Efficacy, safety, and tolerability of lysergic acid diethylamide for the treatment of depressive symptoms: A meta-analysis and systematic review

Background: Since the Food and Drug Administration designated lysergic acid diethylamide (LSD) as a “breakthrough” treatment for generalized anxiety disorder, accumulating randomized clinical trials (RCTs) evaluating LSD’s anxiolytic effects have also reported improved depression symptoms. Evaluating the safety and efficacy of LSD in treating depression symptoms is warranted. Methods: MEDLINE/PubMED, Embase, and PsychINFO were searched from inception to December 9, 2025. RCTs evaluating efficacy of LSD on depression symptoms in adults with mental disorders were included. Cochrane Risk of Bias Tool 2.0 and χ 2 and I 2 tests measured quality and heterogeneity. This review was preregistered on PROSPERO (CRD420251063539). Results: Of 465 screened studies, 5 RCTs met selection criteria ( N = 227). Our synthesis and random-effects meta-analysis demonstrated that LSD treatment significantly reduced depression symptoms compared with the comparator (unadjusted standardized mean difference = −0.69; 95% CI: −0.96 to −0.42, p = 0.0000005; adjusted standardized mean difference = −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. 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). Conclusion: Our findings suggest that LSD, with and without psychological support, reduces depression scores in clinical populations. This review is limited by small sample size. Future well-designed RCTs are needed to establish the efficacy and safety of LSD in managing depression.