Abstract

As psychedelic‐assisted therapy practice advances, it becomes increasingly important to recognize potential adverse effects and drug‐drug interactions for the successful integration of this novel psychiatric treatment paradigm into existing mental health care systems. As these medications move outside of carefully controlled clinical trial settings and closer to outpatient behavioral health clinics, it will become imperative to more thoroughly understand all of the safety risks with these agents. This talk will provide a brief overview of the current pharmacodynamic and pharmacokinetic scientific literature of three separate psychedelic‐assisted therapy medications ﴾psilocybin, MDMA, ketamine﴿ under investigation for a variety of medical indications. Coadministration of certain psychiatric medications that also bind to 5‐HT2A receptors, such as buspirone and antipsychotics ﴾chlorpromazine, haloperidol, risperidone﴿, have reduced the subjective effects of psilocybin by ~40–99%, which could theoretically decrease efficacy. Psilocybin’s primary active metabolite is a substrate for UGT1A9 and UGT1A10 enzyme glucuronidation, so coadministration of medications inhibiting these enzymes may theoretically increase dose‐related adverse effects of psilocybin.
Recent exposure to antidepressants has been shown to reduce the efficacy of MDMA for PTSD, and if combined with monoamine oxidase inhibitor antidepressants may have substantial safety risks including death. Ketamine efficacy may be diminished by medications that act on glutamate systems, such as memantine, lamotrigine and clozapine. Oral ketamine is also highly susceptible to drug‐drug interactions with CYP2B6, CYP2C9 and CYP3A4 enzyme inhibitors or inducers.

In the process of establishing best clinical practices for psychedelic‐assisted therapy it will be critical to evaluate each specific mediation’s unique pharmacological profile in order to mitigate the risk of adverse effects and drug‐drug interactions in the course of providing optimal mental health care. Each drug’s pharmacodynamic mechanism of action, binding affinity and pharmacokinetic metabolic profile presents unique safety considerations for the successful implementation of psychedelic‐assisted therapy into broader psychiatric practice. This presentation will address what is currently known about the safety of psilocybin, MDMA, and ketamine, while also considering what clinical questions require further investigation.