With great power comes great responsibility: Promise and caution in the new psychedelic renaissance

• Ketamine, psilocybin, ayahuasca, LSD, and MDMA show antidepressant effects; ketamine’s rapid relief lasts ∼1 week in treatment-resistant depression. • Psilocybin (Hedge’s g = 1.289) and ayahuasca (46 % major improvement) excel; LSD and MDMA results vary. • Subjective experience and altered consciousness, facilitated in safe settings, drive therapeutic benefits. • Strict supervision and regulatory compliance are essential to minimize adverse reactions. • Policy shifts toward legalization require standardized guidelines and ethical frameworks. Clinicians and researchers are showing increased interest in psychedelic-assisted therapy for patients who don't show improvement from using conventional antidepressants. This updated review integrates recent developments, including data on lesser-studied compounds like DMT and 5-MeO-DMT, findings from large clinical trials, and evolving regulatory landscapes. In treatment-resistant depression, Ketamine stands out for its fast-acting effects; however, these benefits are often short-lived. Psilocybin and Ayahuasca have shown meaningful symptom reduction in both randomized trials and real-world settings. Emerging data on LSD and MDMA-assisted psychotherapy further suggest potential in mood disorder treatment. Several policy changes have created new frameworks for legal therapeutic use. Oregon legalized supervised psilocybin therapy in November 2020, Colorado passed Proposition 122 in November 2022, and Australia approved the prescription use of psilocybin and MDMA in February 2023. These milestones reflect a growing international shift toward integrating psychedelics into regulated mental health care. Although the mentioned outcomes are encouraging, these treatments must occur under professional supervision and local regulations to reduce the risk of adverse events. These therapies generally take place in a controlled setting with trained facilitators who help guide these introspective experiences and altered levels of consciousness.