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

This open-label study (n=20) expands on earlier work by Robin 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 (Cohen’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 (Cohen’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 ‘Top 10 Articles on Psychedelics in the Treatment of Depression

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 × 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.”

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

Psilocybin is a naturally occurring plant alkaloid that is being increasingly researched as a treatment for a range of different psychiatric disorders. It has shown promise in the treatment of depression, anxiety, alcohol and tobacco addiction, and terminal diagnosis anxiety.

Studies involving other serotonergic psychedelics combined with psychological support have found similarly promising outcomes. Ayahuasca is also well-known for its long-term well-being-promoting and anti-addiction properties. A recent population survey found lower rates of suicidality and psychological distress associated with psychedelic drug use.

Psilocybin, like all serotonergic psychedelics, initiates its characteristic effects via serotonin 2A receptor (5-HT2AR) agonism. 5-HT2AR signalling has been associated with better responses to conventional antidepressants, and 5-HT2AR antagonists have been found to augment the antidepressant effects of SSRIs.

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Study details

Compounds studied

Topics studied
Depression Treatment-Resistant Depression

Study characteristics
Open-Label Follow-up

20 Humans


Authors associated with this publication with profiles on Blossom

Robin Carhart-Harris
Dr. Robin Carhart-Harris is the Founding Director of the Neuroscape Psychedelics Division at UCSF. Previously he led the Psychedelic group at Imperial College London.

Rosalind Watts
Rosalind Watts is a clinical psychologist and clinical lead at the Psychedelics Research Group at Imperial College London. She is also known for developing the 'Accept, Connect, Embody' psychedelic therapy model.

Mendel Kaelen
Mendel Kaelen is a neuroscientist and entrepreneur, researching and developing a new category of psychotherapeutic tools for care-seekers and care-providers. Mendel has researched the incomparable effects of music on the brain during LSD-assisted psychotherapy. His work has determined how LSD increases enhanced eyes-closed visual imagery, including imagery of an autobiographical nature. This gives light to how music can be used as another dimension in helping psychotherapists create the ideal setting for their patients.

David Nutt
David John Nutt is a great advocate for looking at drugs and their harm objectively and scientifically. This got him dismissed as ACMD (Advisory Council on the Misuse of Drugs) chairman.

David Erritzoe
David Erritzoe is the clinical director of the Centre for Psychedelic Research at Imperial College London. His work focuses on brain imaging (PET/(f)MRI).

Amanda Feilding
Amanda is the Founder and Director of the Beckley Foundation. She's called the 'hidden hand' behind the renaissance of psychedelic science, and her contribution to global drug policy reform has also been pivotal and widely acknowledged.


Institutes associated with this publication

Imperial College London
The Centre for Psychedelic Research studies the action (in the brain) and clinical use of psychedelics, with a focus on depression.

Compound Details

The psychedelics given at which dose and how many times

Psilocybin 10 - 25
mg | 2x

Linked Research Papers

Notable research papers that build on or are influenced by this paper

Patients’ accounts of increased connectedness and acceptance after psilocybin for treatment-resistant depression
This follow-up survey to an open-label study (n=20) on psilocybin for treatment-resistant depression (TRD) found that connection (vs disconnection) and acceptance (vs avoidance) of emotions were the two main mechanisms through which the therapy was successful.

Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study
This is the first modern study (n=12) on psilocybin and its effects on treatment-resistant depression (TRD). It shows that two sessions with psilocybin (10mg and 25mg) in combination with psychological support can reduce depressive symptoms over periods of one week to three months after treatment. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred.

Effects of psilocybin therapy on personality structure
This open-label study (n=20) found that dosages of psilocybin (10, 25mg) in a supportive setting, for those with treatment-resistant depression (TRD), changed their personality. At 3-month follow-up, Neuroticism was decreased, Extraversion and Openness were increased. The changes were similar (but more pronounced) to changes after conventional antidepressant treatment.

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