Over the past five years, the literature on the psychiatric use of psychedelic and related treatments has expanded substantially. Several randomized controlled trials and pooled analyses have been conducted in mood disorders, treatment-resistant depression, and post-traumatic stress disorder. Trial methodology, however, remains a fundamental source of uncertainty, and despite the popularity of the field, the clinical evidence is still weak. Psilocybin produces consistent and often large improvements in major depressive disorder, yet in the most rigorous trials, the predefined primary endpoint does not always reach statistical significance. At the same time, a synthetic psilocybin (COMP360) met its primary endpoint in two phase 3 trials in 2025-2026, representing the most advanced regulatory evidence in the field to date. MDMA (3,4-methylenedioxymethamphetamine; "ecstasy")-assisted psychotherapy has the largest phase 3 dataset in post-traumatic stress disorder, but in 2024 the US Food and Drug Administration declined to approve the product on ethical grounds. Evidence for LSD (lysergic acid diethylamide) and ayahuasca in depressive and anxiety symptoms is considerably weaker and cannot yet be interpreted within an evidence-based medicine framework. The therapeutic use of psychedelics can no longer be regarded as merely a theoretical question or a subcultural movement: the clinical effect is consistent and, in several trials, markedly strong. Nevertheless, according to the international system grading the certainty of evidence, the level of certainty remains low or very low for several indications. The main reasons are practical unblinding, small sample sizes, trial heterogeneity, and a lack of long-term safety data. Despite encouraging phase 3 data, psilocybin and the classic psychedelics should be considered experimental treatments. For MDMA, the phase 3 results are promising but have not proven sufficient for regulatory approval. Orv Hetil. 2026; 167(37): 1461-1467.
