Psilocybin Therapy for Treatment-Resistant Depression: What the Science Shows

What Is Psilocybin-Assisted Therapy for Depression?

Psilocybin is a naturally occurring tryptamine compound found in over 200 species of mushrooms. When ingested, it is rapidly converted to psilocin, which acts primarily as an agonist at serotonin 5-HT2A receptors in the brain. Unlike traditional antidepressants that require daily dosing, psilocybin therapy typically involves one or two dosing sessions embedded within a structured therapeutic framework that includes preparation sessions, the dosing experience itself (lasting 4–6 hours under clinical supervision), and integration therapy sessions afterward.

Treatment-resistant depression (TRD) affects approximately 30% of the 280 million people worldwide living with major depressive disorder, according to the World Health Organization. TRD is defined as failure to achieve adequate response after at least two trials of antidepressant medications at adequate doses and duration. Current treatment options for TRD include electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and esketamine (Spravato), but each has significant limitations in efficacy, accessibility, or side effects.

The therapeutic model for psilocybin-assisted therapy was developed through decades of research at institutions including Johns Hopkins University, Imperial College London, and New York University. The approach emphasizes "set and setting"—the patient's mindset and the physical environment—as critical factors in therapeutic outcomes. Trained therapists provide non-directive support during the dosing session and help patients process and integrate their experiences in subsequent sessions.

What Did the COMPASS Pathways Phase 2b Trial Show?

The COMPASS Pathways Phase 2b trial (published in NEJM, November 2022) was the largest randomized controlled trial of psilocybin for depression at the time. It enrolled 233 participants across 22 sites in 10 countries, all with treatment-resistant depression who had failed 2–4 adequate antidepressant trials. Participants were randomized to receive a single dose of 25mg, 10mg, or 1mg (active control) of COMP360, a synthetic formulation of psilocybin, alongside psychological support.

At the primary endpoint of 3 weeks, 29.1% of participants in the 25mg group achieved remission (MADRS score ≤10) compared to 7.6% in the 1mg control group (p=0.002). The 25mg group also showed a significantly greater reduction in MADRS scores (mean change of -12.0 points vs. -5.4 in controls). The 10mg dose did not show statistically significant separation from the control. Response rates (at least 50% reduction in MADRS) were 36.7% in the 25mg group.

Adverse events were generally mild to moderate and transient. The most common were headache (reported by 56% in the 25mg group), nausea (25%), and dizziness (14%). However, suicidal ideation was reported in some participants across all groups, prompting careful monitoring protocols. COMPASS Pathways has since initiated Phase 3 trials (COMP005 and COMP006) required for potential FDA approval, with results expected by 2025–2026. The FDA granted breakthrough therapy designation for COMP360 in 2018, acknowledging the preliminary evidence of substantial improvement over existing therapies.

How Does Psilocybin Work in the Brain?

Psilocin, the active metabolite of psilocybin, acts as a partial agonist at serotonin 5-HT2A receptors, which are densely distributed in the prefrontal cortex and other regions involved in mood regulation, cognition, and self-referential processing. Functional MRI studies conducted at Imperial College London by Robin Carhart-Harris and colleagues have shown that psilocybin decreases activity in the default mode network (DMN)—a brain network associated with self-referential thinking, rumination, and the sense of ego. Overactivity of the DMN has been consistently linked to depression.

Psilocybin also increases global brain connectivity, allowing brain regions that don't normally communicate to form transient connections. This has been described as increasing the brain's "entropy" or flexibility, potentially allowing patients to break free from rigid, negative thought patterns characteristic of depression. Research published in Nature Medicine (2022) by Daws et al. demonstrated that psilocybin therapy increased brain network integration and that the degree of this increase correlated with clinical improvement at 3 months.

Emerging evidence suggests psilocybin promotes neuroplasticity through increased expression of brain-derived neurotrophic factor (BDNF) and stimulation of dendritic spine growth. A 2021 study by Shao et al. in Neuron showed that a single dose of psilocybin in mice increased dendritic spine density in the prefrontal cortex by approximately 10%, with effects lasting at least one month. This structural neuroplasticity may underlie the durable antidepressant effects observed in clinical trials, distinguishing psilocybin from conventional antidepressants that primarily modulate neurotransmitter levels.