This article (2017) reviews the history of the regulation of LSD research through the 1962 Kefauver-Harris Amendments (making it harder to do psychedelic research) and their implementation over the course of the ensuing decade.

Abstract

“Human research with hallucinogens such as lysergic acid diethylamide (LSD) has been ongoing in the USA since 1949. During the 1960s, LSD was investigated for a variety of psychiatric indications, including the following: as an aid in treatment of schizophrenia; as a means of creating a “model psychosis”; as a direct antidepressant; and as an adjunct to psychotherapy. Studies with all drugs, including LSD, have always been conducted under federal regulatory controls, including the 1938 Food Drug and Cosmetic Act (FDCA; which ensured the safety of drugs) and the 1962 Kefauver-Harris Amendments to the FDCA (which described appropriate scientific methodology and ensured drug efficacy). This paper details how the 1962 Amendments introduced numerous safety and efficacy requirements that must be in satisfied during clinical drug research—and how human studies conducted with LSD in the 1960s struggled with their fulfillment. Information is provided from Senate hearings, case law, and interviews with key investigators. Examples are also drawn from scientific papers and symposia published during and since that period, with a focus on information from clinical studies conducted with LSD by psychiatrist Albert Kurland at the Spring Grove State Hospital, near Baltimore, MD. While Kurland largely conformed with these new regulations, other investigators often fell short of complying with scientific standards and federal requirements. Thus, the human hallucinogen studies of the 1960s are best understood as providing pilot data on safety and efficacy, as well as testable hypotheses for current hallucinogen studies conducted under modern scientific and regulatory standards.”

Author: Katherine R. Bonson

Summary

Human research with hallucinogens such as LSD has been ongoing in the USA since 1949. However, in the 1960s, many investigators struggled with complying with federal safety and efficacy requirements, and thus, the studies are best understood as providing pilot data on safety and efficacy.

Every month, there is a story in the news heralding a clinical study being conducted in the USA with a hallucinogenic drug. These studies are all conducted under an investigational new drug (IND) application, an oversight mechanism by the Food and Drug Administration.

This paper will discuss how changes in FDA policies in the 1960s affected clinical research with hallucinogens such as lysergic acid diethylamide (LSD). These changes improved scientific standards and subject protections, which led to the curtailment of many unethical research practices.

Although the methodological discrepancies in the older hallucinogen studies may be excused, the data from these studies is valid and reliable for informing modern regulatory decision-making.

The early years of LSD treatment and research

LSD was first tested on humans in 1947, when a Swiss psychiatrist tested it on 16 healthy volunteers and 6 patients with psychosis. Two years later, a Boston psychiatrist brought the drug to the USA for testing.

Under the 1938 Food Drug and Cosmetic Act, drug companies had to submit data to FDA before their drug could be marketed nationally in the USA.

The FDCA allowed companies to distribute drug samples to doctors for investigational use, and this is how thalidomide was tested on pregnant women in the USA, resulting in children with phocomelia.

Many companies utilized this system of distributing investigational drugs, including Sandoz. Psychiatrists used LSD for a variety of untested indications, including the treatment of schizophrenia, creating a Bmodel psychosis, and as a direct antidepressant.

Relation of LSD to psychosis

Delysid can be used in analytical psychotherapy to elicit release of repressed material and provide mental relaxation, and in experimental studies on the nature of psychoses to induce model psychoses of short duration in normal subjects.

Psychiatrists studied LSD for psychosis and understanding the condition, but it is not clear how well the study designs and treatment of subjects comported with current standards of protecting patient safety.

Aid in treatment of schizophrenia

Anthony Busch and Warren Johnson conducted a human study with LSD in 1950, in which 29 patients were exposed to doses far beyond those recommended by Sandoz. The authors concluded that LSD Bre-activates anxiety and fear with just enough euphoria to permit recall of the provoking experiences.

Although LSD was given with therapeutic intent to patients with psychosis through the 1960s, it made things worse.

BModel psychosis^

Hallucinogens, such as mescaline, can produce a Bmodel psychosis. Scientists were interested in whether LSD could produce psychotic-like responses, in order to gather clues about the biochemical factors of clinical disease, such as schizophrenia.

As Nobel-prize winning biochemist Julius Axelrod observed, a very astute psychiatric nurse can tell the difference between anybody who took LSD and amphetamine.

In 1956, Canadian psychiatrist Humphrey Osmond created the new term Bpsychedelic to replace Bhallucinogen, which conveyed that LSD produced a hallucinatory state of psychosis.

Antidepressant and adjunct to psychotherapy

LSD was proposed as a daily pharmacotherapy for depression by Swiss psychiatrist Gion Condrau in 1949. However, this regimen did not produce the desired antidepressant results.

LSD was proposed as an adjunct to psychotherapy in the 1930s to 1960s, based on its unusual psychological effects.

LSD is not utilized as a medication in the usual sense, but as an activating mechanism that brings about a unique experience.

There were two sequential approaches to psychotherapy with LSD: psycholytic and psychedelic. Psycholytic therapy administered 50 – 200 g of LSD once or twice a week prior to therapy, for a duration up to several months, while psychedelic therapy administered 400 g of LSD in a single session.

Second force (psychoanalytic) and third force (humanistic) psychology perspectives emphasize the unconscious and self-actualization, while first force psychology focuses on observable behavior. These perspectives differ from behaviorist perspectives on research.

Regulations to protect subject safety and scientific integrity

The regulation of human drug research by FDA and ICH has two primary goals: to protect the rights, safety and well-being of study subjects, and to confirm that the study design is scientifically appropriate.

In 1935, a Supreme Court case made a legal distinction between scientific investigations and medical malpractice. In 1958, Congress held hearings on the quality of drug company-sponsored clinical studies, which culminated in the 1962 Kefauver-Harris Amendments to the FDCA.

The 1962 Amendments established that FDA had to determine that a drug was not only safe before marketing, but also effective for a specific medical indication. The AMA stood against the 1962 Amendments, stating that only extensive clinical use by large numbers of physicians could determine efficacy.

The 1938 FDCA prohibits the distribution of drugs that are adulterated or misbranded into interstate commerce, but allows for the transport of unapproved drugs across state lines for research purposes.

The 1962 Amendments stopped toxic drugs from being distributed as samples. Investigators had to agree not to share the drug with other investigators and submit adequate nonclinical safety testing data to FDA before initiation of human trials.

FDA’s Frances Kelsey reported that many clinical trials were poorly performed prior to 1962, and that FDA reviewers were left to interpret what specific kind and amount of information drug companies or investigators needed to provide in order for a clinical study to proceed under an IND.

The requirements of an IND include information regarding the drug’s chemistry and manufacturing, animal toxicology, the proposed clinical study protocol, and the qualifications of the investigator and research facility.

After the IND requirements had taken effect in 1963, many investigators who had been administering LSD to patients felt that they did not need to prove that LSD was reasonably safe to continue running human studies.

FDA evaluates experimental drugs based on data from adequate and well-controlled investigations conducted under an IND. These investigations must include subjects with a specific medical condition, a standardized test drug and control condition, and adequate sample size.

The Supreme Court ruled that isolated case reports, random experience, and reports lacking the details which permit scientific evaluation will not be considered as corroborative support for well-controlled studies.

IND: chemistry and standardization of study drug

Access to standardized experimental compounds changed dramatically in the 1960s, producing a very complicated history.

Sandoz submits INDs for LSD

Sandoz first made FDA aware of LSD in 1953, following their distribution of the drug to European psychiatrists. The FDA agreed with Sandoz that LSD should only be available to qualified research psychiatrists.

Sandoz submitted an IND for LSD in 1963, but the chemistry information was proprietary and therefore not publicly available. Researchers needed to obtain a letter of authorization from Sandoz to access the chemistry data.

Sandoz was not interested in giving licenses to researchers to conduct human studies with LSD. This left many researchers angry and frustrated, especially after the way Sandoz had freely distributed the drug previously.

In 1963, precursor chemicals to synthesize LSD were widely available, but Sandoz was the only entity that had submitted chemistry information under an IND.

Illicit sources of LSD for research

When clinical laboratories could not obtain LSD legally, they ceased research and refrained from using it.

Investigators who were especially invested in maintaining their human LSD research sought access to LSD through illicit sources. Some investigators had no actual mental health credentials, while others had purchased a Bmedical degree from a fake university.

Stolaroff made contact with Bernard Roseman and Bernard Copley, who promised to sell him LSD made by underground chemists. The men were arrested, based on violations of the FDCA, but claimed they could not be prosecuted because the drug had been synthesized within California.

No charges were placed against Stolaroff for seeking to obtain an experimental drug from an illicit source, but the truth of his allegations had already been confirmed in 1966 when FDA Commissioner Goddard testified about the Menlo Park case.

As psychiatrist Abramson stated, it’s virtually prohibited for a private physician to use LSD unless his patient buys it on the black market.

Further restriction on access to LSD

In 1965, Congress passed the Drug Abuse Control Amendments (DACA), which allowed FDA to regulate depressants, stimulants, and hallucinogens. This law prohibited the manufacture, compounding, processing, or sale of the listed drug classes unless permitted by the government for wholesale distribution, research, or medical applications.

Sandoz withdraws their IND

Sandoz decided to stop production and distribution of LSD in 1965, in part because their patent had expired in 1963 and because of the increasing incidence of LSD use for recreational purposes.

Sandoz notified FDA that they wished to withdraw their IND for LSD, and NIMH was given 21 g of LSD, which was enough to supply 210,000 doses of 100 g each to acceptable laboratories conducting human research.

According to newspaper coverage, BSandoz regretted having to withdraw the investigational drug applications for LSD, but subsequently provided LOAs to 17 investigators who were able to submit their own INDs and successfully receive LSD for their clinical experiments.

Goddard testified that Sandoz had approved 70 projects prior to withdrawing from direct support and investigation of the drug. Of these, 9 were submitted by investigators who had been given LOAs by Sandoz, and 9 were allowed to proceed by FDA.

FDA-PHS psychotomimetic advisory committee

In 1967, NIMH separated from the NIH to become its own bureau in the Public Health Service (PHS). The FDA-PHS Psychotomimetic Agents Advisory Committee (PAAC) was formally established and met six times a year to review and approve proposed animal and human studies.

IND: scientifically designed clinical studies

In the USA, the federal government funded clinical scientific studies with LSD. These studies tested a limited number of subjects, used patients with loosely diagnosed psychiatric disorders, and often did not use a valid control condition.

None of the NIMH-funded clinical studies with LSD qualified as Badequate and well-controlled for evaluating safety and efficacy at the level expected for studies submitted in an NDA. Therefore, it is difficult to discern the strength of the safety signals or evaluate evidence of efficacy from these early published clinical studies with LSD.

It would be ideal to be able to analyze the original clinical protocols as submitted in an IND, but most are held as confidential and FDA cannot disclose the existence of an IND unless it has been publicly acknowledged.

Based on publicly available information, it is possible to deduce whether an investigator had an IND for a clinical study with LSD. Kurland’s studies with LSD must have conformed to 1938 and 1962 FDA regulations in light of current scientific standards.

Animal toxicology testing

Currently, FDA requires sufficient animal toxicity testing before allowing clinical studies to begin. However, the requirement was variable before the 1962 Amendments.

Sandoz had extensively distributed samples of LSD, despite the lack of extensive nonclinical data demonstrating that the drug was not toxic. The FDA supported the Sandoz IND for LSD in 1963, despite the paucity of nonclinical toxicity data.

Kelsey was hesitant on the clinical use of LSD because of the lack of data from animal reproductive toxicology studies.

A double-blind, FDA-approved study was conducted in 1969 to evaluate the reproductive toxicity of LSD. The study showed that there is no definite evidence that pure LSD damages chromosomes of human lymphocytes in vivo.

A controlled study of LSD therapy with alcoholics

Kurland’s group published two papers evaluating LSD as an adjunct to psychotherapy with a large number of alcoholics. The patients first received intensive psychotherapy for 2 weeks, followed by a psychedelic procedure with LSD at either 450 g or 50 g.

A study evaluated changes in the patients before and after LSD sessions using 12 psychological tests that measured personality, intelligence functioning and impairment. LSD produced improvements in those individuals who received either the treatment dose (450 g) or the active control dose (50 g), but the degree of improvement was not provided.

Choice of control condition and blinding

The Kurland alcoholic study raises the issue of the value of an active control compared to a placebo control, yet double-blind controlled studies have been demonstrated to be inappropriate methodology for studying LSD.

Most modern psychiatric drug studies only evaluate behavioral or psychological changes produced by the test drug in comparison to a neutral placebo – even when the test drug produces AEs that easily distinguish active from inactive treatment.

In Kurland’s study with alcoholics, both threshold and psychedelic doses of LSD reduced drinking behavior 12 – 18 months after drug treatment. However, it is not possible to determine whether LSD was better than no drug treatment.

Informed consent

Researchers recognized that adequately informing a potential subject about an LSD study would be difficult, given the individualized responses produced by the drug. There were two schools of thought on the question of whether to obtain consent for study participation.

LSD was tested in schizophrenic patients who were unlikely to be informed that the drug might exacerbate their psychotic symptoms. Similarly, opioid-addicted prisoners at the Addiction Research Center in Lexington, KY, were not usually informed about what they were receiving or what to expect.

For those who believed LSD might have a valuable role in psychotherapy, providing some knowledge about the drug effects was part of the proper preparation of a subject so that the LSD session would be beneficial.

Kurland’s published papers describe how the study patient was given an informational and expectation-structuring packet of articles about LSD treatment, and how the consent document did not contain genuine safety information for the potential subject to consider.

Use of LSD by investigators

FDA Commissioner Goddard testified that reports of nonmedical use of LSD by investigators had come to FDA as early as 1961.

In 1969, Kurland’s group initiated a program in which mental health professionals would be allowed to receive one to three LSD sessions in order to better understand unconscious processes and improve their own therapeutic skills and empathy.

At this time, psychologists were taking LSD outside of regulated studies, and Sanford Unger said that at the time, it seemed logical and desirable to try LSD.

Conclusions

Scientists have been fascinated with the unique pharmacological and psychological effects of LSD and other hallucinogens for over 70 years. Currently, INDs are submitted to FDA for human studies with hallucinogens and are evaluated according to a variety of regulations.

Many rules and regulations are in place to prevent the exploitation of human beings for intellectual curiosity, unethical financial gain, or worse. These regulations are in place to assure that human rights are upheld during clinical research.

The 1962 Amendments to the 1938 FDCA listed specific methodology required for human drug studies, but these were not immediately adopted by most clinical sites.

Although we may wish to presume that all hallucinogen research groups were as scientifically dedicated as Kurland’s, much of the research in this period falls short of ideal scientific methodology.

No detailed, carefully controlled study has been performed on the efficacy of LSD-assisted psychotherapy for any psychiatric condition. The many claims of dramatic therapeutic changes must thus be regarded as not proven.

The data from these older studies suggest possible psychiatric applications of hallucinogens, but they are still in the small-scale, pilot study phase.

Researchers in the USA continued to administer LSD to patients with anxiety and depressive disorders under an IND until 1987. The reason for the severe reduction in hallucinogen studies in humans in the 1960s and 1970s is likely to have been regulatory issues.

Sandoz rejected FDA’s proposal to submit an NDA for LSD, and the clinical studies conducted with the drug remained small and inconclusive, leading to NIMH closing down their intramural (in-house) human research with LSD in 1968.

In 1970, the U.S. Congress placed LSD into Schedule I of the CSA, which created additional requirements for researchers who wished to conduct clinical studies with LSD. The slow review time of INDs and Schedule I licenses by government agencies likely led to a decrease in the number of laboratories willing to engage in the regulatory endeavor.

NIMH had spent 20 years funding research with 2500 individuals who participated as subjects in 116 clinical studies with LSD, but had little to show for their investment in terms of progress towards an approved drug product.

In July 1975, NIMH abruptly terminated all extramural funding of clinical studies with LSD, likely to distance itself from the negative press surrounding the MKULTRA program, which had waived the requirement for researchers to obtain informed consent.

NIMH (and NIDA) resumed funding clinical research with hallucinogens in 2015, but most current studies are small-scale Phase 1 or Phase 2 pilot studies that lay the foundation for future large-scale Phase 2 and 3 studies.

This paper contributes to the history of human research with hallucinogens by providing specific regulatory reasons why LSD research diminished and by systematically focusing on the degree to which researchers conducting studies with LSD complied with FDA regulations.