Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder. A Randomized Clinical Trial

Alan K. Davis, PhD; Frederick S. Barrett, PhD; Darrick G. May, MD; Mary P. Cosimano, MSW; Nathan D. Sepeda, BS; Matthew W. Johnson, PhD; Patrick H. Finan, PhD; Roland R. Griffiths, PhD

JAMA Psychiatry, 2020, E1-E9.

doi : 10.1001/jamapsychiatry.2020.3285

 

IMPORTANCE : Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression.

OBJECTIVE : To investigate the effect of psilocybin therapy in patients with MDD.

DESIGN, SETTING, AND PARTICIPANTS : This randomized, waiting list–controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population).

INTERVENTIONS : Two psilocybin sessions (session 1: 20mg/70 kg; session 2: 30mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay.

MAIN OUTCOMES AND MEASURES : The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of 17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR).

RESULTS:  Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d = 2.2; 95%CI, 1.4-3.0; P < .001) and week 8 (Cohen d = 2.6; 95%CI, 1.7-3.6; P < .001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d = 3.0; 95%CI, 1.9-4.0; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 3.1; 95%CI, 1.9-4.2; P < .001). In the overall sample, 16 participants (67%) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (7 GRID-HAMD score).

CONCLUSIONS AND RELEVANCE : Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment resistant depression.

TRIAL REGISTRATION : ClinicalTrials.gov   –  Identifier: NCT03181529

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,1 and the relative risk of all-cause mortality for those with depression is 1.7 times greater than the risk for the general public.2 In the United States, approximately 10% of the adult population has been diagnosed with MDD in the past 12 months,3 and the yearly economic burden of MDD is estimated to be $210 billion.4

Although effective pharmacotherapies for depression are available, these drugs have limited efficacy, produce adverse effects, and are associatedwith patient adherence problems.5 Although many patients with depression showed reduced or remitted symptoms after treatment with existing pharmacotherapies,6 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.7,8

Most of the current pharmacotherapies for MDD, including thewidely used selective serotonin reuptake inhibitors, increase levels of brain monoamine neurotransmitters such as serotonin and norepinephrine (typically by blocking reuptake).6 A growing body of evidence suggests that newer ketamine-like medications exert therapeutic efficacy in MDD through effects on glutamate neurotransmission.9,10 Ketamine hydrochloride, a nonselective N-methyl-Daspartate 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.10,11 However, ketamine has high abuse liability, and its administration involves moderate physiological risk that requires medical monitoring.12

The combined serotonergic and glutamatergic action of psilocybin13-15 (a classic hallucinogen) and the preliminary evidence of the antidepressant effects of psilocybinassisted therapy (among patients with life-threatening cancer or patients with treatment-resistant depression)16-18 indicate the potential of psilocybin-assisted therapy as a novel antidepressant intervention.19 Moreover, psilocybin has lower addiction liability and toxic effects compared with ketamine20-22 and is generally not associated with long-term perceptual, cognitive, or neurological dysfunction.23

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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