The psychedelic research hiatus and its relevance today

The psychedelic renaissance (i.e. the resurgence of scientific research into psychedelic substances) concerns evaluating substances such as LSD and psilocybin in the treatment of mental illness such as depression, anxiety and PTSD. Preliminary small-scale studies have indicated impressive results (Bogenschutz & Ross, 2016) and psilocybin-assisted psychotherapy was recently designated a breakthrough therapy by the FDA (Brooks, 2019).

Western medicine once showed great interest in these substances, as they constituted a major and promising field of study, starting late in the 1940s and lasting until the early 1970s. Although still in the infancy of the field, by 1963, one thousand research papers had been published.

By 1968, NIMH had spent $30 million on intramural psychedelics research programs (Asher, 1975)[1]. Despite the massive interest, the research almost dried up almost completely in the early 1970s.

Some 50 years later, this hiatus in research is about to end as the research is gaining pace. Still, a persistent misconception lingers on, as prohibition is invariably being blamed for the hiatus of research. As students in the theory of science will testify — correlation doesn’t necessarily equal causation.

The misconceptions are partly illustrated by recent claims that the NIMH stopped funding research with LSD in 1968 because LSD was made illegal at that time (Nutt et al., 2020). Furthermore, in Dr. Nutts way of arguing, the UN narcotic conventions may constitute “the worst censorship of scientific research ever” (Nutt, 2014) and even compared them to the Catholic Church banning Copernicus writings in 1616 and threatening him with death, should he not desist in his research (Nutt, 2014).

This text details why the common perception of why the research dried up is (mostly) false and why the topic still holds relevance.

The ‘truth is rarely pure and never simple’ (in the words of Oscar Wilde).

The first class of antipsychotic drugs (such as Chlorpromazine) were developed in the early 1950s. Such drugs fit like a hand in a glove into a system relying on statistical methods and replicable results. The psychedelics on the other hand offered all but replicable results/experiences that could be forced into the same system of classification.

In essence, psychedelics represented a paradigm that did not allow them to be included in the medical framework. Surely, enabling experiences involving religious and mystical elements did not reduce the clash of paradigms?

The development of antipsychotic drugs partly catapulted society into the future by leaving behind some medieval treatments of mental illness.

For the first time, efficient psychopharmacological treatments against illnesses involving hallucinations and delusions were being utilised. Promoting psychedelics in this context must have been laborious as they (appeared to) prompt just such effects (Richert & Dyck, 2019).

Coupled with that, the antipsychotic drugs required merely one pill to take effect, while the ‘psychedelic approach’ required sessions lasting upwards of 10 hours with assistance from a team of medical professionals. This made it a time-consuming and expensive practice.

The 1960s witnessed the “Thalidomide catastrophe” erupting, induced by mothers using a new sedative drug, causing their offspring to suffer birth defects as a result. This brought the medical community and society at large to realise that drugs could potentially have such adverse effects. Coincidentally, medical findings indicated that the offspring of LSD users were at serious risk of contracting chromosome damages (Cohen et al., 1967). The findings have been disproved since, but deterred many researchers at the time from pursuing research, and sensational news coverage aggravated the situation (Dahlberg et al., 1968).

Swedish newspapers reported in 1968 on how ‘yet another Thalidomide catastrophe’ erupted, as a mother with a history of LSD usage gives birth to a deformed child. Contemporary Swedish articles described scientific agreement that LSD provokes leukemia, tumours and ‘mongoloidism’.

As a response to the Thalidomide catastrophe, the U.S introduced a legion of regulations in the field of clinical drug research (Turner, 2012) to ensure that drugs administered to humans were safe and had proven efficacy.

The experimentation of Thalidomide on humans prior to clinical evaluation was made possible due to a regulatory loophole that enabled substances to be subject to “investigational use by experts qualified by scientific training and experience to investigate the safety of drugs”. (Bonson, 2018)

The initial experimental phase of psychedelic research is partly in debt to this particular loophole in making research possible, despite the lack of documented safety and efficacy. Upon enforcing the regulations, a range of improper research practices decreased. However, these adjustments, unfortunately turned out to severely impair psychedelic research (Bonson, 2018).

The golden standard of clinical drug research — randomized controlled trial (RCT), became standardised. The standard was targeted at taking the direct biological actions of drugs into account for evaluation. All other factors constituted biases to be eliminated. (Oram, 2018). RCT however, is fundamentally incompatible with the psychedelic treatment. LSD is perceived as lacking inherent therapeutic effects, but rather displaying therapeutic effects through its ‘extra-pharmacological’ effects (the experiences) it exerts.

Besides, the RCT model assumes that neither the research subjects nor the researchers are able to determine if the drug or placebo has been administered. Naturally, this constitutes a major challenge with regards to psychedelics. The researchers tried adjusting in accordance with the new regulations, but in doing so, renounced established methods that had proved to be effective. This paved way for the research to produce mediocre results, aggravating already dwindling scientific interest into psychedelics (Oram, 2018). Ensuing discussions on appropriate methodology in the research protocols pitted researchers against each other. (Richert & Dyck, 2019).

In 1963, the aforementioned regulations had caused scientists who wished to conduct research with LSD to be forced to provide data on its chemistry and manufacturing details to the FDA.

However, Sandoz was reluctant to share such proprietary and patented data (Bonson, 2018). When required by the FDA, the company only provided very limited animal toxicity data to prove safety. Sandoz never conducted trials to properly assess the safety and efficacy of LSD. In the 1950s, Sandoz ignored FDAs request to submit an application that would constitute a first step towards the formal registration of LSD as an approved drug.

Unpublished documents indicate that Sandoz applied to have LSD registered in Sweden, but later withdrew their application.

More than a decade later, the NIMH could not allow LSD to indefinitely remain in limbo, without the goal of it being an approved drug.

Practically, the limbo violated the new regulations as well (Bonson, 2018). This contributed to NIMH shutting down their intramural (inhouse) human research with LSD in 1968 (Hart & Ksir, 2013). At this point, it had only included limited trials, with poor design, lacked controls and randomisation (Bonson, 2018). In 1975, NIMH shut down the extramural research grants (funding of external clinical trials) into human research with LSD. This event has been linked with the revelation of the highly controversial ‘MKULTRA’ program that NIMH may have wanted to distance itself from. (Bonson, 2018)

Psychedelics were of little interest to pharmaceutical companies as the intervention seemed to treat illness, rather than alleviate symptoms. Consequently, the financial imperatives were lacking; fully recovered patients would not require continued medication. The patent for LSD expired in the 1960s, certainly making it even less appealing for pharmaceutical companies at that point in time.

It is important to note that the early research was indeed promising by its contemporary standards, but the methodological discrepancies are too severe to be overlooked by modern standards. The old data cannot be used in regulatory decision making as the results are neither reliable nor valid. (Bonson, 2018)

Regarding earlier statements on the role of prohibition in the curtailment of research, it cannot be completely ruled out that this played some role.

But, most importantly, researchers at the time were unable to comply with regulations in the field of drug evaluations and the actions of Sandoz exacerbated the situation. The actions of the US government in the 1960s with regards to medical research have been largely misunderstood as their actions are not at all as reactionary or repressive as they often are represented as being (Oram, 2016).

The UN’s Convention of Psychotropic Substances (CPS) of 1971 placed psychedelics in Schedule 1 (high potential for abuse and without acknowledged medicinal value). This was prompted by widespread abuse and the fact that science still had failed at determining their efficacy and safety as therapeutic interventions.

Modern population studies however have failed to find evidence that the use of psychedelics constitutes an independent risk factor for mental health problems (Johansen & Krebs, 2015).

The preamble of CPS speaks of how: “the use of psychotropic substances for medical and scientific purposes is indispensable and […] their availability for such purposes should not be unduly restricted.” (United Nations, 1971).

Despite that CPS stipulates the importance of research being conducted with such substances, it currently acts impeding on research by creating obstacles through making special permits a requirement etcetera (Nutt et al., 2013).

It still remains fully possible to conduct such research though.

CPS may not ever have been taken into effect, should Sweden not have exerted great diplomatic pressure on the US, as its pharmaceutical industry heavily opposed the treaty (Eriksson & Lundström, 1970). Depicted is Bror Rexed signing CPS on behalf of Sweden.

Not only didn’t prohibition singlehandedly end research or ban it from being conducted, but a complete legalisation may actually cause a backlash to the research, and science still “has a lot to learn about the immense power and potential risk of these molecules, not to mention the consequences of unrestricted use.” (Pollan, 2019).

The need for contemporary research is pressing and the field of psychedelic science will face challenges such as:

• Designing appropriate clinical drug trial evaluation protocols that resolve the issue of double-blinding and how to account for the ‘extra-pharmacological’ effects of LSD and similar psychedelics.
• The substances will likely not carry an appeal to pharmaceutical companies. This is an issue that must properly be addressed as pharmaceutical companies are ordinarily the driving force behind drug development and marketing.
• The field of psychiatry and medicine at large must study the distinct characteristics of these extraordinary pharmacological agents to investigate whatever possible treatment modalities they have to offer. When entertaining this notion, such investigations may unveil anomalies in the medical paradigm to such extent that a scientific model crisis ensues in the Kuhnian sense of the word.

The path forward must consider all facts at hand and build on honesty, not only with regard to potential medical findings and adverse reactions. Cherry picking, even in the field of historiography, is unlikely to be fruitful in the long run for the growing field of research into the therapeutic potentials of psychedelics.

Let us give psychedelics an honest chance by facing the actual challenges at hand — humankind and the world at large are in desperate need of what these curious compounds purportedly have to offer.

Sources

Asher, J. (1975, November). Whatever happened to Psychedelic Research? Monitor on Psychology — American Psychological Association, 4–5.

Bogenschutz, M. P., & Ross, S. (2016). Therapeutic Applications of Classic Hallucinogens. In A. L. Halberstadt, F. X. Vollenweider, & D. E. Nichols (Eds.), Behavioral Neurobiology of Psychedelic Drugs (Vol. 36, pp. 361–391). Springer Berlin Heidelberg. https://doi.org/10.1007/7854_2016_464

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Brooks, M. (2019, November 25). FDA Grants Psilocybin Second Breakthrough Therapy Designation for Resistant Depression. Medscape Medical News. https://www.medscape.com/viewarticle/921789

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[1] The number has been adjusted for inflation.