Psilocybin
Psilocybin is the principal psychoactive prodrug found in Psilocybe and related mushroom genera. It is dephosphorylated in the body to psilocin, which drives its effects at serotonin 5-HT2A receptors. Among classic tryptamine psychedelics it has the strongest modern clinical evidence base, with randomised controlled trials in treatment-resistant depression, major depressive disorder, and end-of-life distress.
01 Overview
Psilocybin is an indoleamine tryptamine that occurs naturally in over 200 mushroom species. Ingested orally, it is rapidly hydrolysed by alkaline phosphatase to psilocin, the active metabolite. Effects typically begin within 20-40 minutes and last 4-6 hours, producing altered perception, mood, and thought, along with visual distortions and changes in the sense of time and self.
Since the 2010s psilocybin has been studied in numerous controlled trials, including phase 2 work in treatment-resistant depression and single-dose studies for depression and anxiety in life-threatening illness. It received FDA Breakthrough Therapy designation for treatment-resistant depression and for major depressive disorder. It remains a Schedule I substance in the United States despite this research activity.
02 Mechanism
Acts as a prodrug for psilocin, a partial agonist at serotonin 5-HT2A (and 5-HT2C, 5-HT1A) receptors in cortical pyramidal neurons, altering thalamocortical signalling and default-mode network connectivity.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Threshold | 2–5 mg | Oral | Subperceptual to mild; roughly 0.2-0.5 g dried Psilocybe cubensis. |
| Common | 10–25 mg | Oral | Full psychedelic effect; 25 mg is the typical fixed dose used in depression trials. |
| Heavy | 30–50 mg | Oral | Intense, potentially overwhelming; higher risk of anxiety and difficult experiences. |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Antidepressant responseRandomised trials in treatment-resistant and major depression report rapid, substantial symptom reduction after supervised dosing. | Large reductions in depression scores sustained weeks after 1-2 doses | Clinical | |
| Visual and perceptual alterationGeometric visuals, intensified colour, and altered perception of time and self. | Dose-dependent | Clinical | |
| Mystical-type / peak experienceSubjective experiences of unity and meaning that predict durability of clinical benefit in trials. | Correlates with therapeutic outcome | Clinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| Transient hypertension and tachycardiaModest, short-lived rises in blood pressure and heart rate during the acute phase. | Mild | Common | Clinical | |
| Nausea and headacheNausea early in the experience and post-session headache are frequently reported. | Mild | Common | Clinical | |
| Acute anxiety / panicTransient fear, paranoia, or panic during the acute experience, more likely at high doses or in unsupportive settings. | Moderate | Common at higher doses | Clinical |