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Psilocybin with psychological support for treatment-resistant depression

An open-label feasibility study

by

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

Lancet Psychiatry 2016; 3: 619-27

© Carhart-Harris et al.

Published Online: May 17, 2016 http://dx.doi.org/10.1016/S2215-0366(16)30065-7
See Comment page 592

*Contributed equally

Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK: (R L Carhart-Harris PhD, M Bolstridge MD, J Rucker MD, C M J Day MD, D Erritzoe MD, M Kaelen BSc, Prof D J Nutt DM);
Department of Pharmacy and Pathology, South London and Maudsley NHS Foundation Trust, London, UK: (Prof D Taylor PhD); The Institute of Psychiatry, Psychology and Neuroscience: (J Rucker) and Institute of Pharmaceutical Science: (Prof B Forbes PhD), King's College London, London, UK; Department of Psychiatry: (M Bloomfield MD), Clinical Psychology and Clinical Effectiveness: (Prof S Pilling PhD), and Clinical Psychopharmacology Unit: (Prof V H Curran PhD), University College London, London, UK; Barts Health Pharmaceuticals, Barts Health NHS Trust, The Royal London Hospital, London, UK: (J A Rickard PhD); and The Beckley Foundation, Beckley Park, Oxford, UK: (A Feilding).

Correspondence to: Dr Robin L Carhart-Harris, Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine, Imperial College London, London W12 0NN, UK
r.carhart-harris@imperial.ac.uk

Table of Contents:
Summary
 Background
 Methods
 Findings
 Interpretation
 Funding
Research in context
 Evidence before this study
 Added value of this research
 Implications of all the available evidence
Introduction
Methods
 Study design and participants
 Procedures
 Outcomes
 Statistical analysis
 Role of the funding source
Results
Discussion
Acknowledgments
References
Supplementary appendix
 Supplementary information
 Acute subjective and physiological effects of psilocybin
 1.1. Aim of study
 1.2 Background of the study
2. Project outline
 2.1 Main study design
3. Basic safety and scientific background
4. Study design
 4.1. Primary outcome measure
 4.2. Volunteers
  4.2.1. Screening procedure
  4.2.2. Inclusion criteria
  4.2.3. Exclusion criteria
  4.2.4. Withdrawal Criteria
5. Regulatory Issues and informed consent
 5.1 Ethics Approval
 5.2 Consent
 5.3 Confidentiality
 5.4 Audits and Inspections
 5.5. Monitoring
6. Patient recruitment strategy
7. Drug specific ethical and safety considerations
 7.1. Suicide and persistent adverse events
 7.2 Definitions and reporting of Adverse Events & Reactions
 7.2.1 Reporting Procedures
8. Study time line
9. Day 1, screening time line
10. Functional MRI
11. Day 5, Functional MRI and prep session with therapist
12. Follow-up
13. Dosing and patient management
 13.1. Dosing procedure
 13.2 Dosing parameters and algorithm
 13.3 Patient management
14. Standard Operating Procedure for managing adverse events
15. Time commitments
16. Purchasing and storing drug
17. Analysis
18. Dosing day timeline
19. Monitoring
20. IMP details
21. Dosing algorithm
22. References

Summary

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.

Funding

Medical Research Council.

Research in context

Evidence before this study

We searched PubMed up to Jan 30, 2016, using the terms "psilocybin", "hallucinogens", "psychedelics", and "depression". We did not find any clinical trials assessing psilocybin as a treatment for depression, but we did find population analyses, review articles, and imaging studies lending support to this approach. We also found one report documenting enduring decreases in depressive symptoms after a single dose of psilocybin in a randomised controlled trial of psilocybin-assisted psychotherapy for end-of-life anxiety, one report on an open-label trial showing rapid decreases in depressive symptoms that endured for up to 21 days after a single dose of ayahuasca, and two early reports or case studies on the effects of lysergic acid diethylamide on "neurotic" and depressive symptoms describing "improvements", albeit without validated measures of symptom severity.

Added value of this research

To our knowledge, this is the first investigation of the safety and efficacy of psilocybin as a treatment for major depression. Our findings imply that psilocybin might have value as a treatment option in the management of treatment-resistant depression. Single oral administrations of 10 mg (safety dose) and 25 mg (treatment dose) psilocybin were well tolerated and led to enduring reductions in symptom severity after the two sessions.

Implications of all the available evidence

The results of this small-scale feasibility study should help to motivate further research into the efficacy of psilocybin with psychological support for major depression. Larger-scale randomised controlled trials are warranted to better examine the potential of psilocybin as a treatment option for this highly prevalent, disabling, costly, and difficult-to-treat disorder. More broadly, the present study should help to catalyse the re-emergence of a promising research area in psychiatry.

Introduction

Psilocybin is a naturally occurring plant alkaloid found in the Psilocybe genus of mushrooms. Psilocybe mushrooms have been used for millennia for healing purposes, but were only discovered by modern science in the late 1950s.1,2 Psilocybin is a prodrug of psilocin (4-hydroxy-dimethyltryptamine), a serotonin receptor agonist and classic psychedelic drug whose principal psychoactive effects are mediated by serotonin 2A (5-HT2A) receptor agonism.3 Psilocybin therefore has a novel pharmacology in the context of currently available antidepressant medications, because selective serotonin-reuptake inhibitors are not direct 5-HT2A receptor agonists.

Enhanced cognitive flexibility,4 associative learning,5 cortical neural plasticity,6 and antidepressant responses have been reported with 5-HT2A receptor agonism in animals,7 and increased and sustained improvements in wellbeing8 and optimism9 have been observed after psychedelic experiences in human beings. Findings from human imaging studies with psilocybin have supplemented these discoveries, showing changes in brain activity suggestive of antidepressant potential; for example, a range of effective antidepressant treatments have been found to normalise hyperactivity in the medial prefrontal cortex and we found reduced blood flow in this region with intravenous psilocybin.10 Moreover, data obtained from large-scale population studies have recently challenged the view that psychedelics negatively affect mental health,11-13 with one study's findings showing lower rates of psychological distress and suicidality among people who had used psychedelics within their lifetime than among those who used no psychedelics but an equivalent amount of other drugs.11 In modern trials, psychedelics have been found to reduce anxious,14,15 depressive,15,16 and obsessive-compulsive symptoms,17 as well as addictive behaviours,18,19 often for several months after just one or two exposures. Extensive historical and modern evidence now supports the view that, administered in a controlled environment with appropriate support, psychedelics have a favourable safety profile.20

Depression is a major public health problem; it is a leading contributor to the global burden of disease, affecting hundreds of millions of people worldwide, and costing the USA alone more than US$200 billion each year.21 Antidepressant medications and cognitive behavioural therapy can be effective for some patients, but around 20% do not respond to any intervention, and many of those who do respond, eventually relapse.22 We aimed to investigate the safety and feasibility of psilocybin in patients with treatment-resistant depression, and to establish an initial impression of its efficacy. We postulated that the treatment would be well tolerated and depressive symptoms would be substantially reduced from baseline at all assessment points, for up to 3 months after treatment.

Methods

Study design and participants

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.23 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.

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 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.

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.

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 effects8) 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)24 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 well-being 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.

Patients attended one further study visit to the research facility 1 week after their high-dose session, during which all baseline questionnaires and assessments were repeated and an opportunity was provided for further psychological debriefing (the 1 week follow-up visit). Assessments of HAM-D, MADRS, and GAF were again done by MBo. Subsequent assessments of clinical progress were done via email 2, 3, and 5 weeks after the high-dose session; we assessed only QIDS during subsequent follow-up, so as not to overload the patient. Final follow-up was done remotely at 3 months after the high-dose session, and included QIDS, BDI, STAI-T, and SHAPS. Patients were made aware that they could contact the study psychiatrists at any time if their depression deteriorated. Figure 1 summarises the screening, intervention, and follow-up procedures in this study.

Figure 1 - Schedule of study interventions.

Outcomes

The main objective of this study is to optimise the protocol for the administration of oral psilocybin in this patient group, while gaining an initial impression of treatment efficacy. The primary outcome measure to assess feasibility was patient-rated subjective intensity of psilocybin's effects, which we report on a 0-1 scale. We assessed the safety of the intervention through clinical monitoring during and after dosing sessions, and during 3 months of face-to-face and remote follow-up. We also aimed to assess the preliminary efficacy of psilocybin in patients with treatment-resistant depression; the primary outcome measure for this endpoint was mean change in the severity of self-reported depressive symptoms (with the 16 item QIDS) from baseline to 1 week after the high-dose psilocybin session. The QIDS was chosen as the primary outcome measure due to its brevity, increasingly widespread use, and validity at 1 week intervals.25 We chose to assess the primary efficacy endpoint at 1 week after the high-dose session to allow comparison with previous studies of ketamine infusion for treatment-resistant depression;26 the low-dose session was conceived a priori as a safety session rather than a treatment session. We also assessed change in BDI, STAI-T, and SHAPS between baseline and 1 week and 3 months of follow-up, and change in HAM-D, MADRS, and GAF between baseline and 1 week of follow-up.

Statistical analysis

In this feasibility study, we did not perform a formal power calculation. We planned to recruit 12 patients to provide an initial impression of the tolerability and efficacy of this novel treatment approach. A subsequent protocol amendment (Oct 6, 2015) increased the recruitment to 20 patients to provide statistical power for fMRI imaging. Here, we report findings for the 12 patients initially enrolled; outcome and fMRI data for all 20 patients will be reported separately.

Due to the small population, two-tailed Wilcoxon signed ranks tests were performed for non-parametric data. Two-tailed t tests were also performed and the relevant t values are provided in the appendix. We provide 95% CIs around the mean differences. We calculated effect sizes using the Hedges' g formula, which is more appropriate for small sample sizes. Hedges' g values are very similar to Cohen's d values for dependent data.

This trial is registered with the ISRCTN registry, number ISRCTN14426797. The registration was initiated on March 30, 2015, and finalised on July 7, 2015 (delay caused by administrative issues); recruitment started on April 21, 2015, after initiation of public registration.

Figure 2 - Trial profile.

Role of the funding source

The study funder had no role in the design, data collection, analysis, interpretation, or writing of the report. The corresponding author had full access to all of the data in the study and had final responsibility for the decision to submit for publication.

Results

Enrolment started on May 1, 2015, and finished on Aug 25, 2015. 72 people were initially considered for the study, most of whom self-referred after hearing about this trial through public outreach work (eg., public presentations by the investigators and media reports). 38 were considered appropriate for a telephone screen, from which 18 were invited for a formal screening visit, and 12 were ultimately recruited for the trial (figure 2), of whom ten were self-referrals. Patients' demographic and clinical characteristics are shown in table 1. Nine of the 12 patients met criteria for severe or very severe depression at baseline (BDI score ≥30), with the remaining three patients meeting criteria for moderate depression (BDI score 19 to <30). 11 patients had received some form of psychotherapy before participation in the study.

SexAge,
years
Ethnic
origin
Employment
status
Estimated illness duration, yearsBaseline scoresPast unsuccessful medications*Past psychotherapyEducationWeekly alcohol intake, unitsPrevious psilocybin use (time since last use)
BDIHAM-DSTAI-T
1Female43Black CaribbeanEmployed30361972SSRI (two), SNRI (two), NDRI, NSSRI, MAOINonePostgraduate1None
2Male40HispanicUnemployed25332876SSRI (two), SNRI, NDRI, NSSRI, Na+ channel blocker (two), ketamine infusion, TCACognitive narrative therapyPostgraduate0None
3Male37WhiteEmployed17221863SSRI (two), SNRICognitive behavioural therapy, group therapyPostgraduate0None
4Female30WhiteStudying10261867NDRI, NSSRICognitive behavioural therapyPostgraduate0One use (6 months)
5Male34WhiteUnemployed12382571SSRI (three), TCACognitive and mindfulness behavioural therapyUndergraduate0None
6Female57WhiteUnemployed29392378SSRI (four), SNRI, SARICounsellingSecondary education2Two uses (45 years)
7Male52WhiteUnemployed27332257TCA, SARICounselling, mindfulnessSecondary education0Three uses (30 years)
8Female37WhiteEmployed17391771SSRI (two), TCACounsellingUndergraduate2None
9Male37WhiteUnemployed15322671SSRI (three), SNRICounselling, cognitive behavioural therapyPostgraduate6None
10Female36Black CaribbeanUnemployed8472875SSRI (two), NSSRICounsellingUndergraduate18Three uses (14 years)
11Female64WhiteEmployed15241772SSRI (four), SNRI (two), NDRI, MAOI, Na+ channel blocker, SARI, DRICognitive behavioural therapyPostgraduate1Three uses (48 years)
12Male45WhiteEmployed8351768SSRI, TCACognitive behaviouralUndergraduate0None
BDI=Beck Depression Inventory. HAMD-D=Hamilton Depression Rating scale. STAI-T=State-Trait Anxiety Inventory. SSRI=selective serotonin-reuptake inhibitor. SNRI=serotonin-noradrenaline reuptake inhibitor. NDRI=noradrenaline-dopamine-reuptake inhibitor. NSSRI=noradrenaline and specific serotonin-reuptake inhibitor. MAOI=monoamine oxidase inhibitor. TCA=tricyclic antidepressant. SARI=serotonin antagonist and reuptake inhibitor. DRI=dopamine-reuptake inhibitor. *One medication from each class, unless otherwise stated.
Table 1: Baseline and demographic characteristics, by patient.

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). No patients required tranquilising medications (oral lorazepam and risperidone) during the dosing sessions. Psilocybin's acute psychedelic effects typically became detectable between 30 min and 60 min after dosing, peaked between 2 h and 3 h after dosing, and subsided to negligible levels at which the patient could be assessed for discharge at least 6 h after dosing (appendix). Self-rated experiences on the 11D-ASC questionnaire from the two sessions are shown in the appendix. Results from interim patient questionnaires (QIDS, BDI, and STAI-T), done immediately before the low-dose session to monitor for substantial changes since enrolment, did not differ from baseline (data not shown). Interim questionnaires done the day after the high-dose session showed some reduction in depressive symptoms (data for HAM-D in appendix; data for QIDS and STAI-T not shown).

SeverityTiming or onsetDuration
Patient 1
Transient anxietyMildOnset of both sessions60 min
Transient headacheMildDay after high-dose sessionOne day only
Transient confusionMild (core drug effect)Peak of both sessions60-120 min
Patient 2
Transient anxietyMildAnticipatory anxiety only (both sessions)30 min
Patient 3
Transient anxietyMildAnticipatory anxiety only (both sessions)30 min
Transient confusionMild (core drug effect)Peak of both sessions60-180 min
Patient 4
Transient anxietyMild (low dose), moderate (high dose)Onset of both sessions and peak of high dose60 min (low dose), 120 min (high dose)
Transient nauseaModerateOnset phase of high-dose sessionArose and subsided within 60 min
Transient confusionMild (core drug effect)Peak of both sessions60-180 min
Transient paranoiaMildPeak of high-dose sessionArose and subsided within 30 min
Patient 5
Transient anxietyModerate (low dose), severe (high dose)Onset of both sessions and peak of high dose60 min (low dose), 150 min (high dose)
Transient headacheMildDay after high-dose sessionOne day only
Transient confusionMild (core drug effect)Peak of both sessions60-120 min
Patient 6
Transient anxietyMildAnticipatory anxiety only (both sessions)30 min
Patient 7
Transient anxietyMildAnticipatory anxiety only (both sessions)30 min
Transient confusionMild (core drug effect)Peak of both sessions60-180 min
Patient 8
Transient anxietyMild or negligibleAnticipatory anxiety only (both sessions)30 min
Patient 9
Transient anxietyMild (low dose), moderate (high dose)Onset of low-dose and high-dose session60 min (low dose), 150 min (high dose)
Transient headacheMildDay after high-dose sessionOne day only
Transient confusionMild (core drug effect)Peak of both sessions60-180 min
Patient 10
Transient anxietyMildOnset of both sessions60 min
Transient nauseaMildOnset and peak of low-dose sessionSubsided after 90 min
Transient headacheMild or moderateDay after high-dose session2 days
Transient confusionMild (core drug effect)Peak of both sessions60-180 min
Patient 11
Transient anxietyModerate (both sessions)Onset phase and peak of both sessions150 min (both sessions)
Transient nauseaMild (high dose)Onset phase of high-dose sessionArose and subsided within 60 min
Transient confusionMild (core drug effect)Peak of both sessions60-180 min
Transient paranoiaMildPeak of low-dose sessionArose and subsided within 60 min
Patient 12
Transient anxietyMildAnticipatory anxiety only (both sessions)30 min
Transient confusionMild (core drug effect)Peak of both sessions60-180 min
Table 2: Adverse events by patient.

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.

Figure 3 - Mean depression severity (QIDS) over time.
Depression severity determined by self-rated 16-item QIDS. QIDS scores of 16-20 are considered to reflect severe depression, scores of 11-15 are considered moderate depression, scores of 6-10 are considered mild depression, and scores of 5 and less are considered absent depression. All post-treatment assessments were obtained after the high-dose session (ie., 1 week post-treatment refers to 1 week after the high-dose session). Hedges' g values versus baseline are shown. QIDS=Quick Inventory of Depressive Symptoms.

QIDS depression scores were significantly reduced from baseline to 1 week and 3 months post-treatment, with the maximum effect at 2 weeks (figure 3, table 3). BDI and clinician-administered ratings confirmed these results (figure 4, table 3). All patients showed some reduction in depression severity at 1 week that was sustained in the majority for 3 months (appendix). According to standard criteria for determining remission (eg., a score of ≤9 on the BDI), eight (67%) of the 12 patients achieved complete remission at 1 week and seven patients (58%) continued to meet criteria for response (50% reduction in BDI score relative to baseline) at 3 months, with five of these (42%) still in complete remission (figure 4, table 3). STAI-T anxiety scores were also significantly reduced at 1 week and 3 months post-treatment, as were SHAPS anhedonia scores for 1 week and 3 months post-treatment (table 3).

QIDSBDI STAI-T SHAPS HAM-D MADRS GAF
Baseline1 week2 weeks3 weeks5 weeks3 monthsBaseline1 week3 monthsBaseline1 week3 monthsBaseline1 week3 monthsBaseline1 weekBaseline1 weekBaseline1 week
Mean (SD) 19.2 (2.0)7.4 (4.9)6.3 (4.6)6.4 (5.1)8.2 (5.4)10.0 (6.0)33.7 (7.1)8.7 (8.4)15.2 (11.0)70.1 (5.840.6 (14.2)54.8 (14.5)7.5 (3.7)1.4 (2.7)2.8 (3.7)21.4 (4.5)7.4 (6.9)31.0 (5.0)9.7 (9.8)50.3 (9.2)77.7 (13.0)
Difference versus baseline (95% CI)..-11.8 (-9.15 do -14.35)-12.9 (-10.64 do -15.16)-12.8 (-9.9 do -15.6)-11.0 (-7.7 do -14.2)-9.2 (-5.69 do -12.71)..-25.0 (-20.1 do -29.9)-18.5 (-11.8 do -25.2)..-29.5 (-22.03 do -36.97)-15.3 (-7.77 do -22.83)..-6.1 (-4.46 do -7.74)-4.7 (-3.29 do -6.11)..-14.0 (-9.6 do -18.4)..-23.3 (-17.1 do -29.5)..27.3 (18.0 do 36.6)
Z..-3.1-3.1-3.06-2.9-3.0..-3.1-3.1..-3.1-2.9..-3.1-3.1..-3.0..-3.1..-3.0
Hedges' g*..3.13.23.22.72.0..3.22.0..2.71.4..1.91.3..2.4..2.7..2.4
p value*..0.0020.0020.0020.0030.003..0.0020.002..0.0020.004..0.0020.002..0.003..0.002..0.003
Follow-up refers to the period starting after the second (high-dose) administration of psilocybin. Clinician-administered ratings (HAM-D, MADRS, and GAF) were completed only at baseline and 1 week after the high-dose session. QIDS=Quick Inventory of Depressive Symptoms. BDI=Beck Depression Inventory. STAI-T=State-Trait Anxiety Inventory. SHAPS=Snaith-Hamilton Pleasure Scale. HAM-D=Hamilton Depression Rating scale. MADRS=Montgomery-Åsberg Depression Rating Scale. GAF=Global Assessment of Functioning. *Compared with baseline.
Table 3: Clinical ratings at baseline and follow-up.

Discussion

In this open-label, single-arm pilot study, we sought to examine the feasibility of administering psilocybin to patients with treatment-resistant depression as a prelude to a larger randomised controlled trial. Our results support the view that, done with appropriate safeguards (eg., careful screening and adequate therapeutic support), psilocybin can be safely administered to this patient group.

Figure 4 - Depression severity (BDI) over time, by patient.
Figure shows depression severity (BDI) over time plotted for each of the 12 patients. Mean values (SD) are shown as well as the relevant effect sizes (Hedges' g) versus baseline. BDI=Beck Depression Inventory.

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.27

Spontaneous recovery in refractory depression is rare, and many of the patients in the present study reported having depression for much of their adult lives (mean estimated illness duration 17.8 years [SD 8]). Key questions for future research therefore should address why the therapeutic effect observed in the present study is so large, and if it can be replicated when tighter experimental controls are introduced. Because the treatment in our study consisted of not just two psilocybin administrations but also psychological support before, during, and after these sessions, as well as a positive therapeutic environment for the sessions, the relative effects of these factors need to be determined, which can only be done by conducting further trials with appropriate control conditions.

A logical next step would be to carry out a placebo-controlled randomised trial in which the level of therapist contact is consistent between conditions. This would enable any between-group differences in clinical outcomes to be attributed to psilocybin rather than the psychological support provided. However, a positive interaction between these variables seems likely, and inert placebo-based blinds are known to be ineffective in studies involving conspicuous experimental interventions, because patients can easily discern whether they are in the active condition or not. Use of an active placebo for the control condition might therefore be worth considering. Additionally, randomised comparative efficacy trials (eg., with an optional crossover component) incorporating another treatment for refractory depression (eg., ketamine infusion) could also be explored.

The magnitude and persistence of the antidepressant effects observed here are not incongruent with what has been observed previously with psilocybin in chronic psychiatric conditions. For example, 80% of long-term heavy tobacco smokers demonstrated abstinence from smoking 6 months after two treatment sessions with psilocybin.18 Alcohol-dependent patients demonstrated significantly reduced drinking behaviours over 8 months after one or two psilocybin sessions.19 Significantly decreased anxiety and depression scores were observed 3 and 6 months after a single dose of psilocybin in patients with anxiety related to end-stage cancer,15 and improvements in well-being lasting for more than 1 year were observed in healthy individuals given a single dose of psilocybin.8 Rapid and enduring decreases in depressive symptoms were also recently found in a small-scale feasibility trial involving the psychedelic brew, ayahuasca.16

It is important to consider the limitations of this pilot study; for example, although all patients showed some clinical improvements for at least 3 weeks after treatment, and no serious or unexpected adverse reactions were observed, enduring improvements beyond 3 weeks were not observed universally, and five of the 12 patients showed a degree of relapse at 3 months.

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,28 which might have further enhanced positive outcomes. Future double-blind randomised controlled trials could address the role of expectancy and suggestibility by measuring and controlling these variables. For example, patients could be asked about their pre-treatment expectations, suggestions could be controlled between conditions, and outcomes from self-referred patients could be compared with those from patients referred via clinicians. From a more pragmatic perspective, if expectancy or suggestibility are found to be influential in the context of psychedelic therapy, they could be treated as exploitable components of the treatment model rather than confounding variables.

Serotonergic antidepressants have been found to downregulate the primary receptor target of psilocybin (the 5-HT2A receptor) and attenuated subjective responses to psychedelics have previously been reported in individuals chronically medicated with serotonergic antidepressants.29 Thus, patients may be required to withdraw from concurrent antidepressant medication before receiving psilocybin and this should only ever be done with care. In conclusion, we sought to assess the safety and tolerability of psilocybin plus psychological support in patients with unipolar treatment-resistant depression. Our findings support the feasibility of this approach and the magnitude and duration of the post-treatment reductions in symptom severity motivate further controlled research. Psilocybin has a novel pharmacological action in comparison with currently available treatments for depression (ie., 5-HT2A receptor agonism) and thus could constitute a useful addition to available therapies for the treatment of depression.

Contributors
RLC-H and DJN designed the study and RLC-H wrote the report. RLC-H coordinated the study, and collected and analysed the data. MBo was the lead psychiatrist on the trial. MBo, JR, CMJD, DE, and MBl provided psychological support for the patients. All authors critically revised the report or contributed important intellectual content.

Declaration of interests
DT has received research funding and lecture honoraria from Servier, and lecture honoraria from Lundbeck. The other authors declare no competing interests.

Acknowledgments

This study was funded by an MRC clinical development scheme grant (MR/J00460X/1). MK was supported by the Beckley Foundation and this work was carried out as part of the Beckley/Imperial Research Collaboration. The research was carried out at the NIHR/Wellcome Trust Imperial Clinical Research Facility. We would like to thank Robert Sullivan (Meridian West London, London, UK) for provision of high-quality audio equipment for the dosing sessions.

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Supplementary appendix

This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

Supplementary information

T-values for main tests
QIDS
Baseline vs 1-week post-treatment: t =8.9
Baseline vs 2-weeks post-treatment: t =11.3
Baseline vs 3-weeks post-treatment: t =8.9
Baseline vs 5-weeks post-treatment: t =6.7
Baselines vs 3-months post-treatment: t =5.1

BDI
Baseline vs 1-week post-treatment: t =9.9
Baseline vs 3-months post-treatment: t =5.4

STAI
Baseline vs 1-week post-treatment: t =7.8
Baseline vs 3-months post-treatment: t =4.0

SHAPS
Baseline vs 1-week post-treatment: t =7.3
Baseline vs 3-months post-treatment: t =6.4

HAM-D
Baseline vs 1-week post-treatment: t =6.2

MADRS
Baseline vs 1-week post-treatment: t =7.5

GAF
Baseline vs 1-week post-treatment: t =5.7

HAM-D data for weeks following each dose
Baseline = 21.4 ± 4.5
One week post low dose = 10.7 ± 7.8
One week post high dose = 7.4 ± 6.9

Acute subjective and physiological effects of psilocybin

Dose 1 (10 mg)Dose 2 (25 mg)
Time since dose (hrs)BPMBPIntensity (0-4)BPMBPIntensity (0-4)
Baseline80.1 (11.9)126.6 (11.7)0 (0)78.4 (8.3)128.8 (13)0 (0)
0.582.6 (13.8) 130.2 (12.8)0.5 (0.5)81.3 (13.1)135.1 (17.1)0.8 (0.7)
178.8 (13.6) 131.2 (18.5)0.8 (0.7)80.1 (14.4)138.6 (14.6)1.6 (1)
277.3 (15.8) 134.4 (16.4)1.5 (1)81.8 (12.6)135.9 (23.2)2.8 (0.8)**
375,6 (9.3) 131.7 (15.9)1.5 (0.8)81.2 (11.5)130.2 (17)2.8 (0.9)**
474.9 (5.8) 128 (20.2)1.3 (0.9)77.1 (11.1)124.4 (20.2)2.1 (1)
576.6 (8.4) 128.8 (14.9)0.5 (0.5)75.5 (8.4)119.3 (30.9)1.2 (0.8)
ASC dimensionDose 1 (10 mg)Dose 2 (25 mg)
Experience of unity0.35 (0.36)0.39 (0.27)
Spiritual experience0.31 (0.30)0.32 (0.34)
Blissful state0.34 (0.34)0.49 (0.35)
Insightfulness0.36 (0.31)0.49 (0.35)
Disembodiment0.4 (0.35)0.46 (0.31)
Impaired cognition0.22 (0.22)0.55 (0.27)**
Anxiety0.25 (0.28)0.42 (0.26)**
Complex imagery0.42 (0.31)0.36 (0.3)
Elementary hallucinations0.47 (0.46)0.38 (0.27)
Audio/visual synaesthesia0.32 (0.28)0.47 (0.33)
Special meaning0.32 (0.33)0.45 (0.32)
Global score0.34 (0.28)0.43 (0.25)*
Table S1. Acute measures: Mean values (SD). For upper section of table, ** = p < 0.01 high-dose value vs low-dose value, Bonferonni corrected by a factor of 2. Responses for the 11 dimension altered states of consciousness questionnaire (11D-ASC) are presented in the lower section of the table. The range of possible scores = 0-1, with 0 = "not at all" and 1 = "much more than usually". ** = p < 0.01 high-dose vs low-dose value, Bonferonni corrected by a factor of 11, * = p < 0.05, no correction required.

Patient #QIDS
BL, 1wk, 2wks, 3wks, 5wks, 3m
BDI
BL, 1wk, 3m
STAI T
BL, 1wk, 3m
SHAPS
BL, 1wk, 3m
HAM-D
BL, 1wk
MADRS
BL, 1wk
GAF
BL, 1wk
119, 2, 3, 4, 4, 836, 4, 872, 29, 428, 0, 519, 335, 452, 82
220, 4, 5, 4, 9, 433, 2, 376, 31, 353, 0, 028, 834, 638, 75
322, 17, 14, 13, 15, 1522, 17, 1863, 33, 5811, 5, 1018, 1527, 2059, 62
414, 7, 2, 4, 11, 726, 0, 967, 26, 501, 0, 018, 026, 058, 95
519, 12, 13, 15, 19, 2238, 22, 3671, 66, 7314, 4, 825, 1634, 1343, 65
619, 6, 7, 7, 8, 1529, 4, 2478, 58, 659, 0, 123, 1631, 1753, 67
718, 1, 1, 0, 2, 133, 2, 257, 28, 298, 0, 022, 032, 138, 95
819, 14, 11, 14, 11, 1439, 23, 2971, 64, 6711, 8, 717, 1824, 2357, 56
920, 7, 8, 8, 8, 1232, 7, 1571, 41, 668, 0, 326, 532, 438, 82
1021, 9, 7, 5, 8, 547, 16, 1675, 39, 567, 0, 028, 542, 2746, 78
1118, 3, 1, 1, 1, 1224, 1, 2072, 32, 713, 0, 017, 228, 158, 82
1221, 7, 3, 2, 2, 435, 6, 268, 40, 467, 0, 017, 127, 063, 92
Means (SD): BL, 1wk (2-5wks, QIDS only), 3m19.2 (2), 7.4 (4.9), 6.3 (4.6), 6.4 (5.1), 8.2 (5.4), 10 (6)33. 7 (7.1), 8.7 (8.4), 15.2 (11)70.1 (5.8), 40.6 (14.2), 54.8 (14.5)7.5 (3.7), 1.4 (2.7), 2.8 (3.7)21.4 (4.5), 7.4 (6.9)31 (5), 9.7 (9.8)50.3 (9.2), 77.7 (13)
Hedges' g*: 1wk (2-5wks, QIDS only), 3m3.1*, 3.2*, 3.2*, 2.7*, 2*3.2*, 2*2.7*, 1.4*1.9*, 1.3*2.4*2.7*2.4*
Table S2. Individual patient clinical ratings: Displayed are various rating scale values at various different time points. The clinician administered ratings were only completed at baseline and 1 week post-dosing. BL = baseline. * = p < 0.01.

1.1. Aim of study

Our long term objective is to test the efficacy of psilocybin as an intervention for treatment-resistant major depressive disorder31 but the primary objective of this pilot study is to optimise the protocol for the administration of oral psilocybin in this patient group. The knowledge and experience gained from this pilot study will be used to inform a subsequent randomised control trial (RCT) that will evaluate the anti-depressant properties of psilocybin. A secondary aim of the pilot is to use functional magnetic resonance imaging (fMRI) to try and identify how psilocybin affects brain activity before and after the psilocybin intervention.

1.2 Background of the study

This MRC-funded study is designed to optimise the procedures for a subsequent RCT of psilocybin as an intervention for treatment-resistant depression. The burden of depression is severe and increasing. Preventing relapse is a major challenge in depression; first line medications can decrease symptom severity but large numbers of patients fail to respond. Psilocybin is a naturally occurring compound that is structurally similar to the endogenous neurotransmitter serotonin. It had a brief history of use in psychotherapy in the 1960s but this was cut short for political reasons before its efficacy could be properly assessed. In recent years, a growing number of studies, including our own, have shown that psilocybin can be safely administered to human subjects7 and there are now consistent reports of persistent improvements in well-being after just single exposures to psilocybin12 10, 14.

2. Project outline

2.1 Main study design

This pilot study will involve 20 patients meeting DSM-IV criteria for major depression of a moderate to severe degree (17+ on the 21-item Hamilton Depression Rating Scale, HAM-D) that have failed to clinically respond to at least two different classes of antidepressant drug treatment (adequate dose, compliance and minimal duration of 6 weeks31) within the current episode. The main objective of the pilot study will be to establish feasibility and optimise procedures for a subsequent randomised clinical trial. The primary outcome of this pilot study will be the intensity of the subjective effects of orally administered psilocybin in this patient group. All 20 patients will receive the active drug psilocybin in two oral doses: a low (tester) dose and the other a high (active) dose 7 days apart. The doses that will be used in this study have been chosen based on previous research on the subjective effects of orally administered psilocybin10-12, 14, 19, 35 and through discussions with leaders in the field that are currently working with oral psilocybin in clinical trials, including those involving patients with symptoms of depression.

Optimum doses for this study will be those that produce subjective effects of an appropriate intensity. To determine this, we will use a standard rating method; namely, patients provide a verbal rating of the intensity of subjective effects on a rating scale from 0 to 10, with 0 equalling 'no effects' and 10 equalling 'extremely intense effects'. Based on the previous literature and discussions with relevant experts, we have determined that 10mg (low dose) and 25mg (high dose) will provide effects of an appropriate intensity for this study. More specifically, it can be predicted that 10mg will produce effects rated 4-6/10 for intensity and 25mg will produce effects rated 7-9/10 and the pilot study will test this. Doses of 30mg psilocybin have been administered to healthy volunteers and patients suffering from anxiety and depression in previous trials (mostly individuals with no previous experience with psychedelic drugs) without major complications. Therefore, the proposed maximum dose (25mg) falls within this safe range. Please see the dosing algorithm below for how the low and high dose may be changed depending on the responses of the first 6 patients. The intention of the low/high dosing protocol is to give patients an initial low dose to enable them to have an impression of the drug effects at an attenuated intensity. We believe this to be a cautious and sensible approach. Thus, on the second dosing day patients will have an improved understanding of the procedure, some idea of the drug's effects and will be habituated to their surroundings and research team, all of which will augur well for receiving a higher active dose of the drug.

There will be around 11 days from screening to the first dosing session to allow the analysis of screening data (e.g. blood tests) to determine eligibility and enable contact to be made with their GP and/or mental health practitioners. Eligibility will be ascertained by the study psychiatrist who will thoroughly screen all patients to identify and confirm the presence of treatment-resistant major depression. Supporting information from relevant mental health professionals and general practitioners will be obtained prior to entry into the trial to confirm diagnosis and ensure that all patients meet the inclusion criteria.

The procedure for recruitment will be as follows: the patient's immediate care team will be made aware of the study (see below re the improved access to psychotherapy, IAPT, scheme) and will identify a patient and ask them if they are willing to be contacted by us. The primary caregiver will then inform us of their patient's interest and will provide a contact telephone number and/or email. The patient will be issued with an A4 summary sheet containing a brief summary of the study and our contact details. After the patient has initiated contact with us, we will inform them about the nature of the study and organise an appropriate time for an initial telephone screen. We will ask the patient if we can contact their GP/psychiatrist (this will be done via an email using a standard letter) and we will ask the patient to provide us with a letter of consent for us to do this. If the patient appears to be eligible (post-telephone screen and post-contact with their GP/psychiatrist), a date for the first screening visit will be arranged.

Typically, a patient would be screened on a Monday, scanned on a Friday and dosed the following Thursday. There will be 1 week from the final dosing session to the final formal follow-up assessment. Patients will be in the study for 26 days in total, see section 8, study time line, after which they will be allowed treatment as usual.

All patients will be contacted at regular intervals in the period following dosing to prompt them to complete the rating scale Quick Inventory of Depressive Symptoms. This will provide an indication of whether their depression has responded to psilocybin. The criteria for determining response will be a reduction of 25% in the (QIDS)30 scores from baseline (screening), and remission will be scores of ≤5 on the QIDS29. Patients will be assessed remotely (i.e. electronically completed QIDS) for six months at which point the study will end.

In total, patients will be required to make at least 6 visits:

Visit 1/day 1: Screening and initial meet with the research team that will supervise the dosing
Visit 2/day 5: Scan 1 in IMANOVA followed by preparation/practice session with therapy team in CRF
Visit 3/day 11: Dosing session 1: low-dose psilocybin (10mg or 15mg) + post-session debrief
Day 12: Telephone follow-up
Days 12-17: remote QIDS
Visit 4/day 18: Dosing session 2: high-dose psilocybin (25mg ±5mg) + post-session debrief
Visit 5/day 19: Follow-up 2 and scan 2 in IMANOVA
Days 20-25: remote QIDS
Visit 6/day 26: Follow-up 3 (primary end point)
Day 32/week 5 (2 weeks post-dose): remote QIDS
Day 39/week 6 (3 weeks post-dose): remote QIDS
Day 53/~ month 2 (5 weeks post-dose): remote QIDS
Day 81/~month 3 (9 weeks post-dose): remote QIDS
Day 165/~month 6 (21 weeks post-dose): remote QIDS

Post-day 26, when we contact patients to request the completion of the QIDS, we will also ask them the open-ended question of whether they have anything to report in terms of persistent effects, whether positive or negative.

We will contact patients daily via telephone, email or text from day 12 to day 26 and thereafter on week 5, 6 and 8, and months 2, 3 and 6, to prompt the electronic completion of the QIDS30. Each patient will be issued with a study diary at screening and this will include all the important dates when they are expected to visit the study centre and to complete QIDS.

We may ask to see a patient before the follow-up visit on day 26, or after completion of the study, if adverse events are reported. On dosing days, we will also insist that patients be accompanied home by a friend or family member who can supervise and ensure that they are safe when returning home. We will ask for this person's contact details so that we can contact them if we have any difficulties contacting the patient him or herself. Both the patient and their 'chaperone' will be encouraged to contact us should any problems arise, particularly those that are felt to be attributed to the study intervention. In this way, any concerns in the immediate period or thereafter can be easily brought to our attention. We will be monitoring the patient's response in the ensuing weeks remotely via the QIDS. However, if we have any concerns about their mental state, we will liaise with their GP and/or mental health practitioners who may implement appropriate interventions if they deem fit. If the patient cannot nominate a significant other to accompany them home safely after a dosing session, a member of our study team will do this.

It will not be necessary for patients to withdraw from their antidepressant medication or psychological therapy when entering the study, since withdrawal may exacerbate depressive symptoms, and it will be informative to know whether psilocybin can be effective as an add-on to primary interventions. If a patient does decide he/she would like to withdraw from their medication, it will be necessary for them to be medication-free for at least 4 weeks prior to receiving their first dose of psilocybin. There will be 26 days from entry into trial (screening, visit 1) to the final follow-up visit (visit 6), after which patients may return to their normal treatments if they so wish.

The 4 week washout period should prevent any sudden exacerbation of symptoms during the study itself. However, if after withdrawal, symptoms show a marked increase at any point, we will discuss with the patient and their GP or consultant whether the patient should withdraw from the trial so that previous medications can be resumed or new ones given.

Secondary outcome measures in this study will be the mean change in QIDS scores from pre-dosing baseline at day 1 (visit 1) to follow-up at day 26 (visit 6, 1 week after the final dosing session). The QIDS is preferable to observer-rated scales such as the HAM-D because it measures internal states, is more sensitive to treatment effects, and covers more of the diagnostic criteria for depression30. The Montgomery and Asberg Depression Rating Scale (MADRS18) and HAM-D32 will also be carried out at screening (visit 1, day 1), follow-up 2 (visit 5, day 19) and follow-up 3 (visit 6, day 26).

The HAM-D and MADRS ratings will be performed by clinicians with experience in its use. Assessors will not be directly involved in the dosing sessions. We have identified 1 primary assessor plus a substitute. A single patient will have the same assessor throughout the trial.

Additional outcome measures completed will include the MADRS, HAM-D, Beck depression inventory (BDI), global assessment of functioning (GAF33), Beck Anxiety Inventory (BAI34), Dysfunctional Attitudes Rating Scale (DARS2 ), the NEO personality inventory (NEO-PI17), Peters 21-item delusional inventory (PDI25), the Ruminative Responses Scale (RRS28), the dynamic emotional expression recognition task (DEER-T)26, cued autobiographical memory task (AM-T)37, Spielberger's Trait Anxiety Inventory (STAI), the Positive and Negative Symptoms Scale (PANSS), Snaith Hamilton Anhedonia Pleasure Scale (SHAPS), the Life Orientation Task (LOT-R), the Tellegen Absorption Questionnaire (Tellegen), the 5-Dimension Altered States of Conscious Scale (5D-ASC), the Psychotic Symptoms Inventory (PSI) and the Strunk Prediction of Future Life Events (POFLE) and Prediction of Personality Characteristics (PC) task. With the exception of the 5D-ASC, these assessments will all be carried out at screening and during the final follow-up visit on day 26. The SHAPS, LOT-R will be carried out at screening and repeated on day 19 and 26. Visual Analogue Scales (VAS) and the 5-D ASC will be used to measure subjective states during the dosing sessions and electronic versions of the QIDS will be completed daily in the 2 weeks following the first dosing session, plus also at week 5, 6, 8 and month 3 and 6. With prior consent, we will also send a patient's significant other a small number of self-constructed questions at day 26 (or 8 days after the second dosing session) to enquire whether they have noticed any changes in the patient's behaviour since the intervention. The significant other will also complete a brief questionnaire on the patient prior the first dosing session.

3. Basic safety and scientific background

The LD50 of psilocybin in rats is 280mg/kg24; thus, in terms of toxicity, its margin of safety is very large. We intend to give no more than 25mg. Psilocybin has been given to several hundred patients and volunteers in modern studies. In a thorough review of dosing sessions in 110 healthy subjects, dysphoric experiences/bad trips were rare and dose-dependent and there was no evidence of subsequent drug abuse, flashback phenomena or prolonged psychoses27, 35. Consistent with magic mushrooms user reports, the majority of subjects described their experiences as enriching, insightful and beneficial - but not something they would regularly repeat. Psilocybin is not habit forming in animals27 or humans. We recently asked a large sample of experienced drug users to rank the relative harms and benefits of 11 of the most widely used recreational drugs in the UK4; users ranked magic mushrooms as the least harmful and one of the most beneficial drugs. The most commonly cited benefits were facilitated psychological insight and improved well-being. In a separate survey, without being explicitly cued, 5% of 503 magic mushroom users reported that magic mushrooms had alleviated their depressive symptoms, and 3.6% of 247 ketamine users reported this for ketamine6. Ketamine is currently being trialled for treatment resistant depression, with evidence of an impressive short-term efficacy (39, 1) but our survey results imply that psilocybin is safer than ketamine - and at least as effective.

Reports from the 1960s on the use of psilocybin in psychotherapy indicate clear benefits over harms13; however, these studies suffer from a lack of experimental control and standardised assessments. More recently, pilot studies have tested the efficacy of psilocybin in OCD19 and anxiety related to terminal cancer14: In the former study, short-term reductions in compulsive symptoms were reported by all of the patients. In the latter study, trait anxiety was significantly decreased 1 and 3 months post session and depression scores were significantly decreased at 6 months. No clinically significant adverse events were observed in either study. In a large sample of healthy volunteers, orally administered high dose psilocybin induced mystical or spiritual-type experiences in over 60% of subjects11. Sixty seven percent rated their experience as either the single most meaningful experience of their lives - or among the top five. In a follow-up after 14 months, 64% of the sample maintained that the acute experience had led to a significant improvement in their sense of well-being or life satisfaction12.

In the last two years, we have completed one pilot study7, two fMRI studies3 and one MEG study involving psilocybin infusion. We have carried out 54 dosing sessions in total and have seen no adverse events. Infused during scanning so to capture the transition from normal waking consciousness to the drug state, we found significant decreases in CBF and brain activity after psilocybin infusion and no increases in any region. It is important that the most consistent regional deactivation after psilocybin was in the medial prefrontal cortex (mPFC), a region that is consistently hyperactive in depression8. Medial prefrontal activity correlates with rumination9 and symptom severity in depression38, and is highly predictive of relapse9. Successful treatment with a variety of interventions, including ECT, SSRIs, cognitive behavioural therapy, sleep-deprivation, mindfulness meditation, and placebo, all normalise mPFC activity8.

4. Study design

4.1. Primary outcome measure

Patient's ratings of the subjective intensity of psilocybin's effects, rated on a 0-10 scale, with 0 equally 'no effects' and 10 'extremely intense effects'.

4.2. Volunteers

Sample size: 20 patients
Males & females
18+ years old.

We will aim to recruit a similar number of male and female patients. Patients will be at least 18 years of age with must have an acceptable level of physical health as determined by a medical screening that will include: routine blood tests, ECG, blood pressure and heart rate, neurological exam and psychiatric assessment (MINI). We will take and store a blood plasma sample at screening for genotyping and baseline Brain Derived Neurotropic Factor (BDNF) levels, a marker of neurogenesis. Patients with cardiovascular abnormalities, epilepsy, personal or family histories of psychosis or psychotic symptoms (including mania), or histories of suicide attempts, will not be allowed to participate. As in previous trials, we will include patients who have previous experience with psychedelic drugs, although it is anticipated that most will be 'psychedelic-naïve'. All patients will have a good command of the English language. Patients will have HAM-D scores of at least 17, and will have failed at least two classes of antidepressant in the current episode. Women must not be pregnant or breast-feeding and appropriate use of contraception is mandatory.

4.2.1. Screening procedure

  1. Informed consent
  2. Full history-taking and physical examination
  3. Psychiatric assessment (MINI)
  4. Routine Blood Screen and sample
  5. ECG
  6. Urine drug screen
  7. Height & weight measurements
  8. Breathalyser
  9. Completion of Clinician administered rating scales (HAM D & MADRS)
  10. Completion of secondary outcome measures as detailed in 2.1

4.2.2. Inclusion criteria

  1. Major depression of a moderate to severe degree (17+ on the 21-item HAM-D).
  2. No improvement despite two courses of antidepressant treatment for adequate duration (6 weeks minimum) within current episode31.
  3. No MR contraindications.

4.2.3. Exclusion criteria

  1. Current or previously diagnosed psychotic disorder.
  2. Immediate family member with a diagnosed psychotic disorder.
  3. Medically significant condition rendering unsuitability for the study (e.g., diabetes, epilepsy, severe cardiovascular disease, hepatic or renal failure etc).
  4. History of suicide attempts.
  5. History of mania.
  6. Blood or needle phobia.
  7. Positive pregnancy test at screening or during the study.
  8. Current drug or alcohol dependence.
  9. Allergy to gelatine or lactose.
  10. Lack of appropriate use of contraception.
  11. Breast-feeding.

4.2.4. Withdrawal Criteria

  1. Withdrawal of Consent.
  2. Development of concurrent physical illness that necessitates their removal from the trial.
  3. Deterioration of mental health warranting additional interventions and support.
  4. Dependent or problematic alcohol and illicit substance use.

GPs and all pertinent health professionals will be informed of their patient's involvement in the study and will be encouraged to voice any misgivings or reservations they have about their patient entering the study or continuing with it once it has begun. On entering the study, should there be any deterioration in the patient's physical or mental health that may compromise their ability to continue in the trial, then we will reach an informed decision, once we have contacted the relevant health professionals, about whether the patient should continue in the study. This will all be done in discussion with the patient and the extended research team. Since we will be following the patient's progress in the period after dosing, we will be in a position to determine whether any added support or treatment is required should the patient's mental health deteriorate. Any information that comes to light during the study will be communicated to their main health professional in the community who will be in the best position to provide treatment if they consider it necessary.

5. Regulatory Issues and informed consent

5.1 Ethics Approval

The study will be conducted according to the revised declaration of Helsinki (2000), the International Committee on Harmonisation Good Clinical Practice guidelines and NHS Research Governance Framework. Ethics and R&D approval will be obtained.

5.2 Consent

Consent to enter the study will be sought from each participant only after a full explanation has been given, information sheet given and time allowed for consideration. Signed participant consent will be obtained for each patient. It is the right of the patient to refuse to participate without giving reasons and this will be respected. All patients are free to withdraw at any time from the protocol interventions without giving reasons and without prejudicing their further treatment.

5.3 Confidentiality

Patient's identification data will be required for the registration process. The research team will preserve the confidentiality of patients taking part in the study.

5.4 Audits and Inspections

The study may be subject to inspection and audit by Imperial College London and/or Imperial College Healthcare NHS Trust under their remit as sponsor and other regulatory bodies to ensure adherence to GCP. Prof Alan Young of Imperial College will Head a data monitoring committee for this study which will utilise the Inform System of Imperial College.

5.5. Monitoring

Any trial-related monitoring including audits and regulatory inspections will be permitted and direct access to source data and documents will be provided.

6. Patient recruitment strategy

Primary recruitment will be via referrals from mental health practitioners working in the field who have knowledge of the trial and feel that their patients fulfill the inclusion criteria (see below re the IAPT scheme, which will serve as our primary source of recruitment). This study will be adopted by the Mental Health Research Network (MHRN). Professor David Nutt sees patients through the Central & North West London Trust and Prof Steve Pilling via the Camden and Islington Trust (http://www.candi.nhs.uk/): both will act to encourage referrals to the study and the latter will be our primary source of referrals. We have strong links (through Steve Pilling) with the Improvement of Access to Psychotherapy Treatments (IAPT) scheme which runs out of the Camden and Islington Trust and who see many treatment-resistant depressed patients fitting this study's entry criteria. This will be our primary source of recruitment.

We will also liaise with fellow mental health practitioners working in other London Mental Health Trusts and mental health practitioners working in Oxford (Oxford Health Foundation NHS Trust) and Bristol mental health Trusts (Avon & Wiltshire Mental Health Partnership) to assist recruitment if necessary. We may also recruit via word of mouth should any patients want to participate having heard or read about the trial in the media or otherwise. In each case patients will be thoroughly screened by the study psychiatrist to ensure that they comply with our inclusion criteria before entry into the trial. General practitioners will be contacted in every case to inform them of the details of the trial and to enquire whether they have any concerns about their patient entering the trial. Until we have confirmed the patient's background medical and psychiatric history, patients will not be allowed to enter the trial.

7. Drug specific ethical and safety considerations

Recent independent assessments of the harms of popular drugs of abuse, conducted by international experts22, 23, 36 and experienced drug users4, 20 have consistently rated magic mushroom as one of the least harmful recreational drugs. Commonly cited risks include: prolonged psychotic reactions, flashback phenomena/hallucinogen persisting perceptual disorder (HPPD), and bad trips. Prolonged psychotic responses are extremely rare in clinical studies with psilocybin (<1%35), even with very high doses11, and none have been reported in modern studies or studies with patients14, 19. The risk of flashback phenomena is also minimal. Typically, flashbacks or HPPD refers to drug-like visual perceptual effects (e.g. 'trails' or geometric patterns) occurring when no drug has been taken. The two largest surveys on this phenomenon found that very few psychedelic drug users (3-4%) report perceptual changes that are distressing to them 6. There have been no cases of flashback-like symptoms occurring in modern clinical studies with psilocybin 35 - even with very high doses11.

Negative acute psychological experiences or 'bad trips' do occur more frequently however, but they are strongly dose-dependent10, 35. In a sample of 36 healthy subjects given a high oral dose of psilocybin (30mg), 11 subjects reported strong anxiety at some point during their session11. However, the anxiety was short-lived in every case and no persistent negative mood effects were reported. Most of the subjects reported that their experience had been insightful and beneficial and this positive appraisal of their experience was sustained12. This is consistent with the claim that psychologically 'challenging' psychedelic drug experiences can be especially beneficial - if properly mediated. In our own work, dosing 40+ subjects with 2mg psilocybin IV, 30 of which took place in a spatially restrictive and noisy MRI scanner, anxiety scores were not significantly higher after psilocybin than placebo. No subjects showed panic or asked for their scans to be aborted. Patients with psychiatric vulnerabilities are thought to be more likely to experience bad trips, but we will strive to minimize this risk thorough psychological preparation, good patient-staff rapport and a positive environment. Bad trips are best managed psychologically12 15 and administration of a benzodiazepine would only be used in cases of severe panic. Detailed protocols are available on the safe management of clinical research with psychedelics15.

Note also that by administering a low dose of psilocybin in the first dosing session (10mg as the default low dose) we will be able assess tolerability prior to the administration of the higher dose (25mg). If a patient has a negative response to the 10mg dose, then he/she will be withdrawn from the trial. Moreover, the initial low dose may be useful therapeutically, allowing patients to accommodate to the effects of psilocybin prior to administration of a higher dose.

The summary of side effects associated with oral psilocybin on page 24 of the investigator's brochure will serve as the reference safety information for this trial.

7.1. Suicide and persistent adverse events

There have been no cases of increased suicidality in modern trails with psilocybin. The risk of suicide with placebo treatment is low (0.4% suicides and 2.7% attempts) and no higher than that with active treatments (0.7% and 3.4%16). The risk of suicide will be further minimized by excluding patients with histories of suicide attempts or planning. We will also give patients a study psychiatrist's and psychotherapist's contact number in cases of emergency. We have written a standard operating procedure for dealing with any adverse events and this is detailed below in section 14.

7.2 Definitions and reporting of Adverse Events & Reactions

  1. Adverse Event (AE): Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.
  2. Adverse Reaction (AR): All untoward and unintended responses to a medicinal product related to any dose administered.
  3. Unexpected Adverse Reaction (UAR): An AR, the nature or severity of which is not consistent with the applicable product information.
  4. Serious Adverse Event (SAE) or Serious Adverse Reaction: Any untoward medical occurrence or effect that at any dose i) results in death ii) is life-threatening iii) requires hospitalization iv) results in persistent or significant disability or incapacity.
  5. Suspected Unexpected Serious Adverse Reactions (SUSAR): any suspected adverse reaction related to a medicinal product that is both unexpected and serious.

Most AEs and ARs that occur in this study, whether they are serious or not, will be expected treatment-related toxicities due to the drugs in this study. The assignment of the causality will be made by the team including the principle investigator responsible for the care of the participant using the following definitions:

  1. Unrelated: There is no evidence of any causal relationship.
  2. Unlikely: There is little evidence to suggest there is a causal relationship and there is another reasonable explanation for the event.
  3. Possible: There is some evidence to suggest a causal relationship however the influence of other factors may have contributed to the event.
  4. Probable: There is evidence to suggest a causal relationship and the influence of other factors is unlikely.
  5. Definitely: There is clear evidence to suggest a causal relationship and other possible contributing factors can be ruled out.
  6. Not Assessable: There is insufficient or incomplete evidence to make a clinical judgment of the causal relationship.

Should any uncertainty exist regarding causality we will discuss within the team and farther afield with local clinicians and representatives. In the event that no agreement is made the MHRA will be informed of both points of view.

7.2.1 Reporting Procedures

All adverse events will be reported and depending on the nature of the event, the following reporting procedures will be followed:

  1. Non serious AR/AEs: all such toxicities, whether expected or not, should be recorded as part of a case report and sent to the research team within one month.
  2. Serious AR/AEs: Fatal or life threatening SAEs and SUSARs should be reported on the day that the research team is aware of the event. The SAE form requires nature of event, onset, severity, corrective treatment given, outcome and causality. Additional information will be sent within 5 days if the reaction has not resolved at the time of reporting. An SAE form will be completed within 24 hours.
  3. SUSARs: a SAE report form will be completed by the staff at the site of where the adverse reaction occurred and sent immediately signed and dated to the research team with relevant treatment forms and anonymised copies of all relevant investigations. We will ensure that the MHRA, REC and the Sponsor are notified of all SUSARs occurring during the study according to the following timeline: fatal and life threatening within 7 days of notification and non-life threatening within 15 days. All investigators will be informed of all SUSARs occurring throughout the study. Any serious adverse events or reactions that are expected or otherwise will be reported to the sponsor immediately.

8. Study time line

DateEventPrimary assessmentsDuration
RecruitmentQIDS (via web/email or telephone)25 minutes
Visit 1
Day 1
Screening at CRFBDI, BAI, QIDS, MADRS + HAM-D4 ¼ hours
Visit 2
Day 5
Scan 1 at IMANOVA
plus session with therapist
Brain function5 hours
Visit 3
Day 11
Dosing session 1 at CRFBDI, BAI + QIDS8 hours
Days 12-17Follow-up 1 & remote monitoringQIDS (via email or telephone)5 mins each day
Visit 4
Day 18
Dosing session 2 at CRFBDI, BAI + QIDS8 hours
Visit 5
Day 19
Follow-up 2 at CRF + scan 2 at IMANOVABDI, BAI, QIDS, MADRS + HAM-D2 hours + 2 hours for scan
Days 20-25Remote monitoringQIDS (via email or telephone)5 mins each day
Visit 6
Day 26
Follow-up 3 at CRFBDI, BAI, QIDS, MADRS + HAM-D2 ½ hours

9. Day 1, screening time line

TimeEventSetting
9amSubject arrivesCRF
9-9:30amInformed consentCRF
9:30-10:15amHealth assessment (inc. blood sample, ECG, blood pressure)CRF
10:15-11:30amMADRS, HAM-D and questionnairesCRF
11:30am-1pmMINI, open discussion and preparation for drug sessionCRF
1:00pmPatient returns homeCRF

10. Functional MRI

Patients will undergo 2 fMRI scans as part of this study, on the day after screening (day 5) and one on the day after the second dosing session (day 19). Patients will also be allowed an "acclimatisation" scan of ~ 5 minutes. This is an initial exposure to the MRI scan, to assess whether they can tolerate the scanning environment. The acclimatisation session will take place as part of the screening visit.

After entering the scanner, all volunteers will undergo a preliminary structural scan. They will be asked to relax. They may also be asked to carry out some simple psychological tasks (e.g. see5). Subjective ratings will be given. Pulse and blood oxygen levels will be measured throughout. Functional scanning will last approximately 50 minutes.

Set-up & structural scanFunctional scanning
~10 mins~50 mins
Figure 1. Basic scanning protocol.

11. Day 5, Functional MRI and prep session with therapist

TimeEventSetting
9:00amSubject arrivesIMANOVA
9:00-9:30amMR screenIMANOVA
9:30am-10:30amScanIMANOVA
10:30-11:30amQuestionnairesIMANOVA
11:30amPatient returns to CRFCRF
12:00-3:00pmPrep session with therapist
Lunch break at 1pm
CRF

12. Follow-up

TimeEventSetting
9amSubject arrivesCRF
9-9:45amBlood sample + behavioural testsCRF
9:45-10:05amHAM-D and MADRSCRF
10:05-11:30amQuestionnairesCRF

Follow-up visits will involve assessment via the HAM-D and MADRS and the completion of some questionnaires. The DEER-T and the AM-T will also be completed. A blood sample will be taken on follow-up 2.

13. Dosing and patient management

13.1. Dosing procedure

It is strongly advised that psychedelic drugs only be taken in a positive environment where the patient feels comfortable and relaxed and is supported by a psychotherapist or psychiatrist15. Efforts will be made to arrange the intervention room to promote relaxation without compromising medical safety. Mobile phones will be switched off during every session and efforts will be made to minimize unexpected interruptions.

Following patients' arrival, the study psychiatrist will determine whether the patient is in a medically fit state to proceed with dosing later and will carry out any physical examinations if this is indicated. This will be supplemented by measuring of vital signs and urine drug screen/breathalyser. Patients will have been strongly advised to refrain from alcohol approximately 24 hours prior to their arrival as alcohol may compound the effects of the drug and potentially interfere with its effects. Patients will be psychologically prepared for the experience at screening and we will simulate a dosing session in a pre-dosing preparatory session on the morning of each dosing day. We will advise the patient to surrender to the experience and relaxing music will be used to facilitate calm and a relaxed, accepting mind-set. We will caution patients to expect some anxiety, and they will be encouraged to let us know if they feel this. Consistent with published guidelines on managing psychedelic-drug sessions, patients will be advised to accept feelings of anxiety and to allow the experience to unfold naturally, without psychological resistance15.

For each session, patients will sit in a reclined position with their head supported. They will be advised to close their eyes and relax.

13.2 Dosing parameters and algorithm

The patient will be provided with psilocybin capsules (x times 5mg capsules) which they will be requested to take with a glass of water to ensure the capsule is swallowed completely. The low dose will be 10mg or 15mg and this will always be administered in the first dosing session. The high dose will be 25mg (±5mg) and this will be given in the second session. This approach is motivated by safety and therapeutic considerations.

The desired effect for the initial low dose is mild/moderate subjective effects rated at 4-6/10 for intensity (0-10 scale with 0 equalling no effects and 10 extremely intense effects). Thus, although there is prior data to support the assumption that 10mg psilocybin will achieve this effect, if, after the first 6 patients have been dosed, it does not, then we will increase it to 15mg.

The desired effect for the 'high' dose is one that produces moderate-strong subjective effects rated 7-9/10 for intensity. Given the extensive literature on the effects of 25mg and higher doses of oral psilocybin, we do not anticipate it will need to be increased or decreased. However, if the desired intensity (rating of 7-9/10) is not observed in the first 6 patients, we will consider increasing it to 30mg or decreasing it to 20mg for the subsequent 6 patients.
It is important to be clear that a decision to increase or decrease doses will be discussed by the study psychiatrist and the principal investigator (PI), with the PI making the final decision.

13.3 Patient management

The research team of Professor Roland Griffiths at John Hopkins University is experienced in supervising psilocybin sessions in healthy and patient populations. On their advice, we will 'check-in' with the patients at regular intervals (e.g. every 15-30 minutes). Otherwise, we will respond to the patient if they initiate contact with us. It is advised that active-intervention is kept to a minimum during the acute experience. The patient is encouraged to explore their own mental space. Simple guided imagery may be used to assist relaxation. The following is an example of a guided imagery script: "Imagine it is a beautiful sunny day...you are walking on a beach...the sky is blue...the water is crystal clear...you hear the sound of gentle waves lapping, as the light breeze caresses your skin...the white sand feels warm on your bare feet and between your toes...you are wearing flowing light clothes and breathing deeply, inhaling the smell of fresh ocean air... a sense of freedom washes over your body... you lie down and let your body sink into the warm soft sand... you're completely relaxed... you sink deeper and deeper into relaxation."

All sessions will be supervised by at least 2 individuals who will be introduced to the patient at screening. A medical doctor and study psychiatrist will be present at every dosing session and he/she will administer the drug or placebo. Typically, there will be an experienced psychotherapist and psychiatrist present at each session. Sessions will take place in a purpose built clinical research facility with extensive nursing and emergency support (the NIHR/Wellcome Trust Imperial Clinical Research Facility, CRF).

The effects of orally administered psilocybin last for approximately 5-6 hours peaking at 2-3 hours postadministration10. With the patient's prior consent, dosing sessions will be video and/or audio recorded and we may also video and/or audio record post-session interviews during follow-up visits. Patients will remain under supervision for at least 7 hours post-administration of psilocybin or until the effects have sufficiently subsided (as determined by the study psychiatrist). Taxis can be ordered to take patients home but they must be accompanied either by a member of the study team or by a significant other. Patients will be asked to text or call us when they return home. Twenty-four hour emergency contact numbers will be provided. Overnight care facilities are available in the clinical research unit in case of unexpected adverse events that require an overnight stay.

14. Standard Operating Procedure for managing adverse events

  • Prior to administration of the drug we aim to fully prepare each participant to ensure that they are aware of what to expect. We will also ensure that they are met by all members of the research team and have the opportunity to visit the room in which the drug will be administered. Professor Griffith's team have used this approach and believe it to significantly reduce the possibility of any psychological adverse events following administration and serve to put patients at ease in the process. If patients know what to expect beforehand and are comfortable within their surroundings prior to receiving the drug, then this will reduce the risk of any untoward events.
  • Patients will be escorted and chaperoned by a member of the research team at all times throughout their participation in the study and for the 3 to 4 hours during which they will be under the acute effects of psilocybin they will always be supported by a team member.
  • The acute effects of the drug should be over within six hours following administration; however we will carefully monitor the patient for the duration of their stay at the study centre.
  • Staff will be vigilant of any overly unusual behaviour, anxiety and paranoia. This will be brought to the attention of the research team in a discreet manner so as to not exacerbate the situation.
  • Interpersonal exchanges that would be readily overlooked in a normal state of awareness may assume extreme and confusing meaning for persons under the influence of a psychedelic substance. Staff will be aware of this and adopt an open and non-judgemental manner, allowing the patient to speak freely without challenge.
  • On occasion nursing staff may be called upon to monitor a patient but this will be rare as there will normally be sufficient personnel from the research team to perform this function.
  • We do not envisage any serious side-effects from administration of the drug; however, patients may experience anxiety reactions or paranoid thoughts. These are likely to be short-lived and will be managed by psychological approaches such as reassurance and adopting a calm and supportive demeanour and by using behavioural techniques such as guided imagery.
  • If the situation was to deteriorate even further, the research team may have to be more proactive in their attempts to reduce distress and this may require an assertive tone of voice and/or the laying of hands on the individual if their behaviour becomes erratic for example. This would only be done in an attempt to alleviate the patient's distress and maintain their and the research team's safety.
  • In the unlikely event that a patient becomes behaviourally disturbed, medical personnel will be on hand to administer tranquillisation if necessary.
  • Typical doses administered would be PO 5 - 10mg diazepam initially then titrated to effect.
  • If such an adverse event was to occur, the study psychiatrist will closely monitor the patient at all times and in no circumstances will they be permitted to leave the unit until the psychiatrist is satisfied that they are in a fit state to do so.
  • On discharge from the unit the patient will be reviewed which will encompass an assessment of their current level of risk and whether they have returned to their normal level of functioning. Once this is performed the psychiatrist in collaboration with the rest of the team will decide whether it is indeed safe for them to leave the unit and return home.
  • Ideally, patients will be met by a family member or friend (the responsible other) after completing a dosing day so that this individual can accompany the patient home, supervise them and ensure their safety. If not possible a member of the research team will accompany them home to ensure their safe arrival.
  • Overnight care facilities at the clinical research facility are available should these be required, especially if the drug effects have not completely abated and the patient needs ongoing supervision and/or monitoring.
  • On discharge phone numbers for each member of the research team will be provided to the patient and their responsible other to ensure immediate contact if required. We will also have contact details for the patient and the responsible other so that we may contact them later that evening to check whether there are any issues that may have arisen.
  • Appropriate follow-ups after dosing days are in place for monitoring the patient's status and mental health condition throughout the study and afterwards. We will therefore be able to detect and assess any delayed or persisting adverse events.
  • Patients and family members will be encouraged to contact us should their mental or physical health deteriorate. Although our options of managing their current difficulties will be limited after the study is complete, we will be able to offer referral to the relevant services. If indicated, we will offer a further follow-up at the clinical research facility so that we can review the patient in person.

Should we have any concerns about the patient's mental health and safety during the study or follow-up and consider that a community intervention is necessary, we will contact the patient's primary caregiver i.e. their GP or primary mental health practitioner, to discuss to potentially implement this. It may well be that the study psychiatrist is required to make an urgent referral to the local crisis/ home intervention service who may be called upon to assess the patient in the community to determine subsequent management. In an emergency situation, where the patient needs to have their mental health assessed and managed immediately, the local emergency duty team can be contacted requesting that an urgent mental health act assessment be convened to decide whether involuntary hospital admission is required.

15. Time commitments

Screening will take ~4 hours for consent, health and psychiatric assessment.
Scanning will take ~2 hours, including ~1hr minutes in the scanner. This is followed by the prep session with therapist on which will take 2 hours. Thus, visit 2 will take ~4 hours.
Each dosing day will take ~8 hours.
Follow-up visit 2 will take ~2 hours with the addition of 2 hours for scanning and follow-up visit 3 will take 2 ½ hours.

16. Purchasing and storing drug

Psilocybin free-base will be purchased and made to Good Manufacturing Practice standards in accordance with Medicines and Healthcare Products Regulatory Agency (MHRA) regulations. The drug will be stored in a secure laboratory in a locked fridge. Home Office permission for possession and storage will be obtained.

17. Analysis

The primary outcome for the pilot study is the intensity ratings given during dosing and since there is no control condition, data can be analysed as we progress. T-tests will be run to compare the intensity of the low and high doses. Functional MRI analyses will include: resting state functional connectivity, changes in CBF from baseline and activation to a simple psychological task. We expect that approximately two-thirds of the patients will agree to fMRI scans. With a sample of approximately 8 we may only be able to present preliminary findings at this point but of course, the fMRI scanned sample will increase with the occurrence of the RCT.

18. Dosing day timeline

TimeEventSetting
9:00amSubject arrivesCRF
9:00-9:30amBrief assessment including vital signs/ UDS/ alcohol testCRF
9:30-10:30amPatient prepared and relaxed (music)CRF
10:30amAdministration of drugCRF
10:30am-4:30pmAcute drug experienceCRF
4:30-5:30pmThorough debriefing + questionnairesCRF
5:30pm+Patients assessed for suitability to return homeCRF

The dosing day timeline will be subject to adaptation as we proceed but we will not keep patients at the study centre for longer than is necessary to carry out procedures although on occasion we may be obliged to request them to stay longer or overnight to ensure their safety.

19. Monitoring

The study will be monitored internally by the Centre for Neuropsychopharmacology, through the Trust via InForm and it may also be audited by the MHRA and imperial JRCO.

20. IMP details

Psilocybin freebase (GMP) will be supplied by THC-pharm© (Frankfurt, Germany) with a certificate of analysis detailing purity and GMP quality. The psilocybin will be exported to Prof Val Curran of UCL who holds the necessary Home Office (HO) License for Schedule 1 drugs. Following HO guidelines, Prof Curran will transport the psilocybin to the Guy's and St Thomas' (GSTT) manufacturing pharmacy who also hold a HO License for Schedule 1 drugs. GSTT will weigh and encapsulate the product in accordance with GMP guidelines. Following HO guidelines for transport of Scheduled drugs, the psilocybin will then be transported to Prof Ilan Rabiner of Imanova, who also holds the required HO license. When a patient is to be dosed with psilocybin, Imanova will dispense the IMP to the study psychiatrist. The IMP will be given a shelf-life of 12 months. Storage conditions are light-protected and room temperature. Previous data has shown that psilocybin is stable for at least 6 years when stored under these conditions21.

21. Dosing algorithm

22. References

  1. M. Aan Het Rot, C. A. Zarate, Jr., D. S. Charney, and S. J. Mathew, 'Ketamine for Depression: Where Do We Go from Here?', Biol Psychiatry, 72 (2012), 537- 47.
  2. I. M. Blackburn, S. Jones, and R. J. Lewin, 'Cognitive Style in Depression', Br J Clin Psychol, 25 ( Pt 4) (1986), 241-51.
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