675512 JOP0010.1177/0269881116675512Journal of PsychopharmacologyRoss et al.
`
`research-article2016
`
`Original Paper
`
`Rapid and sustained symptom reduction
`following psilocybin treatment for anxiety and
`depression in patients with life-threatening
`cancer: a randomized controlled trial
`
`Stephen Ross1,2,3,4,5,6, Anthony Bossis1,2,4, Jeffrey Guss1,2,4,
`Gabrielle Agin-Liebes10 , Tara Malone1, Barry Cohen7,
`Sarah E Mennenga1, Alexander Belser8 , Krystallia Kalliontzi2,
`James Babb9 , Zhe Su3, Patricia Corby2 and Brian L Schmidt2
`
`Journal of Psychopharmacology
`2016, Vol. 30(12) 1165 –1180
`© The Author(s) 2016
`
`Reprints and permissions:
`sagepub.co.uk/journalsPermissions.nav
`DOI: 10.1177/0269881116675512
`jop.sagepub.com
`
`Abstract
`Background: Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical
`outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression.
`Methods: In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and
`received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety
`and depression assessed between groups prior to the crossover at 7 weeks.
`Results: Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to
`decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-
`up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60–80% of participants continued with clinically
`significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards
`death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression.
`Conclusions: In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant
`effects in patients with cancer-related psychological distress.
`Trial Registration: ClinicalTrials.gov Identifier: NCT00957359
`
`Keywords
`Psilocybin, psychedelic, cancer, depression, anxiety, mystical experience
`
`Introduction
`Enduring clinically significant anxiety and/or depressive symp-
`toms are common in patients with cancer, present in 30–40% of
`patients in hospital settings (Mitchell et al., 2011). These symp-
`toms are associated with a variety of poor outcomes, including
`medication non-adherence, increased health care utilization,
`adverse medical outcomes, decreased quality of life, decreased
`social function, increased disability, hopelessness, increased
`pain, increased desire for hastened death, increased rates of sui-
`cide, and decreased survival rates (Arrieta et al., 2013; Brown
`et al., 2003; Jaiswal et al., 2014).
`Although pharmacotherapeutic and psychosocial interven-
`tions are commonly used to treat anxiety and depression in
`cancer patients, their efficacy is mixed and limited (Grassi
`et al., 2014; NCCN, 2014). There are no US Food and Drug
`Administration approved pharmacotherapies for cancer-related
`psychological distress, the onset of clinical improvement with
`anti-depressants is delayed, relapse rates are high, and significant
`side effects compromise treatment adherence (Freedman, 2010;
`Li et al., 2012).
`
` 1 Department of Psychiatry, New York University School of Medicine,
`New York, NY, USA
` 2 New York University College of Dentistry, Bluestone Center for
`Clinical Research, New York, NY, USA
` 3 Department of Child and Adolescent Psychiatry, New York University
`School of Medicine, New York, NY, USA
` 4 Department of Psychiatry, Bellevue Hospital Center, New York, USA
` 5 NYU Langone Medical Center, New York, NY, USA
` 6 New York University-Health and Hospitals Corporation (NYU-HHC)
`Clinical and Translational Science Institute, New York, NY, USA
` 7 Department of Psychology, New York University, New York, NY, USA
` 8 Department of Applied Psychology, New York University Steinhardt
`School of Culture, Education, and Human Development, New York,
`NY, USA
` 9 Department of Radiology, New York University School of Medicine,
`New York, NY, USA
`10 Palo Alto University, Palo Alto, CA, USA
`
`Corresponding author:
`Stephen Ross, NYU School of Medicine/Bellevue Hospital, 462 First
`Avenue, NBV 20E7, New York, NY 10016, USA.
`Email: stephen.ross@nyumc.org
`
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`Journal of Psychopharmacology 30(12)
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`With a growing body of evidence linking higher levels of
`existential/spiritual wellbeing (in cancer patients) with improved
`quality of life and decreased depression/hopelessness/suicidality
`(Breitbart et al., 2000; McClain et al., 2003; Nelson et al., 2002),
`the need to develop effective therapeutic approaches to mitigate
`this domain of distress has become increasingly recognized
`within the disciplines of palliative care and psycho-oncology
`(emphasized within the last two decades by the Institute of
`Medicine,
`the World Health Organization,
`the National
`Comprehensive Cancer Network, the Joint Commission, the
`National Consensus Project, and the National Quality Forum)
`and improvement in these domains is now accepted as an integral
`component in the care of cancer patients (Puchalski, 2012). A
`number of manualized existentially oriented psychotherapies
`have been developed to address these existential/spiritual issues,
`with some empirical support from clinical trials (Lemay and
`Wilson, 2008), and several of these approaches were integrated
`into the therapy platform developed for this study. There are cur-
`rently no pharmacotherapies or evidence-based combined phar-
`macological-psychosocial interventions to treat this particular
`type of distress and unmet clinical need in cancer patients
`(Breitbart et al., 2010).
`Psilocybin, a tryptamine serotoninergic psychedelic, exerts its
`consciousness altering effects via 5HT2A agonism (Vollenweider
`and Kometer, 2010). It has a well-established physiological and
`psychological safety profile in human laboratory and clinical trial
`research (Johnson et al., 2008), is not known to be addictive and
`may have anti-addictive properties (Bogenschutz and Johnson,
`2016; Krebs and Johansen, 2012; Ross, 2012). It can produce
`highly salient spiritual/mystical states of consciousness associ-
`ated with enduring (months to years) positive changes in cogni-
`tion, affect, behavior, and spirituality (Doblin, 1991; Griffiths
`et al., 2006, 2008, 2011; Pahnke, 1963). From the early 1960s to
`the early 1970s, clinical research utilizing the serotoninergic
`psychedelics, primarily lysergic acid diethylamide (LSD), to
`treat terminal cancer-related psychological and existential dis-
`tress was conducted at major academic medical centers in the
`United States with a total of several hundred participants. These
`studies occurred largely in the context of open-label trials and
`showed improvements in the following symptom domains: anxi-
`ety, depression, fear of dying, quality of life, and pain (Grob
`et al., 2013; Grof et al., 1973; Kast, 1966; Kast and Collins, 1964;
`Pahnke et al., 1969).
`Research into the use of hallucinogen treatment models for
`psycho-spiritual distress in advanced or terminal cancer ceased in
`the mid 1970s with the passage of the Controlled Substance Act
`of 1970, which placed all of the serotoninergic psychedelics into
`schedule I of the US Drug Enforcement Administration’s classi-
`fication of regulated psychoactive substances.
`Building upon hallucinogen research with cancer patients
`from over four decades ago, two recently published randomized
`controlled trials (RCTs) with serotoninergic psychedelics to treat
`cancer-related psychological distress, one using psilocybin in
`patients with advanced-stage cancer conducted at Harbor-UCLA
`(Grob et al., 2011) and the other using LSD in patients with a
`variety of life-threatening illnesses including but not limited to
`cancer diagnoses (Gasser et al., 2014), suggested acute and sus-
`tained treatment benefits. The University of California Los
`Angeles RCT in patients with advanced-stage cancer included
`a cohort of 12 participants and reported on the medical
`
`and psychiatric safety of administering low-dose psilocybin
`(0.2 mg/kg) in conjunction with psychotherapy, and revealed
`trends towards reduced depression and anxiety in the psilocybin
`group compared to the control condition (Grob et al., 2011).
`In the present RCT, the primary hypothesis was that psilocy-
`bin, in conjunction with targeted psychotherapy, would signifi-
`cantly decrease anxiety and depression symptoms (compared to
`an active control, niacin, and the same dose of psychotherapy as
`the experimental group) in patients with life-threatening cancer
`diagnoses.
`
`Methods
`Study design and interventions
`This randomized, blinded, controlled, crossover, study was
`designed to investigate the efficacy of a single psilocybin dosing
`session (0.3 mg/kg) versus one dosing session of an active con-
`trol (niacin 250 mg), administered in conjunction with psycho-
`therapy, to treat clinically significant anxiety or depression in
`patients with life-threatening cancer (see Supplementary Methods
`for information on inclusion/exclusion criteria, blinding proce-
`dures, medication sessions and psychotherapy procedures). The
`trial employed a two-session, double-blind, crossover (7 weeks
`after administration of dose 1) design to compare groups.
`Participants were randomly assigned to two oral dosing session
`sequences: psilocybin (0.3 mg/kg) first then niacin (250 mg) sec-
`ond, or niacin (250 mg) first then psilocybin (0.3 mg/kg) second
`(Figures 1 and 2). Randomization did not stratify for any demo-
`graphic (i.e. gender, race, spiritual/religious affiliation) or clini-
`cal characteristics (i.e. stage of cancer, prior hallucinogen use).
`Drug administration dose 1 (psilocybin or control) occurred 2–4
`weeks (mean 18 days) after baseline assessments and the crosso-
`ver occurred 7 weeks (mean 52 days) after dose 1, at which point
`drug administration dose 2 occurred. Data assessments occurred
`at baseline (2–4 weeks prior to dose 1), 1 day prior to dose 1, day
`of dose 1 (7 hours post-dose), 1 day after dose 1, 2 weeks after
`dose 1, 6 weeks after dose 1, 7 weeks after dose 1 (1 day prior to
`dose 2), day of dose 2 (7 hours post-dose), 1 day after dose 2, 6
`weeks after dose 2, and 26 weeks after dose 2 (Figure 2). The
`total duration of study participation was approximately 9 months
`(mean 253 days). The primary outcome variables were anxiety
`and depression assessed prior to the crossover. Secondary out-
`come measures (assessed before and after the crossover) included
`assessments of existential distress, quality of life, and spirituality,
`as well as measures assessing immediate and sustained effects of
`psilocybin administration on subjective (e.g. mystical) experi-
`ence, cognition, affect, spirituality, and behavior.
`
`Study sample and setting
`Of 108 participants pre-screened, 42 gave informed consent
`and of these 29 patients were randomly assigned and received
`treatment with single-dose psilocybin or single-dose niacin
`control (Table 1 and Figure 1). The study was approved and
`monitored by the institutional review board of the New York
`University (NYU) School of Medicine. The majority of par-
`ticipants were recruited from a clinical cancer center at an aca-
`demic medical facility (NYU Langone’s Perlmutter Cancer
`Center). Data were collected from 18 February 2009 to 22
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`Ross et al.
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`Figure 1. CONSORT diagram.
`
`October 2014 and the analysis was conducted from 3
`November 2014 to 11 December 2015.
`Nearly two-thirds of participants (62%) had advanced cancers
`(stages III or IV). The types of cancer included: breast or repro-
`ductive (59%); gastrointestinal (17%); hematologic (14%); other
`(10%). In accordance with the study’s inclusion criteria, all par-
`ticipants carried an anxiety-related diagnosis per the severe com-
`bined immunodeficiency (SCID) (Diagnostic and Statistical
`Manual of Mental Disorders (DSM)-IV) with the majority meet-
`ing criteria for an adjustment disorder (26, 90%) and the rest for
`generalized anxiety disorder (three, 10%). Nearly two-thirds
`(59%) had previously been treated with anti-depressant or anxio-
`lytic medication, but none were on any psychotropics at the time
`of study enrollment, per the inclusion/exclusion criteria.
`
`Assessments
`Safety assessments. Adverse events (AEs) attributed to study
`medications (psilocybin, niacin) were monitored throughout the
`trial, including during and after medication administration
`sessions.
`Cardiovascular measures were assessed during medication
`sessions. Systolic and diastolic blood pressure (BP) and heart
`rate (HR) were measured at the following time points during the
`medication dosing sessions: baseline, 30, 60, 90, 120, 180, 240,
`300, 360 minutes post-dose administration.
`
`Primary Outcome Measures. Clinical primary outcome mea-
`sures (anxiety, depression) were assessed at baseline, 1 day prior
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`1168
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`Journal of Psychopharmacology 30(12)
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`Figure 2. Interventions and assessments schedule.
`Temporal relationships between drug administration, psychosocial interventions, and assessments.
`Prep PT: preparatory psychotherapy; 1-day pre-D1: 1 day prior to dose 1; Dose 1: dosing session 1; 1-day post-D1: 1 day after dose 1; Post-integrative PT: post-integra-
`tive psychotherapy; 2-wks post-D1: 2 weeks after dose 1; 6-wks post-D1: 6 weeks after dose 1; Safety prep for D2: safety preparation for dosing dose 2; 1-day pre-D2: 1
`day prior to dose 2; Dose 2: dosing session 2; 1-day post-D2: 1 day after dose 2; 6-wks post-D2: 6 weeks after dose 2; 26-wks post-D2: 2 weeks after dose 2.
`
`to dose 1, 1 day after dose 1, 2-weeks after dose 1, 6 weeks after
`dose 1, 7 weeks after dose 1 (corresponding to 1 day prior to dose
`2), 1 day after dose 2, 6 weeks after dose 2, and 26 weeks after
`dose 2: Hospital Anxiety and Depression Scale (HADS) (Zig-
`mond and Snaith, 1983), self-rated subscales of anxiety (HADS
`anxiety or HAD A), depression (HADS depression or HAD D)
`and total (HADS total or HAD T) combined score in patients
`with physical health problems (e.g. cancer); Beck Depression
`Inventory (BDI) (Beck et al., 1988) self-report depression mea-
`sure; Spielberger State-Trait Anxiety Inventory (STAI) (Spiel-
`berger, 1983) self-report measure of state (STAI state or STAI S)
`and trait (STAI trait or STAI T) anxiety.
`
`Secondary outcome measures. Cancer-related existential
`distress (demoralization, hopelessness, attitudes and affect
`associated with disease progression and death) was assessed
`at baseline, 2 weeks post-dose 1, and 26 weeks post-dose 2:
`Demoralization (DEM) scale (Kissane et al., 2004), self-report
`measure of the cancer-related demoralization syndrome (e.g.
`despair, helplessness, existential distress such as loss of
`hope/meaning/purpose in life, a sense of ‘giving up’, desire for
`hastened death); Hopelessness Assessment and Illness (HAI)
`
`scale (Rosenfeld et al., 2011) self-report measure of hopeless-
`ness in advanced cancer; Death Anxiety Scale (DAS) (Templer,
`1970) a self-report questionnaire assessing the level of death
`anxiety; Death Transcendence Scale (DTS) (VandeCreek, 1999)
`a self-report measure of positive attitudes and adaptations to the
`finitude of life.
`Quality of life was assessed at baseline, 2 weeks post-dose 1
`and 26 weeks post-dose 2: World Health Organization Qualify of
`Life scale, brief version (WHO-Bref) (WHO, 1994), self-report
`measure of quality of life in four domains (physical, psychologi-
`cal, social relationships, environment).
`Spirituality was assessed at baseline, 2 weeks post-dose 1
`and 26 weeks post-dose 2: Functional Assessment of Chronic
`Illness Therapy-Spiritual Well-Being (FACIT-SWB) (Brady
`et al., 1999) a self-report measure of spiritual wellbeing gener-
`ating three scales: meaning/peace, faith, total spiritual wellbe-
`ing score. The meaning/peace scale assesses one’s sense of
`inner peace, meaning, and purpose in life and corresponds to
`the more existential components of religious or spiritual prac-
`tice. The faith scale measures strength and comfort derived
`from one’s faith and emphasizes the more ritualized compo-
`nents of religious/spiritual practice.
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`Table 1. Demographic and clinical characteristics of study participants.a
`
`Characteristic
`
`Categories
`
`Psilocybin first
`
`Niacin first
`
`n=14
`
`n=15
`
`Total
`
`n=29
`
`Sex
`
`Age; mean (SD)
`Race
`
`Religious/
`spiritual beliefs
`
`Site of cancer
`
`Stage of cancer
`
`SCID (DSM-IV)
`diagnosisb
`
`Hallucinogen
`use
`Employment
`status
`
`Educational
`attainment
`
`Marital status
`
`Living
`arrangements
`
`Female
`Male
`Range 22–75
`White/Caucasian
`Black/African American
`Hispanic/Latino
`Asian
`American Indian/Native American
`Other
`Atheist/agnostic
`Jewish
`Catholic
`Other Christian
`Other faith/tradition
`Breast
`Reproductive
`Digestive cancers
`Lymphoma/leukemia
`Other types
`Stage IV
`Stage III
`Stage II
`Stage I
`Other
`Adjustment disorder w/anxiety and depressed mood, chronic
`Adjustment disorder w/anxiety, chronic
`Generalized anxiety disorder
`No
`Yes
`Full-time employed
`Part-time employed
`Full-time student
`Unemployed
`Self-employed
`Retired
`Long-term disability
`Grade 7–12 w/o graduating high school
`Graduated HS or equivalent
`Part college
`Graduated 4-year college
`Completed grad/professional school
`Never married
`Widowed
`Cohabitation
`Divorced
`Married
`Live with spouse/partner/family
`Live alone
`Other; lived with roommates
`
`50%
`7
`50%
`7
`52 (15.03)
`13
`93%
`0
`0%
`0
`0%
`0
`0%
`0
`0%
`1
`7%
`4
`29%
`4
`29%
`2
`14%
`3
`21%
`1
`7%
`4
`29%
`3
`21%
`3
`21%
`2
`14%
`2
`14%
`3
`21%
`4
`29%
`1
`7%
`5
`36%
`1
`7%
`2
`14%
`10
`71%
`2
`14%
`7
`50%
`7
`50%
`6
`43%
`2
`14%
`1
`7%
`2
`14%
`1
`7%
`0
`0%
`2
`14%
`1
`7%
`0
`0%
`1
`7%
`5
`36%
`7
`50%
`5
`36%
`0
`0%
`2
`14%
`1
`7%
`6
`43%
`11
`79%
`2
`14%
`1
`7%
`
`73%
`11
`27%
`4
`60.27 (9.45)
`13
`87%
`0
`0%
`0
`0%
`0
`0%
`0
`0%
`2
`13%
`10
`67%
`1
`7%
`0
`0%
`1
`7%
`3
`20%
`5
`33%
`5
`33%
`2
`13%
`2
`13%
`1
`7%
`7
`47%
`4
`27%
`4
`27%
`0
`0%
`0
`0%
`6
`40%
`8
`53%
`1
`7%
`6
`40%
`9
`60%
`5
`33%
`2
`13%
`0
`0%
`1
`7%
`1
`7%
`6
`40%
`0
`0%
`0
`0%
`1
`7%
`3
`20%
`4
`27%
`7
`47%
`3
`20%
`2
`13%
`0
`0%
`3
`20%
`7
`47%
`9
`60%
`6
`40%
`0
`0%
`
`62%
`18
`38%
`11
`56.28 (12.93)
`26
`90%
`0
`0%
`0
`0%
`0
`0%
`0
`0%
`3
`10%
`14
`48%
`5
`17%
`2
`7%
`4
`14%
`4
`14%
`9
`31%
`8
`28%
`5
`17%
`4
`14%
`3
`10%
`10
`34%
`8
`28%
`5
`17%
`5
`17%
`1
`3%
`8
`28%
`18
`62%
`3
`10%
`13
`45%
`16
`55%
`12
`41%
`4
`14%
`1
`3%
`2
`7%
`2
`7%
`6
`21%
`2
`7%
`1
`3%
`1
`3%
`4
`14%
`9
`31%
`14
`48%
`8
`28%
`2
`7%
`2
`7%
`4
`14%
`13
`45%
`20
`69%
`8
`28%
`1
`3%
`
`aThe two dose-sequence groups did not significantly differ on any demographic or clinical characteristic measures.
`bPsychiatric classification was based on the structured clinical interview for the DSM-IV (SCID-IV).
`Nearly two-thirds (59%) of participants had previously been treated with anti-depressant or anxiolytic medication, but none were on any psychotropics before study
`enrollment per inclusion/exclusion criteria.
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`Figure 3. Primary outcome variables: cancer-related anxiety and depression (pre-crossover).
`Means (±SE) for primary outcome measures are shown in the two treatment groups at the following time points: baseline (psilocybin first n=14, niacin first n=15), 1 day
`pre-dose 1 (psilocybin first n=14, niacin first n=15), 1 day post-dose 1 (psilocybin first n=14, niacin first n=15), 2 weeks post-dose 1 (psilocybin first n=14, niacin first
`n=14), 6 weeks post-dose 1 (psilocybin first n=14, niacin first n=14), 7 weeks post-dose 1 (psilocybin first n=12, niacin first n=14). Asterisks indicate significance level
`of between-group t-tests. Effect sizes, represented as Cohen’s d, are shown above time points at which the treatment groups differ. Closed points represent significant
`within-group differences relative to scores at baseline.
`
`Subjective drug effects/mystical experience was assessed at 7
`hours after drug administration sessions and retrospectively at 26
`weeks post-dose 2: the Mystical Experience Questionnaire (MEQ
`30) (Barrett et al., 2015) is a self-report questionnaire that evalu-
`ates discrete mystical experiences induced by serotoninergic
`psychedelics and is sensitive to detecting psilocybin-induced
`mystical experiences (MacLean et al., 2012). In addition to an
`MEQ total score, the questionnaire generates four empirically
`derived factors: mystical; positive mood; transcendence of time
`and space; and ineffability. A retrospective version of the MEQ
`30 (MEQ retrospective scale) was administered at 26 weeks post-
`dose 2. See Supplementary Methods section for more informa-
`tion on the MEQ 30 and for other measures of subjective drug
`effects/mystical experience measured 7 hours after drug adminis-
`tration sessions.
`Persisting effects of psilocybin were assessed at 2 weeks
`post-dose 1 and 26 weeks post-dose 2: the Persisting Effects
`Questionnaire (PEQ), a self-report measure of changes in atti-
`tudes, moods, behaviors and spiritual experiences, sensitive to
`the longitudinal effects of psilocybin administration (Griffiths
`et al., 2006, 2008, 2011). All participants (including in both
`the psilocybin first and niacin first groups) were asked at
`26 weeks after dose 2 to reflect on the meaningfulness, spiritual
`
`significance and changes in wellbeing relative to what they
`guessed was
`their psilocybin dosing experience
`(see
`Supplementary Methods secondary outcome measures).
`See Supplementary Methods for other secondary outcome
`measures.
`
`Statistical analysis
`Whenever multiple time points were included in the analysis for
`continuous measures, repeated measures regressions, from the
`mixed effect repeated measurement (MMRM) model, were per-
`formed in SAS PROC MIXED using an AR(1) covariance struc-
`ture and fixed effects of group and time. Comparison t-tests from
`the MMRM analyses are reported for the primary and the con-
`tinuous secondary outcome measures (see below).
`For the primary outcome measures (anxiety, depression) in
`the two dosing sequences, planned between-group comparisons
`were made at the following time points: prior to the crossover at
`baseline, 1 day pre-dose 1, 1 day post-dose 1, 2 weeks post-dose
`1, 6 weeks post-dose 1, 7 weeks post-dose 1 (corresponding to 1
`day pre-dose 2) (Figure 3) and after the crossover at 1 day post-
`dose 2, 6 weeks post-dose 2, and 26 weeks post-dose 2 (Figure
`4). Between-group effect sizes were calculated using Cohen’s d.
`
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`Ross et al.
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`Figure 4. Primary outcome variables: cancer-related anxiety and depression (post-crossover).
`Means (±SE) for primary outcome measures are shown in the two treatment groups at the following time points: baseline (psilocybin first n=14, niacin first n=15), 1-day
`pre dose-1 (psilocybin first n=14, niacin first n=15), 1 day post-dose 1 (psilocybin first n=14, niacin first n=15), 6 weeks post-dose 1 (psilocybin first n=14, niacin
`first n=14), 7 weeks post-dose 1 (1 day pre-dose 2) (psilocybin first n=12, niacin first n=14), 1 day post-dose 2, 6 weeks post-dose 2 (psilocybin first n=12, niacin first
`n=11), 26 weeks post-dose 2 (psilocybin first n=11, niacin first n=12). Asterisks indicate significance level of between-group t-tests. Closed points represent significant
`within-group differences relative to scores at baseline.
`
`Planned within-group comparison t-tests were conducted for
`each of the dosing sequences comparing the baseline to each of
`the following time points: 1 day pre-dose 1, 1 day post-dose 1, 2
`weeks post-dose 1, 6 weeks post-dose 1, 7 weeks post-dose 1 (1
`day pre-dose 2), 1 day post-dose 2, 6 weeks post-dose 2, 26
`weeks post-dose 2 (Figures 3 and 4). Within-group effect sizes
`for the dosing sequences were calculated at each time point, com-
`pared to baseline, using Cohen’s d (Supplementary Table 1). To
`assess whether the magnitude of psilocybin-induced change in
`anxiety and depression differed across treatment groups, we
`compared change scores on the six primary outcome measures
`across each participant’s active (psilocybin) treatment session
`(from 1 day prior to psilocybin treatment to 1 day after psilocybin
`treatment) with one-way analysis of variance (ANOVA).
`For primary outcome measures (HAD D, BDI, HAD A, HAD
`T) that have empirical support in defining anti-depressant or
`anxiolytic response, clinically significant responses rates were
`defined as a 50% or greater reduction in the measure at a particu-
`lar assessment point relative to baseline. Anti-depressant symp-
`tom remission (HAD D, BDI) was defined as 50% or greater
`reduction in depressive symptoms plus HADS D ⩽7 (Hung et al.,
`2012) or BDI ⩽12 (Reeves et al., 2012; Riedel et al., 2010),
`respectively. Planned chi-square analyses were performed to
`
`compare the percentage of participants, in the psilocybin first
`versus the niacin first groups, who met criteria for anxiolytic or
`anti-depressant response, or anti-depressant remission (BDI,
`HAD D) at the following time points: 1 day post-dose 1, 7 weeks
`post-dose 1, and 26 weeks post-dose 2 (Figure 5).
`For cardiovascular measures assessed during the medication
`sessions, repeated measures regressions, from the mixed effect
`repeat measurement (MMRM) model, were conducted in SAS
`PROC MIXED using an AR(1) covariance structure and fixed
`effects of time, drug (psilocybin vs. niacin) and group (niacin
`first vs. psilocybin first) collapsed across treatment order at time
`points: baseline, 30, 60, 90, 120, 180, 240, 300, 360 post-dosing
`(Supplementary Figure 1).
`For the secondary outcome measures (cancer-related existen-
`tial distress, quality of life, spirituality, persisting effects of psilo-
`cybin), planned between-group comparisons were conducted
`generating the following comparisons: 1. niacin first group 2
`weeks post-dose 1 versus psilocybin first group 2 weeks post-dose
`1; 2. niacin first group 2 weeks post-dose 1 versus niacin first
`group 26 weeks post-dose 2; 3. niacin first group 2 weeks post-
`dose 1 versus psilocybin first group 26 weeks post-dose 2; 4. psilo-
`cybin first group 2 weeks post-dose 1 versus psilocybin first group
`26 weeks post-dose 2 (Figure 6 (bottom), Supplementary Table 2).
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`Figure 5. Percentage of participants with anti-depressant or anxiolytic response rates and anti-depressant symptom remission.
`Percentages of participants in each treatment group who met criteria for anti-depressant or anxiolytic response or anti-depressant symptom remission (BDI, HAD D) at
`1 day post-dose 1 (psilocybin first n=14, niacin first n=15), 7 weeks post-dose 1 (psilocybin first n=12, niacin first n=14) and at 26 weeks post-dose 2 (psilocybin first
`n=11, niacin first n=12). Asterisks indicate significance level of between-group comparisons at each time point.
`
`Ratings of persisting effects attributed to the medication ses-
`sions were expressed as proportions for four items (see
`Supplemental Methods): positive behavioral change; meaning-
`fulness, spiritual significance, and increases in personal wellbe-
`ing. Planned chi-square analyses were performed: niacin first
`group at 2 weeks post-dose 1 and psilocybin first at 2 weeks post-
`dose 1, niacin first at 2 weeks post-dose 1 and psilocybin first at
`26 weeks post-dose 2. McNemar tests were used to compare
`these proportions between the psilocybin first group at 2 weeks
`post-dose 1 and the psilocybin first group at 26 weeks post-dose
`2 and between the niacin first group at 2 weeks post-dose 1 and
`the niacin first group at 26 weeks post-dose 2 (Figure 6 (top)).
`Subjective drug effects/mystical experiences were compared
`between groups using an independent sample t-test run in SAS at
`three time points: 7 hours post-medication administration in ses-
`sions 1 and 2; and at 26 weeks post-dose 2 (Figure 7 (top)).
`Anxiety and depression change scores for the primary outcome
`measures (∆HADS T, ∆HADS A, ∆HADS D, ∆BDI, ∆STAI S,
`∆STAI T) were calculated from baseline to 6 weeks post-dose 1
`with either psilocybin or niacin. Spearman rank correlation coef-
`ficients were calculated between the change scores and partici-
`pant ratings on the MEQ total at 7 hours post-dose 1 to assess the
`relationship between subjective mystical experience and change
`
`in clinical outcomes. Significant relationships were further exam-
`ined using partial correlations to control for end of session partic-
`ipant-rated ‘intensity’ (item 98 from the HRS). In order to
`examine the mystical experience (using MEQ 30 scores) as a
`mediator of psilocybin versus niacin treatment on anxiety/depres-
`sion outcomes, a bootstrap analysis was performed using the
`PROCESS macro (Hayes, 2013, Figure 7 (bottom)). The boot-
`strapping method is a non-parametric approach that does not
`assume a normal distribution of the mediated effect, is appropri-
`ate with small sample sizes, and was used to estimate 95% confi-
`dence intervals (CIs) for the mediation effect (Hayes, 2013). See
`Supplemental Methods.
`See Supplementary Methods for additional statistical
`analysis.
`
`Results
`Demographics
`As reported in Table 1, of the 29 participants who completed dose
`1, the majority were Caucasian (90%) and women (62%). The
`average age was 56.3 (range 22–75) years. Approximately half of
`the participants reported some organized religious faith versus
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`Figure 6. Secondary outcome measures: existential distress, quality of life, spirituality, persisting effects attributed to psilocybin administration.
`(Top) Percentage of participants that reported ‘among the top 5’ or ‘the single most’ personally meaningful and spiritually significant experiences, ‘moderate’, ‘strong’ or
`‘extreme’ positive behavioral change, and ‘increased moderately’ or ‘increased very much’ wellbeing or life satisfaction on the Persisting Effects Questionnaire (PEQ). As-
`terisks indicate significance level of comparison to the niacin first group at 2 weeks post-dose 1. There were no significant differences between the psilocybin first group
`at 2 weeks post-dose 1 versus the psilocybin first group at 26 weeks post-dose 2. (Bottom) Secondary measures of cancer-related existential distress (DEM, HAI, DAS,
`DTS), quality of life (WHO-Bref) and spirituality (FACIT). Measures are shown at 2 weeks post-dose 1 (psilocybin first n=14, niacin first n=14) and at 26 weeks post-dose
`2 (psilocybin first n=11, niacin first n=12); asterisks indicate significance level of comparison to the niacin first group at 2 weeks post-dose 1. There were no significant
`differences between the psilocybin first group at 2 weeks post-dose 1 versus the psilocybin first group at 26 weeks post-dose 2.
`
`atheist/agnostic (52% vs. 48%) and slightly less than half reported
`no prior history of hallucinogen use (45%). Ninety per cent of
`participants met DSM-IV criteria for cancer-related adjustment
`disorder with anxious ± depressed features. The two dose-
`sequence groups did not significantly differ on demographic or
`clinical characteristic measures. No dichotomous factors (i.e.
`gender, prior hallucinogen use vs. none, spiritual faith/religion
`vs. none, early vs. late cancer stage) significantly interacted with
`the primary outcome measures in between-group comparisons.
`
`Safety assessments
`Adverse events. There were no serious AEs, either medical or
`psychiatric, in the trial that were attributed to either psilocybin or
`niacin. Regarding psychiatric AEs, no pharmacological interven-
`tions (e.g. benzodiazepines, anti-psychotics) were needed during
`dosing sessions, no participants abused or became addicted
`to psilocybin, there were no cases of prolonged psychosis
`
`or hallucinogen persisting perceptual disorder (HPPD), and no
`participants required psychiatric hospitalization. In terms of AEs
`attributable to psilocybin, the most common medical AEs were
`non-clinically significant elevations in BP and HR (76%), head-
`aches/migraines (28%), and nausea (14%); the most common
`psychiatric AEs were transient anxiety (17%) and transient psy-
`chotic-like symptoms (7