Psychedelic medical treatments are currently experiencing a renaissance, but prior research during the 1950s and 1960s, primarily in the United States, ended in controversy and frustration. The backdrop of the culture wars of the day (themselves influenced by the same drugs presently in question) explains part of the political backlash that brought research to a halt. But the medical enterprise was also in the middle of reinventing itself around ideals of objective clinical trials, and that suited the development of some treatments more than others.

On Good Friday in 1962, 30 Christian theological students gathered at Marsh Chapel in Boston to partake in a study into the psychological experience of a psychedelic trip within a religious setting (Pahnke, 1963)⁠. The study had been designed by Walter Pahnke, a psychiatrist pursuing a doctoral qualification in religion and society, under the supervision of Dr. Timothy Leary of the Harvard University Center for Research in Personality (Lander, 2011)⁠.

Prior research by Harvard anaesthesiologist Henry Beecher in the mid-1950s investigated the influence of the mind in response to treatment. Beecher popularised consideration of the placebo effect and pushed for double-blind trials to control for it (Beecher, 1955)⁠, kickstarting an era where the double-blind trial would reign supreme, but to the detriment of contemporary psychedelic research. However, Beecher also helped introduce the concept of ‘set and setting’: the effect of one’s mood, expectation and internal mindset; and the external environment, atmosphere and stimuli, respectively (Mashour, 2005)⁠.

At the Marsh Chapel, set and setting were planned to “maximise the possibility that mystical phenomena would occur” (Pahnke, 1963)⁠: participants spent two hours in the week prior with a study leader, building rapport and trust with the leaders and discussing expectations for the experience. The chapel setting was in a series of private rooms adjacent to the public worship space, dimly lit with candles and stained glass windows. At 10:30am, 15 participants were given a dose of psilocybin, the other 15 received nicotinic acid (vitamin B3), intended to produce feelings of relaxation, as a control. The public sermon commenced at noon, featuring organ music, readings and prayer was transmitted live via high fidelity speaker to the private rooms. Post-sermon discussion was held at 3pm, and participants were dismissed by 4:30pm.

Reverend Mike Young attributes the experience to his decision to become a minister despite prior doubts (Ruggiero, 2013)⁠. A follow up study at 25 years found that all psilocybin subjects participating in the follow-up (all but two of the original psilocybin subjects), but none of the placebo subjects, considered the experience to have made a “uniquely valuable contribution to their spiritual lives” (Doblin, 1991)⁠.

Use of psychedelic substances has been documented in cultures across the world since ancient times, from the Americas to Africa, Europe, China and even Australia (Lander, 2011). Mushrooms called teonanacatl were sacred to the Aztecs (Nichols, 2020)⁠, with archaeological evidence suggesting they may have been used for medicinal and religious purposes as early as 500BC (Kohn & Hofmann, 1981). A lay person, would seek advice from a curandero or curandera (“healing priest”) regarding their condition, which need not be limited to their health. The Curandera would administer teonanacatl and lead a ceremony of prayer, song and counsel, during wich the teonanacatl would divulge the information asked of it, such as which herbs would render the most effective cure, or the welfare of distant loved ones (Kohn & Hofmann, 1981)⁠.

Spanish colonialists recorded mention of teonanacatl ceremony, but considered it to be work of the devil and drove the practice underground (Nichols, 2020)⁠. Western anthropologists first observed the practice in 1938, and first invited to partake in 1955 (Kohn & Hofmann, 1981)⁠. The mushrooms were ultimately identified as the psilocybin-laden Psilocybe caerulescens, Panacolus campanulatus, and Stropharia cubensi.

The effects of psychedelic consciousness-altering preparations have been put to use in ceremony, for religion, or as medicine in cultures across the world – but many traditional cultures don’t delineate between healing and ceremony as we might in the West. In parallel with Western discovery of psilocybin, Albert Hofmann, a Swiss chemist employed by Sandoz Laboratories, was the first to synthesise and subsequently discover the psychoactive properties of lysergic acid diethylamide (LSD) in April 1943, and the drug has been considered a “reference-standard” psychedelic ever since (Carhart-Harris & Goodwin, 2017)⁠.

While Pahnke’s Marsh Chapel paper has been considered “one of the preeminent experiments in the literature” (Doblin, 1991)⁠, a far greater body of psychedelic research had been conducted by psychologists and psychiatrists in the 1950s. Tens of thousands of patients had been studied over a period of 15 years under treatment for alcoholism and mood disorders (Carhart-Harris & Goodwin, 2017)⁠, and modern meta-analyses show a pattern of promising results (Krebs & Johansen, 2012; Rucker et al., 2016)⁠. The primary vehicle for experimental treatment was psychedelic psychotherapy – a form of talk therapy with the patient in a psychedelic state, pioneered by Canadian researchers Humphry Osmond, Abram Hoffer, and Alfred Hubbard (Oram, 2014)⁠.

Psychotherapy research in the 1950s was conducted in the context of a medical community coming to terms with the thalidomide birth defect crisis. The United States Food and Drug Administration had been aware that manufacturers were distributing experimental drugs to physicians under the guise of research, allowed by contemporary regulations, but with the ulterior dual purpose of popularising their usage prior to regulatory approval (Carpenter, 2010)⁠. The resulting US Drug Amendments act of 1962 granted the FDA power to regulate drug research and development, with a stringent requirement of “adequate and well-controlled investigations” to prove the safety and efficacy of new treatments (Kefauver-Harris Amendments, 1962; Oram, 2014)⁠.

While the FDA provided no additional clarification as to what constituted an “adequate and well-controlled investigation” until 1970, administration officials and elite researchers soon came to regard the double-blind random controlled trial as the gold standard for meeting regulatory requirements (Cantor, 1997; Oram, 2014)⁠⁠. FDA Medical Director Joseph Sadusk commented in 1964 that, “Obviously, many experimental factors must be controlled... This is preferably done by placebo comparisons in well-designed double-blind clinical studies.”, although he also conceded that “this is not the only type of study that can be called well-controlled.” (Oram, 2014).

The 1962 amendments and subsequent de-facto insistence on double blind, random controlled trial methodology presented two challenges to contemporary psychedelic psychotherapy research. The first was that the regulations lent themselves to a biological model of mental illness, where drugs act on the brain to correct physical or chemical imbalances (Healy, 1999)⁠. Talk therapy, by virtue of being non-invasive, non-medicinal, and directed at the mind rather than the brain, remains beyond the remit of regulation by the FDA (Oram, 2014)⁠.

Modern commentary reflects that an incentivised focus on trial design over therapeutic methods has resulted in a contemporary mental health practice that relies heavily on drugs, lacks clinical innovation, and delivers poor patient outcomes (Deacon, 2013)⁠. One axiom of early psychedelic psychotherapy was that the drug experience would not necessarily be an effective treatment without conversation. This proved difficult to reconcile with regulations that sought to isolate the effects of a drug specifically from effects from the mind: placebo was to be well-accounted for, but not set or setting. In fact, there is an implicit conflict between cultivation of set and setting, and maintaining an impartial experimental environment where subjects are free from suggestion.

The other glaring problem for psychedelic research was the difficulty of finding a suitable active placebo, as the onset of the psychedelic trip effectively revealed the blind to both participants and researchers. Nicotinic acid was selected as a placebo for the Marsh Chapel experiment, as it produced hot flushes and somatic effects similar to what the subjects were expecting from psilocybin (expectations of the experience were discussed in order to create a comfortable mindset in participants) (Pahnke, 1963)⁠. Doblin’s (1991)⁠ 25-year follow up study found that as the effects of nicotinic acid wore off in the control group and the psilocybin response became stronger in the experimental group (the former acting over a shorter timeframe than the latter), it became obvious to all participants which pill they had taken.

Beyond the 1962 amendments, issues of reputation and culture were at play. Leary, who could be described as a poster boy for the psychedelic movement, was known for his enthusiastic use of psychedelics in informal and classroom settings (Beecher & Leary, 2016)⁠. He was dismissed from his post at Harvard in 1963, allegedly for failing to meet his teaching duties. Recreational use of LSD was on the rise, and played a significant role in the emerging counterculture of the 1960s. Informal mystical and spiritual experiences gave rise to “acid churches” in New York State (Lander, 2011)⁠.

Such cultural controversies led to Sandoz, at the time the sole licensed manufacturer of LSD, to cease manufacturing the drug in 1965 (Carhart-Harris & Goodwin, 2017)⁠; legal prohibition followed in 1966. In 1970, President Nixon enacted the Controlled Substances Act, with LSD’s listed in schedule I, meaning it was deemed to have “no currently accepted medical use in treatment in the United States” (Belouin & Henningfield, 2018)⁠. While narrow exceptions for research are possible for schedule I substances, the classification serves as a discouraging barrier to doing so. The scientific and regulatory matters made continued psychedelic research difficult, but mainstream cultural headwinds rendered it nearly impossible to the extent the trail would remain dormant for the next twenty five years.

Bloor’s principle of symmetry supposes that true and false knowledge claims share similar causes (Bloor, 1976)⁠. Regarding scientific progress and controversy, we could attribute success or failure equally to people or process, but instead we tend to praise ‘good scientific method’ and blame unsuccessful researchers. In the case of psychedelic psychotherapy, one view is that progress stalled due to the personal failure of researchers to conform to consensus requirements of experimental method. But conversely, rigid insistence on a particular kind of experimental methodology will undoubtedly hinder certain avenues of research.

The double blind randomised control study was promoted partly on the basis that individual physicians, thought to be trained in scientific objectivity, were instead being easily influenced by the marketing efforts of drug manufacturers (Cantor, 1997)⁠. A 1956 conference on the evaluation of psychiatric drugs, co-sponsored by the US National Institute of Mental Health, drew an expert quorum of almost 1000. While there was widespread agreement on the benefits of objective and statistically sound trials, doubts about the universal suitability of placebo controlled trials were dismissed by the convenors. Indeed, methods such as the observational study have proven their utility – showing that cholera spread through water, not air, in Victorian London, or showing the first link between smoking and lung cancer (Snow, 2016)⁠.

The consequence of systematic research bias is clearly illustrated when contrasting psychedelic psychotherapy’s failure to gain legitimate medical acceptance with comparable contemporary developments. Physical interventions such as electroshock therapy and lobotomy suited the biological model of mental illness (Harman, 1963)⁠, and drugs such as amphetamines and opiates had high abuse potential and cultural disapproval, but acted on the body rather than the mind and stood up better in placebo controlled trials (Oram, 2014)⁠.

A second wave of psychedelic research has commenced in recent years. Clinical studies have investigated applications in treating mental health, anxiety, depression and other addictions (Nichols, 2020)⁠. Researchers have several decades of developments from other fields, such as brain imaging, to use to form new lines of inquiry into safety and effectiveness (Carhart-Harris & Goodwin, 2017)⁠. Some of the controversy of the 1960s is now at a distance and a new generation can evaluate the landscape with fresh eyes.

Early psychedelic research can thus be viewed as an illustration of the difficulties of cross-cultural communication. Harman (1963)⁠ observed that “a number of the early enthusiasts for the potentialities of LSD and psilocybin [came] from outside the medical profession”; Barber (1961) adds that "medical specialists have a long history of resisting scientific innovations from what they define as 'the outside'". Rituals such as the placebo controlled double blind trial were important to the insiders, just as burial rites were important to communities in West Africa during the 2014 ebola crisis (Furman, 2020)⁠. Concessions to cultural understanding are often necessary to gain acceptance as an outsider, and the delineation between inside and outside may be closer than one would expect.

With culture comes language. The LSD-consuming subculture had experienced hallucinations so vivid, that the sober English language may not have given them ways to describe it to the mainstream. Sherwood (1968)⁠ describes the struggle: “Such words as Self^†, Being, and Reality are used, not as defined concepts in any final sense, but as desperate endeavours to communicate a quality of experience which borders on the incommunicable”. Perhaps our language needs to expand to accommodate new psychedelic experience; perhaps more people ought to ‘participate’ in the experience in order to comprehend discussions about it. The deficit model of communication may not be the most suitable for psychedelic visions.

Where the psychedelic experience brings about a subtle shift in values, perhaps illustrated by the Marsh Chapel experimental group, research priorities or directions may change as a result. A dialogue about values may have helped pick apart the universal mandate for the double blind trial, trepidation at mixing medicine and mysticism, or changed the notion that a medical practitioner ought to stay at arm’s length from the treatment they provide (unlike a curandera, who may readily partake). Moreover, unresolved differences in values may have made it difficult for the medical vanguard to lend their epistemic trust (Furman, 2020)⁠ to the psychedelic enthusiasts.

Modern psychedelic researchers have benefitted from a shift in culture: there is now a greater acceptance and legalisation of drugs such as marijuana; a party culture surrounding MDMA has developed despite remaining illegal (Ter Bogt et al., 2002)⁠; the Western world has had a few decades to integrate aspects of LSD culture, and some even self-medicate for personal mental health (Carhart-Harris & Goodwin, 2017)⁠. Perhaps modern researchers and their correspondents have had greater opportunities to gain informal participatory experience with the drug.

Footnote.

† The psychedelic experience of “ego dissolution” or “ego death” (Nour et al., 2016)⁠ is distinct from, and possibly more pleasurable than, the literary experience of “nullification of the self” (Montgomery, 1995)⁠.

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