A clinical research perspective on the regulation of medical and non‐medical use of psychedelic drugs

Recent experience with off-label use of ketamine and recent challenges experienced in research with MDMA and psilocybin provide additional perspectives on how best to continue development of experimental psychedelic medications. Andrews et al. 1 provide a valuable perspective by noting the parallels between the ongoing deregulation of cannabis and what is now happening with psychedelics. The article paints an accurate picture of how biased media attention and market forces have distorted the public's view of psychedelics and blurred the line between medical and non-medical use. If psychedelics continue down the path blazed by cannabis, the result will likely be increased harms from poorly regulated use, and rigorous clinical research may be impeded. Scientists in the field bear a special responsibility to counteract exaggeration and to emphasize the importance of the distinctions between clinical research, clinical medicine, and non-medical use of psychedelic drugs. Agreeing with this assessment, I have a few additional thoughts about the current situation and what we can do to promote a better outcome. In one sense, psychedelic medicine is already a reality, in that three psychedelic drugs acting primarily as N-methyl-D-aspartate receptor antagonists are currently approved for medical use: racemic ketamine, esketamine and dextromethorphan (available as an over-the-counter cough suppressant). Although esketamine and racemic ketamine (off-label) are established treatments for treatment-resistant depression, empirically-supported treatment models do not attempt to capitalize on their consciousness-altering properties, but rather treat them as side effects 2. However, recent years have seen a marked increase in off-label prescribing of ketamine for many different psychiatric disorders, sometimes using treatment models that may include aspects of psychedelic or psycholytic therapy 3, 4. Much of what is being done with ketamine currently lacks empirical support, and there is an urgent need for better regulation of ketamine prescribing 5 as well as further research on the possible indications and models of treatment. Should psychedelics such as psilocybin and 3,4-methyl​enedioxy​methamphetamine (MDMA) be approved for clinical use, comprehensive risk evaluation and mitigation strategies should be implemented to ensure that the patients will receive treatment under conditions likely to maintain the safety and efficacy demonstrated in controlled clinical trials. Important elements would include careful screening, preparation, and monitoring and support of patients before, during and after treatment, by clinicians with adequate licensure and training. As with any medication, off-label use should be supported by evidence that the treatment could be effective and that the possible benefits outweigh the risk to the patient. The current situation with ketamine provides an object lesson on the importance of such regulatory guardrails. The evidence base for psilocybin- and MDMA-based treatments has grown dramatically in the past several years with the completion of phase 2 and phase 3 multi-site trials in patients with major depression and post-traumatic stress disorder, respectively 6-9. To make further progress in the study of medical uses of psychedelics, the clinical research community will need to tackle the thorny methodological problems that are inherent to research on psychedelics. Many of these issues (e.g. unblinding, expectancy effects, interactions with psychotherapy or other non-pharmacologic treatment, moderating effects of patient characteristics and desired outcomes) are relevant to most if not all psychopharmacologic research, although they are often ignored in clinical trials. More particular to psychedelics is the possibility that a significant proportion of the treatment effect may be mediated by what the patient experiences under the influence of the drug. One of the more consistent findings in clinical psychedelic research has been moderate to strong correlations between aspects of the drug experience and subsequent clinical improvement 10-15. However, without further information it is not possible to know whether these experiences are an epiphenomenon or are causally related to at least some of the therapeutic effects. The complicated challenges of psychedelic research have been discussed extensively during the past several years by stakeholders including regulatory and health research agencies, pharmaceutical corporations and consultants, academic institutions and research scientists. These complications are a big part of why research on psychedelics is interesting and important. Methodological innovations designed to address these challenges will likely be applicable to other areas of pharmacologic research. Benefiting from the lessons of the 1960s, the early 21st century and the present day, we now have the opportunity to think more clearly about both medical and non-medical use of psychedelics. If we avoid repeating the mistakes of the past and continue to improve the quality of clinical research, we may finally learn what useful roles psychedelic drugs can play as medicines. Michael P. Bogenschutz: Conceptualization; writing—original draft; writing—review and editing. During the past 36 months I have received support for research from: Mind Medicine, Tilray Canada, Lykos Therapeutics and B. More. I currently serve on the Advisory Board of: Ajna Labs, Journey Colab and Bright Minds Biosciences.