Introduction
Over the past two decades, there has been a revival of research on the use of the psychedelic drugs psilocybin and MDMA to treat anxiety in terminal illness, depression and addiction (Bogenschutz & Ross, Reference Bogenschutz and Ross2018; Langlitz, Reference Langlitz2013; Pollan, Reference Pollan2019). A common claim made by advocates of psychedelic drugs is that promising research on psychedelic drugs in the 1950s and 1960s was prematurely ended by Richard Nixon's ‘War on Drugs’ (e.g. Bradley, Reference Bradley2021; Drug Science & Mind Medicine Australia, 2021; Shortall, Reference Shortall2014).
Historical scholarship suggests that a more complex confluence of factors contributed to the abandonment of this research (Novak, Reference Novak1997; Oram, Reference Oram2014, Reference Oram2016, Reference Oram2018). This history illustrates what Pollan (Reference Pollan2019) has described as over-exuberant advocacy for psychedelic drugs. The possibility of renewed exuberance suggests the need for their cautious re-introduction into psychiatric practice, assuming that the positive results of phase 2 clinical trials are supported by larger trials in more representative patient samples (Perkins et al., Reference Perkins, Sarris, Rossell, Bonomo, Forbes, Davey and Castle2021).
In this paper, the term ‘psychedelic’ is used as defined by Grinspoon and Bakalar (Reference Grinspoon and Bakalar1979), namely as a drug which ‘more or less reliably produces thought, mood, and perceptual changes otherwise rarely experienced except in dreams, contemplative and religious exaltation, flashes of vivid involuntary memory, and acute psychosis … without causing physical addiction, craving, major physiological disturbances, delirium, disorientation, or amnesia’ (Grinspoon & Bakalar, Reference Grinspoon and Bakalar1979, p. 9). The psychedelics are usually taken to comprise mescaline, psilocybin, LSD, DMT, and the plant-based drugs, ibogaine and ahayuasca. MDMA is also often included although it does not produce the perceptual effects of the classic psychedelics (Johnson, Hendricks, Barrett, & Griffiths, Reference Johnson, Hendricks, Barrett and Griffiths2019). The effects of this class of drugs share more of a family resemblance than common pharmacological mechanisms of action (Grinspoon & Bakalar, Reference Grinspoon and Bakalar1979; Johnson et al., Reference Johnson, Hendricks, Barrett and Griffiths2019).
Research on psychedelic drugs in the 1950s and 1960s
Psychedelics and model psychoses
The visual and cognitive effects of mescaline, psilocybin and LSD led psychiatrists in the 1930s and 1940s to hypothesise that schizophrenia (Dyck, Reference Dyck2008; Jay, Reference Jay2019; Langlitz, Reference Langlitz2013) was a disorder produced by ‘toxic amines’ (Jay, Reference Jay2019). Humphry Osmond and colleagues suggested that adrenochrome, a derivative of adrenalin, was the amine responsible (Barber, Reference Barber2018; Dyck, Reference Dyck2008; Hoffer, Reference Hoffer2004; Osmond & Hoffer, Reference Osmond and Hoffer1959). Other psychiatrists, who were not able to replicate Osmond and Hoffer's work (Mills, Reference Mills2010), argued that disturbed dopamine function provided a more plausible biochemical basis for the psychoses (Healy, Reference Healy2002; Kendler & Schaffner, Reference Kendler and Schaffner2011; Madras, Reference Madras2013).
Therapeutic uses of psychedelic drugs
In the 1950s Osmond and Hoffer used LSD to treat alcohol dependence (Barber, Reference Barber2018; Dyck, Reference Dyck2008; Mangini, Reference Mangini1998). They used an approach that they came to describe as ‘psychedelic therapy’ in which high doses of LSD produced mystical experiences (Osmond, Reference Osmond1957) that they believed were necessary for successful treatment engagement with alcoholics anonymous (Barber, Reference Barber2018; Blewett & Chwelos, 1959; Reference Blewett and Chwelos2002; Dyck, Reference Dyck2006). They reported that half of their patients who were given LSD were still abstinent 6 months after treatment (Barber, Reference Barber2018; Blewett & Chwelos, 1959; Reference Blewett and Chwelos2002; Hoffer, Reference Hoffer, Aaronson and Osmond1970). Critics of Osmond and colleagues (see Mangini, Reference Mangini1998; Smart & Storm, Reference Smart and Storm1964) argued that their studies were too small, poorly controlled, and their assessments of outcomes were biased (Barber, Reference Barber2018; Dyck, Reference Dyck2006; Novak, Reference Novak1997). Their positive results were not replicated in later controlled trials (Mangini, Reference Mangini1998), a meta-analysis of which found patients given LSD had better outcomes 6 months after treatment but were no better off at 12 months (Krebs & Johansen, Reference Krebs and Johansen2012).
In Europe and North America some psychiatrists treated anxiety and depression using LSD as part of psychoanalytically oriented psychotherapy (Langlitz, Reference Langlitz2013, p. 39). This approach, described as psycholytic therapy, involved giving repeated low doses of LSD to reveal and abreact unconscious traumatic memories. The unconscious content that was revealed tended to reflect the psychotherapeutic orientation of the therapist, with patients variously reliving birth traumas, disclosing early childhood sexual abuse or discovering the collective unconscious (e.g. Cohen, Reference Cohen1967; Cohen & Eisner, Reference Cohen and Eisner1959; see Trope et al., Reference Trope, Anderson, Hooker, Glick, Stauffer and Woolley2019 for a review). In uncontrolled case series, psycholytic therapists reported 70% improvement in symptoms in neurotic disorders (e.g. Cohen & Eisner, Reference Cohen and Eisner1959) and investigators later reported that LSD substantially reduced anxiety and distress in patients who had terminal cancer (e.g. Kast, Reference Kast1966, Reference Kast1967; Pahnke, Kurland, Unger, Savage, & Grof, Reference Pahnke, Kurland, Unger, Savage and Grof1970; Ross, Reference Ross2018).
What role did the Controlled Substances Act play?
A popular claim is that the passage of the 1970 Controlled Substances Act (CSA) largely brought about the end of therapeutic research on psychedelic drugs by their inclusion in the same schedule as heroin, cannabis and cocaine as drugs with high abuse potential and no medical use (Shortall, Reference Shortall2014). The CSA is, in turn, depicted as the outcome of Richard Nixon's ‘War on Drugs’ (Lee & Shlain, Reference Lee and Shlain1985). Historical scholarship reveals that this is a misreading of the CSA which reduced prison sentences for drug possession and increased Federal funding for the treatment of heroin, the major illicit drug of concern at the time (Courtwright, Reference Courtwright2005; Spillane, Reference Spillane2004). The imposition of draconian penalties for illicit drug use occurred in the mid-1980s in response to a crack cocaine epidemic (Courtwright, Reference Courtwright2001).
Timothy Leary is a bogeyman for many new psychedelic researchers (Giffort, Reference Giffort2020) who see his advocacy of psychedelic drug use as a major contributor to the end of psychedelic research in the USA (Hartogsohn, Reference Hartogsohn2017; Pollan, Reference Pollan2019; Shortall, Reference Shortall2014; Siff, Reference Siff2015; Stevens, Reference Stevens1998). Leary was not alone in his advocacy. The novelist Ken Kesey was a West Coast psychedelic evangelist (Jay, Reference Jay2019) who advocated ‘freaking freely’ at ‘Electric Kool-Aid Acid Tests’ (Wolfe, Reference Wolfe1968). The music of The Doors (who took their name from Huxley's book) and the Beatles' Sergeant Pepper's Lonely Hearts' Club Band (1967) helped to make LSD use a countercultural sacrament (Stephenson, Reference Stephenson2014). LSD was first banned in the mid-1960s in California, in response to media reports of ‘bad trips’, psychoses, accidental deaths and suicides among users (Siff, Reference Siff2015). This negative media coverage differed sharply from the very positive coverage that the therapeutic use of LSD had received in the popular media in the 1950s and early 1960s (Siff, Reference Siff2015).
In 1969 the media provided sensational reports on Charles Manson's use of LSD to recruit and control a ‘Family’ of followers whom he convinced he was ‘the son of man’ (O'Neill & Piepenbring, Reference O'Neill and Piepenbring2019; Riley, Reference Riley2019). Manson incited his followers to commit a series of gruesome murders in Los Angeles in 1969 and their murder trial generated enormous adverse publicity for LSD (Didion, Reference Didion1979; Lee & Shlain, Reference Lee and Shlain1985; Riley, Reference Riley2019). Manson was not a singleton. In Australia, Anne Hamilton-Burns founded a ‘Family’ cult that she ran from 1963 to 1987 in which she used LSD to convince her followers that she was the reincarnation of Jesus Christ. One of these followers was a psychiatrist with a license to prescribe LSD (Lomax, Reference Lomax2017).
The varied experiences reported by psychedelic users in the 1950s and 1960s exemplifies heightened suggestibility under psychedelic drugs that is implicitly acknowledged in the key role ascribed to ‘set and setting’ (Hartogsohn, Reference Hartogsohn2020). LSD has been described as a ‘pharmacological chameleon’ that ‘changes its psychedelic pigmentation in response to the cultural settings in which it is used’ in ways that ‘magnify and amplify the content of one‘s experience’. In the hands of unscrupulous persons these drugs can be used for malign as well as therapeutic purposes, as Shortall (Reference Shortall2014) has argued was the case in the US Army and the CIA's attempts to use psychedelic drugs as weapons of chemical warfare.
Other major contributors to the abandonment of psychedelic research
The standard account of the reasons for the abandonment of psychedelic research ignores the important roles played by several other factors that have been highlighted in recent historical scholarship (Cornwell & Linders, Reference Cornwell and Linders2002; Dyck, Reference Dyck2006).
First, the decline in LSD research began 7 years before the passage of the Controlled Substances Act in 1963 when research on psychedelic drugs was caught up in US Federal legislation that tightened the regulation of pharmaceutical research (Bonson, Reference Bonson2018; Oram, Reference Oram2014, Reference Oram2016). The legislation arose from the Thalidomide tragedy that occurred when physicians prescribed the drug to pregnant women without evidence of safety (Carpenter, Reference Carpenter2010). Before 1963 any clinician could undertake ‘clinical research’ on an unapproved drug without conducting a formal clinical trial or seeking approval from an ethics committee (Bonson, Reference Bonson2018). Clinical research on a ‘promising’ new drug usually involved giving the drug to patients, often the long-stay residents of mental hospitals, and making clinical judgments about their efficacy and safety. This was the way research was conducted on lithium in the 1940s, and chlorpromazine, tricyclic antidepressants, and LSD in the 1950s (Healy, Reference Healy2002; Lee & Shlain, Reference Lee and Shlain1985).
Under the new FDA regulations (Oram, Reference Oram2014, Reference Oram2016) ‘clinical research’ required a formal Clinical Trial Notification (CTN) that included a dossier of preclinical evidence to show that the drug was safe and likely to be of therapeutic value. It also required a detailed protocol for a randomised controlled trial (RCT) to assess the drug's safety and effectiveness in treating a defined clinical disorder (Oram, Reference Oram2014). Research on psychedelic drugs came under these new regulations because very few RCTs had been conducted to assess their safety and efficacy before 1963 (Bonson, Reference Bonson2018; Oram, Reference Oram2014, Reference Oram2016).
A major difficulty in meeting the FDA requirements was conducting double-blind trials with drugs whose effects were so evident to patients. These difficulties were increased by Sandoz's decision to only provide the preclinical information on these drugs required for CTNs to university-based researchers (Oram, Reference Oram2014, Reference Oram2016).
One of the most important adverse effects of Leary's psychedelic advocacy occurred in 1965, 5 years before the passage of the Controlled Substances Act, when Sandoz decided that it would no longer provide LSD for research (Hoffman, Reference Hoffman1980; Siff, Reference Siff2015). The company believed that its reputation was damaged by Leary's advocacy of nonmedical use and media reports of psychoses, accidental deaths and suicides attributed to LSD (Hoffman, Reference Hoffman1980). This decision restricted research on LSD in the USA to researchers based in universities and funded by the National Institute of Mental Health.
The passage of the Controlled Substances Act in 1970 increased the difficulties in doing controlled trials but, contrary to common belief, it did not stop research on psychedelic drugs (Oram, Reference Oram2014). The FDA continued to support, and the NIH continued to fund clinical trials of LSD well into the 1970s (Oram, Reference Oram2014). The State of Maryland funded a research group until 1979 that conducted randomised clinical trials on LSD and other psychedelic drugs at the Spring Grove Hospital. These included trials of psychedelics in the treatment of alcoholism, neurotic disorders and anxiety in terminal illness (Pahnke et al., Reference Pahnke, Kurland, Unger, Savage and Grof1970).
The results of the later controlled trials of psychedelic drugs were much less positive than the earlier uncontrolled reports of Osmond and Hoffer and others (Oram, Reference Oram2018; Yensen & Dryer, Reference Yensen and Dryer1993). In 1979 the Maryland government decided to end its funding for several reasons, namely, interpersonal disputes between researchers in the group; the bad publicity that LSD had received in the wake of a US Senate Committee report on the CIA's research on LSD in 1977 (US Senate Select Committee on Intelligence, 1977); and an independent scientific review of the Centre recommended that its funding should be allocated to research on schizophrenia (Oram, Reference Oram2018).
Other factors discouraging therapeutic research on psychedelics
In the late 1950s Sidney Cohen, who had used LSD in psychodynamic psychotherapy, reported psychoses and suicide attempts among patients who were given LSD by psychotherapists in Los Angeles (Novak, Reference Novak1997). Cohen advocated for tighter controls over the clinical use of LSD to prevent inappropriate clinical use bringing a promising treatment into disrepute (Cohen & Dilman, Reference Cohen and Dilman1962).
Psychedelic research also came under suspicion within the research community in the 1960s because of the ‘exuberant’ advocacy of early researchers (Brecher & Consumer Reports Editors, Reference Brecher1972; Pollan, Reference Pollan2019). This is exemplified by Humphry Osmond's statement on the LSD (p429) in 1957:
I believe that these agents have a part to play in our survival as a species. For that survival depends as much on our opinion of our fellows and ourselves as on any other single thing. The psychedelics help us to explore and fathom our own nature.
Lessons for contemporary psychedelic research
Contemporary researchers on the therapeutic use of psychedelics have distanced themselves from Timothy Leary and explicitly discouraged the nonmedical use of these drugs (Giffort, Reference Giffort2020). They have conducted randomised controlled clinical trials of psychedelic drugs that satisfy the FDA's requirements for their approval for medical use (e.g. Johnson et al., Reference Johnson, Hendricks, Barrett and Griffiths2019; Nichols & Hendricks, Reference Nichols, Hendricks, Müller and Cunningham2020). These studies have investigated psilocybin rather than LSD because psilocybin has a shorter period of action (4–6 h) than LSD (8–12 h), its pharmacology is better understood, it is less likely to produce ‘bad trips’, and it does not carry the cultural baggage of LSD (Pollan, Reference Pollan2019).
What remains to be seen is whether the researchers' ‘sober sentiments’ will characterise the way that these drugs are used if they are approved to treat depression and PTSD, in light of the encouraging results of phase 2 trials on psilocybin for depression and MDMA for PTSD (Jerome et al., Reference Jerome, Feduccia, Wang, Hamilton, Yazar-Klosinski, Emerson and Doblin2020; Luoma, Chwyl, Bathje, Davis, & Lancelotta, Reference Luoma, Chwyl, Bathje, Davis and Lancelotta2020; Muttoni, Ardissino, & John, Reference Muttoni, Ardissino and John2019; Reiff et al., Reference Reiff, Richman, Nemeroff, Carpenter, Widge, Rodriguez and McDonald2020). If psilocybin is approved to treat intractable depression patients, it is unlikely that its use will be restricted to approved indications. For example, prescribers will be able to use psilocybin off label as a first-line treatment for depression (Carhart-Harris & Goodwin, Reference Carhart-Harris and Goodwin2017) and as a treatment for anxiety disorders (Muttoni et al., Reference Muttoni, Ardissino and John2019).
Medical cannabis as a worrisome precedent
There is a real possibility that psychedelic drugs may follow the example set by ‘medical cannabis’. First, some advocates of psychedelic drugs are seeking approval to use these drugs before they have been approved for medical use by using the same compassionate access provisions that were used to allow medical cannabis use (Mind Medicine Australia, 2019). Allowing access via special access schemes before formal regulatory approval may allow the use of MDMA to treat all anxiety disorders, various types of addiction, and patients with terminal illnesses. We may also see lobbying for compassionate access to other psychedelic drugs such as, LSD, mescaline, and DMT.
Second, attempts are being made in the USA to use popular referenda to legalise the adult use of psychedelic mushrooms (Decriminalize Nature, 2020; Peters, Reference Peters2021; Smith, Reference Smith2021), the same approach used by advocates after California became the first US state to permit physicians to prescribe cannabis if they ‘deemed [it] appropriate’ in 1996 (Kilmer & MacCoun, Reference Kilmer and MacCoun2017). Some states may legislate to give patients the right to try psychedelic drugs (Sliwoski, Reference Sliwoski2020). The medical cannabis industry in the USA is also investing in companies that produce psychedelic drugs (Bogot, Horn, & Kwan, Reference Bogot, Horn and Kwan2021). These policies would enable the medical use of psychedelics to get well ahead of any evidence on their efficacy and safety for common psychiatric indications, as has happened with medical cannabis (Martin, Hall, Fitzcharles, Borgelt, & Crippa, Reference Martin, Hall, Fitzcharles, Borgelt and Crippa2020).
We can also expect arguments to be made for allowing patients to use plant-based psychedelic drugs, such as mushrooms, ayahuasca and ibogaine, because of the putative ‘entourage’ effects of the whole plant (e.g. Ribeiro, Reference Ribeiro, Labate and Cavnar2018). These claims appeal to a popular cultural meme that ‘natural’ medicines derived from whole plants are safer and more effective than ‘synthetic’ pharmaceuticals, a meme often used by the ‘medical cannabis’ industry. The adult use of psychedelic mushrooms has already been decriminalised by referenda in several US cities including Denver, Colorado (BBC News, 2019). There is a proposal for citizen-initiated referenda to allow the adult use of mushrooms in California (Roberts, Reference Roberts2021).
Conclusions
The history of psychiatric research on psychedelic drugs is not a simple story of early research prematurely banned because of Richard Nixon's ‘War on Drugs’. The history of early research indicates that these drugs are especially likely to produce exuberant advocacy when used outside supervised clinical settings e.g. for the purposes of spiritual enlightenment. This history suggests the need for caution by medical regulatory authorities and clinicians in the therapeutic use of psychedelics (Perkins et al., Reference Perkins, Sarris, Rossell, Bonomo, Forbes, Davey and Castle2021). Clinical use should occur under supervision in research and teaching settings to minimise the risks of a recurrence of the social misadventures in the 1950s and 1960s when the use of these drugs spread into unsupervised clinical practice and explorations of spirituality and creativity. The latter may be difficult to avoid if referenda in the USA pass that allow the adult use of psychedelic mushrooms and other psychedelic plants.
Acknowledgements
I thank Sarah Yeates for her assistance in preparing this article.
Declaration of interests
I signed the amicus curiae brief prepared by Emeritus Professor Robert Gable for a case argued before the US Supreme Court in 2005.* This brief supported the use of ayahuasca for religious purposes by members of O Centro Espírita Beneficiente União do Vegetal.
* Gable R et al. (2005). Brief of Robert Gable EdD PhD, Harriet de Wit PhD, Wayne Hall PhD, et al. as Amici Curiae in support of respondents in the Supreme Court of the US: Gonzales et al. v. O Centro Espírita Beneficiente União do Vegetal, et al. (04-1084) on Writ of Certiorari to the US Court of Appeals for the 10th Circuit. Austin, Texas: Graves, Dougherty, Hearon & Moody. Retrieved from https://rgable.files.wordpress.com/2012/02/amicus-brief-of-gable-et-al1.pdf
