Background Psilocybin may help treat obsessive–compulsive disorder (OCD). To date, only one open-label study of psilocybin for OCD exists, necessitating further investigation with a randomized controlled design. The neural correlates of psilocybin’s effects on OCD have also not been studied. Objectives This first-of-its-kind trial aims to evaluate the feasibility, safety, and tolerability of psilocybin in the treatment of OCD, provide preliminary evidence on the effects of psilocybin on OCD symptoms, and elucidate neural mechanisms that may mediate psilocybin’s effects on OCD. Design We use a randomized (1:1), double-blind, placebo-controlled, non-crossover design to examine the clinical and neural effects of either a single dose of oral psilocybin (0.25 mg/kg) or active placebo-control agent (250 mg of niacin) on OCD symptoms. Methods and analysis We are enrolling 30 adult participants at a single site in Connecticut, USA who have failed at least one trial of standard care treatment (medication/psychotherapy) for OCD. All participants will also receive unstructured, non-directive psychological support during visits. Aside from safety, primary outcomes include OCD symptoms over the past 24 h, assessed by the Acute Yale-Brown Obsessive–Compulsive Scale and Visual Analog Scale ratings. These are collected by blinded, independent raters at baseline and the primary endpoint of 48 h post-dosing. Total follow-up is 12 weeks post-dosing. Resting state neuroimaging data will be collected at baseline and primary endpoint. Participants randomized to placebo will be offered the chance to return for an open-label dose of 0.25 mg/kg. Ethics statement All participants will be required to provide written informed consent. The trial (protocol v. 5.2) was approved by the institutional review board (HIC #2000020355) and registered with ClinicalTrials.gov (NCT03356483). Discussion This study may represent an advance in our ability to treat refractory OCD, and pave the way for future studies of neurobiological mechanisms of OCD that may respond to psilocybin.

https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1178529/pdf

Safety, tolerability, and clinical and neural effects of single-dose psilocybin in obsessive–compulsive disorder: protocol for a randomized, double-blind, placebo-controlled, non-crossover trial

Fungi produce diverse metabolites that can have antimicrobial, antifungal, antifeedant, or psychoactive properties. Among these metabolites are the tryptamine-derived compounds psilocybin, its precursors, and natural derivatives (collectively referred to as psiloids), which have played significant roles in human society and culture. The high allocation of nitrogen to psiloids in mushrooms, along with evidence of convergent evolution and horizontal transfer of psilocybin genes, suggest they provide a selective benefit to some fungi. However, no precise ecological roles of psilocybin have been experimentally determined. The structural and functional similarities of psiloids to serotonin, an essential neurotransmitter in animals, suggest that they may enhance the fitness of fungi through interference with serotonergic processes. However, other ecological mechanisms of psiloids have been proposed. Here, we review the literature pertinent to psilocybin ecology and propose potential adaptive advantages psiloids may confer to fungi.

The Evolution and Ecology of Psilocybin in Nature.

Psilocybin is a tryptamine alkaloid found in some mushrooms, especially those of the genus Psilocybe. Psilocybin has four metabolites including the pharmacologically active primary metabolite psilocin, which readily enters the systemic circulation. The psychoactive effects of psilocin are believed to arise due to the partial agonist effects at the 5HT2A receptor. Psilocin also binds to various other receptor subtypes although the actions of psilocin at other receptors are not fully explored. Psilocybin administered at doses sufficient to cause hallucinogenic experiences has been trialed for addictive disorders, anxiety and depression. This review investigates studies of psilocybin and psilocin and assesses the potential for use of psilocybin and a treatment agent in neuropsychiatry. The potential for harm is also assessed, which may limit the use of psilocybin as a pharmacotherapy. Careful evaluation of the number needed to harm vs the number needed to treat will ultimately justify the potential clinical use of psilocybin. This field needs a responsible pathway forward. need for clinical supervision of hallucinogenic experiences. 7 Other limitations include drug safety concerns. This review investigates the pharmacology, risks, and benefits of psilocybin and scope the suitability of this agent as a future pharmacological treatment for a multitude of neuropsychiatric conditions.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/AA1FB4F49C14BA3F398238D6E5A3947A/S1092852922000888a.pdf/div-class-title-psilocybin-in-neuropsychiatry-a-review-of-its-pharmacology-safety-and-efficacy-div.pdf

Arnie Phillips

Papers

Psilocybin in Neuropsychiatry: a review of its pharmacology, safety and efficacy.