Journal of Psychoactive Drugs

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Psilocybin-Assisted Therapy: A Review of a Novel

Treatment for Psychiatric Disorders

Kelan Thomas Pharm.D., M.S., Benjamin Malcolm Pharm.D., M.P.H. & Dan
Lastra B.S.

To cite this article: Kelan Thomas Pharm.D., M.S., Benjamin Malcolm Pharm.D., M.P.H. & Dan
Lastra B.S. (2017): Psilocybin-Assisted Therapy: A Review of a Novel Treatment for Psychiatric
Disorders, Journal of Psychoactive Drugs

To link to this article: http://dx.doi.org/10.1080/02791072.2017.1320734

Published online: 08 May 2017.

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JOURNAL OF PSYCHOACTIVE DRUGS
http://dx.doi.org/10.1080/02791072.2017.1320734

Psilocybin-Assisted Therapy: A Review of a Novel Treatment for Psychiatric

Disorders
a
Kelan Thomas, Pharm.D., M.S. , Benjamin Malcolm, Pharm.D., M.P.H.b, and Dan Lastra, B.S.c
a
Assistant Professor, Clinical Sciences, Touro University California, Vallejo, CA, USA; bAssistant Professor, Pharmacy Practice and
Administration, Western University of Health Sciences, Pomona, CA, USA; cPharmacy Student, Touro University California, Vallejo, CA, USA

Abstract ARTICLE HISTORY

Recent research suggests that functional connectivity changes may be involved in the pathophy- Received 9 January 2017
siology of psychiatric disorders. Hyperconnectivity in the default mode network has been asso- Revised 13 March 2017
ciated with psychopathology, but psychedelic serotonin agonists like psilocybin may profoundly Accepted 20 March 2017
disrupt these dysfunctional neural network circuits and provide a novel treatment for psychiatric Keywords
disorders. We have reviewed the current literature to investigate the efficacy and safety of Anxiety; depression;
psilocybin-assisted therapy for the treatment of psychiatric disorders. There were seven clinical psilocybin; psychedelic;
trials that investigated psilocybin-assisted therapy as a treatment for psychiatric disorders related substance use
to anxiety, depression, and substance use. All trials demonstrated reductions in psychiatric rating
scale scores or increased response and remission rates. There were large effect sizes related to
improved depression and anxiety symptoms. Psilocybin may also potentially reduce alcohol or
tobacco use and increase abstinence rates in addiction, but the benefits of these two trials were
less clear due to open-label study designs without statistical analysis. Psilocybin-assisted therapy
efficacy and safety appear promising, but more robust clinical trials will be required to support
FDA approval and identify the potential role in clinical psychiatry.

It has been suggested that the psychedelic compound RDoC framework consists of a matrix specifying func-
lysergic diethylamide (LSD) may have been one catalyst tional constructs characterized in aggregate by the genes,
for ushering in the modern era of molecular psychiatry molecules, and circuits used to measure human behavior
during the early 1950s since, roughly a decade after Albert (Cuthbert 2015). In one line of research inquiry consistent
Hoffman discovered LSD, other researchers first recog- with the RDoC framework, Menon (2011) has formulated
nized the chemically similar endogenous neurotransmit- a unifying triple network model of psychopathology and
ter serotonin (Nichols 2004). Interest in these psychedelic suggested that depression may be characterized by
compounds has been recently renewed for investigating enhanced functional connectivity with other nodes of
the therapeutic potential of serotonin (5-HT) agonists, the default mode network (DMN) for pregenual and
like psilocybin, and also learning more about brain activ- subgenual-cingulate cortex (SCC), along with adjoining
ity with these compounds (Nichols 2016). ventromedial prefrontal cortex (vmPFC). The DMN con-
Advances in neuroimaging technology have enabled a nectivity in one neuroimaging study was defined by pos-
more robust investigation of the human brain than was terior-cingulate cortex (PCC) connectivity, which was
possible in the 1950s, when the first edition of the stronger for SCC in major depressive disorder (MDD)
Diagnostic and Statistical Manual of Mental Disorders patients than healthy controls (p < 0.05) (Berman et al.
(DSM) was published and the earliest psychiatric medica- 2010). The subjective scores on the Rumination Response
tions received FDA approval. These advances in technol- Styles (RRS) inventory were also positively correlated with
ogy have prompted the National Institute of Mental SCC-PCC connectivity (r = 0.68, p < 0.001) and research-
Health (NIMH) to propose the Research Domain ers concluded that DMN hyperconnectivity could poten-
Criteria (RDoC) project research initiative in 2009, tially explain the excessive ruminating thoughts of
which provided a framework for new ways of studying depressed patients (Berman et al. 2010). Interestingly,
mental disorders that may eventually inform a more SCC functional connectivity in the DMN has also been
objective diagnostic paradigm than the current nosology positively correlated with duration of the current depres-
of symptom clusters from the DSM (Cuthbert 2015). This sive episode (r = 0.49, p = 0.014) (Greicius et al. 2007).

CONTACT Kelan Thomas [email protected] Clinical Sciences, Touro University California, 1310 Club Dr., Administration & Faculty 2, Vallejo, CA
94592, USA.
© 2017 Taylor & Francis Group, LLC
2 K. THOMAS ET AL.

This emerging evidence may necessitate a paradigm of the inactive metabolite 4-hydroxy-indole-3-acetic acid
shift in how we understand psychiatric disorders and may (4HIAA) (Hasler et al. 1997). It remains unknown if any
offer new explanations for why such disparate treatment specific cytochrome P450 enzymes catalyze the formation
modalities like electroconvulsive therapy (ECT), transcra- of psilocybin metabolites, since human studies of phar-
nial magnetic stimulation (TMS), ketamine infusion, and macokinetic parameters are limited (Yu 2008). Psilocin
psilocybin-assisted therapy all rapidly reduce depression was also found to be glucuronidated by UDP-glucurono-
symptoms. More recently, there have been a series of syltransferases (UGTs) into psilocin glucuronide, with the
neuroimaging studies specifically investigating the effects greatest activity from UGT1A10 in the small intestine and
of psilocybin on functional connectivity networks in the then UGT1A9 in the liver (Manevski et al. 2010). Psilocin
brain (Carhart-Harris et al. 2012; Muthukumaraswamy was shown to be renally excreted, partially in the form of
et al. 2013; Roseman et al. 2014). A recent review evaluat- psilocin glucuronide, and the lower limit of quantitation
ing these psychedelic neuroimaging studies speculated on for psilocin in urine samples (10 μg/L) was usually
psilocybin’s possible mechanism of action for treating reached 24 hours after ingestion (Hasler et al. 2002).
psychiatric disorders: “following psychedelic-induced dis- Psilocybin administered intravenously (IV) demon-
integration within local networks, as well as increased strated a psilocin mean terminal elimination half-life
global interconnectivity, connections responsible for psy- (t1/2β) of 74 minutes, but psilocin’s half-life was
chiatric-disorder-associated hub failures are disrupted 163 minutes when psilocybin was given by mouth
and broken by the emergence of strong, topologically (PO), which suggests that there may be a dose-depen-
long-range functional connections. Then, as the effect of dent effect on metabolism (Hasler et al. 1997). Another
the drug wears off, networks can reconnect in ‘healthy’ study measuring PO psilocybin pharmacokinetic para-
ways, in the absence of the pathological driving forces(s) meters demonstrated a similar psilocin half-life (t1/2) of
that originally led to a hub failure and disease” (Nichols, 135 minutes, elimination constant (ke) of 0.307/h, and
Johnson, and Nichols 2017). The purpose of this article is absorption constant (ka) of 1.307/h (Lindenblatt et al.
to review the pharmacokinetics, pharmacodynamics, and 1998). Psilocin’s bioavailability is estimated to be 52.7%
clinical evidence for psilocybin-assisted therapy as a novel after PO psilocybin administration (10–20 mg), with
treatment approach for psychiatric disorders related to plasma levels detectable 20 to 90 minutes after inges-
anxiety, depression, and substance use. tion (tmax = 85–180 min) and perceptible psychologi-
cal effects at psilocin plasma levels ranging from 4 to
6 ng/ml (Hasler et al. 1997).
Methods
We reviewed the available literature in order to investigate Pharmacodynamics
the potential role of psilocybin-assisted therapy for treating
psychiatric disorders. A PubMed search was performed for Most classic psychedelics, including psilocybin, are
“Clinical Trial” articles on the topic of “psilocybin and non-selective serotonin agonists with psychoactive
psychiatry” published through December 31, 2016. We effects related to agonism of the 5-hydroxytryptamine
also performed a PubMed search on the topics of “psilocy- 2A (5-HT2A) receptor subtype (Lebedev et al. 2015;
bin,” “pharmacokinetics,” and “pharmacodynamics” to Nichols 2016). Psilocin binds with the highest affinity
provide background drug information about this novel to 5-HT2A (Ki = 6 nM) and to a lesser extent 5-HT1A
therapeutic agent with emerging clinical evidence. (Ki = 190 nM), with relatively lower affinity for other
serotonin receptors (McKenna et al. 1990). Agonism of
the 5-HT2A receptor stimulates phospholipase C (PLC)
Results via Gq/11, which leads to downstream activation of
protein kinase C (PKC) and an increased release of
Pharmacokinetics
Ca2+ from intracellular stores (Baumeister et al. 2014).
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) Another independent 5-HT2A receptor activation sig-
is a substituted indolealkylamine from the tryptamine naling pathway stimulates phospholipase A2 (PLA2),
group of compounds (Passie et al. 2002). Psilocybin was which can hydrolyze phospholipids and produce free
shown to rapidly dephosphorylate to an active metabolite, arachidonic acid (Nichols 2004).
psilocin, by alkaline phosphatase and nonspecific esterase Psilocybin’s psychological effects have been attributed to
in the intestinal mucosa (Tylš, Páleníček, and Horáček the 5-HT2A receptor, since the 5-HT2A antagonist ketan-
2014). There may be a first-pass effect with psilocybin serin has reversed psilocybin-induced effects, such as
based on the very low psilocin levels at the time to peak enhanced positive mood and attenuated recognition of
plasma concentration (tmax) and relatively higher levels negative facial expression (Kometer et al. 2012).
 JOURNAL OF PSYCHOACTIVE DRUGS 3

Ketanserin also reduced psilocybin-induced subjective psy- with advanced-stage cancer and reactive anxiety, which
chological effects like oceanic boundlessness (⊿ ~700 was defined by a DSM-IV diagnosis of acute stress
points) and visionary restructuralization (⊿ ~500 points) disorder, generalized anxiety disorder (GAD), anxiety
as measured by the 5-Dimensions Altered States of disorder due to cancer, or adjustment disorder with
Consciousness (5D-ASC) 94-item questionnaire self-rating anxiety. Participants met with study staff for a prepara-
scale (p < 0.0002), along with decreasing psilocybin- tory session to discuss expectations and goals of the two
induced mean error rates in the conflict condition of the experimental sessions. During each of the two six-hour
Stroop test (~4 vs. ~2 errors, p < 0.0001) (Quednow et al. experimental sessions, separated by several weeks, par-
2012). Pretreatment with ketanserin also prevented the ticipants were given either a dose of psilocybin (0.2 mg/
psilocybin-induced reductions in the acoustic startle kg) or niacin placebo (250 mg), along with psychologi-
response measured by prepulse inhibition (PPI) at short cal support. During the second experimental session,
lead intervals (p < 0.008) (Quednow et al. 2012). These each participant was given the opposite treatment they
studies provide compelling evidence that psilocybin’s psy- were randomized to in the first session and followed for
chological effects are mediated primarily by agonism at the six months. The main outcomes were cardiac safety
5-HT2A receptor subtype. (SBP, DBP, HR) and subjective experience (5D-ASC)
This 5-HT2A receptor agonism may be especially sig- during the sessions, followed by Beck Depression
nificant in the cerebral cortex, since in vitro light micro- Inventory (BDI), Profile of Mood States (POMS), and
scopic autoradiography has demonstrated exceptionally State-Trait Anxiety Inventory (STAI) efficacy measures
high concentrations of 5-HT2A receptors localized over at monthly intervals for six months after the second
layer III and V pyramidal neurons of several cortical areas experimental session. Participants wore a Holter car-
in postmortem brain tissue (Pazos, Probst, and Palacios diac monitor for 24 hours, which started at admission
1987). The activation of the 5-HT2A receptors in the and included the entire experimental dose session
reticular nucleus may inhibit thalamic filtering of infor- (Grob et al. 2011).
mation via GABAergic projections, potentially allowing Mean BDI after psilocybin was lower than baseline
cortical areas to receive more sensory information passing after six months (~Δ9 points, p = 0.03), while mean
through (Baumeister et al. 2014). Dynamic causal model- STAI trait anxiety score was lower than baseline after
ing has also demonstrated that deep-layer pyramidal cell one month (~Δ7, p = 0.001) and three months (~Δ6,
excitation could provide a net effect of feedback inhibi- p = 0.03) (Grob et al. 2011). Mean POMS was not
tion, which would be consistent with the decreased brain significantly different than mean baseline score at any
activity and oscillatory power shown on magnetic ence- time point during the six months. Psilocybin increased
phalography (MEG) after psilocybin administration cardiac vital signs during the session between 1–5 hours
(Muthukumaraswamy et al. 2013). after psilocybin administration that peaked at two hours,
In addition to high 5-HT2A receptor expression in the when HR and SBP were greater than placebo, while DBP
cortex, there are also 5-HT2A receptors in the periphery, was not: mean HR 81.5 vs. 70.4 bpm (p < 0.007); mean
where agonism has been associated with contraction of SBP 138.9 vs. 117.0 mm Hg (p < 0.01); mean DBP 75.9
vascular smooth muscle and platelet aggregation vs. 69.6 mm Hg (Grob et al. 2011).
(Nagatomo et al. 2004). Due to the potential risk of cardi- Ross et al. (2016) also conducted a double-blind,
ovascular adverse reactions, psilocybin clinical trials have placebo-controlled, crossover study of 29 participants
frequently monitored cardiac vital signs for safety. In one with cancer-related anxiety and depression. The majority
landmark clinical trial evaluating psilocybin-occasioned met DSM-IV criteria for an adjustment disorder with
mystical-type experiences, psilocybin demonstrated dose- anxiety (n = 26), while the rest (n = 3) met criteria for
and time-related effects on cardiac vital signs with a higher GAD. Participants met with study staff for three two-
mean systolic blood pressure (SBP Δ20.5 mm Hg), diastolic hour preparatory sessions to discuss expectations and
BP (DBP Δ11.3 mm Hg), and heart rate (HR Δ8.2 bpm) goals of the experimental sessions. During each of the
than placebo (p < 0.05) in the highest dose condition (30 two six-hour experimental sessions, separated by seven
mg/70 kg), which were transient and normalized six hours weeks, participants were either given a dose of psilocybin
post-dose (Griffiths et al. 2006). (0.3 mg/kg) or niacin placebo (250 mg), along with
psychological support. During the second experimental
session, each participant was given the opposite treat-
Clinical trials for cancer-related anxiety and
ment they were randomized to in the first session and
depressive disorders
followed for another 6.5 months. The primary outcomes
Grob et al. (2011) conducted the first double-blind, of cancer-related anxiety and depression improvements
placebo-controlled, crossover study of 12 participants and response/remission were measured by self-reported
4 K. THOMAS ET AL.

STAI for anxiety, along with Hospital Anxiety at time points between 90 to 120 minutes post-dose
Depression Scale (HADS) and BDI for depression, (p < 0.05), primarily due to heart rate reductions from
using the following rating subscales: STAI-State (STAI- baseline with the niacin placebo (Ross et al. 2016).
S), STAI-Trait (STAI-T), HADS Anxiety (HAD-A), Griffiths et al. (2016) conducted a randomized, dou-
HADS Depression (HAD-D), HADS Total (HAD-T), ble-blind, crossover study of 51 cancer participants with
and BDI. These primary outcome variables were mea- life-threatening diagnoses and symptoms of depression
sured pre-crossover at baseline, one day pre-dose 1, one- and/or anxiety. The participants with a life-threatening
day post-dose 1, two weeks post-dose 1, six weeks post- cancer diagnosis also met DSM-IV criteria for chronic
dose 1, and seven weeks post-dose 1 (Ross et al. 2016). adjustment disorder with anxiety (n = 11), chronic
After seven weeks post-dose 1, participants first adjustment disorder with mixed anxiety and depressed
receiving psilocybin had lower mean scores on all six mood (n = 11), GAD (n = 5), dysthymic disorder
rating subscales than the participants receiving niacin (n = 5), MDD (n = 14), comorbid GAD with MDD
first (p < 0.05) (Ross et al. 2016). The difference in (n = 5), or GAD with dysthymic disorder (n = 1).
mean HAD-T scores between groups at seven weeks Participants met with study staff for two or more pre-
post-dose was ~Δ7, which demonstrated the largest paratory sessions to discuss expectations and goals of the
effect size of the primary outcomes, represented by two experimental sessions. During each of the two
Cohen’s d = 1.36 (p ≤ 0.001). The other seven weeks approximately six-hour experimental sessions, separated
post-dose 1 estimated differences in mean scores by approximately five weeks, participants were given
between groups, with corresponding Cohen’s d values either high-dose psilocybin (22 or 30 mg/70 kg) or
and p-values as follows: STAI-T ~Δ10, d = 1.29, low-dose psilocybin (1 or 3 mg/70 kg), along with psy-
p ≤ 0.001; STAI-S ~Δ12, d = 1.18, p ≤ 0.01; HAD-A chological support. During the second experimental ses-
~Δ3, d = 1.07, p ≤ 0.01; HAD-D ~Δ3, d = 0.98, p ≤ 0.01; sion, each participant was given the opposite treatment
HAD-T ~Δ7, d = 1.36, p ≤ 0.001; BDI ~Δ6, d = 0.82, they were randomized to in the first session. The pri-
p < 0.05. The depression response was defined by mary outcomes of depression and anxiety response and
a ≥ 50% reduction in score, while remission was remission were measured by the GRID-Hamilton
defined by a ≥ 50% reduction plus HAD-D ≤ 7 or Depression Rating Scale (GRID-HAMD-17) and the
BDI ≤ 12. The following depression response or remis- structured interview guide for the Hamilton Anxiety
sion rates at seven weeks post-dose 1 were higher for Rating Scale (HAM-A assessed with SIGH-A). The
participants first receiving psilocybin than the niacin depression or anxiety response was defined by a ≥ 50%
placebo: response rates by HAD-A (58% vs. 14%, reduction in score, while remission was defined by
p ≤ 0.01), HAD-T (~70% vs. ~20%, p ≤ 0.01), and a ≥ 50% reduction plus GRID-HAMD-17 or HAM-
BDI (83% vs. 14%, p ≤ 0.01), along with remission A ≤ 7, respectively. These primary outcome variables
rates by BDI (~80% vs. ~15%, p ≤ 0.01). The subjective were measured at baseline, five weeks post-session 1,
effects of the psilocybin sessions, measured by the five weeks post-session 2, and six months after baseline.
Mystical Experience Questionnaire (MEQ) total score, Secondary outcome rating scales measured included the
were also positively correlated with the magnitude of BDI, HAD-T, HAD-D, HAD-A, HAM-A, and STAI-T,
score change for the following primary outcomes: among others (Griffiths et al. 2016).
STAI-T, r = 0.40, p = 0.04; STAI-S, r = 0.42, p = 0.03; The GRID-HAMD-17 response rates (92% vs. 32%,
HAD-T, r = 0.49, p = 0.009; HAD-A, r = 0.46, p = 0.01 p < 0.001), HAM-A response rates (76% vs. 24%,
(Ross et al. 2016). p < 0.001), GRID-HAMD-17 remission rates (60% vs.
The most common adverse events related to psilocy- 16%, p < 0.01), and HAM-A remission rates (52% vs.
bin were elevations in BP and HR (76%), headaches 12%, p < 0.01) were all higher for participants receiving
(28%), transient anxiety (17%), nausea (14%), and tran- high-dose psilocybin first than low-dose psilocybin first
sient psychotic-like symptoms (7%) (Ross et al. 2016). at five weeks post-session 1 (Griffiths et al. 2016). After
The mean SBP peaked at ~142 mm Hg, 180 minutes a six-month follow-up, the response and remission
after psilocybin administration, but was higher than the rates were sustained, as demonstrated by a nonsignifi-
niacin placebo at time points between 60 to 300 minutes cant difference between post-session 1 vs. six months in
post-dose (p ≤ 0.01). The mean DBP peaked at ~82 mm the high-dose first group or between post-session 2 vs.
Hg, 180 minutes after psilocybin administration, but was six months in the low-dose first group on these out-
higher than the niacin placebo at time points between 60 comes. The rating scales reductions in mean scores for
to 240 minutes post-dose (p < 0.05). The mean heart rate participants receiving the high-dose first, were greater
was relatively consistent at ~70 bpm after psilocybin than participants receiving low-dose first, were as fol-
administration, but was higher than the niacin placebo lows: GRID-HAMD-17 Δ8.2 (p < 0.001), BDI Δ5.9
 JOURNAL OF PSYCHOACTIVE DRUGS 5

(p < 0.01), HAD-D Δ2.1 (p < 0.05), HAM-A Δ8.2 Clinical trial for obsessive-compulsive disorder
(p < 0.001), and STAI-T Δ5.8 (p < 0.05). The subjective
Moreno et al. (2006) conducted an open-label, dose-
effects of the psilocybin sessions, measured by MEQ
escalation study with nine participants diagnosed with
total score, were also correlated with a reduction in
obsessive-compulsive disorder (OCD) who failed an
scores on the HAM-A (r = −0.59, p < 0.0001) and
adequate trial (> 12 weeks) with at least one serotonin
HAD-D (r = −0.36, p < 0.01) rating scales (Griffiths
reuptake inhibitor. Participants received up to four
et al. 2016).
doses of psilocybin with at least a week between ses-
Adverse events appeared to be more frequent in the
sions. Doses were administered in an escalating fashion
high-dose vs. low-dose psilocybin sessions, with more
(0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg) with the exception of
participants experiencing episodes of transient elevated
a very-low-dose session of 0.025 mg/kg, which was
SBP (> 160 mm Hg: 34% vs. 17%), elevated DBP (>
given in random sequence any time after the first 0.1
100 mm Hg: 13% vs. 2%), nausea/vomiting (15% vs.
mg/kg dose. The Yale Brown Obsessive-Compulsive
0%), physical discomfort (21% vs. 8%), anxiety (26% vs.
Scale (YBOCS) and a visual analog scale (VAS) for
15%), psychological discomfort (32% vs. 12%), and
overall OCD symptom severity were administered
paranoid ideation (2% vs. 0%), but these transient epi-
prior to psilocybin ingestion and at 4, 8, and 24 hours
sodic events were not statistically tested for any differ-
after ingestion. A Hallucinogen Rating Scale (HRS) was
ences (Griffiths et al. 2016).
also administered once, eight hours after ingestion
(Moreno et al. 2006).
A repeated measures ANOVA was used to analyze
Clinical trial for treatment-resistant major efficacy with YBOCS values, which demonstrated a
depressive disorder significant main effect of time (p = 0.046), although
there was no effect of dose or interaction of dose and
Carhart-Harris et al. (2016) conducted an open-label
time (Moreno et al. 2006). The combined baseline
pilot study of 12 participants with moderate to severe
mean YBOCS scores, when stratified by dose groups,
MDD who already failed adequate trials (> 6 weeks)
ranged from 18.3 to 24.1, were reduced 24 hours after
with at least two antidepressants. An initial four-hour
psilocybin administration, and then ranged from 10.7
preparatory psychotherapy session was completed
to 11.3 (p = 0.028). Durability of response was not
prior to the first dose of psilocybin. During the first
studied formally, but two participants reported sympto-
treatment session, a low dose of psilocybin (10 mg)
matic improvement lasting most of the week and one
was administered along with psychological support.
participant achieved long-term remission measured
One week after the low-dose safety session, each
after six months. The only adverse reaction reported
participant completed a high-dose (25 mg) session
was mild and transient hypertension in one participant,
and was followed for assessments at several time
with BP peaking at 142/105 mm Hg four hours after
points: one week, two weeks, three weeks, five weeks,
administration (Moreno et al. 2006).
and three months. The primary outcome was the
difference in the Quick Inventory of Depressive
Symptoms (QIDS) scores from baseline to one week
Clinical trial for alcohol dependence
after the high-dose session, but other rating scales
measured included the BDI, HAM-D, STAI-T, Bogenschutz et al. (2015) conducted an open-label
among others (Carhart-Harris et al. 2016). proof of concept study in 10 participants who met
The mean baseline QIDS was 19.2, while the mean DSM-IV criteria for alcohol dependence, drank heavily
difference after one week was −11.8 (95% CI: −9.15 to (females ≥ 4/day, males ≥ 5/day) at least two of the past
−14.35; Hedges’ g = 3.1) and after three months was −9.2 30 days, and were concerned about their drinking.
(95% CI: −5.69 to −12.71; Hedges’ g = 2) (Carhart-Harris Weekly psychotherapy was provided over 12 weeks,
et al. 2016). The mean differences on other rating scales with four sessions prior to the first psilocybin session,
after one week were as follows: BDI −25.0 (95% CI: −20.1 four between the psilocybin sessions, and four after the
to −29.9; Hedges’ g = 3.2), HAM-D −14.0 (95% CI: −9.6 second psilocybin session. Psychotherapy sessions con-
to −18.4; Hedges’ g = 2.4), STAI-T −29.5 (95% CI: −22.03 sisted of three preparatory sessions, seven motivational
to −36.97; Hedges’ g = 2.7). Adverse events reported enhancement therapy sessions, and two debriefing ses-
during the psilocybin sessions included transient anxiety sions. Psilocybin was administered at a dose of 0.3 mg/
(100%), confusion or thought disorder (75%), nausea kg during the first session and 0.4 mg/kg during the
(33%), headache (33%), and paranoia (8%) (Carhart- second session, with the exception of one participant
Harris et al. 2016). who received 0.3 mg/kg for both sessions. The primary
6 K. THOMAS ET AL.

outcome to determine response was the difference in was self-reported, biologically supported, seven-day
percent heavy drinking days, assessed by the Time-Line point prevalence abstinence at six months. Acute effects
Follow-Back procedure, in participants at baseline of psilocybin were measured using the States of
(during 12 weeks prior to enrollment) and during Consciousness Questionnaire (SOCQ) and post-session
weeks 5 to 12 (one to eight weeks after first psilocybin headache interview (Johnson et al. 2014).
session) of the study. Participants were also followed up There were 12 (80%) who were abstinent after
at 36 weeks and completed an Addiction Research six months and 10 (67%) who were abstinent after
Inventory (ARCI) after each psilocybin session. Acute 12 months (Johnson et al. 2014; Johnson, Garcia-
effects of psilocybin were captured using self-report Romeu, and Griffiths 2016). Three of the 12 who were
scales by participants seven hours after ingestion, abstinent reported self-corrected relapses in the period
including intensity subscales of the HRS, 5D-ASC ques- between the psilocybin session and the six-month follow
tionnaire, and MEQ (Bogenschutz et al. 2015). up. Psilocybin appeared to increase peak BP and HR
The mean percent heavy drinking days was ~35% at over baseline readings 1.5 to 2.5 hours after ingestion:
baseline, which decreased between one to eight weeks mean SBP 153 vs. 125 mm Hg; DBP 87 vs. 71 mm Hg;
after the first psilocybin session to ~9% (mean differ- and HR 87 vs. 68 bpm; but these differences were not
ence = −26.0, 95% CI −8.7 to −43.2). Reductions in heavy statistically tested. The SOCQ revealed that 40% of par-
drinking were not present during the four weeks prior to ticipants experienced strong or extreme ratings of fear,
the first psilocybin session, but the reductions one to fear of insanity, or feeling trapped at some time during
eight weeks after the psilocybin session persisted for the moderate or high-dose psilocybin sessions, but these
32 weeks. Intensity of subjective psilocybin experiences were managed with interpersonal support and had
varied greatly and was negatively correlated with percent resolved by the end of the session (Johnson et al. 2014).
of heavy drinking days, which demonstrated that a
greater intensity of subjective effects on HRS intensity
Discussion
subscale (r = −0.76, p = 0.017), 5D-ASC (r = −0.89,
p = 0.001), and MEQ (r = −0.85, p = 0.004) was correlated New clinical evidence for psilocybin-assisted therapy in
with less heavy drinking days. Psilocybin also produced psychiatry has emerged during the past decade, repre-
transient increases in BP between 30 to 180 minutes after sented by seven studies with a combined total of 135
ingestion and peaked at ~150/90. Other treatment- participants (Table 1). The large effect sizes (Hedges’
related adverse events included mild headache (50%), g > 2) demonstrated in some of these small studies
emesis (10%), diarrhea (10%), and insomnia (10%) warrant more robust clinical trials to ascertain psilocy-
(Bogenschutz et al. 2015). bin’s efficacy for specific psychiatric indications. This
novel treatment approach with limited psilocybin ther-
apy sessions would be remarkably different from the
Clinical trial for tobacco addiction
current treatment paradigm of daily medication.
Johnson et al. (2014) conducted an open-label pilot However, there is some precedent for using alternative
study to assess the feasibility of a psilocybin-based treatment modalities with limited sessions when
intervention for treating tobacco addiction in 15 parti- depressed patients fail antidepressants, such as ketamine
cipants who completed the trial. All participants infusion, ECT, or TMS. One important distinction from
smoked at least 10 cigarettes per day, had multiple these other session-based treatments would be that the
past quit attempts and a present desire to quit smoking. benefits of psilocybin-assisted therapy may only require
A 15-week smoking cessation protocol was followed a few dosing sessions and the effects appear to persist
with psilocybin sessions at weeks 5, 7, and 13 along longer than other treatment options.
with weekly cognitive behavioral therapy (CBT) ses- Another distinction is the use of psychotherapy
sions for smoking cessation during the weeks psilocy- before, during, and after the psilocybin sessions. While
bin was not administered. Each participant set a target these studies demonstrated that psilocybin-assisted psy-
quit date coinciding with the first psilocybin session chotherapy improved symptoms more than psychother-
during week 5 of the study. Participants received 20 apy alone, it is unclear what clinical benefit (if any)
mg/70 kg (0.29 mg/kg) at week 5 and optionally would be derived from psilocybin alone, since there
increased to 30 mg/70 kg (0.43 mg/kg) during weeks were no experimental conditions omitting supportive
7 and 13. Participants were instructed to abstain from psychotherapy. A psilocybin-alone experimental condi-
other medications for smoking cessation during the tion may have been deemed unethical, since Griffiths
study period, although one participant reported use of et al. (2006) suggested that previous research had already
nicotine lozenges. The primary outcome of remission documented that more preparation and interpersonal
 JOURNAL OF PSYCHOACTIVE DRUGS 7

Table 1. Summary of psilocybin-assisted therapy clinical trial designs and outcomes.

Publication, Study Experimental Session Exposures &
Design & Population Primary Outcome Measures Adverse Drug Reactions Efficacy Primary Outcomes
Moreno et al. 2006 4 sessions ≥ 1 week apart: Frequency: YBOCS mean ~10 points
Open-label dose- -psilocybin 0.025 mg/kg transient hypertension (11%) lower than baseline (p = 0.028)
escalation trial for -psilocybin 0.1 mg/kg at 24 hours post-dose
OCD -psilocybin 0.2 mg/kg
n=9 -psilocybin 0.3 mg/kg
Outcomes
Yale-Brown Obsessive Compulsive Scale
(YBOCS) for OCD
Grob et al. 2011 2 sessions several weeks apart: Cardiovascular peak effects (2 h post-dose): BDI mean ~9 points lower
Double-blind, -psilocybin 0.2 mg/kg SBP mean 138.9 vs. 117.0 mm Hg than baseline (p = 0.03) at
placebo-controlled -niacin 250 mg (placebo) (p < 0.01); 6 months post-dose
crossover for cancer- Outcomes HR mean 81.5 bpm vs. 70.4 bpm STAI-T mean ~7 points lower
related reactive Beck Depression Inventory (BDI) for (p < 0.007) than baseline after (p = 0.001) at 1 month
anxiety depression; post-dose
n = 12 State Trait Anxiety Index Trait (STAI-T) STAI-T mean ~6 points lower
and State (STAI-S) for anxiety than baseline (p = 0.03) at
3 months post-dose
Carhart-Harris et al. 2 sessions 1 week apart: Frequency: QIDS mean difference from
2016 -psilocybin 10 mg (low) transient anxiety (100%), confusion or baseline −11.8 (95% CI: −9.15 to −14.35,
Open-label for -psilocybin 25 mg (high) thought disorder (75%), nausea (33%), g = 3.1) at
treatment-resistant Outcome headache (33%), paranoia (8%) 1 week post-high dose
MDD Quick Inventory of Depressive
n = 12 Symptomalogy (QIDS) for depression
Ross et al. 2016 2 sessions 7 weeks apart: Frequency: BDI mean ~6-points lower
Double-blind, -psilocybin 0.3 mg/kg transient elevations in BP and HR (76%), than placebo (p < 0.05, d = 0.82); BDI
placebo-controlled -niacin 250 mg (placebo) headaches (28%), anxiety (17%), nausea higher response rate 83% vs. 14%
crossover for cancer- Outcomes (14%), psychotic-like symptoms (7%) (p ≤ 0.01) and remission rate ~80% vs.
related anxiety and Hospital Anxiety Depression Scale Total Cardiovascular effects: ~15%, p ≤ 0.01 at 7 weeks post-dose
depression (HAD-T) and Anxiety (HAD-A) or SBP mean ~142 mm Hg peaked at 180 HAD-T mean ~7-points lower
n = 29 Depression (HAD-D) subscales for min, but was higher than placebo from than placebo (p ≤ 0.001, d = 1.36); HAD-
anxiety and depression, respectively; 60–300 min post-dose (p ≤ 0.01) T higher response rate ~70% vs. ~20%
Beck Depression Inventory (BDI) for Mean DBP ~82 mm Hg peaked at 180 min, (p ≤ 0.01) at
depression; but was higher than placebo from 60–240 7 weeks post-dose
State Trait Anxiety Index Trait (STAI-T) min post-dose (p < 0.05) HAD-A mean ~3-points lower
and State (STAI-S) for anxiety; Mean HR ~70 mm Hg consistent, but was than placebo (p ≤ 0.01, d = 1.07); HAD-A
Response: ≥ 50% reduction in score higher than placebo from 90–120 min higher response rate 58% vs. 14%
from baseline; post-dose (p < 0.05) (p ≤ 0.01) at
Remission: ≥ 50% reduction in score 7 weeks post-dose
from baseline plus BDI ≤ 12
Griffiths et al. 2016 2 sessions ~5 weeks apart: Frequency (high vs. low dose): GRID-HAMD-17 mean ~8-points lower
Double-blind, -psilocybin 1 or 3 mg/70 kg (low dose) transient elevated SBP > 160 mm Hg (34% for high dose (p ≤ 0.001); GRID-HAMD-17
crossover for cancer- -psilocybin 22 or 30 mg/70 kg (high vs. 17%), elevated DBP > 100 mm Hg (13% response rates higher for high dose 92%
related anxiety and dose) vs. 2%), nausea/vomiting (15% vs. 0%), vs. 32% (p < 0.001)
depression Outcomes physical discomfort (21% vs. 8%), GRID-HAMD-17 higher
n = 51 GRID-Hamilton Depression Rating Scale psychological discomfort (32% vs. 12%), remission rates 60% vs. 16% (p < 0.001)
17-item (GRID-HAMD-17); anxiety (26% vs. 15%), paranoid ideation at 5 weeks post-session 1 dose
Hamilton Anxiety Rating Scale (HAM-A); (2% vs. 0%) HAM-A mean ~8-points lower for high dose
Response: ≥ 50% reduction in score No statistical testing (p ≤ 0.001); HAM-A higher response rates
from baseline; 76% vs. 24% (p < 0.001)
Remission: ≥ 50% reduction in score HAM-A higher remission rates
from baseline plus GRID-HAMD-17 ≤ 7 52% vs. 12% (p < 0.001) at 5 weeks post-
or HAM-A ≤ 7 session 1 dose
Johnson et al. 2014 3 sessions—first on quit date, second Frequency of strong or extreme fear was Abstinence rates were 80%
Johnson, Garcia- 2 weeks later and third 6 weeks later: 40% after 6 months
Romeu, and Griffiths -psilocybin 20 mg/70 kg Mean peak SBP 153 vs. 125 mm Hg; Abstinence rates were 67%
2016 -optional increase to 30 mg/70 kg for Mean peak DBP 87 vs. 71 mm Hg after 12 months
Open-label for second and third sessions Mean peak HR 87 vs. 68 bpm *No statistical testing
tobacco addiction Outcome No statistical testing
n = 15 Abstinence self-reported and biologically
supported (urine cotinine screen) 7-day
point prevalence rates
Bogenschutz et al. 2 sessions 4 weeks apart Frequency: Mean percent of heavy
2015 -psilocybin 0.3 mg/kg first mild headache (50%), emesis (10%), drinking days decreased from ~35% at
Open-label for -psilocybin 0.4 mg/kg second diarrhea (10%), insomnia (10%) after any baseline to ~9% (−26.0%, 95% CI −8.7 to
alcohol dependence Outcome session −43.2) between 1 to 8 weeks after the
n = 10 Percent of heavy drinking days first dose, which persisted for 32 weeks
1–8 weeks after first dose session
8 K. THOMAS ET AL.

support decreased psychological adverse effects com- important to recognize that there was substantial hetero-
pared to the earliest psilocybin experiments. geneity in the populations enrolled, due to different
Preliminary evidence also suggests that the subjec- DSM-IV diagnoses and comorbidities (cancer), along
tive experience during the psilocybin-assisted therapy with different study designs and timelines for measuring
session may be important, given the positive correlation endpoints. If psilocybin-assisted therapy will eventually
between mystical-type experiences and improved clin- become a therapeutic option in clinical psychiatry, future
ical outcomes (Bogenschutz et al. 2015; Griffiths et al. trials must employ consistent methodology to expand
2016; Ross et al. 2016). However, further research is and replicate this emerging evidence base.
needed to determine how subjective effects and clinical
responses are related to psilocybin, psychotherapy, or
the optimal synergistic combination of both. Conclusions
Psilocybin-assisted therapy for depression symptoms The psychedelic 5-HT2A agonist, psilocybin, is begin-
seems to have the strongest clinical evidence thus far, ning to demonstrate potential for treating psychiatric
with four studies demonstrating clinically significant disorders related to anxiety, depression, and substance
reductions on rating scale scores and often with subse- use. Psilocybin-assisted therapy is a new investigational
quently higher response or remission rates (Carhart- psychiatric treatment paradigm characterized by only a
Harris et al. 2016; Griffiths et al. 2016; Grob et al. 2011; few six-hour medication therapy sessions with psycho-
Ross et al. 2016). In these studies, reductions on the BDI, logical support. These psilocybin sessions, supported by
HAD-D, HAM-D, and QIDS have ranged from ~3–25 several weeks of integrative psychotherapy sessions,
points, while response/remission rates (defined by the may significantly improve symptom scores and help
BDI, HAD-T, and HAMD-17 scores) have been ~3–6- patients achieve response or remission within weeks,
fold higher after psilocybin sessions (Carhart-Harris et al. which could persist for many months after taking
2016; Griffiths et al. 2016; Grob et al. 2011; Ross et al. 2016). psilocybin.
Psilocybin also has compelling evidence for anxiety Additional studies are required to determine if psi-
symptoms, with four studies demonstrating significant locybin will be deemed safe and effective enough to
reductions on rating scale scores and often accompa- gain FDA approval. While psilocybin’s clinical utility
nied by higher response or remission rates (Griffiths still remains uncertain, it should be investigated further
et al. 2016; Grob et al. 2011; Moreno et al. 2006; Ross to determine if this novel treatment paradigm has the
et al. 2016). In these studies, reductions on the HAD-A, potential to dramatically improve outcomes in patients
HAM-A, Y-BOCS, and STAI-T have ranged from with psychiatric disorders.
~6–30 points, while response/remission rates (defined
by the HAD-A and HAM-A scores) have been ~3–4-
fold higher after psilocybin sessions (Griffiths et al. 2016; ORCID
Grob et al. 2011; Moreno et al. 2006; Ross et al. 2016).
Kelan Thomas http://orcid.org/0000-0003-2818-270X
The potential to treat substance use disorders has
relatively weaker clinical evidence, but promising
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