Mr. P, age 65, has a history of major depressive disorder (MDD), generalized anxiety disorder, and social phobia. Mr. P’s personality is high in neuroticism and he has often responded to new situations with feelings of impending doom. For him, fear, anxious rumination, helplessness, and catastrophizing are familiar mental processes.
When he was in his 30s, Mr. P had a severe major depressive episode with suicidal ideation and sought care from a psychiatrist. He began a treatment program of psychotherapy and concomitant psychopharmacotherapy with consecutive trials of fluoxetine, sertraline, and amitriptyline, each of an adequate dose and duration. With each medication, Mr. P experienced new adverse effects, including nausea, constipation, tremors, and headache. His psychiatrist transitioned him to bupropion, which helped Mr. P most. For the next several decades, Mr. P continued to experience low-grade depressive symptoms with intermittent exacerbation to mild-to-moderate major depressive episodes, but he remained adherent to his medication and continued psychotherapy.
Shortly after his 65th birthday, Mr. P experiences progressively worsening nausea and abdominal pain. Initially, he assumes the symptoms are secondary to anxiety. Taking his psychiatrist’s advice, Mr. P visits his primary care physician. A work-up reveals that Mr. P has advanced pancreatic cancer, and an oncologist estimates Mr. P has 6 months of life remaining.
Following his cancer diagnosis, Mr. P quickly develops symptoms of MDD despite continuing to take bupropion. Within a week he becomes withdrawn and hopeless, and thinks about ending his life “before God does.” His psychiatrist urges Mr. P to contact the local academic medical center because it is conducting a trial of a “new” drug, psilocybin, to treat anxiety and depression in patients with terminal illness.
Beginning in the 1940s, a growing body of scientific evidence suggested that psychedelic compounds such as lysergic acid diethylamide (LSD) could benefit individuals with various psychiatric maladies. Research interest in LSD and substances with similar effects persisted until the late 1960s. In response to the growing counterculture movement in the United States and the efforts of Harvard researchers Timothy Leary and Richard Alpert to popularize psychedelic drug use in the general population, in 1970 President Richard M. Nixon signed the Controlled Substances Act (CSA) into law. The CSA categorized LSD as a Schedule I drug, rendering its manufacture and distribution illegal. Research into the potential therapeutic benefits of LSD was effectively halted.1 In recent decades, however, there has been a quiet but growing renaissance of scientific interest in the effects of psychedelics on a variety of conditions, including terminal illness–related anxiety and depression, treatment-resistant depression, and substance use disorders (SUDs). One example is psilocybin, which is currently undergoing Phase 2 and 3 clinical trials in North America and Europe for treatment-resistant depression.
As researchers have once again picked up the torch in the pursuit of psychedelic therapeutics, jurisdictions in the United States are also relaxing their stance on these drugs. In 2019 and early 2020, Denver, Oakland, and Santa Cruz became the first 3 cities in the United States to decriminalize the possession of various psychedelic substances.2-4 With the passage of Measure 109 in November 2020, Oregon became the first state to decriminalize the use of psychedelic mushrooms in therapeutic settings.5 The combined forces of increased research and relaxed political concern related to psychedelics might make it possible for the FDA to approve their use for psychiatric conditions. Therefore, it is critical for psychiatrists to understand the psychopharmacology, range of effects, and potential risks and benefits of these agents. In this article, I describe what psychedelics are and how they work, summarize a few research findings about psilocybin, and offer a framework for psychedelic psychiatric practice in the years to come.
What are psychedelics?
Psychiatrist Humphry Osmond first coined the term “psychedelic” in 1957 at a meeting of the New York Academy of Sciences, where he was discussing his research on the effect of LSD on patients at the Weyburn Mental Hospital in Saskatchewan, Canada.6 Prior to 1957, LSD had been described as a “psychotomimetic” drug because it was believed to induce a state of psychosis similar to that experienced in schizophrenia. But LSD does not generally induce frank auditory hallucinations or clearly defined delusional beliefs. Osmond’s new term—derived from the Greek words psyche, meaning “mind,” and delos, meaning “to show”—referred to the “mind-manifesting” capacities of LSD and related drugs.6 Psychedelic drugs can cause an array of changes to an individual’s conscious experience, from relatively mild changes in visual perception to profound derangements in sense of self and reality.
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