Twentieth century opposition to psychedelic research

The rapidly evolving timeline of psychedelic research, as depicted in Figure 1, was stimulated by the discovery of psychoactive properties of LSD by chemist Albert Hoffmann of Sandoz Pharmaceuticals in 1943.Reference Hofmann^17, Reference Stoll ¹⁸ Sandoz Pharmaceuticals contributed to a fertile period of psychedelic research in the 1950s, including the identification of psilocybin in magic mushrooms by Hofmann in 1958.Reference Grinspoon and Bakalar ^{19 ,} Reference Hofmann, Heim, Brack and Kobel ²⁰ LSD was widely used as an adjunct to psychotherapy for a period of about 15 years and it was reported that up to 79% of mood disorder patients demonstrated subjective clinical improvement.Reference Grinspoon and Bakalar ^{19 ,} Reference Rucker, Jelen, Flynn, Frowde and Young ²¹ Throughout the 1950s, psychedelic research occurred with limited opposition or government oversight. In fact, over 130 clinical study grants were government-funded.Reference Nutt ²²

Despite emerging therapeutic interest in psychedelics, many early trials faced skepticism. Major methodological biases were highlighted, including the lack of standardized measures, randomization procedures, adequate sample characteristics, and controlling which limited the validity of the results. Jonathan Cole, president of the American College of Neuropsychopharmacology (1965–66), was one of the first scientists to voice criticism of psychedelic research, emphasizing the lack of evidence for safety and efficacy.Reference Mangini ^{23 (p19),}Reference Cole and Katz ²⁴ However, scientific opposition was not the only avenue in which psychedelic research was discredited.

During the early era of psychedelic research, recreational use increased substantially, especially amongst individuals engaging in the counterculture movement of the 1960s. The psychedelic-associated counterculture movement faced opposition by supporters of the U.S. involvement in the Vietnam, Laos and Cambodia war (1955–1975). Political figures such as President Richard Nixon and President Lyndon B. Johnson voiced opposition to the psychedelic counterculture, claiming the necessity of the war and the importance of upholding patriotic duty. The first major advancements in the development of psychotropic pharmacotherapies occurred around the same time, but these were not met with the same political opposition.Reference Braslow and Marder ²⁵

Timothy Leary was a Harvard psychologist and prominent figure in mid-twentieth century psychedelic counterculture. After undergoing a personal experience with psilocybin in Cuernavaca, Mexico, Leary conducted research on the effects of psychedelics at Harvard University alongside colleague Richard Alpert, advocating for the ability of psychedelics, particularly LSD, to expand consciousness and promote psychological benefits. Leary conducted multiple unapproved projects and widely encouraged psychedelic use by the public, famously quoting “turn on, tune in, drop out.” Both Leary and Alpert were dismissed for these actions from Harvard University in 1963, and the continued promotion of psychedelics eventually led to Leary’s arrest in 1966.Reference Carhart-Harris and Goodwin ¹ President Richard Nixon referred to Leary as “the most dangerous man in America,” with increasing concerns that recreational psychedelic use would pose health concerns and jeopardize war efforts in Vietnam. However, Leary was not alone in advocating for the psychedelic movement. Many other prominent figures including novelists Aldous Huxley and Ken Kesey as well as popular bands such as The Doors and The Beatles contributed.Reference Jay ^{26 ,} Reference Hall ²⁷

Despite emerging political and scientific opposition, the recreational use of psychedelics continued, often in uncontrolled environments. Further, there was an increase in the illegitimate use of psychedelics by sham psychiatrists.Reference Novak ²⁸ The concept of the “bad trip” began to be recognized, referring to negative and distressing psychedelic experiences and contributing to the existing negative perception. However, this was not the first incidence of cultural opposition to psychedelics. Antipsychedelic views were often shared by several religious groups campaigning against Native American peyote use and referring to the substances as “addictive” and “insidious evil.”Reference Newberne and Burke ²⁹

Sensationalist media coverage of psychedelic medicines highlighted the emerging safety concerns associated with these substances, including reports of psychosis, accidental death, and suicide among users.Reference Hall ²⁷ LSD was first banned in California in the mid-1960s as a result of these growing public concerns.Reference Siff ³⁰ In 1969, the adverse public narrative of psychedelics was further perpetuated by the case of Charles Manson, a cult leader who used LSD to convince his followers to partake in mass homicide.Reference Hall ²⁷ The concept of psychedelic neurotoxicity also emerged in which reports suggested that psychedelic users exhibit neurological or cognitive deficits.Reference Schlag, Aday, Salam, Neill and Nutt ^{31 ,} Reference Cohen, Marinello and Back ³² Individuals advocated for stricter regulations on the clinical use of LSD in response to adverse events among patients undergoing psychotherapy.Reference Novak ^{28 ,} Reference Hall ^{27 ,} Reference Brecher ³³

In 1963, the US Federal legislation increased restrictions on pharmaceutical research, requiring ethics approval in the form of a Clinical Trial Notification, which requires methodologically sound preclinical evidence of safety and efficacy.Reference Oram ^{34 ,} Reference Bonson ³⁵ In response to emerging controversy, Sandoz Pharmaceutical withdrew sponsorship of psychedelic trials in 1965.Reference Hofmann ^{17 ,} Reference Oram ³⁴ At this point, psychedelic research was limited to studies funded by the National Institute of Health (NIH). The United Nations classified LSD, psilocybin, and mescaline as Schedule I in 1967, considering them as substances with no or very little medical purpose, a high potential for abuse, and a lack of accepted safety.Reference Nutt, King and Nichols ³⁶ Similar political changes occurred in other countries, including Schedule 3 status under the Controlled Drugs and Substances Act in Canada.Reference Nutt, King and Nichols ^{36 ,} Reference Tupper, Wood, Yensen and Johnson ³⁷

This political and legal opposition led to an unprecedented restriction on research efforts for decades, making it difficult for researchers to conduct studies using psychedelics, with limited funding and resources available. However, a few studies were conducted as supported by the Food and Drug Administration and NIH.Reference Oram ^{34 ,} Reference Pahnke, Kurland, Unger, Savage and Grof ³⁸ Nonetheless, the political opposition to psychedelic research that occurred was unprecedented in the field of psychiatry. This is especially true considering the growing body of positive findings that occurred leading up to scheduling and the relatively favorable safety profile of psychedelics in medically supervised contexts.Reference Nutt ^{22 ,} Reference Nutt, King and Nichols ^{36 ,} Reference Tupper, Wood, Yensen and Johnson ³⁷

The use and study of psychedelics largely occurred “underground” throughout the remainder of the twentieth century, leading to the conduct of methodologically and ethically questionable practices and therapeutic models. For example, some therapists conducted PAP with substances obtained from the illicit market.Reference Smith and Appelbaum ³⁹ Reports also include the use of therapeutic touch as a crucial aspect of practice, raising concerns about boundary violation and misconduct. Unethical conduct even extended to administering high doses of LSD to unprepared, restrained patients.Reference Smart, Storm, Baker and Solursh ⁴⁰

Psychedelic research dwindled for decades until around the turn of the twenty-first century when a renewed scientific interest emerged in their therapeutic potential. Advancements in neuroscience such as neuroimaging techniques and psychopharmacological studies in healthy individuals contributed to the study of psychedelics in the modern age. In addition, small exploratory studies conducted at the early stages provided a base for larger investigations. For example, Rick Strassman and colleagues investigated DMT in the first government-approved study, which illustrated the importance of ‘set’ and ‘setting.’Reference Strassman ⁴¹ Roland Griffiths and colleagues demonstrated the profound and mystical nature of the psychedelic experience.Reference Griffiths, Richards, McCann and Jesse ^{42 ,} Reference Griffiths, Richards, Johnson, McCann and Jesse ⁴³ The first modern clinical trial was a pilot study conducted by Moreno et al (2006) on psilocybin for treatment-resistant obsessive-compulsive disorder. Significant reductions (23–100%) in symptoms occurred in all participants without adverse events, although the improvements did not last.Reference Moreno, Wiegand, Taitano and Delgado ⁴⁴ Many other impactful and pioneering studies occurred during this period of psychedelic research resurgence.Reference Nutt ²²

Sociocultural factors impacting psychedelic research credibility

Despite significant cultural normalization, there remains a social stigma against psychedelics, amongst persisting antidrug views. The classification of psychedelic substances as Schedule I has been a contributor, which also includes an exaggeration of their risks and addictive potential, contrary to the evidence.Reference Nutt, King and Nichols ³⁶ Ironically, psychedelics have actually demonstrated preliminary efficacy in the treatment of addiction and substance use disorders.Reference Dos Santos, Bouso, Alcázar-Córcoles and Hallak ^{10 ,} Reference Hodge, Sukpraprut-Braaten, Narlesky and Strayhan ^{11 ,} Reference Dos Santos, Osório, Crippa and Hallak ⁴⁵ Previous work has shown that public views of high toxicity and adverse events are largely incorrect.Reference Mithoefer, Feduccia and Jerome ^{46 –}Reference Nutt, King and Phillips ⁵¹ Further, the illegal status has contributed to the “underground” use of these substances, which further stigmatizes them in the public eye.

The medicalization of psychedelics as an adjunct to psychotherapy is contributing to a more positive cultural opinion. However, the “hype” surrounding psychedelic research is disproportionate to the available evidence and threatens public credibility if results do not follow through. Yaden (2022) described the “The Gartner Hype Cycle” in which novel scientific advancements trigger substantial public attention, leading to inflated expectations followed by a steep decline when expectations are not met in which public narratives may shift from overly positive to overly negative, before a plateau occurs.Reference Yaden, Potash and Griffiths ⁵²

“Excessive enthusiasm” refers to the influence of personal use of psychedelics by researchers, potentially compromising scientific objectivity and promoting the biased reporting of results.Reference Kious, Schwartz and Lewis ⁵³ Cole & Katz (1964) were one of the first to describe “excessive enthusiasm.”Reference Cole and Katz ²⁴ Today, concerns of researcher bias persist, as discussed in a recent paper titled “Should we be leery of being Leary?”Reference Kious, Schwartz and Lewis ⁵³ “Excessive enthusiasm” may also impact the credibility of psychedelic research at the participant level. Individuals with past psychedelic experiences may be more likely to partake in psychedelic research, to expect positive results and to “break the blind.” This may lead to a self-selecting study population, introducing bias into psychedelic research and ultimately jeopardizing credibility.

Political factors impacting psychedelic research credibility

Legislative restrictions of the 1960s and 1970s were largely made before a thorough understanding of the pharmacological effects of psychedelics was reached, leading to vague reasoning. Ongoing debates about the Schedule I classification of psychedelics highlight significant discrepancies in regulatory criteria, summarized by Nutt et al (2013).Reference Nutt, King and Nichols ³⁶ Although preliminary interest in the therapeutic potential of psychedelic substances was identified by the 1960s, Schedule I criteria claims that there is no or very little medical purpose. At this point, there was evidence of safety for the use of psilocybin under medical supervision, and further investigations to determine the safety and efficacy cannot be conducted due to scheduling.Reference Nutt, King and Nichols ³⁶ In this way, criteria for Schedule I status is paradoxically self-fulfilling as restrictions on research prevent the conduct of safety and efficacy studies that are necessary to challenge the classification.

While there are certainly unique risks associated with psychedelics, many argue that scheduling appears to be based on the assumption of extreme risk. Interestingly, an analysis demonstrated no relationship between the level of harm of psychoactive substances and legal status.Reference Nutt, King, Saulsbury and Blakemore ^{50 ,} Reference Nutt, King and Phillips ⁵¹ The “War on Drugs” launched by the Nixon administration disproportionately targeted marginalized groups and low-income communities, including selective enforcement, racial profiling, and over-incarceration with limited harm-reduction programs.Reference Miron and Partin ⁵⁴ John Ehrlichman, the domestic policy chief for Nixon, was famously quoted in a 1994 interview stating that the administration’s drug policies were intentionally crafted to disrupt and vilify certain communities, irrespective of drug harm. The political narrative of “protecting” the public from psychedelics is especially ironic considering the disturbing MK-Ultra project in which the CIA experimented if LSD could be used for “brain-washing” individuals.Reference Torbay ⁵⁵ In this way, legislative restrictions on psychedelics were made due to a confluence of factors beyond safety concerns or scientific evidence alone.

The scheduling of psychedelics from the 1970s persists in the majority of North America today. In Canada, LSD, psilocybin and psilocin, mescaline, and DMT remain as Schedule 3 substances, while MDMA and ketamine are Schedule 1, impacting the conduct of psychedelic research at numerous levels. For example, granting agencies may be reluctant to fund psychedelic research initiatives due to the misconceptions surrounding safety.Reference Nutt, King and Nichols ³⁶ Further, the illegal status of psychedelics makes it difficult to gain approval for their use in clinical research. The Multidisciplinary Association for Psychedelic Studies took over four years to gain approval to investigate the therapeutic use of MDMA for PTSD, due to legislative hurdles enacted by Health Canada and institutional review boards.Reference Nutt, King and Nichols ³⁶

The status of these substances applies to any quantity, challenging research on submilligram doses, a fear that may be associated with the “leaking” of psychedelic substances into the recreational domain in the mid-twentieth century.Reference Nutt, King and Nichols ³⁶ The restrictions extend to other 5-HT_2A agonists, limiting adjacent lines of research which may improve the mechanistic understanding of psychedelics.Reference Carhart-Harris, Erritzoe and Williams ^{4 ,} Reference Griffiths, Richards, Johnson, McCann and Jesse ^{43 ,} Reference Grob, Danforth and Chopra ⁵⁶ Even once legislative hurdles are overcome, it is difficult to source pharmaceutical-grade psychedelics for research. Manufacturers face numerous hurdles in the development of psychedelics, leading to high costs of custom synthesis that is often too extensive for research grants, $12,000 per gram of psilocybin, for example.Reference Grob, Danforth and Chopra ⁵⁶ Together, numerous political and legal barriers continue to impact the ability to conduct psychedelic research.

Scientific factors impacting psychedelic research credibility

The final area in which psychedelics have faced historical opposition and continue to impact the credibility of the field is through the level of scientific opinion. The “underground” nature in which psychedelics were studied and used throughout the latter half of the twentieth century contributes to skepticism about the scientific validity of the therapeutic claims resulting from this era of psychedelic research. Many early studies were later refuted and retracted.Reference Cohen, Marinello and Back ^{32 ,} Reference Dishotsky, Loughman, Mogar and Lipscomb ^{57 ,} Reference Egozcue, Irwin and Maruffo ⁵⁸ As an evolving field of neuroscience, psychedelic research faces several challenges that are inherent to clinical, neuropharmacological, and psychotherapeutic research fields; in particular, adhering to the accepted gold-standard framework of the randomized controlled trial (RCT).

PAP clinical trials are typically conducted with relatively small sample sizes due to the amount of time and resources required. The absence of a control group is another limitation. Open-label, uncontrolled studies which report reductions in illness severity following PAP are not sufficient to prove efficacy. Another criticism related to sample characteristics is the often-extensive exclusion criteria, excluding participants with comorbidities, drug use, or a family history of psychotic disorders. While there are important safety precautions to uphold, it is argued that populations participating in psychedelic trials are easier to treat.Reference van Elk and Fried ⁵⁹ Further, participants of psychedelic studies are typically Caucasian with socioeconomic stability, limiting generalizability and external validity.Reference Michaels, Purdon, Collins and Williams ⁶⁰ Many psychedelic studies have been conducted as a single session with minimal follow-up, threatening construct validity by making it difficult to determine if the benefit is persistent.Reference van Elk and Fried ⁵⁹

Another methodological criticism is expectancy bias, a form of cognitive bias in which an individual’s expectations about a process or outcome may influence the perception of their own or someone else’s behavior.Reference Colagiuri ⁶¹ Expectancy, including “excessive enthusiasm,” may occur in psychedelic research at the level of the participant, investigator, or therapist and may be responsible for a portion of the therapeutic outcomes observed.Reference Cole and Katz ^{24 ,} Reference Kious, Schwartz and Lewis ⁵³ For example, therapist positive beliefs about psilocybin have been associated with greater openness to involving patients with PAP. Likewise, participants with positive beliefs about psychedelics are more likely to volunteer.Reference Meir, Taylor, Soares and Meyer ⁶² Expectancy may also contribute to negative outcomes if participants expecting a psychedelic experience in the control arm become disappointed upon being informed of their allocation.Reference Gold, Enck and Hasselmann ⁶³ Expectation bias in psychedelic research has not been fully investigated.Reference Constantino, Arnkoff, Glass, Ametrano and Smith ⁶⁴

In the RCT, expectancy is typically overcome through double-blinding, in which neither the researcher administering the substance or the participant is aware of their group allocation. However, blinding is particularly difficult to achieve in psychedelic research, due to perceptual distortions and hallucinations.Reference Colagiuri ⁶¹ ‘Breaking the blind’ is a challenge across psychedelic research, which threatens internal validity as blinding cannot be achieved. Different study designs have attempted to overcome this limitation, such as employing multiple doses to standardize expectation and preparation procedures across study arms or including an active comparator, such as ketamine.Reference Carhart-Harris and Goodwin ^{1 ,} Reference Aday, Heifets, Pratscher, Bradley, Rosen and Woolley ^{65 ,} Reference Wilsey, Deutsch and Marcotte ⁶⁶

The lack of mechanistic understanding of psychedelics is another scientific criticism that limits the credibility of the field. It is difficult to determine the components eliciting any therapeutic outcomes, threatening validity. For example, mysticism, interoception, and cognitive flexibility are prominent in the psychedelic experience but are difficult to isolate and measure objectively.Reference Letheby and Mattu ^{67 –}Reference Vargas, Meyer, Avanes, Rus and Olson ⁶⁹ Furthermore, the psychedelic experience displays inter-individual variability and is context-dependent, producing different outcomes depending on expectancy, the environment and drug administration. Some argue that therapeutic benefits can be attributed, in part, to the music played during dosing or primarily from the psychological support.Reference Nutt ^{22 ,} Reference Kaelen, Giribaldi and Raine ⁷⁰ It is possible that cognitive, psychological, and neurobiological changes elicited by psychedelics play independent or convergent roles in therapeutic outcomes.

Current ethical concerns include the ineffable and variable nature of the psychedelic experience, making it difficult to obtain fully informed consent.Reference Anderson, Danforth and Grob ^{71 ,} Reference Smith and Sisti ⁷² Another concern is the state of high psychological vulnerability elicited by psychedelics. Historically, the inappropriate use of therapist power, including sexual misconduct, has occurred in psychedelic clinical trials.Reference van Elk and Fried ⁵⁹ It is important for specific PAP guidelines and regulatory frameworks to be developed for ethical conduct.

Together, numerous scientific criticisms limit the credibility of modern psychedelic research and efforts to address these methodological limitations remain largely unsuccessful.Reference Munafò, Arillotta, Mannaioni, Schifano, Bernardini and Cantarella ⁷³ As the field progresses, the increased compliance of psychedelic studies with rigorous clinical research protocols has and will contribute to the increased credibility of the field, something that is important to uphold and improve in future work.Reference Nutt, Spriggs and Erritzoe ⁷