Behavioural Investigations of Psilocybin in Animals 1962-2021: A Scoping Review

Abstract Background and Aims Psilocybin is a psychedelic drug that may hold promise for a wide range of human health conditions, yet the identification of therapeutic processes and mechanisms of action remains exploratory. We conducted a scoping review on pre-clinical behavioural investigations of psilocybin in non-human animals to help determine the behavioural effects of psilocybin in non-human animals, to identify studies completed, behavioural tests employed, and what dosing modalities had been studied.

Methods: A librarian-conducted literature search was performed using predefined key terms and search criteria and additional searching was conducted by reviewers, using electronic databases, grey literature sources, and reference lists of relevant articles or reviews. The final search updated occurred in October, 2021. Studies were reviewed, screened and selected against an a priori protocol using Covidence software by multiple reviewers with results plotted across the Research Domains Criteria construct.

Results: From 4124 records identified by database searching, 260 publications were subjected to full-text review with 77 studies included in this scoping review, published between 1962-2021. The preponderance of studies (n=64) investigated behavioural outcomes in rodents. Only 43 studies (55.8%) reported on housing conditions, and seventeen studies (22.1%) failed to report sample size. All studies reported behavioural outcomes following drug administration, with fifty-one studies (66.2%) using psilocybin, thirty studies (42.9%) psilocin, four studies (5.2%) administering whole mushroom extracts (WME), and a further eight studies investigating both psilocybin and psilocin and one study reporting the effects of both psilocin and WME. One hundred and thirty distinct behavioural investigations using fifty different behavioral paradigms were identified. Few adverse events were reported, and even exceedingly high doses were apparently well tolerated.

Conclusion: With seventy-seven publications spanning close to sixty years, there is huge variation in study design and quality. Overall psilocybin presents a unique and strong safety profile with no evidence of biological toxicity, is characterized by unique time and dose-dependent effects, and its pattern of drug action is significantly context and training-sensitive. Data suggest putative effects of psilocybin include acute arousal, dose-dependent sedation, reductions in fear conditioning at low doses, reduced aggression, improved valence, acute disruption of working memory, the rescuing of deficits from chronic stress, and improved learning when combined with repeated environmental exposure after resolution of drug effect.