Psychedelics as an intervention for psychological, existential distress in terminally ill patients: A systematic review and network meta-analysis

Background: The interest in psychedelics as a therapeutic intervention for existential distress of people with terminal illness grounds on their mechanism of action and effect on the spiritual/existential aspects accompanying end-of-life experiences. Aims: This systematic review and network meta-analysis aimed at examining the efficacy and safety of psychedelic compounds for existential distress in terminally ill people. Methods: PubMed, CINAHL, PsycINFO, EMBASE, and clinicaltrials.gov were searched for randomized controlled trials (RCTs) administering psychedelics for existential distress in people with terminal illnesses. Meta-analysis estimated the standardized mean difference (SMD) and odds ratio (OR), with corresponding 95% confidence intervals (95% CI), between treated and control groups in pairwise and network comparisons, using random-effects models. Post-treatment measures of depression and anxiety, as proxies of existential distress, and tolerability were the primary outcomes. Results: Nine studies, involving 606 participants (362 treated with psychedelics: psilocybin, ketamine, 3,4-methylenedioxymethamphetamine, and lysergic acid diethylamide (LSD)) were included. The meta-analysis supported the efficacy of psychedelics on depression (SMD: −0.80 (95% CI: −0.98, −0.63)) and anxiety (SMD: −0.84 (95% CI: −1.20, −0.48)). Network meta-analysis identified psilocybin as the most effective compound for depression, and LSD for anxiety. However, head-to-head comparison between psychedelics did not reach statistical significance. The rates of treatment discontinuation and adverse events between psychedelics and controls were comparable. Conclusions: Psychedelics, especially psilocybins and LSD, showed promising effects on depression and anxiety in people with terminal illnesses. Limitations include the small number of RCTs, methodological issues related to blinding, and the lack of direct comparisons between psychedelic compounds. Larger studies and comparative research are needed to consolidate these findings.