The Current Status of Psychedelics in Psychiatry.

In the 1950s, the Swiss pharmaceutical company Sandoz, which employed the chemist Albert Hofmann, who discovered lysergic acid diethylamide (LSD) and the similar serotonergic psychedelic psilocybin, made these drugs available to the psychiatric research community as the products Delysid and Indocybin, respectively. By the 1960s, these drugs had caused a revolution in brain science and psychiatry because of their widespread use by researchers and clinicians in many Western countries, especially the US. Before LSD was banned, the US National Institutes of Health funded more than 130 studies exploring its clinical utility, with positive results in a range of disorders but particularly anxiety, depression, and alcoholism. However, the displacement of LSD into recreational use and eventual association with the antiVietnam war movement led to all psychedelics being banned in the US. This ban became ratified globally under the 1971 UN Convention on narcotics. Since then, research funding, drug production, and the study of psychedelics as clinical agents has been virtually stopped. Until very recently, no companies would manufacture medical-grade psychedelics, which made getting regulatory approval for clinical research—especially clinical trials—very difficult and in some countries (eg, Germany) impossible. The past decade has seen a resurrection in human psychedelic drug research, especially involving psilocybin. There were 2 drivers to this. The first was the discovery by Griffiths et al1 that a single high dose (25 mg) of psilocybin, given in a psychotherapeutic setting, produced enduring positive changes in mood and wellbeing in people who do not have depression. The second was our series2 of neuroimaging studies in healthy volunteers, which revealed that psilocybin produced profound and meaningful alterations in brain function, especially of the default mode network, consistent with an antidepressant effect. These findings suggested the possible utility of psilocybin for treating depression and initiated the launch of studies in the UK and US that further supported an antidepressant outcome from a single, 25-mg psilocybin dose in people with resistant depression3 and those with anxiety and depression symptoms provoked by life-threatening cancer diagnoses.4,5 There have also been open studies showing efficacy in both alcohol and tobacco dependence.6 Based on these positive findings, at least 2 companies have been set up to take psilocybin to the clinic by funding multicenter, dose-finding studies of psilocybin in depression, and a search of ClinicalTrials.gov (in April 2020) revealed that more than 30 psychedelic drug trials are registered (mostly with psilocybin, although a few are with LSD). These include studies in anorexia, obsessive-compulsive disorder, and addictions, as well as depression. At least 2 of the depression trials7,8 (those of COMPASS Pathways and Usona Institute) are randomized clinical trials compatible with the US Food and Drug Administration and European Medicines Agency registration processes and have been given fast-track status in this field. Many of the trials in other disorders are openlabel designs to gather feasibility and safety data to underpin subsequent double-blind randomized clinical trials. Once these regulatory-standard trials have been conducted, if the outcomes are positive, then it seems plausible that psilocybin will become a licensed medicine for some forms of mental illness when used in an approved treatment model. In the depression trials, the treatment model is becoming standardized as a 4-stage process: assessment, preparation, experience, and integration. Assessment determines if the patient is suitable for psychedelic therapy, both from a mental and physical perspective. Currently, people with a personal or family history of psychosis and bipolar disorder are excluded, as are those with significant health issues (eg, hypertension) because psychedelics transiently increase blood pressure. Certain medications need to be stopped or at least reduced before the treatment, because they can block or attenuate the effect of the psychedelic. Specifically, medicines that block 5-HT2A receptors (eg, amitriptyline, olanzapine, quetiapine, risperidone, trazodone) need to be withdrawn, and serotonin reuptake inhibitors ideally stopped or, if that is not feasible, tapered down, because they produce subsensitivity of the 5-HT2A receptor. In modern studies,3-5 preparation sessions typically take place the day before the drug administration, the participant is prepared for the experience by at least 1 trained therapist, who are often referred to as guides, based on the analogy of the psychedelic experience being a psychological journey. An overview of the dynamics and nature of psychedelic experiences is explained, including how it can be challenging for many people, how any such challenges can be best confronted, and how the participant can get the most out of the experience. During the psychedelic experience, the individual is offered eyeshades and earphones to listen to a music compilation that has been prepared in advance (which they can specify) because music seems to enhance the therapeutic process. For oral psilocybin, the sessions last 4 to 5 hours. Verbal engagement with the therapists is not expected, and most patients go deep into their own visions, thoughts, and memories and do not want to be disturbed. But the guide or guides are present, and with permission, they can hold the patient’s hand to reassure the person that he or she is being looked after. The next day is the integration session—during which the same guide or guides talk through the experience and help the patient make sense of it. Ideally, a small number of standard, talk-based psychotherapeutic sessions are further available for issues that emerged during the psychedelic experience to be processed, VIEWPOINT