The psychedelic research hiatus and its lingering relevance
“The psychedelic renaissance” (i.e., the resurgence of scientific research into psychedelic substances) concerns evaluating substances such as LSD and psilocybin in treating mental illnesses 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. They constituted a significant and promising field of study, starting late in the 1940s and lasting until the early 1970s. Although still in the field’s infancy, by 1963, one thousand research papers had been published.
By 1968, NIMH had spent $30 million on intramural psychedelics research programs (Asher, 1975). Despite the massive interest, the research almost dried up 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, as prohibition is invariably blamed for the research hiatus. As students in the theory of science will testify — correlation does not necessarily equal causation.
The misconceptions are partly illustrated by recent erroneous claims that the NIMH stopped funding research with LSD in 1968 because LSD was made illegal then (Nutt et al., 2020). Furthermore, in Dr. Nutt’s way of arguing, the U.N. 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.
‘Truth is rarely pure and never simple’ (in the words of Oscar Wilde).
The first class of antipsychotic drugs (such as Chlorpromazine) was 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 classification system.
In essence, psychedelics represented a paradigm that did not allow them to be included in the medical framework. Indeed, 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 mental illness treatments.
For the first time, efficient psychopharmacological treatments against illnesses involving hallucinations and delusions were utilized. 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. Psychedelic-assisted psychotherapy is thus 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 congenital disabilities. The medical community and society realized the extensive risk of such unfavorable drug effects. Coincidentally, medical findings indicated that the offspring of LSD users were at serious risk of contracting chromosome damage (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).
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 before the 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 trials (RCT), became standardized. 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).
Psychedelic treatment is challenging to evaluate with RCT. LSD is perceived as lacking inherent therapeutic effects. However, instead of 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 can determine if the drug or placebo has been administered. Naturally, this constitutes a significant challenge concerning psychedelics. The researchers tried adjusting to following the new regulations. However, in doing so, they renounced established methods that proved effective. Renouncing established methods paved the way for the research to produce mediocre results, aggravating already dwindling scientific interest in psychedelics (Oram, 2018).
Ensuing discussions on appropriate methodology in the research protocols pitted researchers against each other (Richert & Dyck, 2019).
The issue of informed consent arose as the new farmaceutical regulations required patients to provide written informed consent in medicine. Nevertheless, as all individuals react differently to psychedelics, the experience is often ineffable and impossible to convey. How is the patient to make an informed consent? Additionally, some schools of thought call for patients not to be informed about all possible adverse reactions as this may provoke an “undue suggestive effect,” which impairs the treatment’s outlook (Bargar, 1964). Naturally, this posed challenges with the requirements of informed consent.
In 1963, as mentioned earlier, the 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 minimal animal toxicity data to prove safety. Sandoz never conducted trials to assess the safety and efficacy of LSD properly. In the 1950s, Sandoz ignored the FDAs request to submit an application that would constitute a first step toward formally registering LSD as an approved drug.
More than a decade later, the NIMH could not allow LSD to remain indefinitely in limbo without the explicit goal of eventually being approved. The limbo violated the new regulations as well (Bonson, 2018). The limbo contributed to NIMH shutting down their intramural (in-house) human research with LSD in 1968 (Hart & Ksir, 2013). At this point, it had only included limited trials, with poor design, and lacked controls and randomization (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).
It is worth commenting that in the same year (1975), the NIMH published a report (Segal, 1975) that stated that research into psychedelics should be encouraged and that the NIMH had successfully “rescued” psychedelic research in 1967 by securing a stockpile of LSD (as Sandoz withdrew the compounds from the market). NIMH further notes that for the past 20 years:
“Virtually every psychological test has been used to study persons under the influence of LSD or other such hallucinogens, but the research has contributed little to our understanding of the bizarre and potent effects of this drug.”
NIMH not only commented on the lack of understanding of the effects of these compounds but also the lack of therapeutical applications:
“During the past several years, relatively little human research has been done with LSD, with most effort going into recording the consequences, both immediate and delayed, of its social use. Attempts to use the drug over the years, either as an adjunct to traditional psychotherapy or as a special type of psychotherapeutic intervention, have not clearly defined a therapeutic use.”
Most people would agree that governments should not endlessly fund research into pharmaceutical compounds in cases such compounds seem to lack efficacy, despite decades of extensive research. Given this background, it seems highly natural for the NIMH to have stopped funding the research in 1975.
The psychedelic intervention seemed to treat illness rather than alleviate symptoms, rendering it of little interest to pharmaceutical companies, which typically constitute the driving force behind farmaceutical research.
Consequently, the financial imperatives were lacking; fully recovered patients would not require continuous medication. The patent for LSD expired in the 1960s, making it even less appealing for pharmaceutical companies now.
The early research was indeed promising by its contemporary standards. However, the methodological discrepancies need to be addressed 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.
Nevertheless, most importantly, researchers at the time were unable to comply with regulations in drug evaluations, and Sandoz’s actions exacerbated the situation. The actions of the U.S. government in the 1960s regarding medical research have been largely misunderstood as their actions are not at all as reactionary or repressive as they often are represented as being (Bonson, 2018).
The U.N.’s Convention on Psychotropic Substances (CPS) of 1971 placed psychedelics in Schedule 1 (high potential for abuse and without acknowledged medicinal value). The control measure was prompted by widespread abuse and the fact that science still failed to determine their efficacy and safety as therapeutic interventions. However, the U.N. did not rule out such applications of psychedelics in the future (United Nations, 1967). Modern population studies have failed to find evidence that psychedelics are 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).
Although CPS stipulates the importance of research being conducted with such substances, it currently impedes research by creating obstacles through implementing special permit requirements, etcetera (Nutt et al., 2013). It remains possible to conduct such research in any case.
Not only did not prohibition singlehandedly end research or ban it from being conducted, but complete legalization 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 issue must be appropriately addressed, as pharmaceutical companies are ordinarily the driving force behind drug development and marketing.
- The field of psychiatry and medicine must study the distinct characteristics of these extraordinary pharmacological agents to investigate whatever treatment modalities they offer. When entertaining this notion, such investigations may unveil anomalies in the medical paradigm to such an extent that a scientific model crisis ensues in the Kuhnian sense of the word.
The path forward must consider all facts and build on honesty, not only about 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 a fair chance by facing the actual challenges at hand — humankind and the world are in desperate need of what these curious compounds purportedly offer.
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