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Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial

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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.
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DOI: 10.1177/0269881116675512
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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).
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
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
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
675512JOP0010.1177/0269881116675512Journal of PsychopharmacologyRoss et al.
research-article2016
Original Paper
2 Journal of Psychopharmacology
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
Ross et al. 3
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
Figure 1. CONSORT diagram.
4 Journal of Psychopharmacology
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.
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.
Ross et al. 5
Table 1. Demographic and clinical characteristics of study participants.a
Characteristic Categories Psilocybin first Niacin first Total
n=14 n=15 n=29
Sex Female 7 50% 11 73% 18 62%
Male 7 50% 4 27% 11 38%
Age; mean (SD) Range 22–75 52 (15.03) 60.27 (9.45) 56.28 (12.93)
Race White/Caucasian 13 93% 13 87% 26 90%
Black/African American 0 0% 0 0% 0 0%
Hispanic/Latino 0 0% 0 0% 0 0%
Asian 0 0% 0 0% 0 0%
American Indian/Native American 0 0% 0 0% 0 0%
Other 1 7% 2 13% 3 10%
Religious/
spiritual beliefs
Atheist/agnostic 4 29% 10 67% 14 48%
Jewish 4 29% 1 7% 5 17%
Catholic 2 14% 0 0% 2 7%
Other Christian 3 21% 1 7% 4 14%
Other faith/tradition 1 7% 3 20% 4 14%
Site of cancer Breast 4 29% 5 33% 9 31%
Reproductive 3 21% 5 33% 8 28%
Digestive cancers 3 21% 2 13% 5 17%
Lymphoma/leukemia 2 14% 2 13% 4 14%
Other types 2 14% 1 7% 3 10%
Stage of cancer Stage IV 3 21% 7 47% 10 34%
Stage III 4 29% 4 27% 8 28%
Stage II 1 7% 4 27% 5 17%
Stage I 5 36% 0 0% 5 17%
Other 1 7% 0 0% 1 3%
SCID (DSM-IV)
diagnosisb
Adjustment disorder w/anxiety and depressed mood, chronic 2 14% 6 40% 8 28%
Adjustment disorder w/anxiety, chronic 10 71% 8 53% 18 62%
Generalized anxiety disorder 2 14% 1 7% 3 10%
Hallucinogen
use
No 7 50% 6 40% 13 45%
Yes 7 50% 9 60% 16 55%
Employment
status
Full-time employed 6 43% 5 33% 12 41%
Part-time employed 2 14% 2 13% 4 14%
Full-time student 1 7% 0 0% 1 3%
Unemployed 2 14% 1 7% 2 7%
Self-employed 1 7% 1 7% 2 7%
Retired 0 0% 6 40% 6 21%
Long-term disability 2 14% 0 0% 2 7%
Educational
attainment
Grade 7–12 w/o graduating high school 1 7% 0 0% 1 3%
Graduated HS or equivalent 0 0% 1 7% 1 3%
Part college 1 7% 3 20% 4 14%
Graduated 4-year college 5 36% 4 27% 9 31%
Completed grad/professional school 7 50% 7 47% 14 48%
Marital status Never married 5 36% 3 20% 8 28%
Widowed 0 0% 2 13% 2 7%
Cohabitation 2 14% 0 0% 2 7%
Divorced 1 7% 3 20% 4 14%
Married 6 43% 7 47% 13 45%
Living
arrangements
Live with spouse/partner/family 11 79% 9 60% 20 69%
Live alone 2 14% 6 40% 8 28%
Other; lived with roommates 1 7% 0 0% 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.
6 Journal of Psychopharmacology
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.
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.
Ross et al. 7
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).
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.
8 Journal of Psychopharmacology
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
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.
Ross et al. 9
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%: one case of transient paranoid ide-
ation and one case of transient thought disorder). The medical
AEs (non-clinically significant elevations in BP and HR, head-
aches, nausea), and psychiatric AEs (transient anxiety, transient
near-psychotic symptoms) attributable to psilocybin are all
known AEs of psilocybin, were transient, tolerable, and consis-
tent with prior trials of psilocybin administration in normal vol-
unteers (Griffiths et al., 2006, 2008, 2011), and patients with
terminal cancer (Grob et al., 2011).
Cardiovascular effects during dosing sessions. Compared
to the control, psilocybin produced statistically significant
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.
10 Journal of Psychopharmacology
differences in the following cardiovascular measures and time
points: systolic BP: 60, 90, 120, 180, 240, 300 minutes; diastolic BP
60, 90, 120, 180 minutes; pulse: 90, 120 minutes (see Supplemen-
tary Figure 1). Cardiovascular effects with psilocybin generally
peaked at 180 minutes post-dosing and decreased towards pre-drug
levels over the remainder of the session. Regarding the psilocybin
first group, peak mean systolic and diastolic BPs were 142/83 (both
recorded at 180 minutes post-dosing), while peak mean HR for this
group was 71 at 300 minutes post-dosing (see Supplementary Fig-
ure 1). There were no serious adverse cardiac events, consistent
with psilocybin’s absence of cardiac toxicity when administered in
controlled laboratory settings (Studerus et al., 2011). The medical
safety, time course, and magnitude of effects on these cardiovascu-
lar measures were consistent with those observed in previous stud-
ies of psilocybin in healthy volunteers (Griffiths et al., 2006, 2011)
and patients with advanced cancer (Grob et al., 2011).
Primary outcomes
For each of the six primary outcome measures (HADS T, HADS
A, HADS D, BDI, STAI S, STAI T), there were significant differ-
ences between the experimental and control groups (prior to the
crossover at 7 weeks post-dose 1) with the psilocybin group
(compared to the active control) demonstrating immediate,
substantial, and sustained (up to 7 weeks post-dosing) clinical
benefits in terms of reduction of anxiety and depression symp-
toms (Figure 3). The magnitude of differences between the psilo-
cybin and control groups (Cohen’s d effect sizes) was large across
the primary outcome measures, assessed at 1 day/2 weeks/
6 weeks/7 weeks post-dose 1 (Figure 3).
Treatment groups did not differ in magnitude of change
(e.g. 1 day before compared to 1 day after) across their respec-
tive psilocybin treatment sessions for any of the primary out-
come measures (BDI: F(1,26)=1.88, P=0.18; HADS A:
F(1,26)=2.59, P=0.12; HADS D: F(1,26)=0.90, P=0.35; HADS T:
F(1,26)=2.63, P=0.12; STAI S: F(1,26)=1.10, P=0.30; STAI T:
F(1,26)=0.58, P=0.45).
For all primary outcome measures, the psilocybin first group
demonstrated significant within-group reductions (compared to
baseline at each post-baseline assessment point) in anxiety and
depression immediately after receiving psilocybin (Figures 3 and
4). These reductions remained significant at each time point,
including the final point at 26 weeks post-dose 2 (approximately
8 months), post-psilocybin dosing. Prior to the crossover, the nia-
cin first group demonstrated either no significant within-group
reductions or a transient reduction that became non-significant
prior to dose 2. For the majority (five/six) of the measures, the
niacin first group demonstrated significant within-group
Figure 7. Subjective effects of psilocybin and relationship of mystical experience to clinical outcomes.
(Top) Subjective effects as measured by the Mystical Experience Questionnaire (MEQ 30) in each treatment group at 7 hours post-session 1 (psilocybin first n=14, niacin
first n=15), 7 hours post-session 2 (psilocybin first n=12, niacin first n=14), and 26 weeks post-dose 2 (psilocybin first n=11, niacin first n=12). Asterisks indicate
significance level of between-group differences. (Bottom) Mediation model in which total scores on the MEQ transmit a portion of the effects of psilocybin versus niacin
treatment on change in anxiety and depression is shown.
Ross et al. 11
reductions in anxiety and depression immediately after receiving
the psilocybin dose (dosing session 2), and these statistically
significant improvements persisted until the end of the study
(approximately 6.5 months post-psilocybin dosing, 26 weeks
post-dose 2, for this group).
Psilocybin produced immediate and enduring anxiolytic and
anti-depressant response rates, as well as significant anti-depres-
sant remission rates (measured by the HADS D and BDI) (Figure
5). For example, 7 weeks after dose 1, 83% of participants in the
psilocybin first group (vs. 14% in the niacin first group) met crite-
ria for anti-depressant response (with the BDI) and 58% (in the
psilocybin first group) for anxiolytic response using the HAD A,
compared to 14% in the niacin first group. At the 6.5-month fol-
low-up (after both groups received psilocybin), anti-depressant or
anxiolytic response rates were approximately 60–80% (Figure 5).
Secondary outcomes
Figure 6 (bottom) shows the comparisons between dose-sequence
groups on the following secondary outcome measures: cancer-
related existential distress (demoralization, hopelessness, atti-
tudes and affect associated with disease progression and death),
quality of life, and spirituality. In the short-term (2 weeks post-
dose 1), psilocybin (compared to control) produced decreases in
cancer-related demoralization and hopelessness, while improv-
ing spiritual wellbeing and quality of life (physical, psychologi-
cal, environmental domains). These effects were sustained at the
final 6.5 month follow-up. Regarding anxiety and attitudes
towards death, the data were mixed. In the short-term (2 weeks
post-dose 1), psilocybin was not significantly associated with
decreased death anxiety or increased death transcendence.
However, at the 26-week post-dose 2 final follow-up assessment,
while death anxiety (as measured by the DAS) continued to
demonstrate no significant reductions, there was a significant
improvement in attitudes and adaptations towards death (as
measured by the DTS) in the psilocybin first group compared to
the niacin first group (assessed at 2 weeks post-dose 1).
Supplementary Table 2 shows participant ratings of persisting
effects attributed to the session experiences. As shown, prior to
the crossover, psilocybin produced significantly greater ratings
(compared to the niacin first group assessed at 2 weeks post-dose
1) of positive persisting effects on: attitudes about life and self,
mood changes, social effects (e.g. increased altruism), behavior,
and spirituality. After the crossover, these effects were sustained at
the final 6.5-month follow-up. When all participants were asked
(26 weeks post-session 2) to reflect on what they thought was
their psilocybin session, 52% and 70% rated the psilocybin expe-
rience as the singular or top 5 most spiritually significant, or the
singular or top 5 most personally meaningful experience of their
entire lives, respectively; while 87% reported increased life satis-
faction or wellbeing attributed to the experience (Figure 6 (top)).
Mystical experience subjective effects and
relationship of mystical experience to clinical
outcomes
Compared to the control, psilocybin produced mystical-type
experiences, consistent with prior trials of psilocybin administra-
tion in normal volunteers (Griffiths et al., 2006, 2008, 2011) and
patients with terminal cancer (Grob et al., 2011) (Figure 7 (top)).
Total mystical experience scores (MEQ 30) at the end of dose 1
(e.g. 7 hours post-drug administration) correlated with change
scores (baseline to 6 weeks after dose 1) on four out of six pri-
mary outcome measures: HADS T (Spearman r=0.39; P=0.04);
HADS A (Spearman r=0.36; P=0.07); HADS D (Spearman
r=0.30; P=0.11); BDI (r=0.49; P=0.01); STAI S (r=0.42;
P=0.03); STAI T (r=0.39; P=0.04).
Partial correlations to control for participant-rated intensity of
drug effect (item 98 from the HRS) continued to demonstrate
significant effects of total mystical experience scores (MEQ
total) on the change scores (baseline to 6 weeks after dose 1) of
the primary outcome measures in five of six measures assessed:
HADS T (Spearman r=0.49; P=0.009); HADS A (Spearman
r=0.46; P=0.01); HADS D (Spearman r=0.35; P=0.07); BDI
(r=0.48; P=0.01); STAI S (r=0.42; P=0.03); STAI T (r=0.40;
P=0.04).
MEQ total scores mediated (indirect effects) a significant por-
tion of the effect of psilocybin versus niacin treatment on four out
of six primary outcome measures with point estimates (ab) and
bias corrected 95% CIs as follows: (HADS T (ab=0.46, SE=0.24,
95% CI 0.01–0.97), HADS D (ab=0.43, SE=0.32, 95% CI 0.01–
1.23), BDI (ab=0.79, SE=0.26, 95% CI 0.23–1.29), and STAI S
(ab=0.65, SE=0.25, 95% CI 0.13–1.16)] (Figure 7 (bottom)).
Thus, the amount by which HADS T, HADS D, BDI, and
STAI S can be expected to increase through MEQ total as a
result of psilocybin versus niacin treatment is 0.46, 0.43, 0.79
and 0.65, respectively.
For other analyses of secondary outcome measures, see
Supplementary Results.
Discussion
Primary outcomes
Single moderate-dose psilocybin, in conjunction with psycho-
therapy, produced rapid, robust, and sustained clinical benefits in
terms of reduction of anxiety and depression in patients with life-
threatening cancer. This pharmacological finding is novel in psy-
chiatry in terms of a single dose of a medication leading to
immediate anti-depressant and anxiolytic effects with enduring
(e.g. weeks to months) clinical benefits. Even though it is not
possible to attribute causality of the experimental drug (in terms
of sustained clinical benefit) after the crossover, the post-crosso-
ver data analyses of the two dosing sequences suggest that the
clinical benefits, in terms of reduction of cancer-related anxiety
and depression, of single-dose psilocybin (in conjunction with
psychotherapy) may be sustained for longer than 7 weeks post-
dosing, and that they may endure for as long as 8 months post-
psilocybin dosing. The acute and sustained anti-depressant
effects of psilocybin in this trial are consistent with a recently
published open-label study of oral psilocybin treatment in
patients with treatment-resistant depression (TRD) in which psil-
ocybin (25 mg) was associated with 1 week and 3 months post-
psilocybin anti-depressant effects (Carhart-Harris et al., 2016).
The within-group analyses for the primary outcome measures
demonstrate that immediately after receiving psilocybin there is
a marked reduction in anxiety and depression scores for both the
psilocybin first and niacin first groups. Also, the magnitude of
psilocybin-induced change across each participant’s active
12 Journal of Psychopharmacology
psilocybin treatment session did not differ across treatment group
for any of the primary outcome measures. Together, this suggests
that the pharmacological/psilocybin intervention produced rapid
anti-depressant and anxiolytic clinical benefits. Both groups
demonstrated significant clinical improvements in anxiety/
depression from baseline relative to the final assessment. It is
unclear from the data whether the sustained benefits in clinical
outcomes were due to psilocybin alone or some interactive effect
of psilocybin plus the targeted psychotherapy. Future research
would be necessary to separate out the various therapeutic contri-
butions of psilocybin versus psychotherapy.
Psilocybin was associated with substantial anti-depressant
response rates (as high as approximately 80% at 6.5 months fol-
low-up). There have been several meta-analyses of placebo con-
trolled trials exploring the efficacy of anti-depressants in the
treatment of cancer-related depression and they have generally
failed to show a clear effect of anti-depressant treatment over
placebo (Iovieno et al., 2011; Laoutidis and Mathiak, 2013;
Ostuzzi et al., 2015). In a meta-analyses of anti-depressants for
major depressive disorder in patients with comorbid medical dis-
orders (including cancer), anti-depressants were more effective
than placebo in some medical conditions (e.g. HIV/AIDS, post-
stroke) but not in cancer patients, where the anti-depressants per-
formed about as well as the approximately 40% placebo response
rate (Iovieno et al., 2011).
Secondary outcomes
Psilocybin decreased cancer-related demoralization (e.g. loss of
meaning/hope/purpose, desire for hastened death) and hopeless-
ness, while improving spiritual wellbeing, general life satisfac-
tion, and quality of life. While a minority of patients with
advanced or terminal cancer experience clinically relevant exis-
tential/spiritual distress, when it occurs its effects are highly con-
sequential (e.g. decreased quality of life, increased depressive
and anxiety symptoms, increased desire for hastened death,
increased suicidal ideation and behaviors) (Puchalski, 2012) and
improving spiritual wellbeing (e.g. through a pharmacological-
psychosocial intervention) could serve as a buffer against these
negative clinical outcomes.
Although affect/anxiety towards death did not improve in the
short-term or longer-term follow-up period, psilocybin was asso-
ciated with improved attitudes and adaptations to death at the
6.5-month follow-up. More research into this important thera-
peutic area is warranted.
Psilocybin experiences were reported as highly meaningful
and spiritual, and associated with positive cognitive, affective,
spiritual, and behavioral effects lasting weeks to months. This
finding is consistent with prior research administering psilocybin
to normal volunteers (Doblin, 1991; Griffiths et al., 2006, 2008,
2011; Pahnke, 1963).
Safety/adverse events
There were no serious AEs, either medical or psychiatric, in the
trial that were attributed to psilocybin. Since the early 1990s,
approximately 2000 doses of psilocybin (ranging from low to
high doses) have been safely administered to humans in the
United States and Europe, in carefully controlled scientific
settings, with no reports of any medical or psychiatric serious
AEs, including no reported cases of prolonged psychosis or HPPD
(Studerus et al., 2011). This finding is consistent with a US popu-
lation (2001–2004 data from the National Survey on Drug Use
and Health) based study that found no associations between life-
time use of any of the serotoninergic psychedelics (including
psilocybin) and increased rates of mental illness (Krebs and
Johansen, 2013). It is important to monitor closely for the emer-
gence of transient difficult psychological states (e.g. anxiety, para-
noia) in these trials and to manage them. Difficult experiences are
not necessarily pathological and can be understood as part of the
therapeutic process (e.g. working through cancer-related psycho-
logical or existential distress through challenging encounters or
emotionally charged confrontations with cancer-related fearful
imagery or symbolism) (Carbonaro et al., 2016).
Limitations/generalizability
This trial was limited by a relatively small sample size, a non-
nationally representative cancer patient population (e.g. 62%
women, 90% Caucasian), which decreases generalizability, a
crossover design that limited the interpretation of clinical bene-
fits after the crossover, and the use of a control with limited
blinding.
Potential anxiolytic and anti-depressant
mechanisms of psilocybin
Neurobiological mechanisms. There is evidence from animal
research that serotoninergic psychedelics exert anxiolytic-like
effects (Nichols, 2015). Several trials using animal models of
anxiety demonstrated acute anxiolytic effects of the serotoniner-
gic psychedelic 2,5-Dimethoxy-4-iodoamphetamine (DOI), a
non-selective 5-HT2a/2c agonist (Nic Dhonnchadha et al., 2003;
Ripoll et al., 2005, 2006). In two rodent studies, one with 5HT2A
knockout mice (Weisstaub et al., 2006) and the other in rats with
anti-sense-mediated 5HT2A downregulation (Cohen, 2005), the
rodents displayed decreased anxiety-like behavior and in the trial
with the 5HT2A knockout mice (Weisstaub et al., 2006), restora-
tion of 5HT2A receptors in the pre-frontal cortex (PFC) re-estab-
lished anxiety-like behaviors. Furthermore, in humans,
fronto-limbic 5HT2A density has been correlated with anxiety
symptoms (Frokjaer et al., 2008). Together, these data suggest
that 5HT2A downregulation may explain some of the rapid and
sustained anxiolytic effects of psilocybin (Vollenweider and
Kometer, 2010).
There is growing evidence that the serotoninergic psyche-
delics produce rapid and sustained anti-depressant effects
(Nichols, 2015). In two recently published open-label trials, one
using a single dose of ayahuasca (Osorio et al., 2015) and the
other using two doses of oral psilocybin (Carhart-Harris et al.,
2016), acute and enduring anti-depressant effects were reported.
In addition to these two open-label trials, there are several lines
of evidence supporting using 5HT2A agonists to treat depression.
In considering changes at the 5HT2A receptor as a potential
mechanism of action: cortical 5HT2A receptor expression is
increased in postmortem samples of patients with depression
who display suicidality (Mendelson, 2000; Pandey et al., 2002;
Shelton et al., 2009); depressed patients with elevated pessimism
Ross et al. 13
display increased PFC 5HT2A receptor binding compared to
control participants (Bhagwagar et al., 2006; Meyer, 2012; Meyer
et al., 2003); and sustained treatment with various anti-depres-
sants (e.g. selective serotonin reuptake inhibitors, tricyclic anti-
depressants) have been associated with a reduction of 5HT2A
receptor density (Gomez-Gil et al., 2004; Yamauchi et al., 2006).
The glutamate system may explain some of the anti-depres-
sant effects of psilocybin. In rodents, serotoninergic psychedelics
enhance cortical glutamatergic transmission, especially in the
medial PFC, and increase activation of cortical α-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors
(Aghajanian and Marek, 1997). In a trial in which rats received
DOI, there was a significant increase in expression of brain-
derived neurotrophic factor (BDNF) mRNA in neocortical areas
(Vaidya et al., 1997). Increased AMPA activation and BDNF
expression as biomarkers of anti-depressant effects are supported
by: cortical AMPA activation is known to stimulate the expres-
sion of cortical BDNF (associated with neuronal growth, differ-
entiation and synaptogenesis) (Hsu et al., 2015); decreased
cortical BDNF is associated with major depression in humans
(Duman, 2004); and cortical BDNF normalizes with anti-depres-
sant treatment (Sen et al., 2008; Shimizu et al., 2003). Similarly,
ketamine (the only other known acute and short-term sustained
anti-depressant) is theorized to exert its anti-depressant effects
via cortical AMPA activation (Zanos et al., 2016) and BDNF
expression (Lepack et al., 2014). However, the anti-depressant
effects of single-dose ketamine in patients with TRD typically
last no more than several days up to 1–2 weeks, not several weeks
to months (DeWilde et al., 2015).
Neuroimaging research with psilocybin is beginning to sug-
gest potential anti-depressant mechanisms of action at the level
of brain structure activity and network connectivity. Task-free
functional magnetic resonance imaging research in normal vol-
unteers under the influence of psilocybin has demonstrated
decreased activity in the medial PFC and decreased connectivity
within the default mode network (DMN) (Carhart-Harris et al.,
2012, 2014). The former is significant because depressive symp-
toms have been associated with increased activity in the medial
PFC (Drevets et al., 2008; Farb et al., 2011) and normalization of
medial PFC activity has been demonstrated with anti-depressant
treatment (Deakin et al., 2008; Holtzheimer and Mayberg, 2011;
Kennedy et al., 2007); and the latter because patients with major
depression (compared to controls) have demonstrated increased
DMN connectivity (Berman et al., 2011, Grecius et al., 2007).
Psycho-spiritual mechanisms. Moderate-dose psilocybin occa-
sioned mystical-type experiences in the cohort of cancer patients
studied, and the intensity of the subjective mystical experience sig-
nificantly mediated (e.g. suggestive of causality) clinical benefit
(e.g. reduction in anxiety and depression symptoms) in the medium
term (e.g. 6 weeks post-dose 1). This result matches with descrip-
tive historical data from open-label LSD-assisted psychotherapy
trials for psycho-spiritual distress associated with terminal cancer,
in which the mystical experience was reported as being an integral
part of the therapeutic effect (Grof and Halifax, 1977). It is further
corroborated by recent open-label trials using psilocybin-assisted
psychotherapy to treat tobacco addiction (Garcia-Romeu et al.,
2014; Johnson et al., 2014) and alcoholism (Bogenschutz et al.,
2015) showing significant correlations between the mystical expe-
rience and improved clinical outcomes.
This finding suggests a potential psycho-spiritual mechanism
of action: the mystical state of consciousness. The mystical expe-
rience is likely to be one of several mediators that transmit the
effect of psilocybin to changes in anxiety and/or depression.
Further enquiry into how particular dimensions of the mystical
experience relate to reductions in anxiety and/or depression in
this population and others, and what factors best predict or pro-
mote mystical experiences, is warranted.
Conclusions
In conclusion, single moderate-dose psilocybin (in conjunction
with psychotherapy) was safely administered to a cohort of
patients with cancer-related psychological distress (e.g. anxi-
ety, depression). It produced rapid and sustained anxiolytic and
anti-depressant effects (for at least 7 weeks but potentially as
long as 8 months), decreased cancer-related existential dis-
tress, increased spiritual wellbeing and quality of life, and was
associated with improved attitudes towards death. The psilocy-
bin-induced mystical experience mediated the anxiolytic and
anti-depressant effects of psilocybin. Psilocybin, administered
in conjunction with appropriate psychotherapy, could become
a novel pharmacological-psychosocial treatment modality for
cancer-related psychological and existential distress. Further
empirical research is needed definitively to establish its safety
and efficacy.
Acknowledgements
The authors would like to thank Organix Inc. for synthesizing the psil-
ocybin and Leonard Liebes for overseeing the compounding process
for the trial. They wish to thank the Bluestone Center for Clinical
Research (BCCR) at the NYU College of Dentistry (COD), along with
Brian Schmidt (director of BCCR), Patricia Corby and Charles
Bertolami (dean of the NYU College of Dentistry) for the gracious use
of research space at BCCR to conduct the study and for scientific col-
laboration. The authors also thank John Rotrosen (NYU School of
Medicine) for serving as chair of the Data Safety Monitoring Board
(DSMB) and for review of the manuscript, as well as Michael
Bogenschutz (NYU School of Medicine), Charles Grob (UCLA School
of Medicine), Charles Raison (University of Wisconsin School of
Medicine), George Greer (Heffter Research Institute), and David
Nichols (Heffter Research Institute) for reviews of the manuscript.
They thank Mary Lynn Nierodzik (NYU School of Medicine) for pro-
viding expertise in determining eligibility criteria from an oncological
perspective. The study was conducted in compliance with United
States laws. Stephen Ross was previously on the board of directors of
the Heffter Research Institute. The authors also thank all of the study
therapists: Drew Bianchi, Anthony Bossis, Todd Bresnick, Seema
Desai, Julie Feuer, Bonnie Glass, Jeffrey Guss, Stephanie Hope,
Krystallia Kalliontzi, Katy Maddox, Casey Paleos, Stephen Ross, Lisa
Sevanick, Michelle Shaw, and Erin Zerbo. Special thanks to Magda
Salvesen and the estate of Jon Schueler for the loan of original artwork
for the study session room. Stephen Ross affirms that he had full
access to all of the data in the study and he takes responsibility for the
integrity of the data and the accuracy of the data analysis. Jim Babb
and Barry Cohen (both members of the statistical team) were responsi-
ble for analyzing the data. Eva Petkova (associate professor, New York
University School of Medicine, Department of Child and Adolescent
Psychiatry, New York, NY) and Zhe Su assisted with creating the
graphics for many of the figures. Note that none of the above-
mentioned individuals (except for the study therapists) were compen-
sated financially for their contributions.
14 Journal of Psychopharmacology
Author comment on supplementary materials
The authors affirm that the research materials relating to this paper can be
accessed.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the
research, authorship, and/or publication of this article.
Funding
The authors disclosed receipt of the following financial support for the
research, authorship, and/or publication of this article: This research was
supported by grants from the Heffter Research Institute, the RiverStyx
Foundation, and the New York University-Health and Hospitals
Corporation (NYU-HHC) Clinical and Translational Science Institute
(CTSI) (NYU CTSA grant UL1 TR000038 from the National Center for
Advancing Translational Sciences, National Institutes of Health).
Funding for the trial was also provided by Carey and Claudia Turnbull,
William Linton, Robert Barnhart, Arthur Altschul, Kelly Fitzsimmons,
George Goldsmith, and Ekaterina Malievskaia.
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Supplementary resource (1)

... A decades-long hiatus on clinical trial research with psychedelic ended in 2006 (Moreno et al., 2006). Since then, supportive evidence for psychedelicassisted therapy has begun to accrue promising results, particularly in the treatment of depressive and anxiety symptoms and disorders (Barbosa et al., 2016;Carhart-Harris et al., 2017Davis et al., 2021a;Gasser et al., 2014;Griffiths et al., 2016;Grob et al., 2011;Moreno et al., 2006;Osório et al., 2015;Palhano-Fontes et al., 2019;Ross et al., 2016;Sanches et al., 2016). Notably, improvements in symptom severity have been observed several months after just one or two isolated doses of the drug Davis et al., 2021a;Gasser et al., 2014;Griffiths et al., 2016;Grob et al., 2011). ...
... An important principle of a context-dependent or relational approach to psychedelics is that the psychedelic experience itself is an important mediator of subsequent therapeutic outcomesand there is much evidence to support this (Carbonaro et al., 2016;Carhart-Harris et al., 2016b;Davis et al., 2019Davis et al., , 2020Davis et al., , 2021bGarcia-Romeu et al., 2015;Gasser et al., 2015;Griffiths et al., 2016Griffiths et al., , 2018MacLean et al., 2011;Passie, 1997;Roseman et al., 2018;Ross et al., 2016;Schmid and Liechti, 2017). Specifically, a number of studies have found that 'peak' or 'mystical' -type experiences, which feature feelings of unity, transcendence of time, space and self, and positive mood, are predictive of subsequent positive therapeutic outcomes (Bogenschutz et al., 2015;Davis et al., 2019;Garcia-Romeu et al., 2015;Griffiths et al., 2016;Murphy et al., 2022;Pahnke, 1963;Roseman et al., 2018;Ross et al., 2016). ...
... An important principle of a context-dependent or relational approach to psychedelics is that the psychedelic experience itself is an important mediator of subsequent therapeutic outcomesand there is much evidence to support this (Carbonaro et al., 2016;Carhart-Harris et al., 2016b;Davis et al., 2019Davis et al., , 2020Davis et al., , 2021bGarcia-Romeu et al., 2015;Gasser et al., 2015;Griffiths et al., 2016Griffiths et al., , 2018MacLean et al., 2011;Passie, 1997;Roseman et al., 2018;Ross et al., 2016;Schmid and Liechti, 2017). Specifically, a number of studies have found that 'peak' or 'mystical' -type experiences, which feature feelings of unity, transcendence of time, space and self, and positive mood, are predictive of subsequent positive therapeutic outcomes (Bogenschutz et al., 2015;Davis et al., 2019;Garcia-Romeu et al., 2015;Griffiths et al., 2016;Murphy et al., 2022;Pahnke, 1963;Roseman et al., 2018;Ross et al., 2016). Another salient dimension of the psychedelic experiences is the challenging experience (CE), which includes feelings of paranoia, anxiety, insanity and grief . ...
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Background Over the last two decades, a number of studies have highlighted the potential of psychedelic therapy. However, questions remain to what extend these results translate to naturalistic samples, and how contextual factors and the acute psychedelic experience relate to improvements in affective symptoms following psychedelic experiences outside labs/clinics. The present study sought to address this knowledge gap. Aim Here, we aimed to investigate changes in anxiety and depression scores before versus after psychedelic experiences in naturalistic contexts, and how various pharmacological, extrapharmacological and experience factors related to outcomes. Method Individuals who planned to undergo a psychedelic experience were enrolled in this online survey study. Depressive symptoms were assessed at baseline and 2 and 4 weeks post-psychedelic experience, with self-rated Quick Inventory of Depressive Symptomatology (QIDS-SR-16) as the primary outcome. To facilitate clinical translation, only participants with depressive symptoms at baseline were included. Sample sizes for the four time points were N = 302, N = 182, N = 155 and N = 109, respectively. Results Relative to baseline, reductions in depressive symptoms were observed at 2 and 4 weeks. A medicinal motive, previous psychedelic use, drug dose and the type of acute psychedelic experience (i.e. specifically, having an emotional breakthrough) were all significantly associated with changes in self-rated QIDS-SR-16. Conclusion These results lend support to therapeutic potential of psychedelics and highlight the influence of pharmacological and non-pharmacological factors in determining response. Mindful of a potential sample and attrition bias, further controlled and observational longitudinal studies are needed to test the replicability of these findings.
... The trials that have been performed with psilocybin are generally of a lower quality. We find two double blind, placebo-controlled studies (Grob et al., 2011;Ross et al., 2016), one waiting list controlled trial (Davis et al., 2021), and one double-blind, active-placebo study (Griffiths et al., 2016). The other studies are all open-label without a control group (Bogenschutz et al., 2015;Carhart-Harris et al., 2016;Johnson, Garcia-Romeu, Cosimano, & Griffiths, 2014;Moreno, Wiegand, Taitano, & Delgado, 2006). ...
... For instance, in the studies of Grob et al. (2011) and Oehen et al. (2013) only around 25% of the sample consisted of psychedelic-naïve subjects. Similarly, in the studies of Griffiths et al. (2016) and Ross et al. (2016), 50% of the sample had previous experience with psychedelic drugs. In the study of Mithoefer et al. (2011) this information is not provided. ...
... In fact, one recently published meta-analysis stated that all published psilocybin studies had a high risk of bias regarding participants and personnel blinding (Goldberg, Pace, Nicholas, Raison, & Hutson, 2020). Some studies (Oehen et al., 2013;Ot'alora et al., 2018;Mithoefer et al., 2018;Grob et al., 2011;Ross et al., 2016) have used active placebos (mainly lower doses of the drug of interest or niacin) in order to try to mask the effects of regular doses of hallucinogens, but this strategy might be detrimental, as those active placebos act like a stimulant, triggering feelings of anxiety (Hendy, 2018). Active placebos should not cause anxiety when studying the potential therapeutic effects of psychedelics on mood, since the comparison might favor the experimental drug. ...
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While the field of psychedelic research is continuously expanding and offers new hope for achieving successful treatments for physical and mental disorders, certain methodological aspects require improvement. Some of the flaws are shared with clinical trials for other kinds of drugs and others are specific to the field. Given that psychedelic research is an emerging field, it is important to address these problems in a timely manner. In this manuscript, we present the main methodological issues in psychedelic research, ranging from the most manageable (e.g., non-representative samples) to the most complex (e.g., limitations of the biomedical model). In addition, given its relevance, we dedicate a section of the manuscript to a discussion of ethical concerns around psychedelic research.
... Both neurobiological and psychological mechanisms related to psychedelics have been identified. These include emotional breakthrough (10), increased psychological flexibility (11), and mystical experience (12) to include oceanic boundlessness [OBN], universal interconnectedness, ego dissolution, and transcendence of time and space (13). OBN can be defined as the boundlessness of self and/or feeling of being one with the universe; the 4 sub-factors of OBN in ASC questionnaires are insightfulness, blissful state, experience of unity, and spiritual experience (14). ...
... A consort flow chart was developed to depict details of the study selection process, according to the PRISMA guidelines (42) [see Figure 1]. A total of twelve studies were selected based on the inclusion criteria, 6 of which were randomized (12,23,24,(45)(46)(47) and the other 6 open-label (14,16,34,(48)(49)(50). Of these studies, five investigated substance use disorder, of which two studies explored Alcohol Use Disorder [AUD] (23, 49), two examined tobacco smokers and were based on the same population dataset (51) but with different follow-up periods (34,50) and, one inspected cocaine dependency (24). ...
... Of these studies, five investigated substance use disorder, of which two studies explored Alcohol Use Disorder [AUD] (23, 49), two examined tobacco smokers and were based on the same population dataset (51) but with different follow-up periods (34,50) and, one inspected cocaine dependency (24). Three studies focused on cancer-related adjustment disorders (12,45,46). In these studies, three types of drugs were used: psilocybin, ketamine, and ayahuasca, with the former being the most common. ...
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The mystical experience is a potential psychological mechanism to influence outcome in psychedelic therapy. It includes features such as oceanic boundlessness, ego dissolution, and universal interconnectedness, which have been closely linked to both symptom reduction and improved quality of life. In this review, 12 studies of psychedelic therapy utilizing psilocybin, ayahuasca, or ketamine were analyzed for association between mystical experience and symptom reduction, in areas as diverse as cancer-related distress, substance use disorder, and depressive disorders to include treatment-resistant. Ten of the twelve established a significant association of correlation, mediation, and/or prediction. A majority of the studies are limited, however, by their small sample size and lack of diversity (gender, ethnic, racial, educational, and socioeconomic), common in this newly re-emerging field. Further, 6 out of 12 studies were open-label in design and therefore susceptible to bias. Future studies of this nature should consider a larger sample size with greater diversity and thus representation by use of randomized design. More in-depth exploration into the nature of mystical experience is needed, including predictors of intensity, in order to maximize its positive effects on treatment outcome benefits and minimize concomitant anxiety. Systematic Review Registration: PROSPERO, identifier CRD42021261752.
... Dozens of clinical trials demonstrate promise for psychedelic-assisted therapy as an intervention for psychological and behavioral challenges that require significant cognitive and motivational shifts to produce change. For instance, prior research finds potential benefits for psychedelic-assisted therapy for promoting smoking cessation (Johnson et al., 2017;Noorani et al., 2018), alcohol cessation (Bogenshutz et al., 2015Garcia-Romeu et al., 2019;Krebs & Johansen, 2012;Nielson et al., 2018), as well as alleviating depression and anxiety (Davis et al., 2020a(Davis et al., , 2020bGriffiths et al., 2016;Ross et al., 2016), obsessive compulsive disorder (Moreno et al., 2006), end of life distress (Griffiths et al., 2016), and post-traumatic stress disorder (Krediet et al., 2020). The mechanism behind these benefits for dramatic behavioral change lies in evidence suggesting that psychedelicassisted therapy can engender profound experiences which facilitate long-lasting positive changes in attitudes, mood, altruism, behavior, psychological functioning, life satisfaction, and key personality domains such as openness (Griffiths et al., 2008MacLean et al., 2011). ...
Article
Full-text available
Before conducting research in an Indigenous community, a researcher, especially a non-Indigenous researcher, must recognize and acknowledge not only the historical impact research has had on Indigenous communities but the current impacts that arise when research is conducted in Indigenous communities. Specifically, one must consider settler colonialism and its continuing impact on Indigenous communities today. Professor of Indigenous Education Linda Tuhiwai Smith (2012) states: “The word itself, ‘research’, is probably one of the dirtiest words in the Indigenous world’s vocabulary”. Smith continues by linking research and Western imperialism and colonialism together, with research being a tool for imperialism and colonialism. Therefore, it is critical to identify how research and its processes have been used to justify the dehumanization of Indigenous people in order to gain and maintain power over Indigenous communities. Researchers must ensure that their research does not perpetuate unequal power dynamics and is based on a collective process. Suggestions for best practices for working with Indigenous people/communities are presented below.
... This is already happening. Clinical trials on the potential therapeutic effects of psychedelics for substance use and mood disorders are well under way (Bogenschutz et al., 2015;Davis et al., 2021;Grob et al., 2011;Ross et al., 2016). Wildman and Stockly dig into this research in chapter 7, but I mention it here because many of these studies use phenomenological scales to track the qualities of participants' experience while or directly after it occurs (e.g., Barrett et al., 2015). ...
Article
Background Classic psychedelic-induced ego dissolution involves a shift in the sense of self and blurring of boundary between the self and the world. A similar phenomenon is identified in psychopathology and is associated to the balance of anticorrelated activity between the default mode network (DMN) – which directs attention inwards – and the salience network (SN) – which recruits the dorsal attention network (DAN) to direct attention outward. Methods To test whether change in anticorrelated networks underlie the peak effects of LSD, we applied dynamic causal modeling to infer effective connectivity of resting state functional MRI scans from a study of 25 healthy adults who were administered 100μg of LSD, or placebo. Results We found that inhibitory effective connectivity from the SN to DMN became excitatory, and inhibitory effective connectivity from DMN to DAN decreased under the peak effect of LSD. Conclusions The effective connectivity changes we identify may reflect diminution of the functional anticorrelation between resting state networks that may be a key neural mechanism of LSD and underlie ego dissolution. Our findings suggest changes to sense of self and subject-object boundaries across different states of consciousness may depend upon the organised balance of effective connectivity of resting state networks.
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Serotonin (5-hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR) signaling is essential for the actions of classical psychedelic drugs. In this study, we examined whether sequence variations in the 5-HT2AR gene affect the signaling of four commonly used psychedelic drugs. We examined the in vitro pharmacology of seven non-synonymous single-nucleotide polymorphisms (SNPs), which give rise to Ser12Asn, Thr25Asn, Asp48Asn, Ile197Val4.47, Ala230Thr, Ala447Val, and His452Tyr variant 5-HT2A serotonin receptors. We found that these non-synonymous SNPs exert statistically significant, although modest, effects on the efficacy and potency of four therapeutically relevant psychedelics. Significantly, the in vitro pharmacological effects of the SNP drug actions at 5-HT2AR are drug specific.
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