(CRD420251063539).

Results: Of 465 screened studies — five RCTs met selection criteria (N = 227). Our synthesis and random-effects meta-analysis demonstrated that LSD treatment significantly reduced depression symptoms compared to the comparator (SMD = -0.65; 95% CI: -0.92 to -0.38, p = 0.000002). Studies varied in design and three of the included studies administered LSD with psychological support, although study-level heterogeneity was not significant (I2 =0%, p = 0.54). Three studies had low risk of bias. All-cause discontinuation demonstrated reasonable acceptability of LSD treatment. Severe adverse events possibly related to study parameters included hospitalizations (N = 3) and acute anxiety/delusions (N = 1).