Psilocybin and psychedelic medicines
Psilocybin, a psychoactive compound of magic mushrooms, was first marketed for clinical research in the 1960s, was then abused as a recreational drug, and went unresearched for 30 years. In trials, only high doses have shown a potential to treat depression in patients with advanced cancer, and one clinical study found that higher doses brought more frequent adverse effects. Psilocybin can be extracted from the mushroom, made by microbial fermentation or synthesised. In 2023 regulators stood at different points on it and on other psychedelics, such as MDMA, LSD, DMT and mescaline.
What psilocybin is and why research on it stopped
Psilocybin is a natural psychoactive tryptamine found in so-called magic mushrooms, most commonly of the genus Psilocybe. A. Hofmann first isolated it industrially, from the Mexican mushroom Psilocybe mexicana, and Sandoz first marketed synthetic psilocybin in the 1960s under the brand name Indocybin. It was marketed at first for clinical research but was abused as a recreational drug, so research on it was put on hold for 30 years.
Effects and adverse effects in trials
Clinical trials have shown that, in small doses, psilocybin can help people reach a mystical experience, an altered state of consciousness. Only high doses showed a potential to treat the depressive state and negative attitude of patients with advanced cancer, as the patients and their observers confirmed. The treatment increased the patients' overall wellbeing. However, a clinical study by Griffiths and colleagues confirmed that higher doses led to more frequent adverse effects: headaches, nausea, dizziness and anxiety. Reports of higher anxiety, though from a small number of patients, are common to almost every clinical trial of psilocybin.
Production
Psilocybin can be isolated from magic mushrooms, produced by microbial fermentation in prokaryotic or eukaryotic hosts, or synthesised chemically from hydroxyindole. Flower and colleagues used genetically modified E. coli to synthesise psilocybin, at about 30 mg/L, and 13 of its derivatives from tryptamine at small scale. This de novo synthesis had been tested only at microscale, and its suitability for industrial-scale production should be analysed. In 2023 microbial fermentation was limited by the need to optimise its methods for higher yield, purification and scale-up.
Status as a medicine
In 2023, according to the executive director of the European Medicines Agency (EMA), no authorised psilocybin product was on the market and 11 clinical trials were ongoing. Australia approved psilocybin for medicinal use in psychiatric patients in 2023. As of July 2023, Australia allowed psilocybin and MDMA (ecstasy) to be prescribed as medicines. In 2023 the director of psychiatry at the US Food and Drug Administration (FDA) still called psilocybin an investigational product.
Regulation of psychedelics
In August 2023 the FDA published a draft, non-binding guidance on developing psychedelics, focused on conducting clinical trials, data collection and patient safety. Under it, an applicant must in general provide sufficient chemistry, manufacturing and controls data, and the application varies with the substance's origin, such as plant material or algae. The EMA indirectly followed the FDA in September 2023 with a draft guideline on clinical trials in major depressive disorder. The draft also concentrates on psychotropics, naming psilocybin, LSD, DMT and mescaline, and acknowledges major challenges in their trials: placebo, comparator, expectancy and unblinding, dosing, maintenance of effect, safety and psychotherapy. It recommends seeking scientific advice before such a trial, because psychotropics are complex and their side effects raise safety concerns.
In a letter of March 2023, the EMA's executive director confirmed that the agency wanted to focus on promoting the development of psychedelics for unmet medical needs, especially mental health conditions, as their risk profile seemed low. In 2023 research on psychotropics in Europe was still very restricted compared with Canada, the US and Australia.
Magic mushrooms are generally considered illegal to cultivate, sell, transport and possess, except in a few countries such as the Netherlands and Austria.