psychotics are disintegrating under the influence of even single doses; long-continued LSD experiences are subtly creating a psychopathology. Psychic addiction is being developed ... " necessitating greater controls on the use of LSD. This editorial by Grinker, who never published any work on LSD and was, according to Abram Hoffer, "uncontaminated by first-hand experience with it", appeared in the same issue of the Archives of Gen eral Psychiatry as Cohen and Ditman 's study of prolonged adverse reactions to LSD, and was subsequently cited as a reference on the severity of the LSD problem by a 1963 editorial in the Journal of the American Medical Associa tion , among others. The lA MA editorial, by Dana Farnsworth of the Harvard University Health Service, ad mitted that research on the psychedelics was vital and should continue. While he decried the "hysterical attitude that could result in the adoption of unwarranted restrictive legislation," he also suggested that "regular use of the hal lucinogens will prepare individuals to 'move up' to other and more powerful drugs such as morphine or heroin" and described psychedelics as "substances which are a real menace to mental and physical health". By March of 1964, lAMA described the use and mis use of the psychedelics as "among the touchiest topics of recent months" and provided "a sober look at the present situation" by Jonathan, two senior psychopharmacologists from the National in stitutes of Mental Health (NIMH). Cole and Katz likened the "psychotomimetics" to the broom of the sorcerer 's apprentice (in that they had walked out of the laboratory and turned on their researchers) and maintained that "rather than being the subject of careful scientific inquiry, these agents have become invested with an aura of magic .... " (p. 758). Nevertheless, Cole and Katz asserted the need for careful study of this class of drugs because of the potential importance of the therapeutic claims made for them in treat ment of otherwise treatment-resistant psychiatric conditions. Cole was the first to publicly favor "the Scotch verdict Cole and Katz' lAMA article was accompanied by Roy Grinker's second editorial warning of the dangers of the drugs he described as "psychomimetic [sic]". Dr. Grinker complained that the use by therapists of LSD made it "impossible to find an investigator willing to work with LSD-25 who was not himself an 'addict"'. This usage is a classic example of a basic misconception described by Fort: "Generally any socially disapproved drug comes to be referred to as narcotics or dope and the user as an addict"). Nevertheless, Grinker's editorial was widely quoted in the popular press, and used as evidence of the dangers of LSD research by the editors of the New England Journal of Medicine (Editor 1966). Battle lines were being drawn. At the May 1964 conven tion of the American Psychiatric Association (APA), the controversies about LSD became "a central point of interest, fear, and warnings". Advertisements announcing the publication of a new journal, the Psyche delic Review, were refused by The Progressive and by American Psychologist. Despite the passion with which the psychedelics were discussed by both pro ponents and opponents, there still seemed to be consensus that what was needed was more and better-designed research. The complex machinery of experimental design and research fu nding was slowly moving to produce "detailed and carefully controlled studies designed to be free from possible distortions due to either bias or enthusiasm".
In June of 1964, the first comprehensive critical assessment of the existing research on the use of LSD in the treatment of alcoholism was published by the Quarterly Journal of Studies on Alcohol. Reginald Smart and Thomas Storm of the Addiction Research Foundation in To ronto, Canada outlined some basic requirements for clini cal research on treatment efficacy: random assignment of subjects, objective comparison of posttreatment outcomes with pretreatment ratings, a control group receiving placebo or nondrug treatment, and follow-up at fixed post treatment intervals. They acknowledged that fai lure to use a control group was common in psychiatric treatment, and pointed out that the exceptional numbers of positive results found in early reports of a new therapy was particularly characteristic of uncontrolled trials. Since none of the studies they exam ined had employed placebo control, Smart and Storm suggested that "a placebo having some immediate but mild sensory effect" could usefully have been employed because of the highly variable effects expected from LSD adminis tration. The fol low-up procedures of the five reviewed studies were also criti cized for their lack of precise outcome measures, pretreatment comparison measures, and fixed follow-up intervalsThe overall assessment was that these deficiencies "raised serious questions concerning the scientific warrant for any belief that LSD is a useful adjunct to the treatment of alco holism". Even so, Smart and Storm also returned the "Scottish verdict of 'not proven"' and called for further study of the therapeutic usefulness of LSD. Because this review was the beginning of a blizzard of controversy about the earliest published research on LSD as a treatment for alcoholism, two significant details are of interest. The first is the use of "not proven" as an assessment of the usefulness of LSD as an alcoholism treat ment. This Scottish expression, infrequently used in U.S. English, has surfaced fairly frequently since then as a description of the status of LSD therapy. It had been employed by Cole and Katz in this context in their March 1964 lAMA article. Since Smart and Storm submitted their critique for publication in October 1963, one wonders if they might possibly have influenced Cole and Katz through some kind of prerelease circulation of their critique. In any case, Smart and Storm's critique was circulated in July, one month post-publication, to thousands of U.S. and Canadian physicians in resume form. By August, Colin Smith had already submitted a reply).
Smith's reply, which appeared in December 1964, was in part concerned with the second significant detail: Smart and Storm's assertion that there had been no calls from the earliest LSD researchers for controlled clinical trials. He pointed out that he had, in fact, recommended that con trolled trials follow the Saskatchewan Hospital group's self-identified exploratory studies, and had further argued that exploratory studies were essential in order to derive a testable hypothesis and to obtain research support for con trolled trials. Smith acknowledged that the current methods for evaluating the effectiveness of alcoholism treatment were unsatisfactory, and prophetically suggested that an alliance of methodologists and clinicians was required for improvement. In addition, Smith addressed an issue not raised by Smart and Storm 's critique: the safety of lysergide treat ment. He cited reports by Cohen, and Cohen and Ditman, on the infrequency of adverse LSD reactions. He pointed out that Hoffer's new and extensive review of the literature on therapeutic use of psychedelics had reached the conclusion that the risk of complications from the use of lysergides in therapy seemed to compare favorably with other psychiatric treatments including those using electro convulsive therapy, tranquilizers, and insulin coma (Hoffe r 1965 ; Smith 1964).
In March of 1965, Hoffer published a comprehensive review article concerning LSD's history; originally titled "D-Lysergic acid diethlyamide (LSD): A review of its present value " [italics added], it was retitled "A review of its present status" before publication. Hoffer depicted the entire history of LSD since the discovery of its psychoactive properties as a series of controversies: whether it produced a model of schizophrenia, whether it was therapeutically useful, and whether its unsupervised use could be controlled. He also divided psychedelic re search into three stages: the early work of Osmond and others in Canada on psychotomimesis and alcoholism treat ment; the expansion, catalyzed by A. L. Hubbard, of psychedelic treatment for "a broad group of behavioral problems and neuroses" by therapists in California; and large-scale trials at Spring Grove Hospital in Maryland and elsewhere. Hoffer pointed out that since most people were unaware of the early studies, they were con ducted in an atmosphere free from both harsh criticism and legal restriction. With the publicity that resulted from the activities of Leary and Alpert at Harvard University, the general public had become aware of the use and abuse of the psychedelics, and widespread media interest had led to the imposition of strict legal controls. The result, in Hoffer's estimation, was a research environment pervaded by fear and mistrust).
In October of 1964, Jerome Levine and Arnold Ludwig (who were planning what was to become the most method ologically complex and frequently cited study of psychedelic therapy for alcoholism) published an excep tionally well-balanced analysis of "the LSD Controversy." They pointed out that, in evaluating LSD therapy, "besides the many methodological and conceptual problems which arise in evaluating the usefulness of any form of psychiat ric therapy, certain other 'non-scientific' factors tend to cloud the issues" in regard to LSD). Among these were the aura of sensationalism created by the notorious adventures of Leary and Alpert; the intro duction of bias and imprecision by therapists' use of the Treatment of Alcoholism Using Psychedelic Drugs substances they were studying; the lack of controls in vir tually all early studies of the psychedelics; and the widely varying estimates of the dangers and risks involved in the use of LSD.suggested that both popu lar accounts and journal editorials gave a "misleading and exaggerated" impression of the research data available, by suggesting that LSD was "fairly dangerous, with rather serious complications, mostly of a mental nature." They maintained that "neither advocates nor critics seemto have enough objective information on which to base their entrenched positions," and called for adequately controlled studies and follow-up evaluations before drawing any final conclusions. Also, two concerns were expressed: that research with LSD would be curtailed because of the accu mulation of "erroneous impressions, incomplete case reports, hearsay accounts, and illogical interpretations" about the dangers of LSD, and that the increasing use of LSD outside of a therapeutic or experimental setting might expose unsupervised users to unforeseen dangers.
While FDA commissioner James Goddard later testi fied that investigations as late as 1963 did not disclose any widespread abuse of LSD, others would claim that by the time the first surveillance of nonmedical and illegal use of LSD was conducted in 1961, there was already more LSD in the community than in the research environment. In May of 1966,asserted that "far more LSD is bought on the black market (it is either imported illegally from Mexico or produced locally by amateur chemists) than is given experimentally or psychotherapeutically". Some researchers suggested that the "psychedelic move ment" had purposely minimized or suppressed reports of adverse reactions; Subcommittee on Executive Reorganization 1966). As hospital admissions became more frequent, they claimed, it had become impos sible "to contain many of the psychotic reactions within the LSD movement itself and to keep them from public attention". While the available data on the occurrence of untoward reactions suggested that they were relatively rare in the research setting, wider avail ability and increased self-experimentation coincided with an increase in the number of hospitalizations following LSD ingestion. Also, physicians in areas where LSD was obtainable for use in unsupervised environments were beginning to see an increase in untoward psychedelic reactions. It was, however, not until December of 1965 that Frosch, Robbins and Stern published the first report on the adverse effects of psychedelics seen in the Bellevue Hospital Emergency Department. From March through June of 1965, 27 patients were admitted to Bellevue Psychiatric Hospital in New York as a result of taking LSD; this sudden increase prompted the fi rst published report of adverse psychedelic reactions to drugs taken outside the research environment, which ap peared in the December 2, 1966 issue of the New England Journal of Medicine. The authors of this report found that adverse reactions could be grouped into three syndromes: acute panic reactions, overt psychoses, and what later came to be called "flashbacks," experiences of perceptual distortion and depersonalization similar to the drug state, but occurring without further drug use. Recovery from panic reactions was usually rapid, and no long-range problems had been noted; but for the other two syndromes the prognosis was unclear, since many patients were still experiencing some "impairment of per formance" when last contacted. In an editorial in the same issue, the editors of the New England Journal suggested that the potential for the devel opment or reappearance of adverse LSD reactions months to years after ingestion was particularly worrisome, and lik ened this possibility to the effect of the mysterious powders that irreversibly transformed Dr. Jekyll into his evil alter ego, Mr. Hyde. The editors stated that LSD was a "danger ous, toxic substance" and that existing inconclusive evidence of its therapeutic value was outweighed by its potential danger. They stated flatly that there was "no pub lished evidence that further experimentation [was] likely to yield invaluable data". The publication of Frosch, Robbins and Stern's article, and of the accompanying editorial, stimulated a spirited discussion. Frank Fremont-, medical director of the Josiah Macy Foundation and chair of the Second Conference on the Use of LSD in Psychotherapy, took exception to the editors' failure to distinguish the growing number of adverse reactions resulting from unsupervised use from the relative infrequency of such reactions in research and therapeutic users. He objected to the sugges tion that further experimentation with LSD was unlikely to be of value as "hardly in keeping with the attitude that en courages sound scientific inquiry." Within a month, the Journal's editors replied that there was a "difference of opin ion" about the potential value of continued LSD research, and that "at best a calculated risk [was] being taken" in such research. In April of 1966, the dis cussion of LSD research's standing in the scientific community was somewhat eclipsed by the manufacturer's withdrawal of its sponsorship from all studies of LSD and psilocybin because of the publicity related to these drugs.
On July 15, 1965, the Drug Abuse Control Amendment (PL 89-74) was passed by Congress, and in February 1966 the manufacture and sale of psychedelic drugs became ille gal in the United States. Possession for personal use was specifically exempted. Sandoz became the only entity legally entitled to manufacture or distribute LSD. Although Sandoz did not design or supervise LSD research, the company, as the filer of the investigational new drug application for its product, remained the official sponsor for government-sanctioned research. Within weeks after the law went into effect, however, Sandoz directed the researchers obtaining their LSD from the company and working under its IND application to return their remain ing supplies of LSD to the manufacturer. On April 7, 1966, the company notified the FDA that it was planning to with draw sponsorship of investigators using LSD and psilocybin as soon as possible (Subcommittee on Execu tive Reorganization 1966). Sensational news of the "first known LSD murderer" on April 11 finally convinced Sandoz to stop distribution of its products, and all supplies of LSD and psilocybin provided by Sandoz were recalled.
Stephen Kessler, a Harvard graduate and Downstate Medical Center medical student, was accused of stabbing the mother of his estranged wife on April 11, 1966. At the time of his arrest, Kessler was reported to have dazedly inquired about what he had done, and claimed amnesia after "flying for three days on LSD". His arrest prompted an emergency meeting of New York law enforcement officials, prosecutors, and representatives of the FDA, who recommended new legislation to make sale or distribution of LSD a fe lony in New York. It also provided a horrifying story (which was widely cited for years afterward) about the potential of LSD to cause harm. At Kessler's trial in October 1967, it was revealed that he had taken doses of 10 to 50Jlg. of LSD on a total of fi ve occasions between the Summer of 1964 and March of 1966, the month preceding the murder. On the days before the murder, Kessler had taken one and one half grains of pen tobarbital, and drunk three quarts of laboratory alcohol, cut with water. Kessler made no men tion of having taken LSD in the month before the murder, but a psychiatrist who examined Kessler after his arrest claimed that Kessler could have taken doses of LSD that he was unable to recall. Because of his history of chronic paranoid schizophrenia, for which he had previously been hospitalized twice at Bellevue, the jury found that he was "not guilty by reason of insanity above and beyond his use of LSD".
Following announcement of the murder, Sandoz ceased LSD production, and all LSD samples were recalled from investigators, except for 12 researchers conducting studies approved by the National Institutes of Health or the Veterans Administration. Sandoz's remaining stock of 21 grams of LSD was transferred by armored car to the Public Health Service (Subcommittee on Executive Reorganization 1966). The company also relinquished in vestigational sponsorship of LSD research. Despite the fact that possession of LSD continued to be legal under fe deral law, researchers who had no investigational exemption were required to return their supplies and reapply for permis sion to conduct LSD research. When PL 89-74 went into effect, 13 grants (four for research on human subjects) were receiving NIMH fu nding). However, Sandoz had been providing LSD (at no cost) to an addi tional 53 recognized studies; those studies were to be the most affected by the new legislation. Since Sandoz had acted as the sponsor of most of the ongoing research, most investigators conducting studies on human subjects had no IND approval apart from that drug company. In addition to the IND application needed to obtain LSD supplies from the NIMH, new regulations also mandated that investiga tors obtain approval of their IND from the FDA before the drugs could be used, not only on human subjects, but also for animal or biochemical studies. Differences between the goals and standards of the two agencies led to delays and policy problems). Senator Abraham Ribicoff characterized this as "empire building" by the agencies in volved (Subcommittee on Executive Reorganization 1966). Sandoz's abdication was considered an act of coward ice by some scientists), but Sandoz defended its action on the grounds that continued sponsor ship of LSD studies had become too burdensome in the prevailing atmosphere of national hysteria. Other researchers fe lt that the transfer of responsibility to NIMH would result in the authorization of more research projects than in the past), but in 1966 there were only 17 investigators studying LSD. By 1968 the num ber of active researchers had dropped to eight, and most of these were conducting studies of LSD abuse or seeking better methods of detecting LSD for forensic purposes (Louria 1968). In Canada, even after the sale or transportation of LSD was prohibited, researchers who were listed with the Min ister of Health could legally obtain LSD directly from Sandoz. Many had ordered more than was immediately needed for fear of supplies being cut off, and so were not severely impacted by Sandoz's termination of production. In England, therapists using LSD pro tested that Sandoz's interruption of their supplies was "petulant and ill-considered," and that the distress caused to patients being successfully treated with LSD would harm Sandoz's reputation more than misuse of LSD (of which there was little evidence in Great Britain) could ever do). Sandoz's representative replied that the company would be happy to turn over a supply of the drug to the appropriate governmental authorities for distri bution, but did not wish to risk its good name in association with "a preparation whose therapeutic usefulness is open to question" and which was, furthermore, "totally uneco nomic to Sandoz".
The FDA and NIMH Assume Control of LSD Research During Senate hearings on the psychedelics in May 1966, Senator Robert Kennedy questioned whether the requirement that investigators reapply for investigational new drug status indicated some unwillingness on the part of the FDA or NIMH for LSD research to continue. The FDA commissioner, James Goddard, acknowledged the need for further controlled experimentation with LSD, but categorically stated that "any new proposal by any investiga tor for the use of LSDhave to be fully documented to limit the use of the drug to specially qualified physi cians in carefully controlled clinical environments. And the plans would have to be limited in scope to gain [the FDA' s] serious attention" (Subcommittee on Executive Reorgani zation 1966: 63). Goddard assured Senator Kennedy that the FDA was "not trying to retard or thwart research" and that the highest priority would be given to processing the IND applications for these studies. Nonetheless, complaints fr om researchers who had relinquished their LSD supplies were soon heard: they were being shuttled from one desk to another within the FDA and the NIMH, but no supplies of LSD for their fo rmerly approved projects were forthcoming. One researcher reported that his correspondence with 30 col leagues in the fi eld of LSD research revealed that "projects [had] been called off, doctors [had] been attacked by hos pital associations as 'kooks,' and [he had) been diagnosed (the psychiatric method of character assassination)". In June of 1967, the Joint Advisory Com mittee on Psychotomimetic Agents (the LSD Committee) was set up to review both requests to the FDA for permis sion to conduct LSD studies and requests to NIMH for supplies of LSD, but the two agencies continued to take different approaches to regulating LSD use. The FDA, which had responsibility for the control of all investiga tional drugs, promulgated rules directly from Washington. NIMH, which had the only legal supply of LSD, hoped to encourage self-regulation and peer review at the individual research institutions. The FDA was concerned primarily with safety issues and the protection of human subjects. NIMH required that studies be not only safe, but well designed).
On June 12, 1966, the Council of the American Psy chiatric Association approved a position statement on LSD: The American Psychiatric Association notes and fully Further, the Association is confident that when conducted by qualified investigators, such research has been and will continue to be carried out with a degree of safety comparable to that of many other drugs. The indiscriminate consumption of this hazardous drug can, and not infrequently does, lead to destructive physi ological and personality changes. The Association most par ticularly deplores its use by some persons in this way as a "mind-expanding" or "consciousness-expanding" experi ence. There is now no substantive basis for this claim. The destructive consequences to some who use it in this expecta tion have not yet been adequately established in the professional and lay press. In the Association's view, the proper way to ensure availability of the drug for research purposes is through the application of the same regulatory mechanisms and public education efforts that are customarily relied upon to protect the public from irresponsible use of experimental and dangerous drugs, and not through total prohibition of its manufacture and use for legitimate purposes. (American Psychiatric Associa tion 1966).
Despite the numerous calls for continued research, the large body of scientific data on these drugs was obscured, at least for the lay public, by sensational newspaper and magazine articles; the governments of both the U.S. and Canada responded to the widespread unsupervised use of psychedelics with increasingly restrictive legislation. In the U.S., the California state legislature passed legislation in early 1966 making the possession of LSD illegal. Expert testimony at the U.S. Senate hearings had specifically dis couraged the imposition of medical, criminal or civil commitment penalties for possession or personal use as tending to discourage persons in crisis from seeking needed help, and as criminalizing something that was less an anti social act than a youthful adventure (Subcommittee on Executive Reorganization 1966). Thomas Lynch, the Cali fornia Attorney General, strongly supported criminal penalties for possession, as well as for sale or manufacture of LSD), but such legislation was rejected twice before the Assembly Criminal Procedures Committee. Under pressure from the press, the gubernatorial candidates, and the Attorney General, the committee finally released the bill but deleted the clause making possession illegal. Criminal penalties for possession were restored by a bare two-thirds margin of the Assembly. The final bill, which was supposed to keep LSD "in the laboratory and the hos pital where it belongs" passed almost unanimously. Eventually every other state passed legislation prohibiting the possession of LSD, and state officials contended over who had passed the toughest laws fi rst. A suit was filed in federal court by the New Jersey State Drug Study Commission to prohibit magazine cover age of the "consciousness-expanding" use of psychedelics after a photo essay in Life attracted widespread attention. The speaker of the New York State Assembly allowed public hearings on anti-LSD legislation to be postponed until after the bill was passed, because of the perceived urgency of the LSD threat. New modifications of PL 89-74 made possession a federal misdemeanor and sale a felony in 1968. Under the Controlled Substances Act of 1970, the psychedelics became Schedule I Controlled Drugs, a designation that indicates lack of safety even in medically supervised use, high abuse potential, and no current accepted medical use. Some researchers continued to insist that "many types of neurophysiological and psychiatric investigation using LSD offer potential benefits"; others felt that the essential questions had been addressed, and that interest in LSD waned because the basic research was not promising. In any case, clinical studies of LSD using human subjects became fewer and fewer.
According to Sidney Cohen, there are good reasons why psychedelic therapy with LSD was administered to more alcoholics than to those in any other diagnostic cat egory. There was a large number of potential candidates for treatment. Often these were persons who had failed one or more previous attempts at therapy for alcoholism. Few were expected to recover spontaneously. From a methodologic standpoint, evaluation was thought to be simple, involving only a straightforward assessment of the amount of drinking. LSD therapy as a method of alcoholism treatment characteristically employed a mini mum number of experiences with large doses of 200 to 300J.Lg. or more. Psychedelic therapy was inexpensive, easy to administer, and consistently reported to be more effec tive than previous treatments. The rapid acceptance of LSD in the treatment of alcoholics on the basis of extravagant claims of early success was followed by criticism of the methods, motives and conclusions of the early researchers. In the contentious atmosphere sur rounding LSD research, arguments over the implications of the reported success of this enthusiastically received and seemingly successful treatment for alcoholism were among the most passionate.
By the time Smart and Storm's critique of the existing reports of LSD therapy for alcoholism was published in 1964, they had already begun work on their own study of the value of LSD treatment. The Addiction Research Foun dation (ARF) of Toronto, Canada had undertaken to support a controlled trial of LSD therapy. Smart and Storm, as research psychologists, were responsible for the study design, the conduct of predrug evaluation and follow-up, and data analysis. Tw o psychiatrists, Earle F. W. Baker and Lionel Solursh, administered the LSD and made psychiat ric assessments. The patients were 30 randomly chosen volunteers from the ARF's To ronto Clinic.
The study was designed to avoid the methodologic problems of previous studies. The patients were random ized to one of three groups of 10: two drug groups, and a control group that received all the procedures and thera pies given to the drug groups except the drug session. Of the drug groups, one received ephedrine sulfate 60 mg. IM as a control drug. The researchers believed that " the most consistent and immediate effect of LSD appear[ed] to be sympathetic activation", and that the headache, nausea, vertigo, palpitations, and nervousness produced by ephedrine "could be confused with lysergide effects". The other drug group received 800�-Lg. of LSD intramuscularly. In 19 of the 20 patients who received a drug, the therapist who administered it guessed correctly which drug had been given. The post treatment therapy and evaluations were completed by therapists who did not know which patients had received LSD. The research team reported that "full blindness was achieved for the patient group,". Patients volunteered "for the study of a new drug", and were not intended to be aware that LSD was being used. When media attention to LSD caused the pa tients to speculate that lysergide was being used, no clarification was provided by the clinical staff. The patients were told that responses to the study drug varied from slight to very dramatic, and were not aware that two different drugs were administered. The researchers claimed that "in nearly every case the patient continued to believe that he had received a magic 'new drug'". Both patients and staff were aware of which patients were in the nondrug control group. The groups were well matched for sex, age, educa tional level, marital status and pattern and extent of drinking. More of the patients in the LSD group were unemployed at the time of admission than in the other groups. All patients received the same series of group therapy sessions and informational sessions on alcohol problems, and all had individual opportunities for occupational and physical therapy, and for psychiatric interviews. The overall approach was described as similar to that of the Yale Plan Clinics (early residential treatment centers that provided multidisciplinary care for alcoholic patients), but with the decreased formalism and increased patient participation of a therapeutic community. The professional staff was ori ented to the goal of total abstinence, and saw alcoholism as "an illness that can be cured or alleviated by medical and psychiatric treatment". Pretreatment evaluations included standard psychologi cal tests and a questionnaire that sought quantifiable Journal of Psychoactive Drugs 397 Treatment of Alcoholism Using Psychedelic Drugs answers on drinking behavior. A psychiatric diagnosis and prognosis was determined after a detailed examination by the therapist who would be administering the drug treat ment. This interview was also intended to develop therapeutic rapport between patient and therapist. All the therapists administering the drug therapy had previous experience with LSD therapy, and had themselves taken LSD. Therapists conducting the pre-and posttreatment evaluations had no personal LSD experience. The investi gators described themselves as skeptical about the value of LSD, and not committed to a belief in its efficacy. The drug sessions were administered at a hospital near the ARF center, in single rooms, with the patients in Posey restraints (a belt of reinforced webbing used to strap patients to the bed). Before the experimental drug, 250 mg. of phenytoin (an anti-seizure medication which may cause sedation) was given intramuscularly to patients who were already receiving it; patients were otherwise drug-free and fasting. A co-therapist team of doctor and nurse conducted a three-hour interview at an unspecified time after drug administration; it is not clear who, if anyone, attended the patient during the remainder of the drug experience. Patients remained at the hospital overnight and "after the drug wore off ... [were] sedated with chlorpromazine if necessary". There was no specification of how this need was determined, nor of how many pa tients received posttreatment sedation. Although the patient was free to bring up the drug session in group or individual therapy, no effort was made to discuss the results of the drug treatment in the standard therapeutic milieu unless the patient initiated it. The drug group patients had a thera peutic interview with the therapist who had administered the drug apporximately fo ur days after treatment. Patients completed inpatient treatment an average of one week after their drug sessions. Follow up was planned for all patients at six months post-discharge, and all but two were evaluated within this time frame. All groups showed a substantial gain in periods of abstinence compared to pretreatment, and a highly signifi cant decrease in the number of drinking occasions. None of the groups differed significantly in the frequency of other alcoholic symptoms, such as drinking on workdays, black outs, and drinking only to get drunk; nor was there any significant difference in the number of posttreatment contacts with the ARF clinic. The researchers concluded that the lack of outcome differences among the treatment groups in any of the areas evaluated indicated "that lysergide, as used in the present study, fai led as an effective adjunct to psychotherapy, in contrast to claims made in previous studies". The research group was aware that their method of LSD administration differed from that reported by other LSD therapists, and that this might affect treatment out comes. They described this possibility as "debatable," however, since their treatment was just as effective as that of other therapists, and they did not expect much potential gain over 80% improvement. They acknowledged that "The results reported do not preclude the possibility of finding some effects of lysergide on drinking, given some very different procedures or personnel. They demonstrate, how ever, that such effects are not associated solely with its pharmacological properties or with the procedures used here. Nevertheless, no valid claim for any effects can be made until the treatment procedures have been in a con trolled study similar to the one reported here". They also suggested that some other characteristic of alcoholic patients, such as social stability or personality variables, might be beneficially affected by LSD treatment, and stated that future analyses of their data would deal with these possibilities. The publication of a monograph on the study, which would provide a more detailed report of the data analysis and of the specifics of methods employed in the study, was in preparation. The ARF research team had set out to design a study that would be more than "simply the chronicling of clinical routine", which they had claimed described most of the existing LSD research. Even with this goal clearly in view, their research was unable to fulfill some of the essentials of an adequate study as described by O'. The small sample size, with only 10 cases for each experimental condition, would have tended to make statistically significant results difficult to obtain. The criterion of a specific diagnosis was not fully met, as the patient group presented a variety of psychiatric diagnoses in addition to chronic alcoholism. A detailed questionnaire on many aspects of the patient's past year of drinking was administered pretreatment, and a detailed psychiatric examination also contributed to the es tablishment of severity measures. Informed consent was not obtained, and an attempt was made to prevent the patients from learning the nature of the drugs being studied. A nondrug control group as well as an active placebo control was part of the study design, as was random assignment of patients to all groups. The need for standardized therapy was addressed by assuring that all groups received the same clinic treatment, and by some standardization of the rou tine of the session day for both drug groups. Although parameters for the psychotherapeutic interview that accom panied all drug sessions were supplied, several aspects of the drug groups' treatment remained unspecified. How many patients received premedication with phenytoin, whether patients were left alone at any time during the drug ses sions, and how the need for sedation and the endpoint of drug effects were assessed were particularly unclear. The study did employ a blinded objective rater, with all follow up testing done by the same evaluator to decrease inter-rater bias. The study placed particular emphasis on the impor tance of fo llow-up; all but two of the patients were assessed Treatment of Alcoholism Using Psychedelic Drugs within the target interval, with the remaining two being followed up within a further two months.
In March of 1967, the Quarterly Journal of Studies on Alcohol published the comments of several other LSD researchers on the design, attitude and conclusions of the ARF study. The ARF research group, whose members had previously criti cized others' findings from uncontrolled and unblinded studies, were themselves criticized for their failure to main tain the double blind. While the ARF group had objected to what they perceived as a positive bias toward the use fulness of lysergide treatment in other researchers, they were admonished for their own display of skepticism. This was interpreted as negative bias, with a likelihood similar to a positive bias of evoking a placebo response. The pro cedures used in the administration of the LSD sessions were also criticized. There was insufficient opportunity for the development of therapeutic rapport. The interview tech nique used during the sessions was derided as one discarded years previously by other researchers in favor of more effective methods. Questions were raised about the use of pre-medication and the restraint of patients during the drug experience. The most severe censure was reserved for the conclu sion oftheARF study: "that lysergide, as used in the present study fa iled as an effective adjunct to psychotherapy, in contrast to claims made in previous studies ". This judgment was criticized on two levels. The ARF study had placed, it was claimed, too much emphasis on the pharmacologic actions of LSD, even referring to it as a "magic new drug." This attitude was contrasted with that of other researchers who emphasized that the psychedelic experience produced by the drug was the therapeutic vehicle, rather than the drug's specific phar macodynamic properties. Because the techniques used were unlikely, in the critics' opinions, to produce a psychedelic experience, the outcomes of the employment of these tech niques were not comparable to those achieved by "true" psychedelic therapy. The second and much stronger criticism was of the prepublication circulation of an earlier version of the report which had included a quite different conclusion. According to this 1964 ARF report: "The results of this study fail, completely, to show that LSD is useful as an adjunct to psychiatric treatment of alcoholism. The con clusion is, therefore, that LSD was not shown to be an effective adjunct to the existing clinical treatment of alco holism. These fi ndings represent a strong indictment of the previous unwarranted assertion that LSD is effective in the treatment of alcoholism" (MacLean & Wilby 1967). Critics of the ARF study found that this conclusion "exceeds the most liberal interpretation of the evidence presented" and was "so fundamentally in error as to be offensive". They accused the ARF research group of irresponsibility in allowing the article to be widely circulated before review by journal ref erees, and claimed that the prestige of impending publication in an important journal, combined with an exaggerated but uncritical confidence in the scientific au thority of the double-blind controlled study design, had permitted their unwarranted conclusions to have far reaching impact. Specifically, MacLean cited the influence of the prepublication report on the California governor and state legislature during their process of framing legislation to control the use of LSD. When the monograph publication of the results of the ARF study was released, some of these criticisms had been addressed, or at least some of the positions taken in the initial report had been modified. In relation to the claim of negative bias, this more extensive report claimed that "all the investigators would have preferred to find that LSD was an effective therapy" but described the ARF research ers as more neutral about the potential usefulness of LSD therapy than previous researchers since "no one was com mitted to a belief in its value". In response to the possible antitherapeutic effects of their intensive therapeutic interview, and their fa ilure to attend to the nuances of the set and setting in which the experimental drugs were administered, the ARF team pointed out that the existing literature contained "a great deal of variation in the procedural details of LSD treat ment", which, if significant, ought to be expected to have resulted in a variation in reported outcomes. Unfortunately, according to the ARF research ers, the failure of previous studies of the therapeutic utility of LSD to meet the requirements for reliable research made it impossible for these reports to be used as a basis from which to predict outcomes based on variations in technique. They offered their own theory of the effect of LSD: that "many of the emotional and behavioral effects of LSD could be accounted for based on the activating [physiologic arousal] effect of the drug, interpreted and elaborated by the subject". They described their belief that what happens under the influence of LSD is pri marily an increase in susceptibility to social influence. They suggested that, absent specific and behavioral criteria for change, a therapist's belief in the drug's unique effects, particularly if reinforced by his own psychedelic experi ences, could influence his assessments of the outcomes of drug treatment. The aspect of the research that preceded their own study that the ARF group found most interesting was the reported effect of LSD on personality in alcoholics. Although they fo und claims of these effects suggestive, their dissatisfac tion with the limitations of the early studies prevented any attempt to evaluate the nature of the changes reported. In their own data, "no clear benefits of LSD therapy were Treatment of Alcoholism Using Psychedelic Drugs detected," but tendencies "sufficient to provoke further interest in LSD research" were found. These included a decrease in neuroticism on the Maudsley Personality Inventory, more loosening of repression and less internal conflict on the Rorshach, and gains in the healthiness of self and in movement of self toward ideal on the Haigh-Butler Q Sort. They concluded that LSD pro moted some therapeutic changes in self-concept, and suggested fu rther experimentation with those aspects of the LSD experience concerned with personality variables would be valuable. In particular they suggested that studies of the types of alcoholic who would benefit most and least from the LSD experience, and of the specific effect of LSD on psychological mechanisms such as self-concept and ideal concept should be made. Smart and his colleagues attempted to evaluate the effect of LSD on social variables such as family relation ships, employment status, and residential mobility. They recognized that using drinking behavior alone as the crite rion for treatment success might result in important effects of LSD therapy being missed. Few differences were noted among the three study groups in replies to questions on family, employment and social stability other than an increased number of the LSD subjects being employed post treatment. The overall analysis of the data on social variables paralleled that of the data on drinking behavior and personality change: none of the changes were more striking in the LSD group than in the alternate and control groups. Overall, although improvements in drinking behavior consistent with those reported by earlier studies of LSD therapy were fo und, they could not be attributed to the use of LSD since they were similar in all treatment groups. The ARF research group concluded that "earlier reports that LSD was an effective adjunct to therapy for alcohol ism may have resulted from lack of adequate controls in the evaluation of its utility".
By the time the ARF monograph was released, two other controlled studies of alcoholism treatment with LSD were nearly completed. Smart and his colleagues com mented on the fact that the preliminary findings of these studies tended to support their contention that when con trol groups were available for comparison, the admittedly dramatic improvement in the drinking behavior of LSD treated alcoholics was not diffe rent from that of alcoholics who had been exposed to other fo rms of treatment. One of these studies, conducted by Wilson VanDusen and his col leagues on all female patients, found that although those who had received lysergide described their experiences as among the most significant of their lives, they were "not noticeably more sober" (VanDusen et at . 1967) than the patients treated by the same alcohol program who received no LSD. The other study mentioned by Smart and colleagues was conducted by Gordon Johnson of the London Clinic, the ARF facility in London, Ontario. Johnson's study com pared four treatment groups. One received only routine clinic care, and no drugs were administered. A second received LSD but no therapist contact during the LSD experience. Another received LSD with four hours ofthera pist interaction. The fourth group received therapist interaction after administration of methamphetamine HCl and sodium amobarbital. Patients were in Posey restraints, and were sedated with chlorpromazine and secobarbital about six hours after drug administration. Only a single blind of the patients was attempted, as it was assumed that the therapists would detect which drug had been adminis tered. Six hours of intake interviews and personality testing preceded the random assignment of patients to experimen tal groups, and interviews and questionnaires were administered on the day fo llowing drug treatment. Follow up was targeted for 12 months after admission and was conducted by independent observers who were not aware of the patients' treatment group. Although all four groups had a statistically significant improvement in drinking behavior, there were no significant inter-group differences. There were no significant changes in marital status, employment, social relations or housing for any group. Johnson concluded that LSD treatment "in this setting con ferred no evident advantages over more conventional modes of therapy"). Smart and his colleagues found that both Johnson's and VanDusen and colleagues' studies supported their conclusion that controlled evaluations did not fi nd LSD to be a useful adjunct to alcoholism treat ment, and that the differences in procedures, dosages and control groups used in these studies tended to increase the generalizability of their fi ndings. A few controlled studies did produce positive findings but these mostly appeared to be short-term effects. A study done at the New Jersey Neuro-Psychiatric Institute at Princeton in 1966 referred to this phenomenon as the "LSD honeymoon," and pointed out that "dramatic shifts in atti tudes and behavior which appear very promising are frequently reported" immediately after LSD treatment. This study compared 29 alcoholic controls who received the regular six-week program of the Institute's Earle Alcoholic Unit with 28 alcoholics who received this program plus two doses of LSD and a group therapy program. There was no placebo control, and the absence of a control group receiving the group therapy pro gram without LSD limited the extent to which therapy was standardized. Limited random assignment was attempted by assigning patients alternately in groups of fo ur to LSD or control groups. Sp ecific diagnosis and severity measures were determined by pretreatment interviews and question naires. Pretesting established a scaled rating of each patient's alcoholism as "essential" (related to persistent inadequa cies of personality) or "reactive" (precipitated by a markedly Treatment of Alcoholism Using Psychedelic Drugs stressful situation.) The LSD group as a whole scored higher in essential alcoholism than the control group, but this difference was not statistically significant. Informed consent was obtained. No attempt to assign objective ra ters was made, but the importance of fo llow-up was addressed by the use of several methods to assure that all patients were contacted. One member of the LSD group and six controls were lost to the 12-month fo llow-up. Patients were followed up at three, six, and 12 months post treatment, and no statistically significant diffe rences in sobriety outcomes, family relations or work patterns were noted. While not significant, the LSD group had "an ini tial marked advantage over the comparison group" in sobriety status at three months, which tended to diminish with time. The sobriety status of the LSD patients, but not of the control group, was signifi cantly better at three and 12 months for reactive (versus essential) alcoholics. The researchers suggested that this might indicate that LSD therapy was of more benefit to patients with more social assets to help them in sustaining their recovery. They speculated that continued therapy, possibly including periodic redosage, might be a useful and economical intervention. Hollister, Shelton and Krieger (1969) also found slightly better short term results for patients treated with 600J.Lg. of LSD than for a control group given dextroam phetamine 60 mg. In their study, no sp ecific diagnosis other than acute alcoholism was provided. The Drinking Behav ior Scale (DBS) used by Hollister and his colleagues was designed to provide a numerical value to indicate the severity of alcoholic impairment. Informed consent was not obtained, and patients were "given as little concrete information as possible about the drugs to be tested"No attempt was made to provide psychotherapy, and the drug experience was intended to be primarily introspective. The only interven tion other than the drug session was a discussion with the patient about problem drinking. There was no treatment manual detailing standardized therapy, but "every effort was made to see that patients were treated exactly alike". Obje ctive raters com pleted both the entry and fo llow-up administrations of the DBS, and the importance of fo llow-up was emphasized in the selection of only those patients whose stable job or residence history suggested that they would be available for follow-up. Despite this, by one year posttreatment, almost half of the patients in each group were not avail able for follow-up, with the remaining patients being mostly those who had responded well to treatment. The mean change in DBS scores indicated that the drinking behavior of the LSD group had improved signifi cantly more than that of the dextroamphetamine group at the two-month fo llow-up, but this difference had all but disappeared at six months, and any advantage remaining for the LSD group at six months had diminished still fur ther at one year. In discussing their results, the researchers mentioned that both groups showed remarkable improve ment, highlighting the importance of a control group. This study was intended to consider LSD as the primary treat ment, in the absence of any therapeutic preparation or intervention during the drug experience.
The extent to which preparation or interventions might contribute to any beneficial impact of LSD treatment was not evaluated in most controlled studies, which were designed to test the experience elicited by the drug alone. This therapeutic method has been described as psychedelic chemotherapy. Many LSD research ers took exception to research designs that assumed that the psychedelic experience, the central behavior-changing event in LSD therapy, was an automatic consequence of drug administration.described this approach as "such a radical departure from accepted methods for producing a beneficial experience" that such studies "could not be regarded as a valid test of the psychedelic method." Bowen and his colleagues conducted a controlled study in which, despite adherence to the accepted psychedelic method described in studies with strongly positive findings, no sig nificant difference in posttreatment adjustment status was found between LSD-treated patients and those receiving only a program of intense training in interpersonal prob lem solving. Although they fo und that long-term gains for LSD-treated patients were no greater than those of con trols, "very real and often dramatic personality changes are frequently observed to occur over the short term [italics original]". In order to help patients integrate their insights and apply them to everyday problems, Bowen and colleagues recommended that a five-day follow-up program be provided at four months and one year post-discharge, including (if indicated) retreatment with LSD.
In a study designed to eliminate most of the methodologic flaws of previous research, a team of researchers (including Albert Kurland, Charles Savage, Walter Pahnke, Stan Grof and Sanford Unger) at the Spring Grove State Hospital in Maryland also fo und short-term improvement in drinking behavior in patients treated with a high dose of LSD; but differences from low-dose treated patients vanished by 18 months posttreatment). The Spring Grove study was placebo controlled, using a treatment group of 90 patients who received 450J.1.g. of LSD and a control group of 45 who received 50Jl.g. of LSD as an active placebo. Although patients were randomly assigned, randomization did not succeed in matching the groups for marital status, education or severity as indicated by num ber of previous admissions. Informed consent was obtained; patients received intensive preparation including 20 hours of psychotherapy. Although all patients were treated alike, there was no manual of standardized therapy. Sp ecifi c diagnoses and some measures of severity were provided by a battery of psychological tests administered before treat ment and at six, 12 and 18 months. Only about three-fourths of the patients were fo llowed for the full 18-month period. Follow-up ratings of adjustment were made by objective raters, an independent team of social workers. Eighty-nine percent of the patients were available for six-month follow-up; 53% of the high dose group, as opposed to 33% of the low dose group, were "essentially rehabilitated" in their drinking behavior at six months. Forty-four percent versus 25% had "good attainment or adj ustment" in their interpersonal relations and occupation, both statistically sig nificant differences {p<0.05). At 12 and 18 months, only 80% of the high dose and 78% of the low-dose patients were contacted for fo llow-up, and, although the high-dose patients tended to maintain their advantage over the low-dose patients, the differences were not statistically significant. The number of patients not available at fol low up and the failure of randomization may have contributed to these results. The patients in this study were intensively prepared for their LSD experience by a three-to fo ur-week period during which they received approximately 12 hours of therapist contact. The LSD sessions themselves were con ducted using the psychedelic method, in comfortable surroundings and with constant therapist attendance. Opportunities for integration of the drug experience were provided by several post-session interviews. This intensive nondrug therapy was one of the possible factors suggested by the researchers to account for the good results seen even in the low-dose patients. They also speculated that, since even 50Jl.g. produced considerable abreaction and cathar sis in some patients, this may have been something other than pure placebo effect.
The most methodologically elaborate and rigorously constructed study of LSD therapy for treatment of alcohol ism was conducted at Mendota State Hospital in Madison, Wisconsin by Ludwig and colleagues. A total of 195 patients were randomly assigned to one of four treatment groups. Three experimental LSD treatment conditions were com pared to a "no treatment" control group that received the standard thirty-day milieu therapy provided by the hospital 's Alcoholic Treatment Center. The specific diagnosis for all patients was alcoholism with no overt psychosis, and an extensive battery of pretreatment tests provided severity measures. A comprehensive, manual-guided introduction to the various treatment conditions was part of all patient intake processing, and informed consent for LSD therapy was obtained. The patients were not informed that their assignment to one of the treatment conditions would be ran dom, however, but were told that the therapy they would receive was chosen for them based on their pretreatment testing. The LSD-treated patients were assigned to one of three treatment conditions: hypnodelic therapy (hypnosis, LSD and psychotherapy); psychedelic therapy (LSD and psycho therapy); or drug therapy (LSD alone). Therapy for each treat ment condition was standardized to the extent that all 13 participating therapists were trained in each treatment method by the principal investigators. Comparative analy ses of the biases, levels of training and patient clinical assessments of each therapist were also analyzed. These studies, which were completed before the treatment condi tion to which each patient was assigned was known to the therapists, revealed no significant differences in treatment outcome for any variance in therapists' characteristics. In addition, patients were randomly assigned to therapists, with each therapist being assigned an equal number of patients from each treatment condition. The treatment team was entirely separate from the objective raters of the follow-up team. Follow-up evaluations were conducted at three, six, nine and 12 months posttreatment; and included contact with relatives at six and 12 months for corroboration of patient reports. All fo llow-up was by face-to-face interview, and less than I 0% of patients were lost to follow-up over the 12-month period. Pretreatment assessments were made in several areas of patient fu nctioning. The Psychiatric Evaluation Profile (PEP) was used to assess patients' attitudes and symptoms. Personality characteristics related to social interaction were evaluated using the California Psychological Inventory (CPI). Information on observable or reportable drinking behavior was obtained by administration of a questionnaire, and by Breathalyzer testing at the time of each follow-up encounter. Patients and their relatives completed the Behavior Rating Scale (BRS) in order to evaluate general areas of behavior (including social, employment and legal fu nctioning) as well as to give fu rther information on drink ing patterns. The Mendota State Hospital researchers also adminis tered the Linton-Langs Questionnaire (an instrument designed to evaluate the effect of LSD on affect, self image, perception and cognition) during the pretreatment assessment and again during the experimental treatment session. The resulting measure of the degree of conscious ness alteration produced by each treatment was then compared to the scores fo r therapeutic or personality change and behavioral adjustment obtained from the CPI, PEP, and BRS. There was no relationship between the depth of alteration in consciousness achieved in any of the treat ment conditions and subsequent personality or behavioral change. At fo llow-up, all treatment groups had a statistically significant change "in the direction of health" over baseline PEP and CPI scores but "no differential outcome results based on the diffe rent treatment techniques". Change in attitude measured at discharge did not significantly predict behavior during or after the first three�month follow-up period. Although the percentages of LSD-treated patients returning to drinking tended to be lower in the first two months post-discharge, these differ ences were not statistically significant. By the third month, differences in drinking behavior between treatment groups were minimal, and about 65% of all patients were drink ing to some extent by the fourth post-treatment month. There were no significant inter-group diffe rences in social adjustment as measured by the BRS. Although some substantial gains occurred, they were similar for all patients, regardless of the therapy they received. The researchers attempted to determine whether certain kinds of patients responded best to certain kinds of treatment using a multifactorial analysis. They described themselves as disappointed "to find that neither patient, treatment nor therapist variables bore any consistent relationship to treat ment outcome". The researchers speculated that the "relatively sus tained therapeutic gains" seen in all treatment groups were not surprising considering the extreme physical and emo tional deterioration of the patients at the time of admission. Simply being involun tarily committed, and thereby forced to stop drinking for 30 days, was expected to leave the patients in a better state than they had been in previous to treatment. Based on their rigorous design, their thorough fo llow up, their extensive analysis of fi ndings, and their consideration of such previously unstudied factors as the influence of therapist characteristics, and the relationship between altered states of consciousness and treatment out come, the research group fe lt that they had arrived at a definitive analysis. They were forced, they said, "to con clude on the basis of overwhelming, consistent, empirical fi ndings emanating from this investigation and by the find ings of other studies that the various LSD procedures do not offer any more for the treatment of alcoholism than an intensive milieu therapy program, and the latter, at best, is quite ineffective at deterring drinking". In addition, they determined that their report "[gave] rise to such inescapable conclusions about the purported efficacy of LSD for the treatment of alco holism as to preclude any further investigation . at least as far as evaluating the usefulness of the particular techniques used in this study"
Th is categorical statement stands as Ludwig and Levine's answer to the three essential questions which some of their own earliest work posed as the standard for evalu ation of any new drug or therapy. The question, Does the new agent offe r an app reciable advantage over existing fo rms of therapy ? would seem to have been answered by their study. As used in their research, LSD therapy, alone or in combination with other treatments, did not demonstrate any significant advantages over intensive milieu treatment for alcoholism. The answer to the second of their essential questions seems Jess clear: To what extent and in what disorders does the agent bring about re lief or effect change? Wo rking from the assumption that treatment implies an intention to change for the better, Ludwig and Levine considered the factors that might be expected to change: knowledge, attitudes, beliefs, symptoms, behavior or social functioning. Addi tionally they questioned the standards by which change would be evaluated as positive: those of the patient, the family, the therapist, or of society. Ludwig and Levine noted that the gains made by alcoholic patients in some areas of performance are not necessarily lost if patients return to drinking after treatment. They pointed out that experiences of insight or changes of attitude such as those described after psychedelic drug therapy may or may not be related to behavior, may have no observable consequences for the patient, or may have consequences that adversely affect the patient's social fu nctioning, well-being and welfare. Fur thermore, any change in attitude or behavior that does occur may be strengthened or undermined by the reaction of important persons in the patient's social environmentLudwig and Levine's findings might be variously interpreted as indicating that either patients do not benefit from LSD therapy, that benefit occurs in an important area that is not well or clearly measured by the criteria exam ined, or that benefits in one domain are counterbalanced by detriments in others or diluted by lack of change in oth ers. In any case, it was perhaps somewhat premature to assume that there was no need to inquire further as to how LSD might bring about relief or effect change in alcoholism or in other conditions. It is the third of Ludwig and Levine's essential ques tions, however, which seemed the most crucial at the time their study was published: What are the dangers or risks involved when this agent is employed? From 1964 to 1968, the fo ur years during which their study was conducted, the risks and dangers reported to be associated with the use of LSD changed significantly. Although panic reactions, suc cessful and unsuccessful suicide attempts, episodes of paranoia, and psychotic decompensation had been reported in association with LSD use, the incidence of such effects was quite low for those under therapist supervision, even Treatment of Alcoholism Using Psychedelic Drugs for patients being treated for psychiatric illnesses. LSD as used in a therapeutic setting compared fa vorably to other forms of psychological treatment in terms of possible adverse effects. As unsupervised use of LSD increased, however, so did the reported freq uency of adverse reac tions. With the publication in 1967 of reports of chromosomal abnormalities produced by LSD and the pos sibility of genetic damage or carcinogenesis, serious questions were raised about the safety of LSD treatment, or even of further experimentation. While the risk of adverse psychological reactions seemed to be low enough to justify continued exploration of the therapeutic poten tial of LSD, the possibility of unseen physical damage with potentially disastrous consequences could only be coun terbalanced by the probability of significant benefit. In the absence of other methodologically acceptable controlled studies, and in an environment of growing concern over the potential societal and physiological implications of unsupervised psychedelic experimentation, the implications of Ludwig and Levine's research fi ndings were clear and discouraging. To these once-optimistic researchers, the effectiveness of LSD therapy for alcoholism appeared to have been a mirage. In 1970, the Lester N. Hofheimer Award for research excellence was presented to Louis Stark, Jerome Levine and Arnold Ludwig by the American Psychiatric Associa tion. The citation for the Hofheimer Award states that: "In a four-year study, these investigators developed a technique for administering a complex but precisely defined sched ule for LSD treatment of chronic alcoholic patients, a method for studying it under controlled conditions and for evaluating the clinical outcome in both qualitative and quan titative terms. Their research design can serve as a paradigm for the study of other psychiatric treatments" (American Psychiatric Association 1970).
Despite its meticulous design, however, Ludwig, Levine and Stark's study was severely criticized by other LSD researchers. Charles Savage, speaking in 1971 to the staff of the Maryland Psychiatric Research Center, com plained that the preparation of both the patients and the staff for the experimental sessions was inadequate, there was no commitment to psychedelic therapy on the part of the staff, and the continuous verbal exchange specified during the minimal amount of therapist contact provided tended to interfere with deep regression and to increase resistance. According to Savage, there was insufficient opportunity provided for post-session integration of the experience, and only a small fr action of the patients reported that they had mystical or transcendent experiences, which were of utmost importance in the success of psyche delic therapy. Savage found the set and setting of the Mendota State Hospital study to be more typical of a chemotherapeutic than a psychedelic treatment process. Previous to the publication of their complete findings in 1970, Savage had expressed similar misgivings about the diffe rences between Ludwig, Levine and Stark's "hypnodelic" techniques and those of researchers employ ing psychedelic therapy. At the 1969 Hahnemann Symposium on psychedelic drugs, in addition to critiquing their therapeutic practices, he noted that Ludwig and Levine had reported good results from their early attempts to treat drug addiction with LSD and hypnosis. Savage claimed that Ludwig's embarrassment at being associated with positive findings on LSD treatment at a time when researchers work ing with LSD were coming to be regarded with suspicion had "changed his thinking" about LSD, and that this change in attitude had been reflected in the negative findings of subsequent studies. In a 1998 interview, Jerome Levine stated unequivo cally that neither the social stigmatization of LSD and psychedelic researchers, nor the influence of governmental regulation had negatively influenced the progress or the outcome of the Mendota Hospital study. He described the study as neither primarily chemotherapeutic nor pharma cologic in design, but rather as an attempt to use hypnosis to direct the LSD experience to a particular goal. He pointed out that the Mendota Hospital study was not intended to replicate or to evaluate the techniques used by other inves tigators. Nevertheless, the objections raised by Savage and others to the overall therapeutic design of Ludwig, Levine and Stark's study tend to emphasize its failure to adhere to some of what were considered the most basic and well recognized principles that had guided previous psychedelic therapy. As early as 1959, a World Health Organization study group on ataractic and hallucinogenic drugs had observed that: " ... the same drug, in the same dose in the same sub ject may produce very different effects according to the precise interpersonal and motivational situation in which it is given" (World Health Organization 1958). Early work with psychedelics at Boston Psychopathic Hospital disclosed surprising differences in the reactions of subjects to LSD depending on the characteristics of the experimental environment, and showed that "impersonal, hostile, and investigative attitudes" aroused hostile responses and increased anxiety and discomfort. Many researchers had described the responsiveness of the psychedelic experience to the expectations of the person receiving the drug and those of the person adminis tering it as among its distinctive features. Psychedelic thera pists held that it was "the experience, and not the medication that was therapeutic" (p. 43), making the treatment situa tion and the therapeutic relationship overwhelmingly important. Ludwig and Levine accepted that both "the actual psy chologic content and consequences of the psychedelic drug experience are capable of considerable modification". While acknowledging that it had been "shown that the environment or setting (con text) in which LSD is given can influence the type of experience produced," they spec ifically selected a clinical setting in preference to "mystic and 'esthetic"' se ttings preferred by other LSD therapists.
Savage's concern that adverse publicity and fe ar of disapproval might have affected the environment of LSD research was shared by other investigators. In the U. S. Senate hearings on research and regulation of LSD held in 1966 (the year in which the Mendota State Hospital study began) Daniel X. Freedman, Charles Clay Dahlberg, and Assistant Secretary of Health, Education and We lfare Phillip R. Lee all testified on the impact of public pressure on LSD research. Lee claimed that adverse publicity made scientists less willing or less eager to study LSD; Dahlberg asserted that research projects, particularly in state hospi tals, had been restricted in response to the labeling of LSD researchers as deviant; and Freedman pointed out that the atmosphere of sensationalism about LSD abuse obscured the importance of LSD research and made fair and dispas sionate consideration of its potential usefulness difficult. Senator Robert Kennedy declared that excessive negative publicity about LSD had caused everyone associated with it to be inaccurately labeled as "a criminal or a kook of some kind" (Subcommittee on Executive Reorganization 1966: 96). Daniel Freedman's pivotal 1968 paper "On the Use and Abuse of LSD" concluded that "we have been more awed than aided by our experience with these drugs". According toreview of scientific publications on LSD in Index Medicus from 1960-1 994, a dramatic reversal from a preponderance of positive to negative reports occurred in 1968, which reflects a strong cohort-period effect on scientific activity in this area. This effect describes a biphasic change in the tone taken by socioscientific publi cations toward a new pharmaceutical discovery in which early enthusiasm is replaced by later "sober reconsidera tion" of adverse findings. At a time of major social and political upheaval , the controversy around psychedelic drugs epitomized many of the conflicts between traditional values and new social and moral arrangements. The emphasis and fu nding of LSD research shifted toward efforts to prove its potential for harm and to discourage its use. Based upon the work of Ludwig, Levine and Stark and other contemporary research, the National Institute of Men tal Health declared in 1975 that: "Attempts by investigators over the years to use LSD as an adjunct to psychotherapy or as a special type of psychotherapeutic intervention have not clearly demonstrated therapeutic value" {Research Task Force 1975). If social policy considerations influenced the direc tion and fi ndings of LSD research, it was not a unique episode in the history of science. According to, "the results of scientific research are often ignored or dis torted in the interest of furthering specific national or international policies." In alcoholism research, for example, Fi II more ( 1984) fo und that problem definitions, prevalence estimates and cost appraisals were all subject to influence by policy considerations as sentiments related to temper ance and prohibition shifted over time.
When the first report of adverse reactions to self administration of psychedelics was published by Frosch, Robbins and Stern in 1965, the researchers pointed out that the usual order of medical investigations, which generally begin with a clinical observation, progress to clinical investigation of observed phenomena, and culminate in laboratory experimentation, had been reversed in the case of LSD. LSD was first synthesized and studied in a laboratory environment. Over whelming anxiety and panic reactions, suicide attempts, and occasional prolonged psychotic episodes were known to occur in patients and research subjects, but the incidence of such effects was quite low in supervised settings. By the second decade after the discovery of LSD, intense public interest and increasing availability had led to its use out side a research or treatment setting, where neither the professional skill nor the pharmacologic interventions that had been used to terminate adverse reactions in patients and research subjects were readily available. No prescreening of highly vulnerable individuals, no control of drug purity, and no accurate determination of dosage were possible. In 1965, a sudden surge in psychiatric admissions after the ingestion of LSD was noted by psy chiatrists, and adverse psychedelic reactions were described by Frosch and his colleagues as a clinical syndrome that included three overlapping types of reaction. This taxonomy was later confirmed by the observations of others, and refined to include two subtypes for each major category of reactions: acute panic and acute confusional Journal of Psychoactive Drugs 405 Treatment of Alcoholism Using Psychedelic Drugs states, early and late recurrence of drug effects without fur ther ingestion, and prolonged psychosis or prolonged anxiety. The major deleterious effects of unsupervised LSD use, as described in the work of Frosch, Robbins, Ungerleider and others, were explained for the May 1966 Senate hear ings on research and regulation of the psychedelics by Stanley Yo lles, head of NIMH. In addition to the major adverse psychiatric effects identified by front-line psychia trists, Yo lles described a fo urth effect, which he characterized as "a gradual deterioration of efficient and effective reality-oriented behavior-loss of interest in work or study, in social relationships or obligations" (Subcom mittee on Executive Reorganization 1966). At the time that the Senate hearings took place, although several researchers had observed and remarked on similar phenomena, only Sidney Cohen had identified them as one of LSD's principal dangerous effects. In a paper read at the Ninth Annual Conference of the Ve teran 's Administration Cooperative Studies in Psychiatry in March of 1966, Cohen had described "dyssocial" behavior as one of the acknowledged nonpsychotic disorders that might complicate the extralegal use of LSD. In LSD-associated dyssocial behavior "a complete loss of previously held val ues and aspirations might result. Motivation to study or work disappears, family ties dissolve and personal cleanli ness is neglected. Speech consists of pseudophilosophical jargon. There is a tendency to form cults or to affi liate with 'beat' elements". Richard Blum, writing in 1964 about a sample of LSD users drawn from psychedelic party-goers, former LSD therapy clients, public psychiatric clinic patients, police identified drug users, and medical and mental health professionals, included reduced work interests and goal striving, greater preoccupation with internal events and self, and changes from prior chronic states, including reduced competitiveness, in a list of major mental effects of LSD use. He denied that this represented a retreat from the world, and suggested instead that a meaning and order which could not be found in empiricism and worldliness were made available by the LSD experience and became part of a per sonal life endowed with significance and order. In another study comparing LSD users with persons who had ben given an opportunity to take LSD and had refused it, Blum and his associates found that LSD accep tors were more inner-focused, or contemplative, and less likely to strive for power or be caught up in work than re jecters. LSD rejecters cared more about work and events in the external world, and also reported more tension, over eating, and alcohol use.had reported a "shifting of basic beliefs" after the psychedelic experi ence, but this was related primarily to the subjects' sense of self-worth and self-acceptance., in his JAMA editorial, had noted "some distressing indica tions that habitual use of the [psychedelic] drugs will lead, in some individuals at least, to looseness in thinking and difficulty in communicating coherently." Some of these "distressing indications" may have been Farnsworth's observations, as head of the Harvard Student Health Ser vice, of the behavior of Timothy Leary and Richard Alpert. According to David McClelland, their chief at the Harvard Center for Research in Personality, the more psychedelics Leary and Alpert and their associates took, "the less they were interested in science". McClelland was well placed to emphasize the poten tial impact of psychedelic drugs on achievement, as he had published two books on the subject: Th e Achieving Societyand Th e Achievement. While McClelland was later credited by some observers as hav ing had a prophetic insight into the possible amotivational consequences of widespread use of the psychedelics because of his observation that they "seemed to encourage withdrawal from social reality and satisfaction in interior reflective existence"), others disagreed. Gerald Klerman, assistant director of the Massachu setts Health Center, criticized Leary and Alpert for failure to observe the rules of scientific investigation, but also used McClelland's concern fo r the potential impact of psychedelics on achievement as an example of "pharmaco logical Calvinism," an attitude motivated by fear of social change, and disavowal of emotion and bodily satisfaction. In Klerman 's assessment, the envi ronment of psychedelic research had been poisoned by a combination of disregard for the scientific proprieties and overreaction that amounted to an academic witch hunt. In his 1963 overview of the uses and misuses of LSD type drugs, Jonathan Cole pointed out that evaluation of personality and behavior changes that might occur after drug use involved value judgments, such as whether a decreased interest in success or competition, replaced by an increased interest in music or poetry, was a positive transformation. None of these observations had led, at the time of the Senate hearings, to a clinical investigation or to a laboratory experiment including operationalization and measurement of "efficient and effective reality-oriented behavior." In 1967, one year after Cohen 's identification of dyssocial behavior as an effect of LSD use, Smart and Bateman called for basic psychological investigations of the presumed, but undocumented, ability of LSD to cause "personality changes,damage to employability, fam ily relationships, and moral and ethical controls". Hollister, in a comprehensive mono graph on the psychological , neurophysiological, and biochemical effects of LSD and related drugs, noted that a personality deterioration consisting of unproductivity in previously promising individuals had been seen to fo llow the repeated use of psychedelics. He did not attribute this unequivocally to the use of drugs, however, suggesting instead that repeated drug use might be a symptom of an already disturbed personality, or a type of modern anti intellectualism which made coherent thinking impossible. In 1969 the National Institute of Mental Health sum marized the previous two years' congressional testimony of its chief in a report to the medical community. Dr. Yo lies again described his concern, not only with drug misuse, but also about the "alienation" of the student population, and students' "rejection of many goals of society, unwill ingness to model themselves on any stable adult leaders, and ... inability to acquire the necessary attitudes and skills for responsible adult behavior" (National Institute of Mental Health 1969). Yolles feared that this widespread rebellion, rejection and refusal would make it difficult to educate young adults about the dangers of drug use, and raised the possibility that many of them might reach adult hood "embittered toward the larger society, unequipped to take on parental, vocational and other citizen roles, and involved in some form of socially deviant behavior" (National Institute of Mental Health 1969). Arguments about the relation of drug use among the young to social alienation and rejection of traditional val ues often concerned which was the cause and which the effect. Writing for "Current Concepts" a section of the New England Journal of Medicine in which an authority is in vited to express his views on a topical issue, Donald Louria raised the possibility that the widespread use of psyche delic drugs "could lead to a whole generation of psychedelic dropouts, incapable of and uninterested in addressing them selves to the important sociologic problems of our times" (Louria 1968). Letters to the editors subsequently chal lenged his article, describing it as a panicky morality lecture, using polemical language, and suffering from the injection of personal prejudice. In particular dispute was his conclusion that the socialization problems of young adults were the result, not the cause, of LSD use-a premise for which no support had been offered). This issue was still unresolved in 1984, when Rick Strassman, in an extensive review of the literature on adverse psyche delic reactions, suggested that the use of LSD may fo llow, rather than precede, certain social attitudes. Overall, Strassman's appraisal was that the evidence seemed to indicate that particular personality characteristics. includ ing eccentricity and noncompetetiveness, may predate the use of LSD. In a 10-year follow-up study of 247 persons who had received medically supervised LSD sessions, McGlothlin and Arnold found little evidence that LSD prodw:ed any lasting change in beliefs, values, attitudes, or behavior. Per sons who preferred a less structured life tended to he mon attracted to LSD than those whose pre fere nce was for the Volume 30 (4). October -Dcccmhcr 19lJX systematic, structured and orderly. A few respondents said that they had experienced decreased competitiveness as an adverse effect of LSD use. In a study of 20 paid volunteer subjects who had taken LSD eight or more times outside a medical setting,found no evidence of increas ing personality or social disorganization. Ludwig and Levine included the "drop-out" effects of LSD use as one of the purported risks or dangers of unsu pervised or prolonged LSD use in their 1970 monograph. They reported that the consensus of experienced clinicians was that long-term LSD users "become progressively more passive, lose ambition and initiative, become more preoccu pied with subjective reality, and develop an increasing antagonism toward social expectations and 'establishment' values".noted that LSD users frequently described a dramatic shift in their value system, in which work, con formity, organization, and materialism had become less interesting to them. They suggested that these users had taken Leary 's slogan, "Turn on, tune in, drop out," quite literally. Others pointed out that "dropping out" could be used to describe any kind of negativism, failure, or avoidance of responsibility, but that the intention of Leary 's injunc tion had been something quite diffe rent. Brian Wellsinsisted that dropping out meant "giving up ambitions and the symbolic rewards of society to pursue the aim of developing inner wisdom and philosophical satisfaction." It was not intended to be a permanent state, but was sup posed to enrich the individual, who then was expected to return to organized society. Significantly, Wells observed that a major obstacle to reintegration fo llowing a period of philosophical exploration and growth was the possibility that society might seek to maintain the alienation as pun ishment for questioning its core values. Wells also speculated that psychedelic drug use might also have no causal role in shaping philosophies, but might simply be a behavior of people who question customs and viewpoints, or even the result of pervasive shifts in cultural values.
Fears that LSD might induce psychosis or unpredict able sociological consequences were eclipsed in March of 1967 by reports of damage to human chromosomes caused by LSD. Maimon Cohen, a geneticist from the State Uni versity of New York at Buffalo, is reported to have become interested in the possible deleterious effects of LSD during a short visit to the Haight Ashbury district of San Fran cisco while attending a medical meeting in 1966). In March of 1967, Cohen and his associates pub lished their first report of the effect on frequ e ncies of chromosome breaks in cultures of human peripheral leukocytes of exposure to various concentrations of LSD for fo ur, 24, and 48 hours. At least a twofold increase in chromosomal abnormalities was detected with all but the lowest concentration at the shortest exposure. In addition, the researchers noted a more than threefold excess in the number of damaged chromosomes over normal in a schizo phrenic patient who had received 15 treatments with LSD). Cohen's findings of in vitro chromosome damage were quickly extrapolated to a potential for teratogenic effects in vivo. The teratogenic potential of drugs used during preg nancy had been fully appreciated for the first time with the occurrence in the early 1960s of 12,000 cases of phoc omelia, a rare congenital defect involving reduction of the proximal portion of the extremities, after pregnant women had ingested the sedative thalidomide. The possibility that LSD could have teratogenic effects was quickly and widely reported in the popular press . Mc Call 's advertised an article on chromosome damage with a picture of a dismem bered baby. The report, "LSD: Danger to Unborn Babies" actually cast doubt on the validity of Cohen's fi ndings, but advised against the casual use of any medications during pregnancy. A Saturday Evening Post fea ture story, "The Hidden Evils of LSD," claimed that new research had found that LSD was "causing genetic damage that poses a threat of havoc now and appalling abnormali ties for generations yet unborn," and that "if you take LSD even once your children may be born malformed or re tarded". It is possible that the social utility of Cohen's chromosome studies contributed to their rapid dissemination. At an NIMH conference on adverse reac tions to psychedelics in September of 1967, Daniel Freedman suggested that "a dire somatic consequence" was just what was necessary to put an end to the controversy over LSD. Jonathan Cole told the Satur day Evening Post that NIMH was so concerned about these fi ndings that it was encouraging new research on chromo some damage. More than 60 studies in this area were completed in the next five years. The lead article in the November 17 issue of the New England Journal of Medicine was a collaboration by, author of the account of adverse LSD effects seen as psychiatric emergencies at Bellevue. This paper pre sented the results of a comparison of the number of chromosome breaks fo und in a sample of 18 LSD users who had been admitted to the Bellevue psychiatric emer gency service with those of 16 control subjects. Two controls with a very high percentage of breaks were dropped from the study before data analysis because of the onset of the symptoms of a viral infection soon after blood samples were obtained. With the exception of these two, the LSD patients had chromosome breakage rates two to fo ur times higher than the controls. There was no mention of the occurrence of viral illness in the LSD patients. In addition, fo ur children who had been exposed to LSD in utero were evaluated and fo und to have morphologic rearrangements of their chromosomes. The researchers recommended that a large epidemio logical study be undertaken to evaluate the potential dangers that they identified: a possible increase in leukemia and other neoplasms in LSD users; a potential for teratogenic effects on the fe tus exposed in utero; and the risk of genetic trans locations producing damage in future generations). An accompanying editorial de scribed LSD as "radiomimetic" --causing somatic mutations and cell depletion similar to those caused by chronic whole body radiation. The editorial emphasized that these findings would require users to reconsider their attitudes toward drug use. For the sake of the biological fitness of the next gen eration, it said, "the time [had] come to stress the negative attributes of psychotomimetic drugs (Editor 1967). Others were not as quick to accept Cohen's conclu sions. Daniel Freedman was one of the first to point out that "reports of chromosomal changes in preparations of lymphocytes raised in tissue culture are not identical with 'genetic damage"'). Maryland Psychiat ric Research Center, one of the few sites of ongoing LSD research on human subjects, took the opportunity to set up a double-blind, controlled study of the before and after rates of chromosomal aberrations in patients exposed to pure LSD, but fo und no definitive evidence of damage after LSD exposure (Tjio,. A Danish study administered massive doses of LSD to mice (lmglkg) and fo und definite evidence of bone marrow damage), but these results were not reproducible in subsequent studies (Waranky & Ta kacs 1968). Other studies questioned the teratogenicity of LSDor pointed out the multitude of chemicals known to produce chromosome breakage in cultured cells, including salicylates, caffeine, theophilline, theobromine, hydrogen peroxide, calcium deficiency, peni cillin, sulfas, tetracycline, and water that was not twice distilled in glass. Two extensive reviews of the literature published in the early 1970s attempted to synthesize the numerous con fl icting fi ndings of various studies.reviewed 68 studies and case reports pub lished from 1967 to 1970, and concluded that "pure LSD ingested in moderate doses does not damage chromosomes in vivo, does not cause detectable genetic damage, and is not a teratogen or a carcinogen in man." They fo und no contraindication to the continued controlled experimental use of LSD other than pregnancy. A review by Sallyin Te ratology examined the possibility of direct or indirect genetic or teratogenic effects on children, and con cluded that the risk of such effects from research or treatment using LSD was small enough that it might be outweighed by potential therapeutic benefits-a decision that should be left to the researcher. Because of the curtailment of research on LSD with human subjects, few subsequent studies provide data on possible chromosome damage effects in humans. Research in animal models has contin ued to support the consensus that LSD is neither teratogenic nor oncogenic, and that it is at most a weak mutagen. The issue of chromosome damage presented the first physiologic reason not to engage in controlled scientific study of psychedelic drugs. Potential subjects of LSD research raised questions about genetic risks, and scien tists raised ethical questions about the safety of research subjects. Officials of the government agencies charged with pro gramming and funding research experienced conflicts between a scientific approach and their personal opinions and morals. The kinds of studies consid ered to be useful and important by funding agencies were linked to social policy by their dependence on congres sional appropriations. The use of LSD was seen by some as symbolic of a social movement of rebellious opposition to government policies, predominant values and conventional behaviors). Dra matic and exciting publicity, even when negative, acted as a lure for those disposed to use psychedelic drugs, and cre ated hostility and anger in those who opposed their use. Drug policies depending primarily on prohibition and law enforcement for control increased profits for those illegal entrepreneurs willing to take the increased risks, and added the danger of adverse legal consequences to the list of pos sible harms resulting from psychedelic drug use. What did not deter the drug entrepreneur, however, demoralized many clinical investigators.
Writing in 1965, Abram Hoffer expressed his dismay with what he suggested were excessively cautionary state ments about the harmful potential of psychedelic drugs made by "reputable scientists who are forced to issue pseudo-scientific statements in order to hide their desire to work with these compounds". By November of 1968, when Hahnemann Medical College Department of Psychiatry sponsored what was described as a comprehensive, multidisciplinary symposium on psy chedelic drugs, the sponsors suggested that the initial fu ror over psychedelic drugs had begun to subside. While it was true that the number of popular articles and news stories about psychedelics peaked in 1967, the effects of the past few years of controversy were only beginning to be fe lt in the research environment. This was reflected in the con tent of the Hahnemann Symposium itself, in which the majority of the papers presented dealt either with the known or suspected hazards of psychedelic drugs, legal issues related to their use, or attempts by researchers studying therapeutic use to address various sources of difficulty and embarrassment in their work. Few studies designed to address legitimate criticisms of previous research were subsequently performed. The series of NIMH-funded studies of LSD therapy that had begun in 1963 at Spring State Grove Hospital in Baltimore, and later continued at Maryland Psychiatric Research Cen ter and the Johns Hopkins University School of Medicine was mostly completed by 1968. Although research with related substances such as dipropyltryptamine (DPT) con tinued there until the mid-1 970s, the Spring Grove studies were the last U.S. clinical trials using LSD and human sub jects for more than two decades. Hybrid models of therapy using aspects of both the psycholytic and psychedelic approaches, which emerged as psychedelic research was coming to an end, received limited exploration, and prima rily used drugs other than LSD. The national attitude toward psychedelic drugs had become profoundly negative. Although this change was rationalized by citing reports of harmful effects), some researchers claimed that mass media sensa tionalism had led publicity-sensitive agencies to become overcautious and fearful. Others noted that the sci entific respectability of LSD research had been so compromised that: "Qualified, recognized researchers, who would be authorized to do the work, apparently, just do not seem to want to risk the possible notoriety, or taint of, or embroilment in, the controversy and mass media confron tations that surround investigations of the psychedelic use of LSD".
At a 1967 conference reviewing the previous 10 years' progress in psychopharmacology, Arnold Ludwig wryly declared that the necessity for more controlled, method ologically rigorous studies of the therapeutic uses of psychedelic drugs was "the obvious and now hackneyed conclusion of almost all the review articles in this area")., in his comprehensive monograph on the history, pharmacological activity, and possible therapeutic applications of the multitude of natu ral and synthetic psychedelic drugs, asserted that "by modern standards of clinical pharmacology" there had not been even one adequate evaluation of the therapeutic use of psychedelics. Although Ludwig and Levine in their own study concluded that LSD therapy did not offe r any advan tage over other forms of alcoholism treatment, they also noted that there was no way to determine for what disorder or to what extent LSD therapy might be of benefit given the confused and incomplete state of previous research. The publication of their study essentially ended the program of LSD research. In their review of studies on LSD treatment of alco holism published through June 1970,offe red no conclusions about the overall effectiveness of LSD treatment for alcoholics because dis parities in improvement criteria and in study designs did not allow them to generalize from the accumulated data. Major variations existed between studies in a number of areas: the theoretical framework of the therapist; the per sonal experiences of the therapy team with psychedelics; whether other therapies were provided concomitantly; and in what attempts were made to influence the "set" (the expec tations, issues and personal characteristics of the patient) or the "setting" (the place and atmosphere of the session). Even within studies, these factors-which were acknowl edged to modify the experience obtained-were nevertheless poorly described and controlled. Although sev eral thousand psychiatric patients, and an equal or greater number of volunteers, were given LSD in treatment or experimental settings, no researcher attempted to determine if LSD therapy was most effective with a particular type of patient, or a specific treatment setting. Definitions of drinking behavior as an outcome mea sure were imprecise, and no common outcome criteria allowed for comparison of study results. A priori determi nation of criteria for improvement was uncommon. Efficacy of treatment was conflated with treatment outcome, and there was little discussion of how fac tors other than the experience of treatment might influence the patients' con dition. In addition, important effects of treatment may have been missed, as little consideration was given to social, medical, legal, fam ilial and occupational changes. In his review of the status of LSD psychotherapy, Ye nsendeclared the literature on the subject to be "rich in the variability of its results, and premature in most of its conclusions." Ye nsen attributed this dubious distinc tion to the collective nai'vete of the investigators of psychedelic drugs, which was shared with their professional contemporaries to an extent that prevented the deficien cies of this body of research from being outstanding for their time. Uncontrolled studies and post hoc definitions of success were commonplace in psychiatric research in the middle decades of this century. In a 1958 critique of psychiatric research, Foulds randomly sampled 72 papers from British and American journals and found that only 44% of the British and 11% of the American studies were controlled. Tw ice as many uncontrolled studies reported successful treatments versus the controlled studies (p<.OO 1 ). Colin Smith complained in 1960 that psychiatry was "in danger of becoming a foetid quagmire of anecdotalism". He claimed that psychiatric research was rich in ideas, but bereft oftestable hypotheses, and that training of psychiatrists in research methodology was nota bly deficient. Since the 1970s, psychotherapy research techniques have changed, as have the expectations and processes of evaluation of modern pharmacology. What has remained fa irly constant, however, is the therapeutic vacuum that exists in the treatment of alcoholism. The most visible change in this area has been the emergence of other prob lems with comparably deficient therapeutic solutions: the widespread occurrence of polydrug abuse in the alcoholic and the growth of other substance-related disorders as significant public health problems. A negative social and political environment served to discourage the pursuit of LSD research at a time when changes in research techniques were just beginning to influence its conduct; the psychedelic program was discon tinued at a crucial point in its development. The few methodologically adequate studies of LSD treatment of alcoholism that had been completed had predominantly negative outcomes, but were criticized for failure to adhere to the psychedelic model of therapy that had been used in the numerous positive exploratory studies. Studies that might have answered these objections were not subsequently performed; governmental support disappeared, the pharma ceutical industry lost interest, and investigators became reluctant to conduct research in a sensitive and controversial areahave suggested that it was "time to take up the work that was laid down unfin ished in the sixties." In fact, lack of money, lack of trained personnel, lack of a sponsoring pharmaceutical house interested in testing the safety and efficacy of LSD, and public disapproval and mistrust of psychedelic drugs have prevented the resumption of research with these substances until very recently. Scientists at the University of New Mexico, Harbor-UCLA Medical Center, the University of Miami, and elsewhere have attempted cautiously to resume human studies of the psychedelics. The University of Maryland and North Charles General Hospi tal had a small LSD program until the mid-1980s. A new amendment to this protocol for substance abuse treatment was approved in 1995, and supplies of LSD have been ob tained from the FDA, but no research has yet been undertaken. Research with DMT and psilocybin at the University of New Mexico has been suspended by the investigator, and ibogaine research at University of Miami has failed to obtain NIDA funding. Outside the United States, a com prehensive medical-psychiatric study of ayahuasca use in a officially sanctioned syncretic church has been completed in Brazil); MDMA research in human subjects is in progress in Zurich, and in the planning stages in Barcelona. Three protocols for MDMA research in the United States are in various stages of the state and federal approval process, and an approved Phase 1 study on the effects of MDMA as a function of dosage in healthy volun teers has been completed by the Harbor-UCLA research group. A study by John Halpern of Harvard University on the neuropsychological effects of peyote use by Native American Church members is in the planning stages. What Sanford Unger 30 years ago hoped for LSD and other psychedelics-that they might enj oy a "rebirth of sober consideration and exploration of use")-may or may not now be possible.
Despite the confusion about the efficacy of LSD treat ment occasioned by the limitations of previous studies, the possibility that LSD could be useful in the treatment of alcoholism remains engaging. Many possible constructions of the findings of historic LSD research have been left unexplored, and many aspects of the data remain unevaluated. An initial difficulty in evaluating the results of LSD therapy is the lack of consistent comparison data on other contemporary alcoholism treatments. In Abuzzahab and Anderson's final tabulation of the 31 alcohol treatment studies they reviewed, 75% of patients receiving a single dose of LSD in controlled studies were "improved" after approximately 10 months of fo llow-up, versus 44. 1% of the controls. At approximately 20 months, 57.5% of the multiple-dose patients were improved, versus 53.8% of controls. The authors' interpretation of these data did not offer any comparison of LSD therapy results to those of other treatments then being offered for alcoholism. Bacon (as cited in) claimed that improvement rates under all existing therapies for alco holism were about 40% in 1963. In a 1967 panel discussion with Jerome Levine and others, Ross MacLean asserted that LSD-treated alcoholics experienced twice as much improvement as those treated with other methods, includ ing Antabuse ® and conditioning techniques. In his review of the literature on drug treatment for alcoholism, J. M.fo und no consistent support for any of the then-current drug therapies, includ ing "antidipsotropics, aversives, ataractics, and hallucinogens." A meta-analysis of controlled studies pub lished between January 1974 and March 1993 fo und that patients who received widely diffe ring fo rms of alcohol ism treatment all consumed substantially less alcohol at the time of fo llow-up than controls (effe ct size = l.l7), regardless of the treatment received). An essential inconsistency exists in the way improve ment is defined. Many researchers have used the achievement of complete abstinence from alcohol as the only criterion for improvement, whereas others include better social functioning, decreased legal or medical prob lems, moderation in continued drinking, or increased insight and self-acceptance as demonstrations of improve ment. Contemporary studies of treatment effectiveness are expected to be far more precise in evaluating improvement than were the studies of LSD treatment, and to consider not only reduction of substance abuse, but also improvement in the personal health and social function of the patient, and reduction of public health and safety risks as treatment outcomes. "Alcoholics" have commonly been treated as a homo geneous population in studies of alcoholism treatment, although current thinking suggests that there are subtypes who may respond differently to different forms of therapy. Measures of the severity of alcohol related impairment have evolved considerably in the last decade. Since the studies of LSD therapy for alcoholism were completed, measures (such as "number of years of drinking," or "previous treatment failure") used in those LSD studies in which any assessment of severity was attempted have been superseded by more precise and com prehensive evaluation tools like the Addiction Severity Index. Although the dose of LSD used and some description of the session environment are usually included in the existing LSD therapy studies, details of the conduct of the sessions are fr equently sketchy. Historic controversies related to therapist experience with the psychedelic drugs, differences in the physical circumstances of sessions, and techniques employed during LSD administration have never been resolved. Descriptions of the precise nature and "dose" of other treatment services provided to the patient are gen erally lacking, and differences in efficacy associated with the non-drug aspects of the treatment programs have never been evaluated. The co:-�cept of alcoholism as a chronic health prob lem has evolved since the LSD studies were performed, and the expectation that relapse is likely without ongoing therapy beyond immediate detoxification and stabilization has gained acceptance. To be considered effective, contem porary treatment programs need not necessarily set total abstinence as their goal. They must, however, produce "sig nificant, pervasive and sustained positive change in the lives ofpatients".
The question of whether LSD treatment is effective for alcoholism has not been convincingly answered by the existing research. Because of the diffe rences in treatment procedures, theoretical backgrounds, biases and beliefs, and definitions of terms that existed among the various teams which conducted LSD research, the question has scarcely been properly asked. The prevalence of alcohol use disor ders, the hope that improved treatments will not only reduce problem drinking but also will decrease its costs to society, and the contemporary emphasis on the control of health care costs make questions about the effectiveness of LSD treatment timely and interesting. Recent advances in out come research on substance abuse treatment and One development in outcome research has been the use of techniques for synthesizing the existing knowledge about psychotherapy. Past attempts to compare psycho therapy outcomes discarded a large portion of the existing data on methodological grounds, in an effort to make sense of the chaos of a large set of studies with different treat ment techniques, therapist philosophies, patient samples and outcome measures. The resulting analyses do not assign more weight to larger or better-designed studies, and valuable data may be lost. This effect was evident in the attempt ofto use a weighted evidence index to compare the cost-effectiveness of LSD therapy for alcoholism with other treatments for which more methodologically adequate studies are avail able, and in Abuzzahab and Anderson's assessment of 31 studies of LSD treatment. An improvement on this technique is direct compari son of studies with different outcome scales by their effect size. Effect size is a statistic that indicates the ratio of the average difference in outcome score for the treated and con trol groups, and the standard deviation of the outcome score of the control group. The effect size will be a number from -3 to +3 that represents the distance between the score dis tributions of the treated and control groups (O'Brien & Woody 1989). A reexamination of the studies reviewed by Abuzzahab and Anderson might be possible using effect size, but only eight of those studies would be eligible for consideration. Even with improved analytic methods, the present body of psychedelic research on alcoholism treatment is diffi cult to assess, as it consists mostly of hypothesis-generating studies, or hypothesis-testing studies with serious methodologic fl aws. Professional interest in the psychedelics waned just as these flaws were being acknowl edged and better-designed studies demanded. Renewed human research with the psychedelics is now becoming possible. Rather than abandon any attempt to profi t from two decades of historic LSD research, new studies should build on the strengths and remedy the deficiencies of this large body of work. If further hypothesis generating/pilot/exploratory studies are performed, they should be used to formulate research questions and docu ment the quality of measures as a basis for designing new hypothesis-testing studies.
What is Expected from LSD Treatment for Alcoholism? Expectations of what treatments for alcoholism should do are not confined to elimination of excessive drinking. The "effectiveness" of any alcoholism treatment is mea sured not only by its ability to change drinking behavior, but also by its impact on social, medical, family, legal and employment problems that are related to alcoholism. Whether these problems contribute to or result from prob lem drinking, the patient, and his or her family, insurance carrier, employer, probation officer and community may expect that effective treatment will help to bring about their resolution. Successful treatment ideally would lead to better health and social functioning for the alcoholic patient, and decreased impact on the pub lic health and safety, as well as a reduction in drinking. Treatment of alcoholism, whether with LSD or other wise, is not merely the detoxification and stabilization of an individual whose drinking has reached a crisis point. Alcoholism is a chronic disease and, although patients should be expected to improve with treatment, relapses after acute treatment is completed are the rule rather than the exception. It is realistic to expect that long-term care will be needed to maintain symptom remission. At the time that research came to an end, the program of LSD therapy was evolving from emphasis on a single conversion-like experience to a type of extended psyche delic therapy in which periodically repeated high-dose sessions were employed. This hybrid treatment was intended to allow periodic access to the transcendental experience that has been postulated to permit rapid personality change, and to encourage self-exploration and therapeutic interac tion, with a gradual re solution of underlying psychodynamic conflicts (McCabe & Hanlon 1977;. Periodic redosage with LSD has also been suggested as a possible method for sustaining the short-term improvement observed after LSD treatment. With the resolution of some of the questions about the somatic consequences of repeated LSD treatment and the evolving understanding that addic tive disorders require life-long treatment, this avenue of inquiry should be reopened and explored. Is There a Particular Type of Patient Who Will Be More Likely to Benefit from LSD Treatment? Patient populations in the present body of LSD research were generally neither adequately described nor precisely diagnosed. Many patients were known to have coexisting psychiatric diagnoses or other substance use problems, but re searchers did not attempt to control for these factors. There was a wide variation in the timing and rate of fo llow-up, and criteria for improvement were not uniform or clearly defined. Contemporary research on substance abuse treat ment generally recognizes that, in addition to the amount, duration and frequency of substance use, the patient's social assets and liabilities at entry to treatment may pre dict treatment outcomes. Medical conditions, family supports, work and educational skills, legal complications and the patient's living environment may present treatment problems.. An adequate study of LSD treatment for alcoholism should begin with the application of accepted diagnostic criteria to obtain a homogeneous patient population with a specific diagnosis (O'Brien & Jones 1994). Reliable and valid instruments for the assessment of substance abuse problems, such as the Addiction Severity Index, allow the evaluation of patient status before and after treatment). Pre-and posttreatment compari sons of both alcohol use and psychosocial problems should be performed at predetermined intervals and should incor porate techniques for quality control, such as collateral reports from friends and family, or objective biological measurements used to validate patient reports of drinking behavior. To minimize demand effects, independent evalu ators should perform these assessments. At least an 85% rate of success in contacting patients at follow-up at six months posttreatment is considered an appropriate rate of contact. If the problems that patients bring to treatment cannot realistically be affected by the intervention provided, an inaccurately negative assessment of the effectiveness of the treatment will result. If areas of fu nc tioning and well-being in which the patient may experience change are not assessed by evaluative measures, the effect of treatment may not be accurately reflected. Past LSD treatment research has suggested that patients may come to accept the severity of their problems and develop motivation for change after LSD therapy. LSD treatments for alcoholism were primarily di rected to the achievement of abstinence, and fe w interventions specifically emphasized the reduction of psy chosocial problems. The effects of these problems on the post-treatment environment of the patient and on the like lihood of sustained improvement are now better appreciated. Improved techniques for the assessment of psychosocial adjustment before and after treatment now permit the evaluation of the possible impact of LSD therapy in areas other than the amount, duration and frequency of alcohol use. Further research with LSD should use these improved evaluative method ologies to determine the impact of LSD therapy in these areas. Exactly What Procedures Are Used? Since the early 1960s, the influence of nondrug vari ables (including the purpose of the study, the expectations of the subject, and the setting in which the drug was administered) have been acknowledged as crucial factors in determining the nature of the research subject's psyche delic experience. Despite this, psychotherapeutic research on LSD has generally fa iled to assess, control, or systematically modify any variables beyond the drug and dose used. Future psy chedelic research should explore the ways in which the content, intensity and effects of psychedelic sessions could be intentionally arranged to facilitate a particular type of experience. In addition to the use of common techniques for quantifying the dose of psychotherapy provided (such as the use of manual-guided procedures for standardiza tion, and training and periodic supervision of therapists) specific processes that are claimed to be significant in LSD therapy (such as changes in defensive structures of the patient and increased expressiveness) might be operation ally defined, attempts to facilitate these processes described, and the effect of LSD treatment in these areas objectively measured. Unless the characteris tics of the patient and of the therapist, the conditions under which the treatment is delivered, and the methods and goals of therapy are specified, any claims about therapeutic effectiveness remain vague and nonspecific. While neither excessive enthusiasm for a promising treatment nor skeptical negativism is appropriate in the researcher, the impossibility of conducting value-free research should be acknowledged. Contemporary psyche delic researchers should locate themselves in the studied environment by examining and revealing their biases and ideology. While this practice is common in the conduct of qualitative research, in the design of quan titative research it would be an innovative or even radical departure. Nevertheless, in the history of LSD research, the preconceived ideas of research scientists and public officials have contributed greatly to the creation of an atmosphere of confusion and mistrust. The renewal of research in this area is an opportunity to avoid per petuating this problem.
Although LSD researchers have noticed and discussed such LSD l!ffects as increased self confidence, decreased tension and frustration, greater emotional stability, and less defensiveness, how these effects might be reflected in long term changes in behavior has had very little systematic study). An effort using modern research techniques to de termine in what specific way LSD effects might be of benefit is both possible and warranted. Improvements in baseline measures of severity, quan tification of treatment services, and instruments measuring the intensity of psychedelic drug effects should make it possible to assess changes produced in both clinical and functional outcomes by the addition of psychedelic expe riences to existing alcohol or other drug abuse treatments. A new instrument, the Hallucinogen Rating Scale, correlates drug effects with specific dosage levels. Improved assessment tools have been developed for evaluation of substance abuse treatment pro grams, including the kind and amount of program services provided, the effectiveness of specific elements of those services in decreasing drinking and reducing psychosocial problems, and the relationship of patient and treatment fac tors to treatment outcome. New studies of LSD treatment for alcoholism should systematically assess the effect of LSD on processes that are claimed to be of significance in therapy.
LSD therapy may potentiate the effects of both specific substance abuse services and psychosocial interventions. In a recent study of 649 opiate-, alcohol-and cocaine dependent adults in 22 treatment programs, similar fac tors predicted treatment outcome, independent of the patient's drug problem, or whether treatment was public or private, inpatient or outpatient. The severity of patients' pretreat ment problems significantly predicted the outcome of treatment at six months. Provision of specific substance abuse services-such as group therapy for denial, 12-Step meetings and drug and alcohol education-fostered patient acceptance of a substance abuse problem, increased moti vation, and influenced changes in substance use behavior. Psychosocial services helped to improve the patient's fu nc tioning in fa mily, legal, social and employment situations. LSD therapy should be evaluated in combination with other patient and treatment factors that have been shown to predict treatment outcomes. New pharmacologic treatments such as naltrexone may help prevent relapse in alcoholic patients by reducing alcohol craving. The possibility that insights achieved during LSD sessions might increase motivation to use these medications should be explored.
The possible value of LSD in a psychiatric or thera peutic context has been almost completely obscured by media sensationalism, unsupervised self-experimentation, poorly designed research, and misinformation. It is diffi cult to obtain legal permission to work with LSD, and there is no fe deral, institutional, or pharmaceutical industry sup port for LSD research. Nevertheless, interest in its potential usefulness persists, and preliminary work to reopen research is under way after more than a quarter century of quies cence. A major part of the existing research on LSD therapy has investigated its potential utility as a treatment for alco holism. Since this program of research carne to an end, progress in research design and treatment evaluation has made available tools and techniques that could help to re solve historic controversies and clarify confusion about its usefulness. The enormous economic impact of alcohol abuse, and its associated morbidities and mortality, is well documented (Robert. Between 25% and 30% of U. S. hospital admissions are due to direct or indirect medical complications from alcohol. Approximately 52% of the American population drinks some beverage al cohol, and for about 10% to 12%, or about 11 to 13 million Americans, the use of alcohol has become an addiction. Only a fraction of those who are dependent on alcohol ever receive formal treat ment, and even for those who are treated, expectations are limited to improvement rather than cure. Treatment for alcoholism, arguably even more than most medical or psy chological interventions, has room for improvement. Despite the methodologic problems of the existing studies, the possibility that LSD might be useful in the treat ment of alcohol problems remains tantalizing. What is now known about LSD therapy for alcoholism neither provides evidence of its efficacy, nor assurance that its maximum therapeutic potential has been achieved.
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