High and Microdosing Psychedelics in Clinical Research Trials
Psychedelics have been at the center of attention, promising to be the long-awaited revolution in the treatment of several psychiatric disorders. Psychedelics are psychoactive substances that can induce visual or auditory hallucinations, perceptual changes, distorted perception of time, altered states of consciousness, and a spiritual or mystical-type experience. Mounting evidence is supporting the efficacy of psychedelics for the treatment of conditions such as depression, end-of-life distress, and alcohol addiction1–4. Psychedelics being studied include compounds such as psilocybin (a compound found in ‘magic mushrooms’), LSD, and ayahuasca or DMT (a compound found in ayahuasca).
With increasing evidence of efficacy, companies are beginning to study additional psychedelics and alternative formulations that could improve the usability of psychedelics on a larger scale. One such alternative approach being investigated is use of low doses that are sub-psychedelic, popularly referred to as microdosing psychedelics. This contrasts with the traditional approach involving medium to high doses that are associated with overt psychedelic effects. Below, we will discuss both the high dose and microdosing psychedelics approaches, including clinical research trial considerations for each dosing regimen.
High Doses of Psychedelics
High doses of psychedelics represent the traditional treatment approach investigated to date. Such doses are associated with marked psychedelic effects, such as sensory perceptual alterations or hallucinations and profound changes in consciousness. Depending on the compound, the experience can last several hours and is done in a clinical setting with continuous supervision.
The overall treatment program includes a very limited number of psychedelic sessions, sometimes even just one, combined with psychological support. Thus far, this treatment regimen has only been administered individually and has not been evaluated in group settings.
Low Doses or Microdosing Psychedelics
Microdosing psychedelics in clinical research trials is being investigated as a dosing regimen that could be administered in an outpatient setting. A microdose is a sub-perceptual dose, that is, a dose below the threshold of noticeable perceptual alterations that would preclude dosing in an outpatient setting. The intention is for patients to be able to take the treatment on their own and continue with their normal daily activities. For example, this could be an alternative to taking antidepressants, which patients can take on their own at home.
Thus, microdosing psychedelics would increase access to psychedelics. High doses have to be administered in a supervised setting by a mental health professional. The clinical research trial session can last up to several hours and at this time can only be provided to one patient at a time, which is costly and limits scalability. A low-dose approach would allow for outpatient treatment, making it more accessible to a larger number of individuals. Microdosing psychedelics also eliminates the psychedelic effects which may be frightening, overly intense, or cause hesitancy for some individuals, thus it is expected to be well-tolerated by a broader range of patients.
Psychedelics Clinical Research Trial Considerations
High Dosing in Clinical Trials
Set and setting are key for high doses of psychedelics. Due to the strong psychedelic effect, high doses need to be administered in a private, therapeutic setting with a facilitator present. Key features of a study design include:
- A private dosing room set up to look like a living room with a warm and inviting character, decorated with plants and artwork. Participants are dosed individually in this room.
- Calm music is played, participants are provided with eye shades. The participant is encouraged to lay down comfortably and focus inward on the experience.
- A trained facilitator is present throughout the experience. The facilitator is a qualified mental health professional, such as a clinical psychologist or registered psychotherapist, who has undergone training for facilitating psychedelic treatment. The facilitator also provides a preparatory session prior to dosing and an integration session after the experience.
- Study staff performing study assessments, such as safety assessments and blood sampling, need to be sensitive to the nature of the psychedelic experience and perform the assessments in a minimally disruptive way.
The above set-up is applicable both to patient trials and early-phase clinical trials in healthy volunteers. For patient trials, the psychedelic treatment is provided along with psychological support or supportive psychotherapy. For studies in healthy volunteers, depending on the study objectives, it may be appropriate to select individuals with past psychedelic experience to reduce the risk of an adverse response.
Microdosing Psychedelics (Low dosage) in Clinical Research Trials
Before proceeding with outpatient clinical trials, initial early-phase trials are conducted in a clinical facility. Such studies collect pertinent information for optimizing the dose and/or formulation for the outpatient studies, including safety outcomes, pharmacokinetics, and pharmacodynamic assessments. Key features of the design may include:
Participants can be dosed in small groups, as is typical for other Phase 1 clinical trials, such as first-in-human studies.
- Participants can be dosed in a typical Phase 1 clinic.
- A specialized facilitator is not necessary. Participants can be supervised by the study investigator and safety staff, who are trained to detect and manage the potential side effects associated with psychedelics.
- The study may employ a single ascending dose (SAD) design to select the optimal dose for subsequent studies
- Frequent assessments of subjective effects (pharmacodynamic assessments) can be conducted throughout the study to characterize the response for establishing the appropriate dose for outpatient dosing.
Such early-phase studies can be conducted in healthy volunteers. Careful consideration of the study population and eligibility criteria must be made to ensure that results will be generalizable to a broad population.
Considerations Common to High Doses and Microdosing Psychedelics
Some factors are applicable and important to consider regardless of the study dose, such as:
- Management of expectancy effects. As with any other psychoactive drug, the response may be influenced by expectancy effects, and a participant may exhibit a placebo or exaggerated response due to this. Certain features can be built into the study to help reduce the impact of expectancy.
- Exclusion of certain psychiatric history. Some psychiatric disorders, such as schizophrenia or other psychosis, may predispose individuals to an adverse response.
- Selection of subjective measures. The measures should capture the responses of interest and be appropriate for the dose being tested. For example, for low doses, would want measures that would be sensitive to small changes. For high doses, need to consider the ability of the subject to respond during the experience, overall measures administered after the peak experience may be more appropriate.
Additional Psychedelic Considerations
Conduct of clinical research trials with psychedelics regardless of dosage requires great care to minimize the risk of adverse responses and ensure that reliable, generalizable results are obtained, particularly for subjective responses. Both high dose and microdosing psychedelics studies present unique challenges as compared with clinical trials of other drugs, including other psychoactive drugs, due to the nature of their effects.
Phase 1clinical trials are a critical milestone for the drug development program, as they inform the design and support the regulatory approval of subsequent efficacy studies. Even for compounds that have previously been administered to humans, such as psilocybin, regulatory agencies such as Health Canada and the FDA usually require conduct of an initial Phase 1 study to characterize the specific formulation.
Why choose BioPharma Services for your next clinical trial with psychedelics?
At BioPharma Services, we have niche, scientifically-oriented expertise in the conduct of early phase clinical trials with special requirements, such as with psychedelics. Whether your approach is high or low dose, we can help design and conduct your study to meet your unique goals, with careful consideration of the many nuances and challenges of psychedelics clinical research trials. With our passion for the potential of psychedelics to revolutionize mental health care, we can be your trusted partner in helping make it a reality.
Written by Sofia Raitsin, Ph.D. – Sr. Pharmacology Scientist at Bio Pharma Services.
Recommended Read – blog posts from BioPharma Services about our Bioanalytical Methods for Psychedelics:
– CLINICAL RESEARCH SPOTLIGHT: PSILOCYBIN AND PSILOCIN METHOD
– CLINICAL RESEARCH SPOTLIGHT: KETAMINE, NORKETAMINE AND HYDROXYNORKETAMINE
Find out why BioPharma might be the right partner for you! Learn more about BioPharma Services and the wide array of services we provide.
BioPharma Services, Inc., a Think Research Corporation and clinical trial services company, is a full-service Contract Clinical Research Organization (CRO) based in Toronto, Canada, specializing in Phase 1 clinical trials 1/2a and Bioequivalence clinical trials for international pharmaceutical companies worldwide. BioPharma has clinical facilities both in the USA and Canada with access to healthy volunteers and special populations.