Prohibited or regulated? LSD psychotherapy and the United States Food and Drug Administration

This study (2016) argues that the American Food and Drug Administration is not as culpable in the decline of LSD-related research after the 1960s as is usually assumed.

Abstract

“Over the 1950s and early 1960s, the use of the hallucinogenic drug lysergic acid diethylamide (LSD) to facilitate psychotherapy was a promising field of psychiatric research in the USA. However, during the 1960s, research began to decline, before coming to a complete halt in the mid-1970s. This has commonly been explained through the increase in prohibitive federal regulations during the 1960s that aimed to curb the growing recreational use of the drug. However, closely examining the Food and Drug Administration’s regulation of LSD research in the 1960s will reveal that not only was LSD research never prohibited, but that the administration supported research to a greater degree than has been recognized. Instead, the decline in research reflected more complex changes in the regulation of pharmaceutical research and development.”

Author: Matthew Oram

Summary

In the 1950s and early 1960s, the use of LSD for psychotherapy was a promising field of psychiatric research in the USA. However, in the 1960s, federal regulations prohibiting LSD research were actually supportive of research.

Senator Robert F. Kennedy criticized the Food and Drug Administration for doing too little to ensure the continuation of research programs exploring the medical potential of the hallucinogenic drug lysergic acid diethylamide.

LSD had been synthesized in 1938 and had become the object of widespread clinical research. However, growing public recreational use of LSD had made the drug the object of increasing public, medical and political concern.

Kennedy described the problem of regulating LSD as a ‘classic example’ of the difficulties of balancing the interests of ‘Government and science’. The government’s backlash against non-medical use of LSD ended legitimate research into its use in psychiatry.

LSD research first came under government control in 1963, when the Kefauver-Harris Drug Amendments of 1962 amended the 1938 Federal Food, Drug, and Cosmetic Act. In 1965, the Drug Abuse Control Amendments prohibited all but personal possession and government-approved research with LSD.

As regulation of LSD increased, the scale of LSD psychotherapy research in the USA began to decline. In 1966, the government shut down all LSD research in the USA, and in 1965, private-practice physicians were especially being prevented from conducting research.

Although the decline in LSD research closely followed the drug’s growing abuse and regulation, a detailed analysis of the provisions and implementation of the new regulations will reveal a much more complicated relationship between the rise in regulation and the decline in research. Sandoz and two independent research sponsors submitted INDs for LSD psychotherapy research in 1963. The FDA terminated the INDs, but voluntarily saved research from complete extinction in 1966.

This article will reveal that the US government’s response to LSD’s medical use was far less reactionary and repressive than has been depicted, and that it highlighted the transformation of drug research and development in the 1960s. The Drug Amendments of 1962 were passed on the back of the thalidomide crisis, and introduced the requirement for proof of drug efficacy for a drug to be approved for sale by the FDA. This article explores how these regulations impacted unconventional but promising forms of psychiatric research.

The IND Regulations and Sandoz Pharmaceuticals

The FDA required drug manufacturers to submit a New Drug Application (NDA) containing proof of safety for the drug when used as directed, but the manufacturer was free to distribute new drugs to qualified researchers so long as they were labelled for investigational use. FDA officers had become increasingly aware that widespread distribution of investigational drugs to physicians was a danger. The danger of thalidomide, a teratogenic sedative, became evident when 16,000 patients received the drug before its dangers became apparent.

The Drug Amendments of 1962 granted the FDA oversight of drug research and development. To safeguard against dangerous and non-research investigational drug use, the FDA created the IND form, which required extensive data on the drug, preclinical research conducted, the investigators and the research plan.

Sandoz Pharmaceuticals submitted INDs for the clinical investigation of LSD and psilocybin in June 1963, but the INDs were very broad in their scope and light on details. They were restricted to researchers working under grants from the NIMH, state agencies or the Veterans Administration.

The FDA’s pharmacology department found that the Sandoz LSD and psilocybin INDs lacked the required level of toxicity data, but the Bureau of Medicine decided that clinical investigation could be continued, with a request for further data.

Sandoz’s decision to restrict its sponsorship of research to hospital-based government-endorsed studies cut off privately funded and non-institutional researchers who had been using LSD. However, independent researchers were still able to submit their own IND forms for clinical research with LSD.

Harold Abramson

Harold Abramson had been conducting research with LSD since 1951, and had become a leading developer of a form of LSD psychotherapy termed ‘psycholytic therapy’. This therapy used LSD to break down patients’ defences, release repressed memories, and produce powerful abreactions.

Abramson was initially listed as an LSD investigator in Sandoz’s IND, but was quickly removed when Sandoz decided to restrict its sponsorship to those working under the NIMH, state agencies and the Veterans Administration. Abramson contacted the FDA to clarify his qualifications, and became a sponsor himself.

Abramson met with the FDA’s Investigational Drug Branch in November 1963 to discuss submitting an IND for LSD research. He suggested that the FDA might have denied him access to LSD because of his criticism of Sansert. Abramson and Evans (1954) had suggested that exposing fish to human urine would show if the fish had been exposed to LSD. They also suggested that exposing fish to schizophrenics’ urine might help uncover a naturally occurring substance causing the illness.

Abramson wrote to Sandoz, asking for preclinical data and details of animal and other research indicating that it was reasonably safe to conduct human research. Sandoz replied coolly, stating that the information could be obtained from no other source.

Abramson was frustrated by Sandoz’s response, and asked if he could become his own sponsor if the data was already filed with the FDA. Achor replied that Sandoz would remain the sole sponsor for LSD.

Abramson was unable to complete an IND with Sandoz, and forwarded his correspondence to Kelsey at the FDA. However, the FDA began to view Abramson with suspicion, and sent an inspector to visit Abramson to investigate his use of LSD on humans.

New York FDA Inspector Irwin Schorr visited Abramson at the South Oaks Research Foundation and told him that he needed Sandoz’s written consent to refer to their pre-clinical data in his IND application. Abramson felt that the government had no jurisdiction over his right to administer any drug to his patients. The FDA terminated Abramson’s IND for LSD based on a lack of information in his IND and his reference to Sandoz’s data. Abramson continued to pursue animal research with LSD, but he never resumed his clinical research with the drug.

Abramson, Sandoz and the FDA felt differently about who was entitled to perform research with investigational new drugs. The FDA held IND data in confidence, but read subsequent applications with an artificial ignorance regarding the data.

The FDA controlled research into drugs by requiring that it be sponsored by the manufacturer. Sandoz used this control to limit LSD research to government-sponsored, hospital-based projects under its IND, while deliberately maintaining a monopoly over LSD sponsorship.

The International Foundation for Advanced Study

The International Foundation for Advanced Study submitted an independent IND for human research with LSD in 1963. The IND was terminated in February 1965 because the researchers did not have the preclinical data required for the IND form and the qualifications of the investigators were questioned.

The International Foundation for Advanced Study was founded in 1961 by electrical engineer Myron J. Stolaroff. It attracted a number of researchers from different backgrounds who shared a common interest in psychedelic drugs.

Savage, who was hired as medical director, had begun research with psychedelics in 1949 and continued at several locations until his arrival at the Foundation. Mogar and Fadiman were also qualified to perform LSD psychotherapy research, but Hubbard, Stolaroff, and Harman were laymen.

The Foundation justified the use of lay researchers on the grounds that there were not enough therapists with training in psychiatry or clinical psychology and experience with psychedelics. Savage found value in Harman’s background in scientific method, research design, communication and statistical theory.

By 1962, the Foundation had published positive results for its first study on LSD and had drawn up grant applications for three sophisticated controlled clinical trials with LSD.

The Foundation was denied further federal funding for its research into LSD, but received some funding from a Public Health Service Fellowship. At 1966 congressional hearings, the FDA was questioned extensively on its regulation of LSD research. The FDA responded that the rejection was not because the research was not ‘bona fide’, but because the National Institutes of Health had some question about the reliability of some of the people there.

The Foundation was excluded from Sandoz’s IND, probably due to its research taking place in an outpatient clinic rather than a hospital. The Foundation’s IND was not terminated until February 1965, despite numerous recommendations for termination from several different FDA officers.

The Foundation’s IND was terminated after Savage’s departure and an undercover agent’s failure to obtain LSD treatment. The Foundation tried to bring credibility back to their application by appointing a new psychiatrist as medical director, but his location in New Jersey suggested this was a token position.

The FDA terminated the International Foundation for Advanced Study’s IND application because of deficiencies in its preclinical and manufacturing data.

The Foundation’s investigative plans included asthma and other physical ailments, suggesting that the researchers had proposed branching into psycholytic therapy.

The Foundation had led the field of psychedelic therapy research in the United States from its inception in 1961. While some of their plans were not realized, they accrued great experience with psychedelics and published their findings in mainstream journals.

The powerful and variable effects of LSD were not prepared for by Hubbard’s experience and innovation, and the FDA denied the foundation an IND for clinical research with any drug, let alone LSD.

Research in the era of prohibition

The first legislation to control LSD specifically was signed into law in July 1965. However, the increasing controversy over LSD abuse had a negative impact on LSD research, and Sandoz withdrew its IND for LSD research in April 1966.

By late 1965, the FDA and NIMH were aware that Sandoz was planning to withdraw its sponsorship of LSD. Therefore, Jonathan Cole called a conference to discuss the future of LSD research.

Sandoz suggested that the NIMH could take over the sponsorship of the LSD research, but the NIMH was unable to take on this role. Three other possibilities were discussed, including the NIMH finding a new source of LSD and the FDA giving LSD an effective NDA.

Sandoz contacted the FDA to inform them that they intended to withdraw their sponsorship of LSD and psilocybin without delay. They explained that they could no longer bear the responsibility for the allocation and distribution of these substances. The earlier plan of sharing the burdens of sponsorship between Sandoz and the NIMH was now off the table. 12 researchers would be allowed to continue using LSD while they wrote up and submitted their own INDs.

Kennedy failed to appreciate the nature of the IND regulations, and therefore failed to give the agencies fair credit for ensuring that research survived at all. Goddard and Yolles explained that the FDA did not want to thwart research, but simply assess the adequacy of research proposals. The NIMH accepted Sandoz’s supplies of LSD to ensure that valuable research continued, and was willing to stimulate research if needed.

LSD research became subject to new regulations under the Controlled Substances Act of 1970, which were designed to tackle drug abuse. The Act created five schedules for drugs, with Schedule I being the most prohibitive.

LSD was placed in Schedule I because it had a high potential for abuse and did not have an approved NDA. This criterion contradicted scientific experience with LSD, but the Department of Justice’s Bureau of Narcotics and Dangerous Drugs considered LSD safe.

The Controlled Substances Act, 1970, prohibited the use of Schedule I drugs for medical research, but there was an exemption for legitimate scientific research. The Attorney General was only allowed to deny registration if the researcher had falsified information in their application.

The Controlled Substances Act did not have an impact on LSD psychotherapy research until 1974, and research faded away to almost nothing before its eventual demise. Difficulties in gaining and maintaining approval for research could have influenced this. The decline in LSD research in the 1970s can be explained by difficulties in evaluating psychedelic therapy through controlled trial methodologies, and by little subsequent encouragement from the scientific community and funding bodies.

Conclusion

During the 1960s, LSD psychotherapy research transformed rather than died, as the government evaluated applications to conduct research according to rules put in place under the Drug Amendments of 1962. This led to fewer formal clinical trials, but more methodologically sophisticated studies.