Psilocybin

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is the major psychoactive alkaloid of some species of mushrooms distributed worldwide. ^[1] It is a naturally occurring serotonergic psychedelic and non-selective agonist at many serotonin receptors, especially the 5-HT2A receptor, found in the Psilocybe genus of mushrooms. ^[2] Psilocybin is a controlled substance in many countries and, in the United States, is classified as a Schedule I drug. ^{[3] [4]}

Psilocybin is primarily a pro-drug that is dephosphorylated by alkaline phosphatase to its active metabolite psilocin, which acts as an agonist or partial agonist at 5-HT2A receptors. ^[3] Its antidepressant and psychedelic effects are thought to involve modulation of the serotonergic system, primarily through 5-HT2A receptor agonism, with contributory indirect effects on dopaminergic and glutamatergic systems. ^[2] It has been theorized that psychedelics such as psilocybin produce long-term clinical improvements by rapidly and lastingly stimulating neuroplasticity, including changes in dendritic complexity and brain-derived neurotrophic factor expression. ^{[5] [6]}

Psilocybin has been designated by the U.S. Food and Drug Administration as a breakthrough therapy for treatment-resistant depression, but the evidence base was judged insufficient for FDA approval of any psychedelic for routine clinical use in psychiatric disorders. ^[7] A systematic review and meta-analysis of 436 participants from seven studies found a significant benefit of psilocybin on depression scores compared with comparator treatment. ^[8] A separate systematic review and meta-analysis of psilocybin-assisted therapy for depression yielded a large effect size in favour of psilocybin, while noting that further studies are needed to evaluate safety and efficacy and optimize treatment protocols. ^[9] A Cochrane review concluded that psychedelic-assisted therapy with classical psychedelics including psilocybin may be effective for treating anxiety and depression in people facing a life-threatening disease, but the certainty of evidence was low to very low. ^[10] As of 2024, psilocybin-assisted psychotherapy remained in phase 3 trials for treating resistant depression. ^[11]

A meta-analysis of acute adverse effects at therapeutic doses found significantly increased rates of headache, nausea, anxiety, dizziness, and elevated blood pressure, though the acute profile appeared tolerable and resolved within 48 hours. ^[12] In a systematic review and meta-analysis of classic psychedelics, serious adverse events were reported for no healthy participants and for approximately 4% of participants with preexisting neuropsychiatric disorders, among which were worsening depression, suicidal behavior, and psychosis. ^[13] In the Cochrane review no treatment-related serious adverse events were reported, and common minor to moderate adverse events for classical psychedelics were elevated blood pressure, nausea, anxiety, emotional distress, and psychotic-like symptoms that subsided when the drug effects wore off. ^[10]