Lasting improvements in depression severity reported in small, proof-of-concept study

Psychotherapy that included two guided sessions of psilocybin use was associated with large, rapid, and sustained antidepressant effects in a proof-of-concept study of patients with major depressive disorder conducted by researchers from the Center for Psychedelic and Consciousness Research at Johns Hopkins School of Medicine.

Twenty-seven adult patients with major depressive disorder and a low risk for suicide were enrolled in the trial, and 24 (89%) completed the intervention and follow-up assessment.

Participants receiving immediate psilocybin-assisted therapy showed greater improvement than those receiving delayed treatment at 1-month follow-up in blinded clinician-assessed depression severity scores and patient-reported secondary outcomes.

Clinically significant antidepressant response to psilocybin therapy persisted for at least 4 weeks, with 71% of study participants continuing to show a clinically significant response a month after treatment, wrote researcher Alan K. Davis, PhD, and colleagues from Johns Hopkins School of Medicine, Baltimore, in JAMA Psychiatry, published online Nov. 4. — appropriate timing, given that Oregon became the first U.S. state to legalize the use of psilocybin for mental health treatment in supervised settings with the passing of Measure 109 on Nov. 3.

Earlier small studies have suggested a benefit for psilocybin-assisted therapy in patients with depression due to life-threatening cancers and in patients with treatment-resistant depression, but this study is the first to examine psilocybin as an addition to psychotherapy for the treatment of major depressive disorder.

Davis and colleagues wrote that, while current pharmacological treatments for severe depression — including selective serotonin reuptake inhibitors (SSRIs) and ketamine-containing agents — help many patients, these drugs have significant limitations including limited efficacy, adverse effects, and less-than-optimal adherence.

“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,” they wrote.

The small study included adults (age 21 to 75 years) with major depressive disorder who were not using antidepressant medications at enrollment and had no history of psychotic disorder, serious suicide attempts, or hospitalizations for depression.

Fifteen patients were randomized to the immediate treatment group, while 12 were randomized to receive delayed treatment, given after an 8-week delay.

The intervention consisted of 2 psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) given orally in the context of approximately 11 hours of supportive psychotherapy.

Among the immediate treatment group, the intervention lasted 8 weeks and involved at least 18 in-person visits, including 2 day-long psilocybin administration sessions. Patients met with 2 session facilitators for a total of 8 hours before the first psilocybin session, and the psilocybin sessions were conducted roughly 1.6 weeks apart.

“During the (psilocybin) sessions, participants were instructed to lie on a couch in a living room-like environment, and facilitators encouraged participants to focus their attention inward and stay with any experience that arose,” the researchers wrote. “To enhance inward reflection, music was played and participants were instructed to wear eye-shades and headphones.”

The primary outcome of depression severity was assessed using the GRID-Hamilton Depression Rating Scale (GRID-HAMD) score 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) questionnaire.

Among the 24 patients completing the intervention and post-session assessment, the mean age was close to 40 years and 16 (67%) were female. The mean baseline GRID-HAMD score was 22.8 (3.9).

Among the main study findings:

  • 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<0.001) and week 8 (Cohen d = 2.6; 95% CI, 1.7-3.6; P<0.001).
  • 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<0.001), 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< 0.001).

Among 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).

The short follow-up, small sample size, lack of placebo control, and exclusion of patients with a moderate to high suicide risk and very severe depression were cited by the researchers as study limitations.

They concluded that larger studies with more diverse patient populations and a placebo control are needed “to better ascertain the safety (e.g., abuse potential of psilocybin, suicide risk, and emergence of psychosis) and efficacy of this intervention among patients with major depressive disorder.”

In an accompanying editorial, University of Pennsylvania Medical Center professor of geriatric psychiatry Charles F. Reynolds III, MD, wrote that these larger trials will hopefully address significant unanswered questions regarding the potential value of psychedelic-assisted psychotherapy as a treatment for major depressive disorder.

“Would double-blind experimental design, entailing the use of pill placebo, or an active comparator with psychotropic effects (e.g., an anxiolytic or an antidepressant) in a model of medication-assisted psychotherapy, yield results that are comparable with those reported by Davis et al. in their single-blind, immediate versus delayed exposure to psilocybin paradigm?” Reynolds asked.

He added that clinical trials must address which patients with major depressive disorder might benefit from psychedelic-assisted psychotherapy, and which patients might be harmed.

“Another question may be, what are the patient and environmental characteristics that moderate or alter the variability of response to medication-assisted supportive psychotherapy? A final set of questions relates to the durability and maintenance of antidepressant response, with respect to both symptom burden and major role functioning. How does psychedelic-assisted psychotherapy fit into both acute and long-term care for depressive illness, not only to get patients well but to keep them well and living lives of meaning and fulfillment?”

  1. Psychotherapy that included 2 guided sessions of psilocybin use was associated with large, rapid, and sustained antidepressant effects in a proof-of-concept study of patients with major depressive disorder.

  2. Clinically significant antidepressant response to psilocybin therapy persisted for at least 4 weeks, with 71% of study participants continuing to show a clinically significant response a month after treatment.

Salynn Boyles, Contributing Writer, BreakingMED™

Funding for this research was provided by a crowd-sourced funding campain, the Riverstyx Foundation, the Steven and Alexandra Cohen Foundation and grants from author and podcast host Tim Ferriss and others.

Researcher Alan K. Davis reported being a board member at Source Research Foundation. Researcher Matthew Johnson reported receiving grants from Heffter Research Institute outside the submitted work and personal fees as a consultant and/or advisory board member from Beckley Psychedelics Ltd, Entheogen Biomedical Corp, Field Trip Psychedelics Inc, Mind Medicine Inc, and Otsuka Pharmaceutical Development & Commercialization Inc. Researcher Roland Griffiths reported being a board member at Heffter Research Institute and receiving grants from Heffter Research Institute outside the submitted work.

Editorial writer Charles F. Reynolds III declared no relevant relationships.

Cat ID: 55

Topic ID: 87,55,192,55,921