The immunomodulatory effects of classical psychedelics: A systematic review of preclinical studies

Emerging evidence suggests that classical psychedelics possess immunomodulatory and anti-inflammatory properties; however, these effects are yet to be well-established. This systematic review aims to provide a timely and comprehensive overview of the immunomodulatory effects of classical psychedelics in preclinical studies. A systematic search was conducted on six databases, including CINAHL, EMBASE, MEDLINE, PsychINFO, Scopus, and Web of Science. Eligible studies targeting classical psychedelics for evaluation of their effects on inflammatory markers and immunomodulation have been included for analysis. Data was extracted from 40 out of 2822 eligible articles, and their risk of bias was assessed using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tool and Quality Assessment Tool for In Vitro Studies (QUIN). Studies examined 2,5-dimethoxy-4-iodoamphetamine (DOI; n = 18); psilocybin (4-PO-DMT; n = 9); N,N-dimethyltryptamine (DMT; n = 8); lysergic acid diethylamide (LSD; n = 6); 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT; n = 3); psilocin (4-HO-DMT; n = 3); and mescaline (n = 2). In 36 studies where inflammatory cytokine levels were measured following psychedelic administration, a decrease in at least one inflammatory cytokine was observed in 29 studies. Immune cell activity was assessed in 10 studies and findings were mixed, with an equal number of studies (n = 5 out of 10) reporting either an increase or decrease in immune cell activity. Classical psychedelics were found to alleviate pre-existing inflammation but promote inflammation when administered under normal physiological conditions. This information is anticipated to inform future clinical trials, exploring classical psychedelics' potential to alleviate inflammation in various pathologies.