This research briefing is co-published with the excellent Report on Psychedelics.

December 6th, 2021

In The Research Briefing:

• The methodological challenges faced in psychedelic clinical trials (and how to fix them)
• Mystical experiences in recreational use associated with improvements in wellbeing
• A novel 5-MeO-DMT formulation proves to be safe in Phase I trial

How can we do better, more accurate, research with psychedelics?

The therapeutic potential of psychedelics is garnering significant attention from academics, elected officials and the public alike. Thanks to solid clinical research, the narrative surrounding these psychoactive substances is changing for the better. The medicalization of psychedelics like psilocybin, MDMA and ketamine is slowly becoming a reality. If therapeutic models using these substances are truly going mainstream, they must withstand the scrutiny of the clinical trial process and address the inherent methodological issues which often occur conducting such trials.

For example, the proliferation of news articles regarding the promise of psychedelic-assisted therapies is paradoxically leading to expectancy effects among clinical trial participants i.e overwhelmingly positive news articles are leading people to believe that psychedelic-assisted therapy will ‘cure’ any mental health problem they may be experiencing. In reality, psychedelics will not work for everyone and are by no means a silver bullet aimed at global mental health.

A recent preprint article explores some of the major methodological issues faced when conducting clinical trials with psychedelics. As well as the issues surrounding expectancy effects, the researchers identified several unique sources of potential bias when conducting such trials:

• The subjective effects of a high-dose psychedelic are often so pronounced that it is difficult to mask participants to their treatment condition.
• The significant hype from positive media coverage on the clinical potential of psychedelics influences participants’ expectations for treatment benefit.
• Participant unmasking and treatment expectations can interact in such a way that makes psychedelic therapy highly susceptible to large placebo and nocebo effects.

The researchers in the present study recommend a number of design elements for future research in order to minimize the risk of bias:

• Study development and design; a 3-arm study is best to test for substance efficacy (psychedelic vs. active placebo vs. inactive placebo) & a single administration session of a psychedelic is recommended.
• Participant recruitment and selection; recruit psychedelic-naïve participants in order to prioritize effective condition masking.
• Expectation bias; investigators should emphasize the uncertainty regarding treatment efficacy & use established measures of expectancy e.g the Stanford Expectations of Treatment Scale.
• It is critically important to distinguish “incomplete exposure” from “deception.”
• Anticipating the placebo effect, measuring the contribution of expectancies, assessing the effectiveness of masking, and systematically reporting these data will set standards and lead to iterative improvements in trial design.

The present study seeks to improve the clinical trial process involving psychedelics. Legitimatizing psychedelic research is no mean feat. However, addressing the issues identified in this study and taking the authors recommendations into account will help to bring psychedelic-assisted therapies to the masses.

Examining the trip-reports of more than 1400 people

Researchers have long been fascinated with the ability of psychedelics to induce mystical-type experiences and the effect such experiences can have on therapeutic outcomes. While tools such as the Mystical Experience Questionnaire have helped researchers to characterize and quantify mystical experiences in the clinical setting, little is known about the implications of such experiences outside of this setting.

The present study sought to examine these implications and the content of mystical experiences in people using psychedelics outside of the clinical setting. To do so, the researchers used a mixed-methods approach. Firstly, text mining analysis was used to assess over two thousand written reports of first-person psychedelic experiences. The results of this analysis yielded a qualitative description with regards to the content of the psychedelic experience. Secondly, the researchers conducted a quantitative analysis of psychometric data from a large survey (n=1424) to explore the associations between psychedelic use, mystical experiences and psychological wellbeing.

The main findings:

• Sentiment analysis of trip reports suggest that emotional valence of psychedelic experiences differ by drug type, and certain psychedelics may allow for extreme deviations in positive and negative experiences.
• Much like in the laboratory setting, encountering a mystical experience depends on drug type and dose response effects, i.e. those who took a higher dose had more mystical experiences.
• Complete mystical experiences are associated with higher self-reported wellbeing on a range of facets including affect, mood disorder, life meaning, life satisfaction, mindfulness, and wisdom, compared to those without mystical experiences.

The study at hand presents an understanding of the natural interactions between humans and psychedelics without the influence of clinical or laboratory interventions. Another way the bias of the researchers was minimized is by using text mining to come to the themes, so as not to impose their preconceived ideas of what people should report from a trip.

Recreational users experience mystical states and these states are associated with improved psychological well being. This has, of course, been known by many who use psychedelics outside of the lab. This analysis adds another data point as to the existence of these positive outcomes and when they happen. Lest we forget, attention to safety is needed when planning any psychedelic experience, be it recreationally or in a laboratory.

Getting 5-MeO-DMT through clinical trials

In the world of psychedelics, 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) is a somewhat controversial substance. Much of this controversy relates to Bufo alvarius, or the Sonoran Desert Toad, which secretes a venom rich in 5-MeO-DMT to keep predators at bay. The recent popularization of psychedelics on television and in the media has led to an increase in the practice of catching and “milking” these toads in order to extract the psychoactive venom. Perhaps unbeknownst to these curious psychonauts, such practices are pushing this species towards extinction.

Given the therapeutic potential of 5-MeO-DMT, researchers are exploring the possibility of utilizing lab-created synthetic alternatives of this molecule. Beckley Psytech is one such company that is currently conducting a Phase I study exploring the safety and tolerability of a novel formulation of intranasal 5-MeO-DMT. Another company in this area of psychedelic science is GH Research who have just published the findings from their Phase I study investigating GH001, their proprietary inhalable 5-MeO-DMT formulation.

This Phase I study assessed the safety, tolerability and impact of four different doses of GH001 in 22 healthy volunteers. Doses included 2 (n=4), 6 (n=6), 12 (n=4) and 18 mg (n=4), as well as an individualized dose escalation regimen (n=4).

Main findings:

• Higher doses of 5-MeO-DMT produced significant increments in the mean intensity of the psychedelic experience as compared to the lowest 2 mg dose across all questionnaires used, bar the Challenging Experience Questionnaire.
• Measures of cognition, mood, and wellbeing were not affected by 5-MeO-DMT.
• 5-MeO-DMT was generally well tolerated as vital signs at 1 and 3 h after administration were not affected and adverse events were generally mild and resolved spontaneously,
• The 5-MeO-DMT dose needed to achieve a peak experience largely varies between individuals suggesting that individualized dose escalation of 5-MeO-DMT may be preferable over single dose administration for clinical applications that aim to maximize the experience to elicit a strong therapeutic response.

Overall, the findings of the present study show that the novel formulation of 5-MeO-DMT, GH001, is safe and is well tolerated. Such findings are important for future therapeutic applications of any 5-MeO-DMT formulation as well as ensuring the conservation of Bufo alvarius.

Research Report Readout

A survey of 83 psychiatrists working for the NHS in the UK asked them about providing psychedelic-assisted therapy in their practice. The majority of respondents (77.2%) felt that psychedelics do hold important therapeutic potential but they feel unprepared to deliver psychedelic-assisted therapy.

Another survey study, this time of 150 people before and after a psychedelic trip, assessed changes in participants personality traits following the experience. It was found that the use of psychedelics was associated with increases in agreeableness and substantive decreases in neuroticism, traits that are related to social functioning. These findings suggest that psychedelics may be used to treat interpersonal elements of personality pathology as well as loneliness.

Hannah Saeger and David Olson make the case for using the therapeutic potential of psychedelics to treat neurodegenerative disorders such as Alzheimer’s disease. The ability of psychedelics to upregulate neurotrophic factors that promote neuronal survival and growth is discussed. Through their effects on structural and functional neuroplasticity and inflammation, psychedelics may prove useful in treating various aspects of neurodegenerative disorders.