This trial received a favourable opinion from the National Research Ethics Service London—West London, was sponsored and approved by Imperial College London's Joint Research and Compliance Office (JRCO), and was adopted by the National Institute for Health Research Clinical Research Network. The National Institute for Health Research/Wellcome Trust Imperial Clinical Research Facility gave site-specific approval for the study. The study was reviewed and approved by the Medicines and Healthcare products Regulatory Agency (MHRA). All participants provided written informed consent. Study and data monitoring was carried out independently by the Imperial Clinical Research Facility and JRCO.

Information about the study's recruitment was sent to general practitioners via the North West London Clinical Research Network. However, patients were also allowed to self-refer to the study if they were UK residents. In every case, patients initiated contact with the research team (via email, letter, or telephone), were sent a study information sheet, and a subsequent telephone screening was arranged, during which the lead psychiatrist on the trial (MBo) obtained information about the patient's demographics, medical and psychiatric history, and other key inclusion or exclusion criteria. The patient's general practitioner or psychiatrist provided written documentation of the patient's diagnosis and mental health background in every case.

This was an open-label feasibility study in patients with treatment-resistant depression; there was no control group. Patients, investigators, raters, and statisticians were not masked to treatment assignment, and all participants received the study intervention (psilocybin administered in two dosing sessions; an initial safety [low] dose and a subsequent treatment [high] dose). The inclusion criteria were major depression of a moderate to severe degree (17+ on the 21-item Hamilton Depression Rating scale [HAM-D]), and no improvement despite two adequate courses of antidepressant treatment of different pharmacological classes lasting at least 6 weeks within the current depressive episode.Exclusion criteria were: current or previously diagnosed psychotic disorder; immediate family member with a diagnosed psychotic disorder; medically significant condition rendering unsuitability for the study; history of serious suicide attempts (requiring hospitalisation); history of mania; blood or needle phobia; positive pregnancy test at screening or during the study; and current drug or alcohol dependence.

Procedures

Psilocybin was obtained from THC-pharm (Frankfurt, Germany) and formulated into the investigational medicinal product (5 mg psilocybin in size 0 capsules) by Guy's and St Thomas' Hospitals' Pharmacy Manufacturing Unit (London, UK). A Home Office Licence for storage and dispensing of Schedule One drugs was obtained.

Screening consisted of written informed consent, a thorough evaluation of the patient's physical and mental health background, a psychiatric interview (Mini-International Neuropsychiatric Interview), clinician assessments of depression severity (the 21-item HAM-D and the Montgomery-Åsberg Depression Rating Scale [MADRS], and Global Assessment of Functioning [GAF]; all assessed by MBo), and additional patient-rated scales (16-item Quick Inventory of Depressive Symptoms [QIDS], Beck Depression Inventory [BDI—original version], Spielberger's State-Trait Anxiety Inventory [form 2, trait version only; STAI-T], and the Snaith-Hamilton Pleasure Scale [SHAPS]). Patients also received a thorough physical health check, consisting of an electrocardiogram, routine blood tests, blood pressure, heart rate, and physical examination. At the end of screening, eligible patients were given an opportunity to meet with the two clinical psychiatrists who would support them through the remainder of the trial.

Eligible patients attended a subsequent visit involving a baseline functional MRI (fMRI) scanning session lasting 60 min, followed by an extensive preparatory session with their allocated psychiatrists; fMRI data will be reported elsewhere. This preparatory session involved inviting the patient to talk openly about their personal history (including thoughts on the origins of their depression), a discussion of psilocybin's psychological effects, and simulation of aspects of the dosing session itself, such as listening to a sample of the session music while wearing eyeshades. The preparatory session typically lasted for 4 h, with lunch and breaks provided.

Patients enrolled in the study attended two subsequent dosing sessions that were separated by 7 days. No more than one patient was dosed on any given day. Patients arrived at the research facility (Imperial Clinical Research Facility) at 0900 h, gave a urine sample for drugs of abuse (including amphetamines, benzodiazapines, opiates, and cannabinoids), performed a breathalyser test for alcohol use, and completed interim QIDS, BDI, and STAI-T assessments to ensure no substantial deviation from baseline measures. They were then taken to a dosing room that was pre-decorated (eg, with low lighting). Patients were invited to relax on a ward bed in a supine or reclined position and music was played through high-quality stereo speakers and earphones. The two psychiatrists sat on either side of the bed. Patients were supervised at all times by at least two staff members.

8 Griffiths R

Richards W

Johnson M

McCann U

Jesse R Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. 24 Studerus E

Gamma A

Vollenweider FX Psychometric evaluation of the altered states of consciousness rating scale (OAV). Dosing commenced at 1030 h in every case. Patients received a low oral dose of psilocybin 10 mg (two 5 mg capsules) on a first dosing day and a high oral dose of psilocybin 25 mg (five 5 mg capsules) on a second dosing day, separated by 1 week. Blood pressure, heart rate, and observer ratings of the intensity of psilocybin's acute psychoactive effects (0–4, with 0 signifying no effects and 4 signifying extreme effects) were measured at baseline (typically 5 min before dosing) and 30, 60, 120, 180, 240, 300, and 360 min after dosing. Subjective ratings of the acute altered state of consciousness using the revised 11 dimension altered states of consciousness questionnaire (11D ASC)were completed 6–7 h after dosing.

Psychiatrists adopted a non-directive, supportive approach, allowing the patient to experience a mostly uninterrupted inner “journey”. Check-ins (ie, asking the patient how they are feeling) occurred at the same timepoints as the physiological recordings. Tranquilising medications (oral lorazepam and risperidone) were available if necessary. The phenomenology of the acute experience, including accounts of the nature of the therapeutic support provided before, during, and after the experience, and considerations related to the music selection and other aspects of the clinical setting, will be discussed in separate publications.

Return transport from the research facility was organised ahead of dosing sessions. Patients were taken to and from the sessions accompanied by a close friend or relative, and had the option of staying overnight in accommodation adjacent to the hospital. Emergency contact details were provided, and patients confirmed their safe return from the research facility.

Patients were contacted via telephone 1 day after their low-dose session to check on their wellbeing and monitor for any adverse events. Patients returned to the research facility 1 day after their high-dose session for a post-treatment fMRI scan lasting 60 min. After the fMRI scan, patients completed interim questionnaires (QIDS, STAI-T, and HAM-D), and were invited back to the research facility where they were met by their psychiatrists to discuss their experience the previous day.