Evidence Mounts for Psilocybin as Depression Tx

Synthetic psilocybin reduced depression severity for patients with major depressive disorder (MDD) when administered with standard psychotherapy, a randomized clinical trial found.

Among 24 patients with MDD, psilocybin plus psychotherapy was associated with significantly reduced GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores by week 1 compared with a waitlist control group that received the intervention after an 8-week delay (8 vs 23.8, P<0.001), reported Alan K. Davis, PhD, of the Center for Psychedelic and Consciousness Research at Johns Hopkins School of Medicine in Baltimore, and colleagues.

This was sustained through week 4 for the immediate treatment group, which corresponded to week 8 for the delayed treatment group (8.5 vs 23.5, P<0.001), the researchers wrote in JAMA Psychiatry.

The publication comes just one day after Oregon voters approved a measure legalizing psilocybin for therapeutic use; voters in the District of Columbia also backed an initiative to decriminalize psilocybin and certain other psychedelic agents.

After everyone had received treatment in the study, 71% of participants had a clinically significant response and 54% were in complete remission 4 weeks after treatment, Davis said.

“Data we have published shows there seems to be something related to a mystical experience that occurs during the drug effect,” Davis told MedPage Today. “It seems to be both the mystical effects and these insights people get during the psilocybin session that seem to be related to the antidepressant effects.”

The study builds on recent research that found psilocybin to be similarly efficacious among patients with treatment-resistant depression as well as patients with cancer who had depression. Last year, the FDA granted synthetic psilocybin breakthrough therapy status for the treatment of MDD.

There are also trials underway examining the efficacy of psilocybin for treating alcohol use disorder, cocaine use disorder, anorexia, and posttraumatic stress disorder, among other conditions, Davis said.

In the present study, many patients experienced sadness, crying, grief, and despair with treatment, resembling experiences of grief psychotherapy, commented Charles F. Reynolds III, MD, of the University of Pittsburgh School of Medicine in Pennsylvania, in an accompanying editorial.

“Such grief work, exquisitely painful and emotionally arousing as it is, becomes a pathway to accepting and coming to terms with the finality of the loss and enabling the bereaved to find new meaning in life, even in the absence of the beloved,” Reynolds wrote.

The therapy also counteracts avoidant maladaptive coping, much like psychedelics are thought to lead to “a recalibration of one’s spectrum of associations,” Reynolds noted.

But for whom psilocybin and psychedelic treatment is most appropriate, as well as how it fits into acute and long-term care regimes, remains elusive, Reynolds said.

There is no panacea for treating depression, he continued. Rather, “personalizing the management of depression has to entail an understanding of the multiple contexts in which depression occurs, including genetic, developmental, psychosocial, cultural, medical, neurocognitive, and spiritual (as reflected in a person’s values, what ultimately matters to them, and so on).”

In the study by Davis and co-authors, patients had two psilocybin sessions, which each included an 8-hour preparatory meeting and a 2-3 hour follow-up meeting. During the session, facilitators sat with patients and instructed them to focus their attention inward and stay with experiences that arose. Participants wore eyeshades and listened to music.

Suicide risk was considered low among most participants at baseline and after treatment, Davis reported. Psilocybin was not compared with placebo or an active comparator, so how it compares with antidepressants on the market remains unclear.

Eligible participants had GRID-HAMD scores of at least 17 and were not on concurrent pharmacotherapy for depression. Patients with a personal or family history of psychotic or bipolar disorder, alcohol or drug use, or lifetime use of ketamine or other hallucinogens were excluded.

Administered in opaque gelatin capsules, the psilocybin dose in the first session was moderately high at 20 mg/70 kg, and high in the second session at 30 mg per 70 kg.

The cohort — mean age 39.8, 67% of whom were female — had baseline GRID-HAMD scores of 22.8. The vast majority of patients were white (92%), most had at least a bachelor’s degree (83%), and roughly half were married.

Quick Inventory of Depressive Symptomatology-Self Rated scores, which are assessed more frequently than the GRID-HAMD, showed a rapid and substantial decrease in depression scores from baseline as soon as 1 day after treatment (16.7 vs 6.3, P<0.001), which remained through week 4 after the second session (6.0, P<0.001), the authors reported.

One patient had a diastolic blood pressure increase of more than 100 mm Hg during a session, but it resolved spontaneously during the session, the team said. Otherwise, there were no other adverse effects except for transient headache and challenging emotional and physical experiences, such as feelings of sadness or trembling.

Study limitations, the team noted, included that the delayed control condition did not adjust for the many hours participants spent with mental health professionals. In addition, there was a lack of diversity in the cohort, and the follow-up period was relatively short.