Psychedelics and Psychedelic-Assisted Psychotherapy, Collin M. Reiff et al., 2019

Psychedelics and Psychedelic-Assisted Psychotherapy

Collin M. Reiff, M.D., Elon E. Richman, M.D., Charles B. Nemeroff, M.D., Ph.D., Linda L. Carpenter, M.D., Alik S. Widge, M.D., Ph.D., Carolyn I. Rodriguez, M.D., Ph.D., Ned H. Kalin, M.D., William M. McDonald, M.D., and the Work Group on Biomarkers and Novel Treatments, a Division of the American Psychiatric Association Council of Research

AJP in Advance, 2019, 1-20.

doi: 10.1176/appi.ajp.2019.19010035


Objective : The authors provide an evidenced-based summary of the literature on the clinical application of psychedelic drugs in psychiatric disorders.

Methods : Searches of PubMed and PsycINFO via Ovid were conducted for articles in English, in peer-reviewed journals, reportingon“psilocybin,” “lysergic acid diethylamide,” “LSD,” “ayahuasca,” “3,4-methylenedioxymethamphetamine,” and “MDMA,” in human subjects, published between 2007 and July 1, 2019. A total of 1,603 articles were identified and screened. Articles that did not contain the terms “clinical trial,” “therapy,” or “imaging” in the title or abstract were filtered out. The 161 remaining articles were reviewed by two or more authors. The authors identified 14 articles reporting on well-designed clinical trials investigating the efficacy of lysergic acid diethylamide (LSD), 3,4- methylenedioxy-methamphetamine (MDMA), psilocybin, and ayahuasca for the treatment of mood and anxiety disorders, trauma and stress-related disorders, and substancerelated and addictive disorders as well as in end-of-life care.

Results : The most significant database exists for MDMA and psilocybin, which have been designated by the U.S. Food and Drug Administration (FDA) as “breakthrough therapies” for posttraumatic stress disorder (PTSD) and treatment-resistant depression, respectively. The research on LSD and ayahuasca is observational, but available evidence suggests that these agents may have therapeutic effects in specific psychiatric disorders.

Conclusions : Randomized clinical trials support the efficacy of MDMA in the treatment of PTSD and psilocybin in the treatment of depression and cancer-related anxiety. The research to support the use of LSD and ayahuasca in the treatment of psychiatric disorders is preliminary, although promising. Overall, the database is insufficient for FDA approval of any psychedelic compound for routine clinical use in psychiatric disorders at this time, but continued research on the efficacy of psychedelics for the treatment of psychiatric disorders is warranted.


Timothy Leary’s dead…” —The Moody Blues, 1968

Although hallucinogens derived from plants have been used in religious practices for centuries, it was not until 1938 that the Swiss chemist Albert Hofmann synthesized the first synthetic hallucinogen, lysergic acid diethylamide (LSD), while working with the pharmaceutical company Sandoz (1, 2). On April 16, 1943, during a series of experiments, Hofmann serendipitously came into physical contact with LSD, which resulted in “an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors” (1). In 1947, Sandoz began to market LSD under the trade name Delysid as an adjunctive psychotherapy medication and as an agent for experimental study on the nature
of psychoses (1).

In 1960, Harvard psychologist Timothy Leary began experiments under the Harvard Psilocybin Project to determine whether psilocybin was an effective adjuvant agent in psychotherapy. Leary also experimented with LSD and eventually became a polarizing figure who was dismissed from Harvard, along with his colleague Richard Alpert, in 1963. The last of the Sandoz patents for the production of LSD expired in 1963, and illicit production of LSD increased as it was being used widely in medically unsupervised settings (1). In 1965, governments in Europe and the United States raised concerns about the general public’s use of LSD and psilocybin. The U.S. Congress passed the Drug Abuse Control Amendments, which made the sale and manufacture of LSD without a license a misdemeanor and forced all researchers who had not been granted Investigational New Drug exemptions by the U.S. Food and Drug Administration (FDA) to relinquish their supplies of LSD (1). Clinical experimentation and research with psychedelics consequently decreased and were ultimately halted by the Controlled Substances Act of the ComprehensiveDrug Abuse Prevention and Control Act of 1970.

Although Timothy Leary died in 1996, the lyrics by Ray Thomas of the Moody Blues almost three decades earlier were prescient: psychedelic research was indeed dead after the passage of the Controlled Substances Act. The following year, President Richard Nixon declared the “War on Drugs,” and much of the experimentation in psychedelics moved underground in counterculture movements that spread
across the United States and Europe.

Over the course of the past decade, there has been a resurgence of research on the potential therapeutic benefits of psychedelic compounds, with the number of published review articles and clinical trial reports steadily increasing. Research on these compounds has been supported by diverse organizations ranging from the United Kingdom Medical Research Council, a nationally funded health agency, to the Multidisciplinary Association for Psychedelic Studies (MAPS), a nonprofit organization that was founded in 1986 to increase the knowledge base of psychedelic substances. Additional support has come from the Heffter Research Institute, a nonprofit scientific organization founded in 1993 that promotes research with the classic hallucinogens and related compounds, and the Beckley Foundation, a U.K.-based research and non-governmental organization focused on pioneering psychedelic research and evidence-based drug policy reform. These organizations have helped fund many pivotal trials and often work with regulatory agencies, including the FDA and the European Medicines Agency, to ensure that studies conform to the requisite regulatory guidelines for eventual approval of clinical use. Contemporary psychedelic drug research has been conducted at leading academic research universities around the world, including Johns Hopkins University, New York University, University of California, Los Angeles, Imperial College London, University of Zurich, and University of Basel. Recently, Johns Hopkins University and Imperial College London established centers for psychedelic research, which aim to investigate the effects of psychedelic drugs on the mind, the brain, and psychiatric disorders.

The U.S. Drug Enforcement Administration (DEA) currently classifies LSD, ayahuasca, psilocybin, and 3,4- methylenedioxymethamphetamine (MDMA) as Schedule I substances, reflecting a lack of any accepted medical use or safety data and their potential for abuse. This review is intended to summarize the evidence base, including all of the available research in the scientific literature, for the safety and efficacy of psychedelic compounds in the treatment of psychiatric disorders.