Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study

Psilocybin is a naturally occurring psychedelic prodrug of psilocin that produces its principal psychoactive effects via serotonin 2A (5-HT2A) receptor agonism. Earlier preclinical and human imaging work has linked 5-HT2A receptor agonism with cognitive and neural plasticity changes and with antidepressant-like effects, and modern clinical studies of psychedelics have reported reductions in anxiety, depressive symptoms, and addictive behaviours after one or two exposures. At the same time, depression remains a major global health burden and a substantial minority of patients do not respond to available treatments, creating a need for new interventions for treatment-resistant depression. Carhart-Harris and colleagues designed this open-label feasibility study to assess whether a protocol of two supervised oral psilocybin administrations, given with psychological support, could be safely delivered to patients with unipolar treatment-resistant major depression and to obtain an initial impression of clinical effects. Their prespecified primary feasibility outcome was patient-rated subjective intensity of psilocybin's effects; the principal efficacy endpoint was change in self-reported depressive symptoms (16-item QIDS) from baseline to 1 week after the high-dose session. The investigators hypothesised that the intervention would be well tolerated and produce substantial reductions in depressive symptoms lasting up to 3 months.

This was an open-label, single-arm feasibility trial with no control group and no masking of participants, investigators, raters, or statisticians. The intended recruitment for the imaging protocol was 20 patients, but the present report covers the first 12 participants enrolled. Inclusion criteria required major depression of moderate to severe degree (HAM-D ≥17) and failure to improve after at least two adequate antidepressant courses of different pharmacological classes during the current episode. Exclusion criteria included current or past psychotic disorder, a first-degree relative with a psychotic disorder, medically significant conditions, history of serious suicide attempts requiring hospitalisation, history of mania, blood or needle phobia, pregnancy, and current drug or alcohol dependence. Recruitment was via general practitioner networks and self-referral; in every case the patient's clinician provided written documentation of diagnosis and history. Procedures combined preparatory psychological work, two dosing sessions separated by 7 days, and follow-up. After medical screening (ECG, blood tests, vitals) and a baseline 60-minute fMRI scan, patients undertook an extensive preparatory psychological session (typically about 4 hours) with the two psychiatrists who would provide support. Dosing occurred in a calm, music-supported clinical room with at least two staff present. Patients received an initial low oral dose of psilocybin 10 mg and, 7 days later, a treatment dose of 25 mg. Physiological monitoring and observer ratings of acute effects were recorded at baseline and at multiple timepoints up to 360 minutes postdose; subjective altered-state effects were assessed 6–7 hours after dosing using the 11-dimension ASC questionnaire. Tranquillising medications (oral lorazepam and risperidone) were available but not used. Follow-up included a telephone check 1 day after the low dose, a posttreatment fMRI and clinical assessment 1 day after the high dose, an in-person 1-week follow-up with repeat assessments and debriefing, email-based clinical questionnaires at 2, 3, and 5 weeks (QIDS only), and a final remote assessment at 3 months that included QIDS, BDI, STAI-T, and SHAPS. The primary feasibility outcome was patient-rated subjective intensity of psilocybin on a 0–1 scale. The primary efficacy outcome was mean change in QIDS from baseline to 1 week after the high-dose session; secondary measures included BDI, STAI-T, SHAPS, HAM-D, MADRS, and GAF at specified timepoints. No formal power calculation was performed for this feasibility report; statistical analyses used two-tailed Wilcoxon signed-rank tests for non-parametric comparisons and two-tailed t tests where appropriate, with 95% confidence intervals reported for mean differences.

Between May and August 2015, 72 people were initially considered, 38 underwent telephone screening, 18 were invited for formal screening, and 12 patients were ultimately enrolled (ten self-referrals). Baseline clinical severity was high: nine of 12 met criteria for severe or very severe depression (BDI ≥30) and the remaining three met criteria for moderate depression (BDI 19 to <30). Most participants (11 of 12) had received prior psychotherapy. All participants completed the two-dose protocol. Mean self-rated intensity of the psilocybin experience was 0.51 (SD 0.36) for the 10 mg session and 0.75 (SD 0.27) for the 25 mg session. Acute psychedelic effects typically emerged between 30 and 60 minutes, peaked between 2 and 3 hours, and subsided to negligible levels by about 6 hours, at which point discharge assessment occurred. No participant required the available tranquilising medications. Adverse events were generally transient and expected: mild transient anxiety at onset (n=12), transient confusion or thought disorder (n=9), mild transient nausea (n=4), and transient headache (n=4). One patient experienced mild, transient paranoia. No prolonged psychotic symptoms or serious or unexpected adverse events were observed. During 3 months of follow-up one participant contacted the study psychiatrists for deteriorating depression and was referred back to their general practitioner. Clinically, self-reported depressive symptoms (QIDS) were significantly reduced relative to baseline at 1 week and at 3 months after the high-dose session, with the largest mean effect observed at 2 weeks. BDI and clinician-administered ratings (HAM-D, MADRS, GAF) confirmed these improvements at 1 week. By standard remission criteria on the BDI (score ≤9), eight of 12 patients (67%) achieved complete remission at 1 week. At 3 months, seven patients (58%) continued to meet response criteria (≥50% reduction in BDI from baseline), and five patients (42%) remained in complete remission. Anxiety (STAI-T) and anhedonia (SHAPS) scores were also significantly reduced at both 1 week and 3 months. The investigators noted that while all patients showed some improvement for at least 3 weeks, five participants displayed a degree of relapse by 3 months.

Carhart-Harris and colleagues interpret these findings as supportive of the feasibility and tolerability of supervised psilocybin administration with psychological support in people with unipolar treatment-resistant depression, and they regard the observed reductions in depressive symptoms as sufficient to justify further controlled research. The reported 1-week response/remission rates (67% remission on BDI at 1 week) and the persistence of response in a majority at 3 months are highlighted as notable, particularly given the long illness durations in this sample. The investigators position these results within prior psychedelic literature showing rapid and sustained improvements after one or two administrations in conditions such as end-of-life anxiety, substance dependence, and smoking cessation. They note that psilocybin's pharmacology (direct 5-HT2A agonism) differs from current antidepressants and might underlie distinct therapeutic mechanisms. Key limitations acknowledged by the authors include the open-label, single-arm design and small sample size, which preclude strong efficacy conclusions and leave the results vulnerable to expectancy and self-selection biases, especially since most participants self-referred. The combination of drug administration and substantial psychological support and a positive therapeutic setting makes it impossible in this design to disentangle the relative contributions of pharmacology versus contextual and psychotherapeutic factors. The authors also caution about inflated effect sizes in early-phase trials and note that five participants showed partial relapse by 3 months. Practical considerations for future trials include the likely need to control for concomitant serotonergic antidepressants, since chronic SSRI use can downregulate 5-HT2A receptors and attenuate psychedelic responses. For future research the authors propose randomised, placebo-controlled designs with equivalent therapist contact between arms, consideration of active placebos to preserve blinding, and comparative trials versus other rapid-acting interventions (for example, ketamine). They also suggest measuring and managing expectancy and suggestibility, which may be influential in psychedelic therapies and could be treated either as confounds or as components of the therapeutic model. Overall, the investigators conclude that their data support further rigorous trials to examine psilocybin's potential as a novel treatment for treatment-resistant depression.