A systematic review of eight randomized controlled trials found that psilocybin (25 mg) produced clinically significant reductions in depressive symptoms on the MADRS and QIDS-SR‑16 scales in treatment-resistant depression, while MDMA‑assisted therapy reduced CAPS‑5 scores in post‑traumatic stress disorder, with 67–71% of participants no longer meeting diagnostic criteria after treatment. Both substances had acceptable safety profiles with mostly transient adverse events. Direct comparative meta‑analysis was not possible due to clinical and methodological heterogeneity. Limitations include small samples, blinding difficulties, and lack of long‑term follow‑up.
Treatment-resistant depression demands new approaches beyond conventional antidepressants. The revival of psychedelics, particularly psilocybin, offers a promising alternative based on modulating neuroplasticity. Studies indicate that single doses of psilocybin promote rapid reduction in MADRS and HAM-D scale scores. This effect arises from BDNF release, increased dendritic spine density, and temporary disintegration of the Default Mode Network, creating a plasticity window for psychotherapy. Psychedelics represent a paradigm shift, offering rapid remission through neurobiological restructuring. Future research should focus on durability of effects and standardization of clinical protocols.