Pharmacists and psychedelic medicine

Pharmacists will increasingly field questions about psychedelic medicines as FDA approval of MDMA for PTSD and psilocybin for major depressive disorder is expected in 2024 and 2025, respectively. Psychedelics differ from other mental health treatments by requiring only a few doses with psychological support, spaced months apart, which may yield enduring symptom improvements. Policymakers have proposed various regulatory frameworks for public access beyond FDA approval, including religious use protected by the Religious Freedom Restoration Act and state-level systems in Oregon and Colorado. Pharmacists must educate themselves on pharmacological mechanisms, adverse effects (e.g., transient anxiety, elevated heart rate, rare serotonin toxicity, valvular heart disease risk with microdosing), and drug–drug interactions. Professional guidelines and a dramatic increase in psychedelic research publications support this emerging field.

Study at a glance

Abstract

In coming years, pharmacists will begin fielding more questions regarding psychedelic medicine, most notably with the imminent FDA approval of 3,4-methylenedioxymethamphetamine (MDMA) for posttraumatic stress disorder (PTSD) expected in 2024 and psilocybin for major depressive disorder (MDD) likely in 2025. Psychedelics are unique medications in many ways, but especially due to the mental health treatment paradigm shift of only taking a few doses with psychological support spaced months apart, which appears to yield enduring improvements in psychiatric symptoms. Another major reason psychedelics are different from other mental health treatments is that policymakers have also proposed various regulatory frameworks for public access outside of the FDA approval process as summarized in this issue of the Journal. Given these various pathways for public access to psychedelics, it will become critically important for pharmacists to educate themselves regarding the pharmacological mechanisms of action, adverse effects, and drug–drug interactions related to various psychedelics. In addition to accessing MDMA and psilocybin in medical settings, people may also be accessing them and other psychedelics like LSD, ayahuasca (DMT + harmala alkaloids), 5-MeO-DMT, ibogaine, and mescaline, outside of medical settings. For example, religious use of psychedelics has been protected by the Religious Freedom Restoration Act, and more recently, states like Oregon and Colorado have passed legislation to establish their own systems of access to psychedelics. Several board-certified psychiatric pharmacists are already trained in psychedelic-assisted therapy and professional organizations like Psychedelic Pharmacists Association (PPA) were founded to advocate, educate, and collaborate with stakeholders in this emerging field. This summer the FDA released a Draft Guidance “Psychedelic Drugs: Considerations for Clinical Investigations” and American Psychedelic Practitioners Association (APPA) also released their first draft of “Professional Practice Guidelines for Psychedelic-Assisted Therapy Practitioners.” These guidance and guideline documents provide useful entry points for pharmacists who are interested in learning more about psychedelic-assisted therapy. There has also been a dramatic increase in journal publications related to psychedelics during the past two decades, with about 50 per year in 2000 to about 700 per year in 2020. There are many potential interdisciplinary research applications for psychedelics, from discovering new treatments to investigating the fundamental phenomenology of consciousness. Pharmacists' specialized knowledge of pharmacodynamics, pharmacokinetics, and drug–drug interactions are particularly important for interdisciplinary care teams and public education, which may help enhance the safety and efficacy of psychedelics in a variety of settings. While most classic psychedelics like psilocybin are categorized by their 5-HT2A partial agonism, there are other “psychedelic” compounds like MDMA that increase serotonin signaling by vesicular monoamine transporter 2 (VMAT2) inhibition or other mechanisms of action depending on the molecule in question. This pharmacological activity may also result in common adverse effects like transient anxiety, illusions, disordered thinking, paranoia, headache, fatigue, nausea, and elevated heart rate or blood pressure. Outside of clinical trials, more rare and potentially serious adverse effects documented from epidemiologic studies or case reports have included seizures, serotonin toxicity, suicidal ideation, and hallucinogen persisting perceptual disorder (HPPD). There have also been reports of psychedelics triggering manic or psychotic episodes in people diagnosed with bipolar disorder or schizophrenia, which is why these populations have been largely excluded from modern clinical trials. As psychedelics move into medical systems, and through other pathways of public access, the most common questions for pharmacists will likely be related to drug–drug interactions. There have been relatively few clinical trials investigating drug–drug interactions, but a recent systematic review summarized the medical literature regarding psilocybin and MDMA drug–drug interactions. Another review also evaluated the risk of serotonin toxicity with psychedelics and found a similar pattern to other medications already on the market, which suggests that when drugs increasing serotonin in the synapse (e.g., SSRI's and MDMA) are combined with drugs preventing metabolism of serotonin (e.g., MAOI's and harmala alkaloids from ayahuasca brew with reversible inhibition of monoamine oxidase A), the risk of serotonin toxicity increases dramatically. Another recent trend in modern psychedelic use is the preponderance of “microdosing” psilocybin or LSD for a variety of reasons despite negligible evidence suggesting any benefit or safety. This is particularly concerning because both psilocybin and LSD have very strong binding affinity for the 5-HT2B receptor in heart valves, which has been associated with valvular heart disease (VHD) for other drugs removed from the market. Similar to microdosed psychedelics, pergolide is a drug with comparable low doses and plasma concentrations that was associated with a lifetime exposure-related risk of VHD and subsequently removed from the market. Therefore, I am very concerned that we may begin to see more VHD cases as more people microdose continuously, and if they are not disclosing microdosing to healthcare providers, it will be very difficult to recognize cardiac deaths related to VHD. Pharmacists are uniquely positioned to facilitate the transition from clinical trials to clinical practice in this emerging field of Received: 1 September 2023 Accepted: 4 September 2023