Reviewed: Davis AK, Barrett FS, May DG, et al. Effects of psilocybin-assisted therapy on major depressive disorder: A randomized clinical trial. JAMA Psychiatry. May 2021;78(5):481-489. doi: 10.1001/jamapsychiatry.2020.3285.

Major depressive disorder (MDD), or clinical depression, affects more than 300 million people globally and is the leading cause of disability worldwide.¹ Drugs for depression have limited efficacy and often cause adverse effects (AEs), must be used for long periods, and have poor patient compliance. About 30–50% of people with depression do not respond fully to available drugs, and 10–30% are considered treatment resistant.

Selective serotonin reuptake inhibitors (SSRIs), a common class of antidepressant medications, increase brain serotonin and norepinephrine levels. Ketamine and its derivatives (e.g., esketamine, which is used for treatment-resistant depression) alter glutamate neurotransmission. Studies report rapid reduction of depressive symptoms after a single dose of ketamine, but it has high abuse potential, and its use requires monitoring. Psilocybin, which can be found in fungi of the genus Psilocybe (Hymenogastraceae) and other genera, has predominantly serotonergic but also glutamatergic effects. It has been shown to reduce depression in treatment-resistant patients and in those with life-threatening or terminal illnesses, such as cancer.² Psilocybin has low abuse potential and toxicity compared to ketamine and, if administered at low doses, is not associated with any long-term perceptual, cognitive, or neurological issues.

Included Participants

The authors conducted a randomized, waiting-list-controlled (a study design in which a group receives delayed treatment) clinical trial at the Johns Hopkins Center for Psychedelic and Consciousness Research in Baltimore, Maryland, from August 2017 to July 2019. Eligible participants had moderate to severe MDD per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria and scored 17 or higher on the GRID-Hamilton Depression Rating Scale (GRID-HAMD). Included participants were 21 to 75 years old, used no drugs at screening, and agreed to abstain from antidepressants for at least five half-lives* before enrollment and up to four months after enrollment. They were medically stable with no history of psychosis or bipolar disorder. Participants were not pregnant or lactating and used birth control. Exclusion criteria included moderate to severe alcohol or drug abuse, including nicotine, in the past year and substantial lifetime (> 10 times) or recent (previous six months) ketamine or hallucinogen use.

Of the 870 pre-screened individuals, 70 had in-person medical and psychological screening (electrocardiogram, blood/urine tests, and structured assessments), and 27 were randomly assigned to immediate treatment (IT; n = 15) or delayed treatment (DT; n = 12). An eight-week delay was used for the DT group instead of placebo to differentiate psilocybin effects from spontaneous improvement. The DT group then received the same psilocybin treatment as the IT group. Randomization was balanced for age, gender, baseline GRID-HAMD score, and treatment resistance scored via the Maudsley Staging Method. Patients, 16 of whom were women, had a mean age of 39.8 years. There were no significant between-group differences in the duration of the participants’ current MDD episodes.

Intervention Period

The eight-week intervention period involved more than 18 in-person visits for each participant, including two day-long psilocybin sessions. The first psilocybin session included preparatory meetings (eight hours), and every psilocybin session included a follow-up meeting (two to three hours). The psilocybin dose was 20 mg/70 kg body weight in session one and 30 mg/70 kg in session two. Psilocybin sessions were held a mean of 1.6 weeks apart, and facilitators were present at all times. During each session, patients reclined in a relaxing environment, wore eye shades and headphones, listened to music, and focused on “inward reflection.”

The IT group completed the GRID-HAMD and other measures at weeks five and eight (one and four weeks, respectively, after their second psilocybin session). The DT group was monitored during the delay by telephone and in-person visits and completed the same measures at weeks five and eight (during the delay), and at weeks 13 and 16 (one and four weeks, respectively, after their second psilocybin session).

There were two dropouts from the IT group, including one who had a strong improvement after one session, and one from the DT group who dropped out after session two. Data from 24 participants (89%; 13 in IT, 11 in DT) were used.

Outcome Measures

GRID-HAMD scores were compared between groups at study weeks five and eight and within groups from baseline to one and four weeks after psilocybin session two. Scores rated severity (0–7 = remission, 8–16 = mild depression, 17–23 = moderate depression, 24+ = severe depression), and a significant response was defined as a score reduction of at least 50% from baseline. Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) rated rapid and sustained effects at baseline, one day and one week post-psilocybin session one, and one day and one week post-session two. Secondary outcomes included standard depression, health, suicidal ideation, and anxiety measures, and blood pressure (BP) and heart rate were monitored before and during psilocybin sessions. The study was large enough to have almost 100% power to detect statistically significant effects (P < 0.05). 

Results

There was a significant difference between GRID-HAMD scores for the IT group vs. the DT group at study weeks five and eight (P < 0.001 for both). There were large effect sizes at weeks five and eight for the IT group (P < 0.001 for both). After psilocybin, 16 participants (67%) at week one and 17 (71%) at week four had clinically significant reductions in GRID-HAMD scores, and 14 (58%) at week one and 13 (54%) at week four were in remission. Within-participant scores decreased at one and four weeks post-psilocybin session two (P < 0.001 for both) compared to baseline.

The more-frequently administered QIDS-SR showed rapid, large decreases in mean depression scores from baseline to one day post-session one through week four post-session two (P < 0.001 for all) in both IT and DT groups.

Secondary mental state measures showed similar improvements between and across groups during the intervention period. A transient increase in BP during session one was within normal parameters and resolved spontaneously. Other AEs included “challenging emotional experiences” (e.g., sadness and fear), physical tremors, and transient headaches, which all resolved spontaneously.

Conclusion

With longer-lasting results than ketamine, psilocybin shows promise for treating MDD, according to the results of this randomized, controlled trial. However, the low number of participants involved in the clinical trial may limit a conclusive comparison with ketamine or other antidepressants. The supportive psychotherapy offered during the psilocybin sessions, in which “facilitators were present in the room and available to respond to participants’ physical and emotional needs during the day-long session,” may have affected the results. Placebo effects have been shown to play a major role in clinical trials associated with MDD and should therefore be taken into consideration.³ Longer studies with more diverse populations are needed. A placebo arm should be used in addition to the delayed treatment approach of this study. 

References

1. Depression fact sheet. World Health Organization website. Available at: www.who.int/mediacentre/factsheets/fs369/en/. Accessed September 26, 2021.
2. Vargas AS, Luis A, Barroso M, Gailardo E, Pereira L. Psilocybin as a new approach to treat depression and anxiety in the context of life-threatening diseases — A systematic review and meta-analysis of clinical trials. Biomedicines. September 2020;8(9):331. doi: 10.3390/biomedicines8090331.
3. Marchesi C, De Panfilis C, Tonna M, Ossola P. Is placebo useful in the treatment of major depression in clinical practice? Neuropsychiatr Dis Treat. 2013;9:915-20. doi: 10.2147/NDT.S44519.