Psychedelic Therapy: A Primer for Primary Care Clinicians – Part I. Historical Perspective and Overview

Background: Psychedelic drugs have recently emerged as plausibly effective pharmacological agents for the management of depression, anxiety, and other neuropsychiatric conditions, including conditions that have not benefited from prior interventions. The latter half of the twentieth century marked a revolution in the treatment of depression, anxiety, and psychosis, exemplified by the introduction of selective serotonin reuptake inhibitors, dopamine antagonists, and other pharmacological agents. Nevertheless, mental illness remains a major public health crisis, affecting nearly one billion individuals worldwide. Areas of Uncertainty: Due to the recency of the resurgence in psychedelic research, there are still only a small number of large, double-blind, placebo-controlled, randomized clinical trials of psychedelics in psychiatric populations. While initial clinical trials of psychedelics for depression were very promising, trials of psilocybin with larger sample sizes (100+ participants) seem to suggest that it may not be more effective than antidepressants.Therapeutic Advances: Esketamine, a dissociative hallucinogen drug, was approved for the management of major depressive disorder by the Food and Drug Administration (FDA) in 2019. As of December 2023, two Phase III trials of 3,4-methylenedioxymethamphetamine (MDMA), a synthetic drug that inhibits the serotonin transporter, have been completed; the results indicate that MDMA is superior to existing pharmacological treatments for post-traumatic stress disorder. A phase III trial of psilocybin, a naturally occurring serotonin receptor partial agonist, is currently underway. The following series details the current state of research in psychedelic therapeutics, including lysergic acid diethylamide (LSD), N-N-dimethyltryptamine (DMT) and ayahuasca, psilocybin, ibogaine, MDMA, and ketamine.

Conclusions: Psychedelic drugs and structural derivatives offer a great deal of promise for the management of a wide range of psychiatric morbidities. It is imperative that clinicians become familiar with these novel agents and learn how to implement psychedelic therapeutics as part of a patient-centered care paradigm.