Psychedelics are a group of drugs that facilitate the experience of non-ordinary states of consciousness through the activation of serotonin 5-HT2A receptors. This group includes psilocybin (a molecule present in 200+ mushroom species), lysergic acid diethylamide (LSD), and mescaline. An expanding body of research suggesting that psychedelics could treat CNS disorders like substance abuse, depression, chronic pain, and schizophrenia has sparked a renewed interest in recent years by drug developers and investors. A recent search of ClinicalTrials.gov shows nearly 300 trials of psychedelics currently registered.

As the field of psychedelic drug development advances, several challenges are surfacing. These challenges include selecting an appropriate control condition, implementing guided therapy, navigating a regulatory landscape with limited guidance, and the sub-field of microdosing.

Selecting an Appropriate Control Condition

A placebo-controlled study design is the gold standard for clinical trials conducted to support a marketing application. Psychedelics (with the probable exception of microdosing) present a unique challenge because of their hallucinogenic effects. These effects would make it apparent to both investigators and participants whether an active substance or the placebo was received. Additionally, since some of the proposed treatments, such as those being tested for treatment-resistant depression, are designed as a single treatment rather than an on-going treatment regimen, cross-over designs may not be feasible. Many early phase studies that have been conducted are open-label. Some studies use a comparison to a behavioral intervention or an active comparator. Still, others are moving forward with a placebo-controlled randomized design despite the likelihood that participants may become aware of their treatment assignment.

Guided Therapy

In many instances, regulators are mandating psychotherapy in conjunction with the administration of psychedelics in a research setting to ensure participants’ physical and psychological safety. This therapy often includes a preparation session between a trained therapist and the participant the day before drug administration to help the participant understand what to expect. The therapist helps the participant practice skills which will help the participant have the best possible experience. During the administration, a therapist trained as a guide is present during the entire experience. At a follow-up integration session after the psychedelic experience, the guide supports the participant through the experience and helps them make sense of it. In some instances, studies offer additional follow-up sessions using talk-based psychotherapy.

Designing the guided therapy is an important part of the study design. Regulators will expect it to be highly structured to ensure each participant has a similar experience and to decrease variability. In the US, two trained therapists are required during the session where the drug is administered. It is crucial that all guides are adequately trained. In addition to appropriate professional credentials and experience related to psychotherapy, training for guides may include a combination of online training, in-person training, clinical training, and on-going professional development.

Limited Regulatory Guidance

For many years, research into psychedelics was extremely restricted and, in some cases, banned. Because of the recency of renewed interest in psychedelic research and the particular challenges research in this area faces, there is limited guidance and precedence available from regulatory agencies about how to proceed. Although new guidance from regulators has been expected for some time, no formal guidance has been published yet. Drug developers will need to seek direct guidance from regulators beginning early in their program.

Microdosing

Microdosing has been practiced for hundreds of years. By the 1960s, there was a growing body of evidence suggesting that microdosing of psilocybin and LSD could potentially increase cognition and creativity. Government agencies halted the majority of scientific investigations of microdosing by the late 1960s over concerns about recreational use. As the investigation of psychedelics for medical use has seen a significant revival in recent years, interest in exploring microdosing has grown as well.

Microdosing is characterized by three features—a low dose that does not impair normal functioning, multiple dosing sessions, and an intention to improve well-being or enhance cognitive processes. The study of microdosing avoids some of the pitfalls of other studies of psychedelics, yet it carries some unique challenges. Because it involves doses so low that any perceptual effects are absent, microdosing avoids the deleterious consequences of hallucinations. Additionally, microdosing does not have the same problems with control conditions. Participants can be properly blinded to a placebo condition because the active component does not result in psychedelics’ pharmacological effects. Some have argued there are fewer safety concerns given historical indications that this is a relatively safe practice.

There are also challenges associated with microdosing. One is that there are no current standards for what dose is considered a microdose. Current studies are using a fairly wide range of doses—anywhere from .045 mg/kg to 0.315 mg/kg. Additional work is needed to determine optimal dosing. The risk-benefit profile is also different. Many other psychedelic studies are targeting diseases and disorders where there is a significant unmet medical need. Existing treatments for conditions like substance abuse, treatment-resistant depression, schizophrenia, and chronic pain leave patients with significant unaddressed or under-addressed symptoms. Most microdosing studies are targeting cognitive improvements in otherwise healthy patients. The bar for safety is much higher for use in a healthy population. Although there is a historical basis for believing that microdosing is safe, there is limited nonclinical and clinical data supporting this belief, and additional animal and human safety studies are needed.

Conclusion

The emerging field of psychedelic drug development presents exciting opportunities to address important unmet medical needs for CNS disorders. While there are some significant challenges, the potential to make significant strides in improving patients’ lives provides a sense of optimism for the future of the field. As a leader in CNS clinical research, VeraSci is well positioned to assist with developing your psychedelic product. Contact us to learn more about how we can support your development program.

References