Psilocybin with psychological support for treatment-resistant depression: six-month follow-up

This open-label study (n=20) expands on earlier work by Carhart-Harris and colleagues on the use of psilocybin-assisted therapy for treatment-resistant depression (TRD).


Rationale Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy.

Objectives Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression.

Methods Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure.

Results Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohenโ€™s d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohenโ€™s d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience.

Conclusions Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.”

Authors: Robin L. Carhart-Harris, Mark Bolstridge, Camilla M. J. Day, J. Rucker, Rosalind Watts, David E. Erritzoe, Mendel Kaelen, B. Giribaldi, M. Bloomfield, S. Pilling, J. A. Rickard, B. Forbes, Amanda Feilding, D. Taylor, H. Valerie Curran & David J. Nutt


This paper is included in our โ€˜Top 10 Articles on Psychedelics in the Treatment of Depressionโ€˜

This is an expansion of the study by Carhart-Harris et al. (2016) in which the number of patients is increased from 12 to 20 and the follow-up period from 3 to 6 months (i.e. 12 of the participants in this study were reported on in the earlier study too).

It is included in a meta-analysis by Goldberg et al. (2020).

The final part of the results dives deeper into what the patients have done since the trial:

“After the 6-month endpoint, information was collected on other treatments received by the patients (Watts et al. 2017). With the exception of patient 2 (who remained on venlafaxine throughout the trial and also received CBT shortly afterward), no patients received additional treatments within 5 weeks of the 25-mg psilocybin dose. Six began new courses of antidepressant medication after the 3-month time point. Five received psychotherapy (CBT, psychodynamic, counseling, and group therapy ร— 2) shortly before or after the 3-month period and five sought and successfully obtained psilocybin (without sanction from the study team) between 3 and 6 months. Removing the five that obtained psilocybin from the 3- and 6-month analyses did not substantially alter the main results: at 3 months, the effect size increased to 1.6 and the p-value remained < 0.001; and at 6 months, the effect size increased to 1.7 and the p-value became 0.018.”

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