Psilocybin-assisted therapy produces a large reduction in depressive symptoms, but the evidence is preliminary and limited by methodological problems. A meta-analysis of nine randomized controlled trials involving 514 participants found a large effect size (SMD = 1.270). However, the certainty of the evidence is rated low due to risk of bias, high heterogeneity, short-term follow-up, and publication bias. Effects were much larger when psilocybin was compared to a waitlist rather than an active placebo, and blinding is compromised by the drug's subjective effects. The authors conclude that robust Phase 3 trials are needed before routine clinical use.
Depressive disorder remains a significant problem in several developed countries. Ketamine, traditionally used for anesthesia, analgesia, sedation, and chronic pain, has unique pharmacodynamic properties that make it effective as a rapid-onset antidepressant, likely by increasing BDNF levels in the hippocampus. Although extracellular glutamate agents are not new for treating depression, the monoaminergic view of depression drives the search for new antidepressants. Ketamine is given intravenously in subanesthetic doses, but monitoring is required due to possible side effects like hypersalivation, tachycardia, and increased blood and intracranial pressure.