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

 Journal of Psychopharmacology  2016, Vol. 30(12) 1165
–1180
©
The Author(s) 2016
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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
Abstract
Background:
Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatrical 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
675512
JOP
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10.1177/0269881116675512Journal of Psychopharmacology
Ross et al.
research-article
2016
Original Paper
1166
Journal of Psychopharmacology
30(12)
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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