Psychedelics as Therapeutics: Gaps, Challenges and Opportunities
The NIH Workshop on Psychedelics as Therapeutics was conducted by the National Institute of Mental Health, the National Institute on Drug Abuse, and the National Institute on Alcohol Abuse and Alcoholism.
The designation “Psychedelics” has meant different things since first coined in 1957. In this workshop we considered classical psychedelics (serotonergic agonists), dissociative anesthetics and entactogens and used “psychedelic’ in an inclusive umbrella fashion. Psychedelic compounds each have their distinctions in mechanisms of action(s), but they have overlapping effects on behavior and on the mind. Psychedelics have well described effects on perception of the exterior world and an individual’s concept of their role within it. But these agents also influence mood, stress management, memory and social functioning. It has been hypothesized that many of these effects may be harnessed to therapeutic benefit in the treatment of serious mental illnesses and substance or alcohol use disorders. However, the high degree of perceptibility of psychedelics presents difficulties in conducting unbiased clinical trials to demonstrate therapeutic efficacy.
The workshop covered the mechanistic understanding of how different psychedelic compounds act and whether perceptual and therapeutic effects might be separated. Clinical study data was presented to understand the current state of understanding of their mode of action and the signs of efficacy seen in trials conducted to date with different patient populations. Those trials highlighted some of the promise of these agents but also the challenge of overcoming confounds in demonstrating clinical therapeutic efficacy of psychedelics. How one might design clinical trials to investigate the safety and efficacy of psychedelic agents to the satisfaction of drug regulatory agencies was then discussed, as was how the settings under which the drugs are administered influences the therapeutic outcomes. Finally, the workshop looked forward to a hypothetical future and the ethical, financial, and practical considerations that might delimit the use of a psychedelic medicine.
Opening Remarks and Keynote Speaker
The meeting is opened by NIMH Director Joshua A. Gordon, M.D., Ph.D. and Franz VollenWeider (University of Zurich) presents an overview of the psychedelic field.
Theme One: Basic and Translational Research
Presenters discuss results of pre-clinical studies, which examine the mechanism(s) of action of psychedelic drugs. The value of the (mouse) head-twitch response to predict psychedelic agents’ clinical efficacy is considered. Presenters report data and discuss whether serotonin 2A receptors (5HT2A) mediate both the mystical and potential therapeutic effects of “classic” psychedelic agents or whether other systems may be involved. Clinical “target engagement” studies demonstrate correlations of 5HT2A receptor occupancy with mystical experiences and show how altered brain network connectivity is associated with psychedelic effects.
- Psychedelics for Mental Health: Translating Preclinical Data Into Clinical Practice
Presenter: Gabriella Gobbi, McGill University
- The Promises and Perils of Psychedelic Pharmacology
Presenter: Bryan Roth, University North Carolina
- How Informative are Preclinical Models of Psychedelic Drug Mechanisms? From 5-HT2A to Another Place far Away
Presenter: Clint Canal, Mercer University
- Optimizing Psychedelics for Treating Neuropsychiatric Disease: The Preclinical Perspective
Presenter: Scott Thompson, University of Maryland
- 5-HT2AR PET Imaging and Functional Connectivity
Presenter: Gitte Knudsen, University of Copenhagen
- Discussion Leader Talk
Presenter: Rob Malenka, Stanford University
Theme Two: Clinical Trials
Researchers discuss the results from clinical trials testing psychedelics as therapeutics for serious mental illnesses, and substance, or alcohol use disorders. The speakers consider what they have learned with regards to safety and efficacy of the compounds, but also outline the confounds they encountered in conducting the research and how they addressed the issues.
- Does Subjective Experience Mediate the Putative Therapeutic Effects of Psychedelics?
Presenter: Michael Bogenschutz, New York University
- Safety and Efficacy of MDMA for the Treatment of PTSD
Presenter: Jennifer Mitchell, University of California San Francisco
- Psilocybin and Smoking Cessation
Presenter: Matthew Johnson, Johns Hopkins University
- Ketamine Assisted Psychotherapy in the Treatment of Alcohol Use Disorder and Other Addictions
Presenter: Celia Morgan, University of Exeter
- MDMA Trial Design, What Have We Learned?
Presenter: Michael Mithoefer, Medical University South Carolina
- Discussion Leader Talk
Presenter: Elias Dakwar, Columbia University
Theme Three: The Future: Overcoming Trial Confounds, and Considering Consequences of Real-World Use
Presenters clarify the role and impact of psychotherapeutic conditions on psychedelic clinical trial outcomes. They also detail the confounds presented by trying to conduct efficacy research with such highly perceptible agents. Whether vulnerable populations should be included in clinical trials is also considered as is how an approved psychedelic drug would be used if approved. An FDA physician-scientist also considers these questions from a regulatory standpoint, discusses potential trial designs that might be used to demonstrate efficacy, and outlines strategies that could be employed to ensure safe use.
- Set and Settings in Psychedelic Clinical Trials and Moving Forward
Presenter: Ido Hartogsohn, Bar-Ilan University
- Overcoming Confounds in Psychedelic Clinical Trials: Designs and Measurement
Presenter: Suresh Muthukumaraswamy, University of Auckland
- Ethical Considerations in Conducting Psychedelic Research
Presenter: Paul Appelbaum, Columbia University
- Considerations of Study Design and Interaction of Medication and Medical Practice in Drug Registration Trials
Presenter: Javier Muniz, U.S. Food and Drug Administration
- Discussion Leader Talk
Presenter: Susan Learned, Independent Pharmaceutical Consultant
- Director’s Summation and Closing Remarks
Presenter: Nora Volkow, National Institute on Drug Abuse
- National Institute of Mental Health
- National Institute on Drug Abuse
- National Institute on Alcohol Abuse and Alcoholism