Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder

Major depressive disorder (MDD) is a substantial public health concern, affecting more than 300 million individuals worldwide. Depression is the number one cause of disability, and the relative risk of all-cause mortality for those with depression is 1.7 times greater than the risk for the general public. In the United States, approximately 10% of the adult population has been diagnosed with MDD in the past 12 months, and the yearly economic burden of MDD is estimated to be $210 billion.

Although effective pharmacotherapies for depression are available, these drugs have limited efficacy, produce adverse effects, and are associated with patient adherence problems. Although many patients with depression showed reduced or remitted symptoms after treatment with existing pharmacotherapies, approximately 30% to 50% of patients did not respond fully and as many as 10% to 30% of patients were considered treatment-resistant, resulting in average effects that were only modestly larger than the effects of placebo. Most of the current pharmacotherapies for MDD, including the widely used selective serotonin reuptake inhibitors, increase levels of brain monoamine neurotransmitters such as serotonin and norepinephrine (typically by blocking reuptake).

A growing body of evidence suggests that newer ketamine-like medications exert therapeutic efficacy in MDD through effects on glutamate neurotransmission. Ketamine hydrochloride, a nonselective N-methyl-d-aspartate receptor antagonist, is the most well-researched of these newer medications. Several studies have demonstrated the efficacy of a single ketamine infusion in rapidly (within hours) reducing depression symptoms and, when effective, lasting from a few days to about 2 weeks. However, ketamine has high abuse liability, and its administration involves moderate physiological risk that requires medical monitoring.

The combined serotonergic and glutamatergic action of psilocybin (a classic hallucinogen) and the preliminary evidence of the antidepressant effects of psilocybin-assisted therapy (among patients with life-threatening cancer or patients with treatment-resistant depression) indicate the potential of psilocybin-assisted therapy as a novel antidepressant intervention. Moreover, psilocybin has lower addiction liability and toxic effects compared with ketamine and is generally not associated with long-term perceptual, cognitive, or neurological dysfunction. The substantial negative public health impact of MDD underscores the importance of conducting more research into drugs with rapid and sustained antidepressant effects.

Current pharmacotherapies for depression have variable efficacy and unwanted adverse effects. Novel antidepressants with rapid and sustained effects on mood and cognition could represent a breakthrough in the treatment of depression and may potentially improve or save lives. Therefore, the primary objective of this randomized clinical trial was to investigate the effect of psilocybin therapy in patients with MDD.

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Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder

Alan K. Davis, PhD; Frederick S. Barrett, PhD; Darrick G. May, MD; et al