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. 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.


Background Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression.

Methods In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin’s effects. Patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797.

Findings Psilocybin’s acute psychedelic effects typically became detectable 30–60 min after dosing, peaked 2–3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0–1 scale) was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week (mean QIDS difference −11·8, 95% CI −9·15 to −14·35, p=0·002, Hedges’ g=3·1) and 3 months (−9·2, 95% CI −5·69 to −12·71, p=0·003, Hedges’ g=2) after high-dose treatment. Marked and sustained improvements in anxiety and anhedonia were also noted.

Interpretation This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach.”

Authors: Robin L. Carhart-Harris, Mark Bolstridge, James Rucker, Camilla M. J. Day, David Erritzoe, Mendel Kaelen, Michael Bloomfield, James A. Rickard, Ben Forbes, Amanda Feilding, David Taylor, Steve Pilling, Valerie H. Curran & David J. Nutt


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

It was followed-up by Carhart-Harris et al. (2017) where they looked at the effects 6-months later (and added 8 patients). And by Roseman et al. (2018) which looked at the influence of the quality of the experience and its prediction on outcomes. And by Watts et al. (2017) which looked at the therapeutic mechanisms.

“Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression”

“The acute effects of psilocybin were well tolerated by all of the patients and no serious or unexpected adverse events occurred. Mean self-rated intensity of psilocybin experience was 0·51 (SD 0·36) for the low-dose session and 0·75 (0·27) for the high-dose session (difference 0·24 [95% CI 0·06–0·41], Z –2·4, p=0·019).

The most common adverse events were transient anxiety (mostly mild) during drug onset (n=12), transient confusion or thought disorder (n=9), mild and transient nausea (n=4), and transient headache (n=4; table 2). These adverse events were expected psychological effects of psilocybin. Subacute headache typically presented 1 day after the psilocybin session and subsided after 1–2 days. Paranoia presented in only one patient, but this was mild and transient. No prolonged psychotic symptoms were observed in any of the patients. One patient contacted the study psychiatrists during the 3 months of follow-up due to deterioration of their depression and was referred to their general practitioner.

Because this was a small-scale feasibility study with an open-label design, strong inferences cannot be made about the treatment’s therapeutic efficacy. However, the data do suggest that further research is warranted. The response rate to psilocybin was 67% (n=8) at 1 week after treatment (HAM-D and BDI), and seven of these eight patients also met criteria for remission. Moreover, 58% (n=7) of the patients maintained their response for 3 months, and 42% (n=5) remained in remission. It is also worth noting that psilocybin has a favourable toxicity profile and is not associated with compulsive drug-seeking behaviours in animals or human beings. The side-effects that we noted were minor, and expected in light of previous studies of psilocybin.”

Because of the small sample, definitely more (double-blinded) research is necessary. Also because there was therapeutic support before, during, and after the session, the relative effects of psilocybin are undetermined.

“One should be cautious of the potential for inflated effect sizes in early trials, particularly when the sample size is small. That all patients showed some improvement in their depressive symptoms for up to 3 weeks after treatment could be suggestive of an expectancy bias. It may also be relevant that most patients in this trial were self-referring and, thus, actively sought this treatment. Psychedelics are known to promote suggestibility, which might have further enhanced positive outcomes.

Again, double-blinded research randomized control trials are of paramount importance to determine the effects of psilocybin in this group. Although one could also argue that you can exploit this bias through the selection of patients with strong positive expectations.

Significant Follow-Up

Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression (Roseman, et al., 2018)

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