675513 JOP0010.1177/0269881116675513Journal of PsychopharmacologyGriffiths et al.
`
`research-article2016
`
`Original Paper
`
`Psilocybin produces substantial and
`sustained decreases in depression and
`anxiety in patients with life-threatening
`cancer: A randomized double-blind trial
`
`Roland R Griffiths1,2, Matthew W Johnson1, Michael A Carducci3,
`Annie Umbricht1, William A Richards1, Brian D Richards1,
`Mary P Cosimano1 and Margaret A Klinedinst1
`
`Journal of Psychopharmacology
`2016, Vol. 30(12) 1181 –1197
`© The Author(s) 2016
`
`Reprints and permissions:
`sagepub.co.uk/journalsPermissions.nav
`DOI: 10.1177/0269881116675513
`jop.sagepub.com
`
`Abstract
`Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease
`depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of
`depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg)
`vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up.
`Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes,
`and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and
`anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were
`sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed
`improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or
`greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on
`session day mediated the effect of psilocybin dose on therapeutic outcomes.
`
`Trial Registration
`ClinicalTrials.gov identifier: NCT00465595
`
`Keywords
`Psilocybin, hallucinogen, cancer, anxiety, depression, symptom remission, mystical experience
`
`Introduction
`Cancer patients often develop a chronic, clinically significant syn-
`drome of psychosocial distress having depressed mood, anxiety,
`and reduced quality of life as core features, with up to 40% of
`cancer patients meeting criteria for a mood disorder (Holland
`et al., 2013; Mitchell et al., 2011). In cancer patients, depression
`and anxiety have been associated with decreased treatment adher-
`ence (Arrieta et al., 2013; Colleoni et al., 2000), prolonged hospi-
`talization (Prieto et al., 2002), decreased quality of life (Arrieta
`et al., 2013; Skarstein et al., 2000), and increased suicidality
`(Shim and Park, 2012). Depression is an independent risk factor
`of early death in cancer patients (Arrieta et al., 2013; Pinquart and
`Duberstein, 2010). Antidepressants and, less frequently, benzodi-
`azepines are used to treat depressed mood and anxiety in cancer
`patients, although evidence suggesting efficacy is limited and
`conflicting, and benzodiazepines are generally only recommended
`for short-term use because of side effects and withdrawal (Grassi
`et al., 2014; Ostuzzi et al., 2015; Walker et al., 2014). Although
`psychological approaches have shown only small to medium
`effects in treating emotional distress and quality of life, with low
`quality of reporting in many trials (Faller et al., 2013), there are
`several promising interventions utilizing existential orientations
`to psychotherapy (Breitbart et al., 2015; Spiegel, 2015).
`
`The classic hallucinogens, which include psilocybin (psilocin)
`and (+)-lysergic acid diethylamide (LSD), are a structurally
`diverse group of compounds that are 5-HT2A receptor agonists and
`produce a unique profile of changes in thoughts, perceptions, and
`emotions (Halberstadt, 2015; Nichols, 2016). Several unblinded
`studies in the 1960s and 70s suggested that such compounds
`might be effective in treating psychological distress in cancer
`patients (Grof et al., 1973; Kast, 1967; Richards et al., 1977);
`however, these studies did not include the comparison conditions
`that would be expected of modern psychopharmacology trials.
`
`1 Department of Psychiatry and Behavioral Sciences, Johns Hopkins
`University School of Medicine, Baltimore, MD, USA
`2 Department of Neuroscience, Johns Hopkins University School of
`Medicine, Baltimore, MD, USA
`3 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins
`University School of Medicine, Baltimore, MD, USA
`
`Corresponding author:
`Roland R Griffiths, Johns Hopkins Bayview Medical Center,
`5510 Nathan Shock Drive, Baltimore, MD 21224-6823, USA.
`Email: rgriff@jhmi.edu
`
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`Journal of Psychopharmacology 30(12)
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`Subsequently, human research with these compounds was
`halted for almost three decades because of safety and other con-
`cerns raised in response to widespread non-medical use in the
`1960s. Recent resumption of clinical research with these com-
`pounds has established conditions for safe administration
`(Johnson et al., 2008; Studerus et al., 2011).
`Two recent double-blind, placebo-controlled studies with
`the classic hallucinogens psilocybin (Grob et al., 2011) and
`LSD (Gasser et al., 2014) examined effects in 12 patients with
`life-threatening illness, including cancer. Both studies showed
`promising trends toward decreased psychological distress. Of
`most relevance to the present study with psilocybin, Grob and
`colleagues showed that a low-moderate dose of psilocybin (14
`mg/70 kg) decreased a measure of trait anxiety at 1 and 3
`months and depressed mood at 6-month follow-up. Also rele-
`vant, a recent open-label pilot study in 12 patients with treat-
`ment-resistant depression showed marked reductions
`in
`depressive symptoms 1 week and 3 months after administration
`of 10 and 25 mg of psilocybin in two sessions separated by 7
`days (Carhart-Harris et al., 2016).
`The present study provides the most rigorous evaluation to
`date of the efficacy of a classic hallucinogen for treatment of
`depressed mood and anxiety in psychologically distressed cancer
`patients. The study evaluated a range of clinically relevant meas-
`ures using a double-blind cross-over design to compare a very
`low psilocybin dose (intended as a placebo) to a moderately high
`psilocybin dose in 51 patients under conditions that minimized
`expectancy effects.
`
`Methods
`Study participants
`Participants with a potentially life-threatening cancer diagnosis
`and a DSM-IV diagnosis that included anxiety and/or mood symp-
`toms were recruited through flyers, internet, and physician referral.
`Of 566 individuals who were screened by telephone, 56 were ran-
`domized. Figure 1 shows a CONSORT flow diagram. Table 1
`shows demographics for the 51 participants who completed at least
`one session. The two randomized groups did not significantly dif-
`fer demographically. All 51 participants had a potentially life-
`threatening cancer diagnosis, with 65% having recurrent or
`metastatic disease. Types of cancer included breast (13 partici-
`pants), upper aerodigestive (7), gastrointestinal (4), genitourinary
`(18), hematologic malignancies (8), other (1). All had a DSM-IV
`diagnosis: chronic adjustment disorder with anxiety (11 partici-
`pants), chronic adjustment disorder with mixed anxiety and
`depressed mood (11), dysthymic disorder (5), generalized anxiety
`disorder (GAD) (5), major depressive disorder (MDD) (14), or a
`dual diagnosis of GAD and MDD (4), or GAD and dysthymic dis-
`order (1). Detailed inclusion/exclusion criteria are in the online
`Supplementary material. The Johns Hopkins IRB approved the
`study. Written informed consent was obtained from participants.
`
`groups. The Low-Dose-1st Group received the low dose of
`psilocybin on the first session and the high dose on the second
`session, whereas the High-Dose-1st Group received the high
`dose on the first session and the low dose on the second ses-
`sion. The duration of each participant’s participation was
`approximately 9 months (mean 275 days). Psilocybin session 1
`occurred, on average, approximately 1 month after study
`enrollment (mean 28 days), with session 2 occurring approxi-
`mately 5 weeks later (mean 38 days). Data assessments
`occurred: (1) immediately after study enrollment (Baseline
`assessment); (2) on both session days (during and at the end of
`the session); (3) approximately 5 weeks (mean 37 days) after
`each session (Post-session 1 and Post-session 2 assessments);
`(4) approximately 6 months (mean 211 days) after Session 2
`(6-month follow-up).
`
`Interventions
`Meetings with session monitors. After study enrollment and
`assessment of baseline measures, and before the first psilocybin
`session, each participant met with the two session monitors
`(staff who would be present during session days) on two or more
`occasions (mean of 3.0 occasions for a mean total of 7.9 hours).
`The day after each psilocybin session participants met with the
`session monitors (mean 1.2 hours). Participants met with moni-
`tors on two or more occasions between the first and second psi-
`locybin session (mean of 2.7 occasions for a mean total of 3.4
`hours) and on two or more occasions between the second session
`and 6-month follow-up (mean of 2.5 occasions for a mean total
`of 2.4 hours). Preparation meetings, the first meeting following
`each session, and the last meeting before the second session
`were always in person. For the 37 participants (73%) who did
`not reside within commuting distance of the research facility,
`49% of the Post-session 1 meetings with monitors occurred via
`telephone or video calls.
`A description of session monitor roles and the content and
`rationale for meetings between participants and monitors is pro-
`vided elsewhere (Johnson et al., 2008). Briefly, preparation meet-
`ings before the first session, which included discussion of
`meaningful aspects of the participant’s life, served to establish
`rapport and prepare the participant for the psilocybin sessions.
`During sessions, monitors were nondirective and supportive, and
`they encouraged participants to “trust, let go and be open” to the
`experience. Meetings after sessions generally focused on novel
`thoughts and feelings that arose during sessions. Session moni-
`tors were study staff originally trained by William Richards PhD,
`a clinical psychologist with extensive experience conducting
`studies with classic hallucinogens. Monitor education varied
`from college graduate to PhD. Formal clinical training varied
`from none to clinical psychologist. Monitors were selected as
`having significant human relations skills and self-described
`experience with altered states of consciousness induced by means
`such as meditation, yogic breathing, or relaxation techniques.
`
`Study design and overview
`A two-session, double-blind cross-over design compared the
`effects of a low versus high psilocybin dose on measures of
`depressed mood, anxiety, and quality of life, as well as meas-
`ures of short-term and enduring changes in attitudes and
`behavior. Participants were randomly assigned to one of two
`
`Psilocybin sessions. Drug sessions were conducted in an aes-
`thetic living-room-like environment with two monitors present.
`Participants were instructed to consume a low-fat breakfast
`before coming to the research unit. A urine sample was taken to
`verify abstinence from common drugs of abuse (cocaine, ben-
`zodiazepines, and opioids including methadone). Participants
`who reported use of cannabis or dronabinol were instructed not
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`Griffiths et al.
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`1183
`
`Assessed on telephone for eligibility (n=566)
`
`Excluded (n=483)
`Not meeting inclusion/exclusion
`criteria (n=411)
`Declined to participate (n=72)
`
`Signed consent and assessed for eligibility (n=83)
`
`Excluded (n=27)
`Not meeting inclusion criteria (n=21)
`Declined to participate (n=6)
`
`Randomized (n=56)
`
`Allocated to low dose psilocybin on 1st session
`(n=27)
`Data obtained for 1st session (n=25)
`Data not obtained for 1st session (n=1,
`anxiety; n=1, disease progression)
`
`Allocated to high dose psilocybin on 1st
`session (n=29)
`Data obtained for 1st session (n=26)
`Data not obtained for 1st session (n=1,
`anxiety, n=1, vomited shortly after capsule
`administration; n=1, family reason)
`
`Data obtained for 2nd session (n=24)
`Data not obtained for 2nd session (disease
`progression, n=1)
`
`Data obtained for 2nd session (n=25)
`Data not obtained for 2nd session (disease
`progression, n=1)
`
`Data obtained at 6 month follow-up (n=22)
`6 month follow-up data not obtained (n=1,
`disease progression; n=1, failure to return
`calls, likely due to disease progression)
`
`Data obtained at 6 month follow-up (n=24)
`6 month follow-up data not obtained (n=1,
`disease progression)
`
`Figure 1. Flow diagram showing participation across the study.
`
`to use for at least 24 h before sessions. Psilocybin doses were
`administered in identically appearing opaque, size 0 gelatin
`capsules, with lactose as the inactive capsule filler. For most of
`the time during the session, participants were encouraged to lie
`down on the couch, use an eye mask to block external visual
`distraction, and use headphones through which a music pro-
`gram was played. The same music program was played for all
`participants in both sessions. Participants were encouraged to
`focus their attention on their inner experiences throughout the
`session. Thus, there was no explicit instruction for participants
`to focus on their attitudes, ideas, or emotions related to their
`cancer. A more detailed description of the study room and
`
`procedures followed on session days is provided elsewhere
`(Griffiths et al., 2006; Johnson et al., 2008).
`
`Instructions to participants and monitors to facilitate dose
`condition blinding and minimize expectancy effects. Expec-
`tancies, on part of both participants and monitors, are believed to
`play a large role in the qualitative effects of psilocybin-like drugs
`(Griffiths et al., 2006; Metzner et al., 1965). Although double-
`blind methods are usually used to protect against such effects,
`expectancy is likely to be significantly operative in a standard
`drug versus placebo design when the drug being evaluated pro-
`duces highly discriminable effects and participants and staff
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`Table 1. Participant demographics for all participants and for both of the dose sequence groups separately+.
`
`Measure
`
`Low-Dose-1st
`(High-Dose-2nd) (n=25)
`
`High-Dose-1st
`(Low-Dose-2nd) (n=26)
`
`All Participants
`(n=51)
`
`Gender (% female)
`Age in years (mean, SEM)
`Race/Ethnicity
` White
` Black/African American
` Asian
`Education
` High school
` College
` Post-graduate
`Relationship status (married or living with partner)
`Lifetime use of hallucinogens
` Percent reporting any past use
` Years since last use (mean, SEM)
`Recent use of cannabis or dronabiol
` Percent reporting recent use
` Users use per month (mean, SEM)
`Cancer prognosis at time of enrollment
` Possibility of recurrence
` Recurrent/metastatic (>2yr anticipated survival)
` Recurrent/metastatic (<2yr anticipated survival)
`Psychiatric symptomsa
` Depressed mood
` Anxiety
`Prior use of medication for anxiety or depressionb
`
`48%
`56.1 (2.3)
`
`50%
`56.5 (1.8)
`
`92%
`4%
`4%
`
`4%
`32%
`64%
`72%
`
`56%
`30.9 (3.2)
`
`52%
` 4.7 (1.6)
`
`32%
`32%
`36%
`
`72%
`68%
`52%
`
`96%
`4%
`0%
`
`0%
`58%
`42%
`65%
`
`36%
`30.0 (4.5)
`
`42%
` 7.0 (2.1)
`
`38%
`42%
`19%
`
`65%
`58%
`50%
`
`49%
`56.3 (1.4)
`
`94%
`4%
`2%
`
`
`
`2%
`45%
`53%
`69%
`
`45%
`30.6 (2.6)
`
`47%
` 5.8 (1.3)
`
`35%
`37%
`27%
`
`69%
`63%
`51%
`
`+There were no significant differences between the two dose sequence groups on any demographic variable (t-tests and chi-square tests with continuous and categorical
`variables, respectively).
`a Psychiatric symptom classification was based on SCID (DSM-IV) diagnoses. All had a DSM-IV diagnosis: chronic adjustment disorder with anxiety (11 participants),
`chronic adjustment disorder with mixed anxiety and depressed mood (11), dysthymic disorder (5), generalized anxiety disorder (GAD) (5), major depressive disorder
`(MDD) (14), or a duel diagnosis of GAD and MDD (4), or GAD and dysthymic disorder (1). Depressed mood was defined as meeting criteria for MDD, dysthymic disorder, or
`adjustment disorder with anxiety and depressed mood, chronic. Anxiety was defined as meeting criteria for GAD, adjustment disorder with anxiety, chronic, or adjustment
`disorder with anxiety and depressed mood, chronic.
`b Data in this row refer to percentage of participants who had received antidepressant or anxiolytic medication after the cancer diagnosis but had terminated the medication
`sometime before study enrollment because they had found it to be unsatisfactory.
`
`know the specific drug conditions to be tested. For these reasons,
`in the present study a low dose of psilocybin was compared with
`a high dose of psilocybin, and participants and monitors were
`given instructions that obscured the actual dose conditions to be
`tested. Specifically, they were told that psilocybin would be
`administered in both sessions, the psilocybin doses administered
`in the two sessions might range anywhere from very low to high,
`the doses in the two sessions might or might not be the same,
`sensitivity to psilocybin dose varies widely across individuals,
`and that at least one dose would be moderate to high. Participants
`and monitors were further strongly encouraged to try to attain
`maximal therapeutic and personal benefit from each session.
`
`Dose conditions. The study compared a high psilocybin dose
`(22 or 30 mg/70 kg) with a low dose (1 or 3 mg/70 kg) adminis-
`tered in identically appearing capsules. When this study was
`designed, we had little past experience with a range of psilocybin
`doses. We decreased the high dose from 30 to 22 mg/70 kg after
`two of the first three participants who received a high dose of
`30 mg/70 kg were discontinued from the study (one from
`vomiting shortly after capsule administration and one for
`
`personal reasons). Related to this decision, preliminary data from
`a dose-effect study in healthy participants suggested that rates of
`psychologically challenging experiences were substantially
`greater at 30 than at 20 mg/70 kg (Griffiths et al., 2011). The low
`dose of psilocybin was decreased from 3 to 1 mg/70 kg after 12
`participants because data from the same dose-effect study showed
`significant psilocybin effects at 5 mg/70 kg, which raised con-
`cern that 3 mg/70 kg might not serve as an inactive placebo.
`
`Outcome measures
`Cardiovascular measures and monitor ratings assessed
`throughout the session. Ten minutes before and 30, 60, 90,
`120, 180, 240, 300, and 360 min after capsule administration,
`blood pressure, heart rate, and monitor ratings were obtained as
`described previously (Griffiths et al., 2006). The two session
`monitors completed the Monitor Rating Questionnaire, which
`involved rating or scoring several dimensions of the participant’s
`behavior or mood. The dimensions, which are expressed as peak
`scores in Table 2, were rated on a 5-point scale from 0 to 4. Data
`were the mean of the two monitor ratings at each time-point.
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`Griffiths et al.
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`Table 2. Peak effects on cardiovascular measures and session monitor
`ratings of participant behavior and mood assessed throughout the
`session+
`
`.
`
`Measure
`
`Low dose
`
`High dose
`
`The two primary therapeutic outcome measures were
`the widely used clinician-rated measures of depression, GRID-
`HAM-D-17 (ISCDD, 2003) and anxiety, HAM-A assessed with
`the SIGH-A (Shear et al., 2001). For these clinician-rated meas-
`ures, a clinically significant response was defined as ⩾50%
`decrease in measure relative to Baseline; symptom remission was
`defined as ⩾50% decrease in measure relative to Baseline and a
`score of ⩽7 on the GRID-HAMD or HAM-A (Gao et al., 2014;
`Matza et al., 2010).
`Fifteen secondary measures focused on psychiatric symp-
`toms, moods, and attitudes: BDI, self-rated depression meas-
`ure (Beck and Steer, 1987); HADS, self-rated separate
`measures of depression and anxiety, and a total score (Zigmond
`and Snaith, 1983); STAI, self-rated measure of state and trait
`anxiety separately (Spielberger, 1983); POMS, Total Mood
`Disturbance Subscale, self-rated dysphoric mood measure
`(McNair et al., 1992); BSI, self-rated psychiatric symptoms
`(Derogatis, 1992); MQOL, self-rated measure of overall qual-
`ity of life (total score) and meaningful existence (existential
`subscale) during life-threatening illness (Cohen et al., 1995);
`LOT-R, self-rated optimism measure associated with illness
`(Scheier and Carver, 1985); LAP-R Death Acceptance, self-
`rated scale assessing absence of anxiety about death (Reker,
`1992); Death Transcendence Scale, self-rated measure of posi-
`tive attitudes about death (VandeCreek, 1999); Purpose in Life
`Test, self-rated measure of life meaningfulness (McIntosh,
`1999); and LAP-R Coherence, self-rated scale assessing logi-
`cally integrated understanding of self, others, and life in gen-
`eral (Reker, 1992).
`
`Community observer-rated changes in participant behavior
`and attitudes assessed at Baseline, 5 weeks after Session 2,
`and 6-month follow-up. Structured telephone interviews with
`community observers (e.g. family members, friends, or work col-
`leagues) provided ratings of participant attitudes and behavior
`reflecting healthy psychosocial functioning (Griffiths et al., 2011).
`The interviewer provided no information to the rater about the
`participant or the nature of the research study. The structured
`interview (Community Observer Questionnaire) consisted of ask-
`ing the rater to rate the participant’s behavior and attitudes using a
`10-point scale (from 1 = not at all, to 10 = extremely) on 13 items
`reflecting healthy psychosocial functioning: inner peace; patience;
`good-natured humor/playfulness; mental flexibility; optimism;
`anxiety (scored negatively); interpersonal perceptiveness and
`caring; negative expression of anger (scored negatively); com-
`passion/social concern; expression of positive emotions (e.g. joy,
`love, appreciation); self-confidence; forgiveness of others; and
`forgiveness of self. On the first rating occasion, which occurred
`soon after acceptance into the study, raters were instructed to base
`their ratings on observations of and conversations with the partici-
`pant over the past 3 months. On two subsequent assessments, rat-
`ers were told their previous ratings and were instructed to rate the
`participant based on interactions over the last month (post-session
`2 assessment) or since beginning in the study (6-month follow-
`up). Data from each interview with each rater were calculated as a
`total score. Changes in each participant’s behavior and attitudes
`after drug sessions were expressed as a mean change score (i.e.
`difference score) from the baseline rating across the raters. Of 438
`scheduled ratings by community observers, 25 (<6%) were missed
`due to failure to return calls or to the rater not having contact with
`the participant over the rating period.
`
`
`
`82.90 (1.35)
`
`Cardiovascular measures (peak effects)
`
` Systolic blood pressure
`142.20 (2.45)
`(mm Hg)
` Diastolic blood pressure
`(mm Hg)
`78.86 (2.17)
` Heart rate (beats per minute)
`
`Session monitor ratings (peak effects)a
` Overall drug effect
`1.37 (0.09)
` Unresponsive to questions
`0.13 (0.07)
` Anxiety or fearfulness
`0.50 (0.10)
` Distance from ordinary reality
`0.94 (0.12)
`
` Ideas of reference/paranoid
`0.05 (0.03)
`thinking
` Yawning
` Tearing/crying
` Nausea/vomiting
` Visual effects with eyes open
` Visual effects with eyes closed
` Spontaneous motor activity
` Restless/fidgety
` Joy/intense happiness
` Peace/harmony
` Psychological discomfort
` Physical discomfort
`
`0.33 (0.11)
`0.66 (0.14)
`0.11 (0.04)
`0.32 (0.09)
`0.93 (0.09)
`1.12 (0.15)
`0.83 (0.12)
`0.69 (0.12)
`1.08 (0.13)
`0.34 (0.08)
`0.31 (0.08)
`
`155.26 (2.87)***
`
`89.68 (1.21)***
`
`84.06 (2.36)***
`
`2.90 (0.07)***
`0.70 (0.12)***
`0.93 (0.15)**
`2.68 (0.10)***
`0.14 (0.05)***
`
`1.28 (0.26)***
`2.01 (0.25)***
`0.44 (0.10)**
`1.83 (0.17)***
`1.75 (0.07)***
`1.86 (0.30)*
`1.28 (0.15)**
`1.90 (0.14)***
`2.01 (0.13)***
`0.91 (0.15)***
`0.62 (0.11)**
`
`+ Data are means (SEM) for peak effects during sessions after low dose (n=50)
`or high dose (n=50) psilocybin collapsed across the two dose sequence groups.
`Asterisks indicate significant differences from the low dose (*p<0.05, **p<0.01,
`***p<0.001).
`a Maximum possible scores for all monitor ratings were 4 except for visual effects
`with eyes closed which was 2.
`
`Subjective drug effect measures assessed 7 h after psilocy-
`bin administration. When psilocybin effects had subsided,
`participants completed four questionnaires: Hallucinogen Rating
`Scale (HRS) (Strassman et al., 1994); 5-Dimension Altered
`States of Consciousness (5D-ASC) (Dittrich, 1998); Mysticism
`Scale (Experience-specific 9-point scale) (Hood et al., 2001,
`2009); and the States of Consciousness Questionnaire (SOCQ)
`(Griffiths et al., 2006). Thirty items on the SOCQ comprise the
`Mystical Experience Questionnaire (MEQ30), which was shown
`sensitive to mystical-type subjective effects of psilocybin in lab-
`oratory studies as well as survey studies of recreational use of
`psilocybin mushrooms (Barrett et al., 2015; MacLean et al.,
`2012). Four factor scores (Mystical, Positive mood, Transcen-
`dence of time and space, and Ineffability) and a mean total score
`(the mean of all 30 items) were assessed.
`
`Therapeutically relevant measures assessed at Baseline, 5
`weeks after each session, and 6-month follow-up. Seven-
`teen measures focused on mood states, attitudes, disposition, and
`behaviors thought to be therapeutically relevant in psychologi-
`cally distressed cancer patients were assessed at four time-points
`over the study: immediately after study enrollment (Baseline
`assessment), about 5 weeks (mean 37 days) after each session
`(Post-session 1 and 2 assessments), and about 6 months (mean
`211 days) after session 2 (6-month follow-up).
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`Journal of Psychopharmacology 30(12)
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`Spirituality measures assessed at Baseline, 5 weeks after
`Session 2, and 6-month follow-up. Three measures of spiritu-
`ality were assessed at three time-points: Baseline, 5 weeks after
`session 2, and at the 6-month follow-up: FACIT-Sp, a self-rated
`measure of the spiritual dimension of quality of life in chronic
`illness (Peterman et al., 2002) assessed on how the participant
`felt “on average”; Spiritual-Religious Outcome Scale, a three-
`item measure used to assess spiritual and religious changes dur-
`ing illness (Pargament et al., 2004); and Faith Maturity Scale, a
`12-item scale assessing the degree to which a person’s priorities
`and perspectives align with “mainline” Protestant traditions
`(Benson et al., 1993).
`
`Persisting effects of the psilocybin session assessed 5 weeks
`after each session and 6-month follow-up. The Persisting
`Effects Questionnaire assessed self-rated positive and negative
`changes in attitudes, moods, behavior, and spiritual experience
`attributed to the most recent psilocybin session (Griffiths et al.,
`2006, 2011). At the 6-month follow-up, the questionnaire was
`completed on the basis of the high-dose session, which was iden-
`tified as the session in which the participant experienced the most
`pronounced changes in their ordinary mental processes. Twelve
`subscales (described in Table 8) were scored.
`The questionnaire included three final questions (see Griffiths
`et al. 2006 for more specific wording): (1) How personally mean-
`ingful was the experience? (rated from 1 to 8, with 1 = no more
`than routine, everyday experiences; 7 = among the five most
`meaningful experiences of my life; and 8 = the single most mean-
`ingful experience of my life). (2) Indicate the degree to which the
`experience was spiritually significant to you? (rated from 1 to 6,
`with 1 = not at all; 5 = among the five most spiritually significant
`experiences of my life; 6 = the single most spiritually significant
`experience of my life). (3) Do you believe that the experience and
`your contemplation of that experience have led to change in your
`current sense of personal well-being or life satisfaction? (rated
`from +3 = increased very much; +2 = increased moderately; 0 =
`no change; –3 = decreased very much).
`
`Statistical analysis
`Differences in demographic data between the two dose sequence
`groups were examined with t-tests and chi-square tests with con-
`tinuous and categorical variables, respectively.
`Data analyses were conducted to demonstrate the appropriate-
`ness of combining data for the 1 and 3 mg/70 kg doses in the
`low-dose condition and for including data for the one participant
`who received 30 mg/70 kg. To determine if the two different
`psilocybin doses differed in the low-dose condition, t-tests were
`used to compare participants who received 3 mg/70 kg (n = 12)
`with those who received 1 mg/70 kg (n = 38) on participant rat-
`ings of peak intensity of effect (HRS intensity item completed 7
`h after administration) and peak monitor ratings of overall drug
`effect across the session. Because neither of these were signifi-
`cantly different, data from the 1 and 3 mg/70 kg doses were com-
`bined in the low-dose condition for all analyses.
`Of the 50 participants who completed the high-dose condi-
`tion, one received 30 mg/70 kg and 49 received 22 mg/70 kg.
`To determine if inclusion of the data from the one participant
`who received 30 mg/70 kg affected conclusions about the most
`
`therapeutically relevant outcome measures, the analyses for the
`17 measures shown in Tables 4 and 5 were conducted with and
`without that participant. Because there were few differences in
`significance (72 of 75 tests remained the same), that participant’s
`data were included in all the analyses.
`To examine acute drug effects from sessions, the drug dose
`conditions were collapsed across the two dose sequence groups.
`The appropriateness of this approach was supported by an
`absence of any significant group effects and any group-by-dose
`interactions on the cardiovascular measures (peak systolic and
`diastolic pressures and heart rate) and on several key monitor-
`and participant-rated measures: peak monitor ratings of drug
`strength and joy/intense happiness, and end-of-session partici-
`pant ratings on the Mysticism Scale.
`Six participants reported initiating medication treatment with
`an anxiolytic (2 participants), antidepressant (3), or both (1)
`between the Post-session 2 and the 6-month follow-up assess-
`ments. To determine if inclusion of these participants affected
`statistical outcomes in the analyses of the 6-month assessment,
`the analyses summarized in Tables 4, 5, 6, 7 and 8 were con-
`ducted with and without these six participants. All statistical out-
`comes remained identical. Thus, data from these six participants
`were retained in the data analyses.
`For cardiovascular measures and monitor ratings assessed
`repeatedly during sessions, repeated measures regressions were
`conducted in SAS PROC MIXED using an AR(1) covariance
`structure and fixed effects of dose and time. Planned comparison
`t-tests were used to assess differences between the high- and low-
`dose condition at each time-point.
`Peak scores for cardiovascular measures and monitor ratings
`during sessions were defined as the maximum value from pre-
`capsule to 6 h post-capsule. These peak scores and the end-of-
`session ratings (Tables 2 and 3) were analyzed using repeated
`measures regressions in SAS PROC MIXED with a CS covari-
`ance structure and fixed effects of group and dose.
`For the analyses of continuous measures described below,
`repeated measures regressions were conducted in SAS PROC
`MIXED using an AR(1) covariance structure and fixed effects of
`group and time. Planned comparison t-tests (specified below)
`from these analyses are reported. For dichotomous measures,
`Friedman’s Test was conducted in SPSS for both the overall anal-
`ysis and planned comparisons as specified below. All results are
`expressed as unadjusted scores.
`For the measures that were assessed in the two dose sequen