Articles
`
`Lancet Psychiatry 2016
`Published Online
`May 17, 2016
`http://dx.doi.org/10.1016/
`S2215-0366(16)30065-7
`See Online/Comment
`http://dx.doi.org/10.1016/
`S2215-0366(16)30087-6
`*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
`
`Psilocybin with psychological support for treatment-resistant
`depression: an open-label feasibility study
`
`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
`
`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.
`
`Copyright © Carhart-Harris et al. Open Access article distributed under the terms of CC BY.
`
`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
`
`www.thelancet.com/psychiatry Published online May 17, 2016 http://dx.doi.org/10.1016/S2215-0366(16)30065-7
`
`1
`
`EXHIBIT C
`
`

`

`Articles
`
`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.
`
`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 behav-
`ioural 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, invest igators, 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.
`
`2
`
`www.thelancet.com/psychiatry Published online May 17, 2016 http://dx.doi.org/10.1016/S2215-0366(16)30065-7
`
`

`

`Articles
`
`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
`
`Recruitment
`
`Enrolment and treatment
`
`Follow-up
`
`Time
`
`Screening visit
`and baseline
`assessment
`
`Telephone
`screening
`
`Baseline
`fMRI and
`preparatory
`session
`
`Interim
`questionnaires
`
`Patients
`contacted
`for remote
`assessment
`
`Post-treatment
`fMRI and assessment
`(interim questionnaires)
`
`Ongoing support from
`study psychiatrists
`if required
`
`1 week
`
`1 week
`
`2 weeks
`
`7 weeks
`
`Unspecified time period
`Remote screening or follow-up
`Clinic screening or follow-up
`Psilocybin dosing session
`
`Each bar represents 1 day
`
`1 week follow-up
`at research facility
`
`3 week follow-up
`(remotely)
`
`Low
`psilocybin
`dose
`
`High
`psilocybin
`dose
`
`2 week follow-up
`(remotely)
`
`5 week follow-up
`(remotely)
`
`3 month follow-up
`(remotely)
`
`Figure 1: Schedule of study interventions
`
`www.thelancet.com/psychiatry Published online May 17, 2016 http://dx.doi.org/10.1016/S2215-0366(16)30065-7
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`3
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`Articles
`
`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 wellbeing and monitor
`for any adverse events. Patients returned to the research
`facility 1 day after their high-dose session for a post-
`treatment fMRI scan lasting 60 min. After the fMRI
`scan, patients completed interim questionnaires (QIDS,
`STAI-T, and HAM-D), and were invited back to the
`research
`facility where
`they were met by
`their
`psychiatrists to discuss their experience the previous day.
`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
`
`72 individuals expressed an interest in
` participating in the trial
`
`38 telephone screened
`
`18 attended screening visit
`
`34 excluded because they did not meet the
`
`entry criteria
`
`20 excluded because they did not meet the
`
`entry criteria
`
`6 excluded because of insufficiently severe
` depression (HAM-D)
`
`12 recruited to the study and fully compliant
` with protocol
`
`See Online for appendix
`
`Figure 2: Trial profile
`
`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.
`
`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
`
`4
`
`www.thelancet.com/psychiatry Published online May 17, 2016 http://dx.doi.org/10.1016/S2215-0366(16)30065-7
`
`

`

`Articles
`
`Baseline scores
`
`Past unsuccessful
`medications*
`
`Past psychotherapy
`
`Education
`
`Weekly
`alcohol
`intake,
`units
`
`Previous
`psilocybin use
`(time since last
`use)
`
`Sex
`
`Age,
`years
`
`Ethnic
`origin
`
`Employment
`status
`
`Estimated
`illness
`duration,
`years
`
`Female 43
`
`Black
`Caribbean
`
`Employed
`
`30
`
`BDI
`36
`
`HAM-D STAI-T
`19
`72
`
`1
`
`2
`
`3
`
`4
`
`5
`
`Male
`
`40
`
`Hispanic
`
`Unemployed
`
`25
`
`33
`
`28
`
`76
`
`Male
`
`37
`
`White
`
`Employed
`
`Female
`
`30
`
`White
`
`Studying
`
`Male
`
`34
`
`White
`
`Unemployed
`
`17
`
`10
`
`12
`
`22
`
`26
`
`38
`
`18
`
`18
`
`25
`
`23
`
`63
`
`67
`
`71
`
`78
`
`SSRI (two), SNRI
`(two), NDRI,
`NSSRI, MAOI
`SSRI (two), SNRI,
`NDRI, NSSRI, Na+
`channel blocker
`(two), ketamine
`infusion, TCA
`SSRI (two), SNRI
`
`NDRI, NSSRI
`
`SSRI (three), TCA
`
`None
`
`Postgraduate
`
`Cognitive narrative
`therapy
`
`Postgraduate
`
`Postgraduate
`
`Postgraduate
`
`Undergraduate
`
`None
`
`None
`
`None
`
`One use
`(6 months)
`None
`
`1
`
`0
`
`0
`
`0
`
`0
`
`2
`
`6
`
`7
`
`8
`9
`
`10
`
`11
`
`Female
`
`57
`
`White
`
`Unemployed
`
`29
`
`Male
`
`Female
`Male
`
`52
`
`37
`37
`
`Female
`
`36
`
`Female 64
`
`White
`
`Unemployed
`
`White
`White
`
`Employed
`Unemployed
`
`Black
`Caribbean
`White
`
`Unemployed
`
`Employed
`
`27
`
`17
`15
`
`8
`
`15
`
`39
`
`33
`
`39
`32
`
`47
`
`24
`
`22
`
`17
`26
`
`28
`
`17
`
`57
`
`71
`71
`
`75
`
`72
`
`12 Male
`
`45
`
`White
`
`Employed
`
`8
`
`35
`
`17
`
`68
`
`Cognitive behavioural
`therapy, group therapy
`Cognitive behavioural
`therapy
`Cognitive and
`mindfulness
`behavioural therapy
`Counselling
`
`Counselling,
`mindfulness
`Counselling
`Counselling, cognitive
`behavioural therapy
`Counselling
`
`Secondary
`education
`Secondary
`education
`Undergraduate
`Postgraduate
`
`0
`
`2
`6
`
`Undergraduate
`
`18
`
`Cognitive behavioural
`therapy
`
`Postgraduate
`
`Cognitive behavioural
`therapy
`
`Undergraduate
`
`1
`
`0
`
`SSRI (four), SNRI,
`SARI
`TCA, SARI
`
`SSRI (two), TCA
`SSRI (three), SNRI
`
`SSRI (two), NSSRI
`
`SSRI (four), SNRI
`(two), NDRI, MAOI,
`Na⁺ channel
`blocker, SARI, DRI
`SSRI, TCA
`
`Two uses
`(45 years)
`Three uses
`(30 years)
`None
`None
`
`Three uses
`(14 years)
`Three uses
`(48 years)
`
`None
`
`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
`
`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.
`
`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 meet-
`ing criteria for moderate depression (BDI score 19 to <30).
`11 patients had received some form of psychotherapy
`before participation in the study.
`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).
`
`www.thelancet.com/psychiatry Published online May 17, 2016 http://dx.doi.org/10.1016/S2215-0366(16)30065-7
`
`5
`
`

`

`Articles
`
`Patient 1
`Transient anxiety
`Transient headache
`Transient confusion
`Patient 2
`Transient anxiety
`Patient 3
`Transient anxiety
`Transient confusion
`Patient 4
`Transient anxiety
`Transient nausea
`Transient confusion
`Transient paranoia
`Patient 5
`Transient anxiety
`Transient headache
`Transient confusion
`Patient 6
`Transient anxiety
`Patient 7
`Transient anxiety
`Transient confusion
`Patient 8
`Transient anxiety
`Patient 9
`Transient anxiety
`Transient headache
`Transient confusion
`Patient 10
`Transient anxiety
`Transient nausea
`Transient headache
`Transient confusion
`Patient 11
`Transient anxiety
`Transient nausea
`Transient confusion
`Transient paranoia
`Patient 12
`Transient anxiety
`Transient confusion
`
`Severity
`
`Timing or onset
`
`Mild
`Mild
`Mild (core drug effect)
`
`Onset of both sessions
`Day after high-dose session
`Peak of both sessions
`
`Duration
`
`60 min
`One day only
`60–120 min
`
`Mild
`
`Anticipatory anxiety only (both sessions)
`
`30 min
`
`Mild
`Mild (core drug effect)
`
`Anticipatory anxiety only (both sessions)
`Peak of both sessions
`
`30 min
`60–180 min
`
`Mild (low dose), moderate (high dose)
`Moderate
`Mild (core drug effect)
`Mild
`
`Onset of both sessions and peak of high dose
`Onset phase of high-dose session
`Peak of both sessions
`Peak of high-dose session
`
`60 min (low dose), 120 min (high dose)
`Arose and subsided within 60 min
`60–180 min
`Arose and subsided within 30 min
`
`Moderate (low dose), severe (high dose) Onset of both sessions and peak of high dose
`Mild
`Day after high-dose session
`Mild (core drug effect)
`Peak of both sessions
`
`60 min (low dose), 150 min (high dose)
`One day only
`60–120 min
`
`Mild
`
`Anticipatory anxiety only (both sessions)
`
`30 min
`
`Mild
`Mild (core drug effect)
`
`Anticipatory anxiety only (both sessions)
`Peak of both sessions
`
`30 min
`60–180 min
`
`Mild or negligible
`
`Anticipatory anxiety only (both sessions)
`
`30 min
`
`Mild (low dose), moderate (high dose)
`Mild
`Mild (core drug effect)
`
`Onset of low-dose and high-dose session
`Day after high-dose session
`Peak of both sessions
`
`60 min (low dose), 150 min (high dose)
`One day only
`60–180 min
`
`Mild
`Mild
`Mild or moderate
`Mild (core drug effect)
`
`Moderate (both sessions)
`Mild (high dose)
`Mild (core drug effect)
`Mild
`
`Mild
`Mild (core drug effect)
`
`Onset of both sessions
`Onset and peak of low-dose session
`Day after high-dose session
`Peak of both sessions
`
`60 min
`Subsided after 90 min
`2 days
`60–180 min
`
`Onset phase and peak of both sessions
`Onset phase of high-dose session
`Peak of both sessions
`Peak of low-dose session
`
`150 min (both sessions)
`Arose and subsided within 60 min
`60–180 min
`Arose and subsided within 60 min
`
`Anticipatory anxiety only (both sessions)
`Peak of both sessions
`
`30 min
`60–180 min
`
`Table 2: Adverse events by patient
`
`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).
`
`6
`
`www.thelancet.com/psychiatry Published online May 17, 2016 http://dx.doi.org/10.1016/S2215-0366(16)30065-7
`
`

`

`Articles
`
`GAF=Global Assessment of Functioning. *Compared with baseline.
`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.
`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
`
`Table 3: Clinical ratings at baseline and follow-up
`
`0·003
`2·4
`
`3
`
`··
`··
`··
`
`36·6)
`(18·0 to
`27·3
`(13·0)
`77·7
`
`1 week
`
`··
`(9·2)
`50·3
`line
`Base-
`
`GAF
`
`0·002
`2·7
`–3·1
`
`–29·5)
`(–17·1 to
`–23·3
`(9·8)
`9·7
`
`1 week
`
`··
`··
`··
`
`··
`(5·0)
`31·0
`line
`Base-
`
`0·003
`2·4
`–3·0
`
`–18·4)
`(–9·6 to
`–14·0
`(6·9)
`7·4
`
`1 week
`
`··
`··
`··
`
`··
`(4·5)
`21·4
`line
`Base-
`
`MADRS
`
`HAM-D
`
`0·002
`1·3
`–3·1
`
`–6·11)
`(–3·29 to
`–4·7
`(3·7)
`2·8
`
`0·002
`1·9
`–3·1
`–7·74)
`to
`(–4·46
`–6·1
`(2·7)
`1·4
`
`3 months
`
`1 week
`
`··
`··
`··
`
`··
`(3·7)
`7·5
`
`line
`Base-
`
`SHAPS
`
`0·004
`1·4
`–2·9
`
`–22·83)
`(–7·77 to
`–15·3
`(14·5)
`54·8
`
`0·002
`2·7
`–3·1
`–36·97)
`to
`(–22·03
`–29·5
`(14·2)
`40·6
`
`3 months
`
`1 week
`
`··
`··
`··
`
`··
`(5·8)
`70·1
`line
`Base-
`
`STAI-T
`
`0·002
`2·0
`–3·1
`
`–25·2)
`(–11·8 to
`–18·5
`(11·0)
`15·2
`
`0·002
`3·2
`–3·1
`–29·9)
`to
`(–20·1
`–25·0
`(8·4)
`8·7
`
`3 months
`
`1 week
`
`··
`(7·1)
`33·7
`line
`Base-
`
`BDI
`
`··
`··
`··
`
`0·003
`2·0
`–3·0
`
`0·003
`2·7
`–2·9
`
`0·002
`3·2
`–3·06
`
`–12·71)
`(–5·69 to
`–9·2
`(6·0)
`10·0
`
`–14·2)
`(–7·7 to
`–11·0
`(5·4)
`8·2
`
`–15·6)
`(–9·9 to
`–12·8
`(5·1)
`6·4
`
`5 weeks3 months
`
`3 weeks
`
`2 weeks
`
`1 week
`
`0·002
`3·2
`–3·1
`–15·16)
`to
`(–10·64
`–12·9
`(4·6)
`6·3
`
`0·002
`3·1
`–3·1
`
`··
`··
`··
`
`–14·35)
`(–9·15 to
`–11·8
`(4·9)
`7·4
`
`p value*
`Hedges’ g*
`
`Z
`
`(95% CI)
`baseline
`versus
`Difference
`
`Mean (SD)
`
`··
`(2·0)
`19·2
`line
`Base-
`
`QIDS
`
`Hedges’ g
`3·1
`p=0·002
`
`Hedges’ g
`3·2
`p=0·002
`
`Hedges’ g
`3·2
`p=0·002
`
`Hedges’ g
`2·0
`p=0·003
`
`Hedges’ g
`2·7
`p=0·003
`
`Baseline
`
`1 week
`
`2 weeks
`
`3 weeks
`
`5 weeks 3 months
`
`25
`
`20
`
`15
`
`10
`
`5
`
`0
`
`QIDS score
`
`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 b