Introduction—Why the Psychedelic Revolution in Psychiatry?

Research leading to the discovery of new pharmacological treatments for psychiatric disorders has been painfully slow. With a few exceptions, including the use of orexin antagonists for insomnia, current medicines are derivatives of drugs discovered in the 1950s through serendipity and refined through pharmacological modifications. For these reasons, most major pharmaceutical companies have retreated from researching brain targets, threatening to halt a progression in research knowledge and possibly inducing the same sort of dark age that antibiotic research has found itself in.

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Nutt D.J. Psychiatry & the psychedelic drugs. Past, present & future. One way out is to revisit drugs that were once used but fell out of use because of political machinations, especially the war on drugs (). Cannabis was the first to be resurrected and the glutamate receptor antagonist anesthetic ketamine has recently been shown to have antidepressant properties, leading to the enantiomer esketamine becoming licensed in the USA and Europe. Now, serotonergic psychedelics, particularly psilocybin (the active compound in “magic mushrooms”) are being resurrected as potential treatments for a range of different psychiatric disorders (). These drugs include LSD, ayahuasca (a drink that contains dimethyltryptamine [DMT] and a monoamine oxidase inhibitor that prevents its breakdown in the gut), as well as 5-MeO-DMT (from the Sonora toad) and mescaline (from the peyote cactus). In the 1950s and 1960s, LSD was widely researched and was considered to achieve major breakthrough treatments by many psychiatrists. At the same time, psilocybin was an experimental medicine supplied by Sandoz as “Indocybin”. However, once LSD became used recreationally by young people, it was banned and most other psychedelics were sucked into the legislation; research on their potential therapeutic efficacy ground to a halt. In the past decade, research on these compounds has been re-established by a few groups around the world, culminating in new centers for psychedelic research at Imperial College London and Johns Hopkins University.

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The Safety and Efficacy of Psilocybin in Participants With Treatment Resistant Depression (P-TRD). 2020b U.S. National Library of Medicine.

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Nutt D.J. Psychiatry & the psychedelic drugs. Past, present & future. Because psilocybin is a Schedule 1 controlled drug, meaning that it has been defined as having high potential for abuse with limited therapeutic utility, it took several years of battling with regulators and ethics committees to gain permission to do clinical research with it, but the struggle was worth it. Its effects on patients suffering from depression were remarkable—e.g., two experiences with psilocybin improved depression scores for weeks, and in some people, years (), positioning it as one of the most powerful therapeutics for treatment-resistant depression. There have also been three placebo-controlled trials of psilocybin for anxiety and depression related to end-of-life diagnoses (reviewed in). Based on this body of positive findings, at least two companies have been set up to take psilocybin to the clinic, funding multi-center dose-finding studies of psilocybin in depression (). In parallel, we will soon be completing a double-blind trial of psilocybin versus the selective serotonin reuptake inhibitor (SSRI) escitalopram in depression (). There have also been studies showing efficacy in alcoholism and tobacco dependence (), and similar studies in anorexia, obsessive-compulsive disorder (OCD), chronic pain, and opioid use disorder are being developed.

Carhart-Harris and Nutt, 2017 Carhart-Harris R.L.

Nutt D.J. Serotonin and brain function: a tale of two receptors. This might seem a strange and disparate set of disorders for a single medicine to work in, and this speaks to the innovative nature of psychedelic therapy. In most studies, the psychedelic is given just once (though in a few studies, twice or three times over a period of weeks) as part of an ongoing psychotherapy course, in complete contrast to currently available medications, which are given at least daily, often with little therapeutic support. We suggest one way of looking at the difference between them is that current medicines suppress symptoms in a similar way that insulin suppresses hyperglycemia in diabetes. Standard antidepressants protect against the stressors that lead to and perpetuate depression, but don’t directly access and remedy underlying biopsychosocial causes. In contrast, psychedelic therapy harnesses a therapeutic window opened up by the brain via the effects of the drugs to facilitate insight and emotional release and, with psychotherapeutic support, a subsequent healthy revision of outlook and lifestyle ().