Psilocybin, a serotonergic psychedelic, may have therapeutic benefits for Substance Use Disorders (SUDs), but its overall efficacy and safety remain uncertain. This systematic review assessed the safety and efficacy of psilocybin for SUDs through a systematic database search conducted via OVID on May 22, 2024, and summarized 26 ongoing clinical trials registered on clinicaltrials.gov. Among 16 published included studies, 7 (43.75 %) focused on Alcohol Use Disorder (AUD), 5 (31.25 %) on Tobacco Use Disorder (TUD), and the remainder on Cocaine Use Disorder (CUD) (1, 6.25 %), Opioid Use Disorder (1, 6.25 %), Nicotine Use Disorder (1, 6.25 %), and multiple SUDs (1, 6.25 %). Study designs included open-label trials (5, 31.25 %), cross-sectional observational studies (6, 37.5 %), qualitative analyses (2, 12.5 %), one double-blind RCT (6.25 %), one pilot fMRI study (6.25 %), and one long-term follow-up (6.25 %). Psilocybin-assisted psychotherapy (PAP) was used in 10 studies (62.5 %), with doses ranging from microdosing to 20-40 mg/70 kg. PAP was associated with significant reductions in alcohol consumption, smoking cessation, and related psychological improvements. AUD studies reported fewer heavy drinking days, increased abstinence rates, and neuroimaging data indicating normalization of brain activity. TUD studies demonstrated high smoking abstinence rates, with mystical experiences predicting long-term outcomes. Findings for other SUDs were mixed, though psilocybin showed potential in reducing opioid dependence and nicotine use. Preliminary evidence supports psilocybin's efficacy and safety for AUD and TUD, particularly with psychotherapy, but larger clinical trials are needed to confirm these findings.
