Clinical trial NCT02061293
Conditions: Alcohol Dependence
Sponsor: NYU Langone Health
Start date: 2014-06-01; Completion date: 2021-07-30
Enrollment: 95 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Several lines of evidence suggest that classic hallucinogens such as psilocybin can facilitate behavior change in addictions such as alcohol dependence. The proposed investigation is a multi-site, double-blind active-controlled trial (n = 180, 90 per group) contrasting the acute and persisting effects of psilocybin to those of diphenhydramine in the context of outpatient alcoholism treatment.

Detailed description:
Two to four sites will participate in this study. Aims of the study are 1) to characterize the acute effects of PO psilocybin 25 mg/70 kg, 30 mg/70 kg, and 40 mg/70 kg in alcohol dependent patients; 2) to evaluate the effect of psilocybin treatment on drinking outcomes for 32 weeks after the first administration, relative to diphenhydramine control; 3) to test whether or not characteristics of the drug administration session experiences mediate effects of psilocybin on short-term (1 week) persisting effects and post-session drinking behavior, 4) to evaluate the explanatory value of changes in alcohol craving, self-efficacy, motivation, and other psychological domains in accounting for the observed experimental effect of psilocybin relative to diphenhydramine control, and 5) to evaluate pre-post changes in drinking in participants after they receive psilocybin in the third session.

The total duration of psychosocial treatment in the double-blind period will be 12 weeks, and double-blind drug administration sessions will occur after 4 and 8 weeks. In the first psilocybin session, a dose of 25 mg/70 kg will be administered. Depending on the response in the first session, the dose for the second session may be increased to 30 mg/70 kg or 40 mg/70 kg, or held at 25mg/70kg. The dose of diphenhydramine will start at 50 mg, and may be increased to 100 mg or held at 50 mg in the second session, depending on response in the first session. Following completion of the double-blind period (34 weeks after randomization) all participants who meet interim safety criteria will be offered an additional session in which psilocybin will be administered. The drug will be administered during 8-hour sessions in an outpatient setting under close medical and psychiatric monitoring. The drug administration sessions will occur in the context of an extended version of Motivational Enhancement Therapy (Motivational Enhancement and Taking Action, META) with the addition of standardized preparation before and debriefing and follow-up after the psilocybin administration sessions. Extensive screening and baseline assessment will be completed, including thorough safety screening and assessment of participant characteristics that could potentially moderate treatment response. Within-session and short-term persisting effects will be assessed. Drinking outcomes and changes in several potential mediators of treatment effect, including motivation, self-efficacy, craving, depression, anxiety, and spiritual dimensions of the experience, will be measured until 50 weeks after the first drug administration session, for a total of 54 weeks from the initiation of treatment.

Arms: arm 1: Psilocybin 25 mg/70 kg PO administered at week 4, 25-40 mg/70 kg PO administered at week 8. arm 2: Diphenhydramine 50 mg PO administered at week 4, 50-100 mg PO administered at week 8.
Interventions: intervention 1: Psilocybin intervention 2: Diphenhydramine intervention 3: Motivational Enhancement and Taking Action (META)
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: Manualized psychosocial intervention based on motivational enhancement therapy, functional analysis, and implementation of a change plan.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title: 
A Double-Blind Trial of Psilocybin-Assisted Treatment of Alcohol 
Dependence 
NCT Number: 
NCT02061293 
Study Number: 
14-00614 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
9/9/2020 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
Protocol # 113080-02 
NYU IRB # s14-00614 
A DOUBLE-BLIND TRIAL OF PSILOCYBIN-ASSISTED TREATMENT OF ALCOHOL DEPENDENCE 
 
Lead Investigator: Michael P. Bogenschutz, M.D. 
Co-Lead Investigator: Stephen Ross, M.D. 
 
Version 4.11 
 September 1, 2020 
 
 


 
 
 
 
 
 
 
 
 
Lead Investigator (LI):  
Michael P. Bogenschutz, M.D. 
 
New York University School of Medicine  
Department of Psychiatry 
 
 
 
Co-Lead Investigator (Co-LI): 
Stephen Ross, M.D. 
New York University School of Medicine  
Division of Alcoholism & Drug Abuse 
Department of Psychiatry 
 
Executive Committee: 
Alyssa Forcehimes, Ph.D. 
 
George Greer, M.D. 
 
John Rotrosen, M.D. 
 
Carey Turnbull 
 
 
 
Statistician:  
Scott Tonigan, Ph.D. 
 
 
 
 
 
 
 


 
 
 
 
 
 
Table of Contents 
1. 
PROTOCOL ABSTRACT..........................................................................................................................................1 
2. 
SPECIFIC AIMS ........................................................................................................................................................2 
3. 
RESEARCH STRATEGY ..........................................................................................................................................3 
3.1 
SIGNIFICANCE......................................................................................................................................................3 
3.1.1 Public Health Impact of Drinking.....................................................................................................................3 
3.1.2 Limitations of Currently Available Treatments for Addiction.............................................................................3 
3.1.3 The Use of Hallucinogens to Treat Addiction ..................................................................................................3 
3.1.4 Recent Clinical Trials of Psilocybin as Treatment for Various Conditions ........................................................4 
3.1.5 Safety of Classic Hallucinogens .....................................................................................................................4 
3.1.6 Relationship of Sacramental Hallucinogen Use to Use of Other Substances ...................................................4 
3.1.7 How Might a Classic Hallucinogen Affect Drinking Behavior? .........................................................................5 
3.1.8 Neuroimaging Studies of Acute Effects of Classic Hallucinogens Human Brain Function ................................5 
3.2 
INNOVATION ........................................................................................................................................................7 
3.3 
APPROACH ..........................................................................................................................................................7 
3.3.1 Design Overview ............................................................................................................................................7 
3.3.2 Primary Outcome ...........................................................................................................................................9 
3.3.3 Preliminary Studies ........................................................................................................................................9 
3.3.4 Recruitment, Pre-screening, and Informed Consent .....................................................................................11 
3.3.5 Randomization and Blinding .........................................................................................................................11 
3.3.6 Study Participants ........................................................................................................................................12 
3.3.7 Sites ............................................................................................................................................................13 
3.3.8 Study Treatments.........................................................................................................................................13 
3.3.9 Concomitant Therapy ...................................................................................................................................19 
3.3.10 Measures .....................................................................................................................................................20 
3.3.11 Data Management and Procedures ..............................................................................................................24 
3.3.12 Statistical analysis and power ......................................................................................................................25 
3.3.13 Study Milestones..........................................................................................................................................27 
3.3.14 Regulatory Considerations ...........................................................................................................................28 
3.3.15 Compensation to Participants.......................................................................................................................29 
4. 
HUMAN SUBJECTS PROTECTIONS .....................................................................................................................29 
4.1 
RISKS TO HUMAN SUBJECTS ...............................................................................................................................29 
4.1.1 Human Subjects Involvement and Characteristics. .......................................................................................29 
4.1.2 Sources of Materials ....................................................................................................................................30 
4.1.3 Potential Risks .............................................................................................................................................30 
4.2 
ADEQUACY OF PROTECTION AGAINST RISKS .........................................................................................................33 
4.2.1 Recruitment and Informed Consent ..............................................................................................................33 
4.2.2 Protection Against Risk ................................................................................................................................33 


 
 
 
 
 
 
4.3 
POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO HUMAN SUBJECTS AND OTHERS .........................................35 
4.3.1 Potential Benefits to Participants ..................................................................................................................35 
4.3.2 Potential Benefits to Others. .........................................................................................................................35 
4.3.3 Risk Benefit Assessment..............................................................................................................................35 
4.4 
IMPORTANCE OF THE KNOWLEDGE TO BE GAINED ..................................................................................................35 
4.5 
DATA AND SAFETY MONITORING PLAN .................................................................................................................35 
4.5.1 General Considerations ...............................................................................................................................35 
4.5.2 Institutional Review Board (IRB) ...................................................................................................................35 
4.5.3 Data and Safety Monitoring Board ................................................................................................................35 
4.5.4 Procedures for Monitoring and Reporting Adverse Events. ...........................................................................36 
5. 
REFERENCES........................................................................................................................................................37 


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1. PROTOCOL ABSTRACT 
Several lines of evidence suggest that classic hallucinogens such as psilocybin can facilitate behavior 
change in addictions such as alcohol dependence. The proposed investigation is a multi-site, double-blind 
active-controlled trial (n = 180, 90 per group) contrasting the acute and persisting effects of psilocybin to 
those of diphenhydramine in the context of outpatient alcoholism treatment.  Two to four sites will 
participate. Aims of the study are 1) to characterize the acute effects of PO psilocybin 25 mg/70 kg, 30 
mg/70 kg, and 40 mg/70 kg in alcohol dependent patients; 2) to evaluate the effect of psilocybin treatment 
on drinking outcomes for 32 weeks after the first administration, relative to diphenhydramine control; 3) to 
test whether or not characteristics of the drug administration session experiences mediate effects of 
psilocybin on short-term (1 week) persisting effects and post-session drinking behavior, 4) to evaluate the 
explanatory value of changes in alcohol craving, self-efficacy, motivation, and other psychological domains 
in accounting for the observed experimental effect of psilocybin relative to diphenhydramine control and 5) 
to evaluate pre-post changes in drinking in participants after they receive psilocybin in the third session. 
The total duration of psychosocial treatment in the double-blind period will be 12 weeks, and double-blind 
drug administration sessions will occur after 4 and 8 weeks. In the first psilocybin session, a dose of 25 
mg/70 kg will be administered. Depending on the response in the first session, the dose for the second 
session may be increased to 30 mg/70 kg or 40 mg/70 kg, or held at 25mg/70kg. The dose of 
diphenhydramine will start at 50 mg, and may be increased to 100 mg or held at 50 mg in the second 
session, depending on response in the first session. Following completion of the double-blind period (34 
weeks after randomization) all participants who meet interim safety criteria will be offered an additional 
session in which psilocybin will be administered. The drug will be administered during 8-hour sessions in an 
outpatient setting under close medical and psychiatric monitoring. The drug administration sessions will 
occur in the context of an extended version of Motivational Enhancement Therapy (Motivational 
Enhancement and Taking Action, META) with the addition of standardized preparation before and 
debriefing and follow-up after the psilocybin administration sessions. Extensive screening and baseline 
assessment will be completed, including thorough safety screening and assessment of participant 
characteristics that could potentially moderate treatment response. Within-session and short-term persisting 
effects will be assessed. Drinking outcomes and changes in several potential mediators of treatment effect, 
including motivation, self-efficacy, craving, depression, anxiety, and spiritual dimensions of the experience, 
will be measured until 50 weeks after the first drug administration session, for a total of 54 weeks from the 
initiation of treatment.  
 
 
 


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2. SPECIFIC AIMS 
Several lines of evidence suggest that classic (5HT2a agonist or partial agonist) hallucinogens such as 
psilocybin can promote behavior change in addictions such as alcohol dependence. In particular, a recent 
meta-analysis of the most rigorous randomized controlled trials of LSD for alcohol dependence (all 
conducted over 40 years ago) demonstrated a consistent medium-sized effect (in terms of reduced alcohol 
use/clinical improvement from alcoholism) of a single high-dose session [1].  The goal of the proposed line 
of research is to use modern clinical trial methodology and evidence-based behavioral treatment to address 
seriously an important question that was never answered satisfactorily: can administration of a classic 
hallucinogen, under carefully controlled conditions and integrated with a high-quality, evidence-based 
behavioral treatment, improve alcoholism treatment outcomes above those of the behavioral treatment 
without the hallucinogen?    
Building on our open-label pilot study [2, 3], we propose a multi-site, double-blind, active-controlled trial (n = 
180) designed to assess the effects of psilocybin when administered orally to alcohol dependent 
participants receiving evidence-based psychosocial treatment as well as preparation and debriefing 
sessions that provide a supportive context for the psilocybin experience.  The duration of psychosocial 
treatment in the double blind period will be 12 weeks, and double-blind drug-administration sessions will 
occur after 4 and 8 weeks. Participants will be randomly assigned to psilocybin or diphenhydramine (n = 90 
per group) in two double-blind sessions.  The first psilocybin session will employ a dose of psilocybin 25 
mg/70 kg. The dose may be increased in the second session to 30 mg/70 kg or 40 mg/70kg based on 
response in the first session. The dose of diphenhydramine will start at 50 mg, and may be increased to 
100 mg in the second session. Following completion of the double-blind period (34 weeks after 
randomization) all participants who meet interim safety criteria will be offered an additional session in which 
psilocybin will be administered, and participants will be followed for an additional 16 weeks. Drinking 
outcomes and changes in several potential mediators of treatment effect, including motivation, self-efficacy, 
craving, depression, anxiety, and spiritual dimensions of the experience, will be measured until 50 weeks 
after the first psilocybin session, for a total of 54 weeks. 
Aim 1: To characterize the acute effects of PO psilocybin 25 mg/70 kg, 30 mg/70 kg, and 40 mg/70 kg in 
alcohol dependent patients:  Hypothesis 1:  The drug will be well-tolerated, and acute effects will be similar 
to those observed in normal volunteers. 
Aim 2: To evaluate the effect of psilocybin treatment on drinking outcomes for 32 weeks after the first 
administration, relative to diphenhydramine control.  Hypothesis 2: A greater decrease in percent heavy 
drinking days will be observed among participants receiving psychoactive doses of psilocybin in 
combination with psychosocial treatment than in those receiving diphenhydramine. 
Aim 3: To test whether or not characteristics of the drug administration session experiences mediate 
effects of psilocybin on short term (1 week) persisting effects and post-session drinking behavior. 
Hypothesis 3: Intensity of experience during the drug administration sessions will predict post-session 
changes in craving, self-efficacy, and motivation, and these changes will in turn predict changes in drinking 
behavior during the 32 weeks following initial drug administration. 
Aim 4:  To evaluate the explanatory value of changes in alcohol craving, self-efficacy, motivation, and other 
psychological domains in accounting for the observed experimental effect of psilocybin relative to 
diphenhydramine control.  Hypothesis 4: Changes in craving, self-efficacy, and motivation will mediate the 
effects of psilocybin treatment on drinking behavior. 
Aim 5: To evaluate pre-post changes in drinking in participants after they receive psilocybin in the third 
session. Hypothesis 5: participants in the control group will show decreases in drinking during the 16 weeks 
following the psilocybin session at week 38. 
 
 


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3. RESEARCH STRATEGY 
3.1 Significance 
3.1.1 Public Health Impact of Drinking 
Of all drugs of abuse, alcohol is possibly the most damaging in the US and globally when factoring in 
preventable death, premature death, disability, healthcare/societal costs, adverse medical and 
neuropsychiatric complications, unintentional injuries, and its significant causal link to suicidal and violent 
behaviors. Alcohol use disorders (AUDs) are highly prevalent in the US, affecting up to 12% of the population 
at some point in their lifetimes [4]. AUDs are among the most disabling of all diseases worldwide, and alcohol 
use is responsible for approximately 4.6% of global disability-adjusted life-years and 36.4% of neuropsychiatric 
disability-adjusted life-years in 2004 [5]. In the US alcohol accounts for 12.1% of disability-adjusted life-years in 
men, and 4.6% in women [5]. In attempting to rank the relative harm of drugs of abuse, Nutt and colleagues 
created a relative ranking scale of harm from drugs of abuse in the UK, (looking at harmful effects both to the 
individual user and community), alcohol ranked first out of all drugs of abuse, ahead of other notoriously 
harmful drugs such as crack cocaine and heroin. With scores of 0–100 (no harm to maximum harm), alcohol 
scored 72 compared to heroin (55, second) and crack cocaine (54, third), with Psilocybe mushrooms coming in 
last (6), rated as the least harmful drug to society [6].  The economic cost of alcohol use is staggering, 
estimated at $185 billion per annum in the US alone, vs. $158 billion for nicotine and $280 billion for illicit drugs 
(higher because of costs related to criminalization) [7]. 
3.1.2 Limitations of Currently Available Treatments for Addiction 
Addictions exemplify the resistance of maladaptive behaviors to interventions aimed at bringing about change.  
Substantial progress has been made in understanding the neurobiological and neuropsychological 
underpinnings of the loss of control that is the hallmark of addiction.  A number of pharmacological and 
behavioral treatments have been developed that target specific aspects of addiction, including motivation, 
coping skills, social support, reward/punishment, and relapse due to stress, priming doses of the drug, or 
exposure to conditioned cues.  However, the effects of currently available treatments remain disappointingly 
small, particularly for pharmacotherapies other than agonist medications such as methadone [8].  Although 
combining effective treatments (either multiple pharmacotherapies or pharmacotherapy plus behavioral 
therapy) is an obvious strategy to increase treatment effect sizes, attempts to improve outcomes by 
combination therapy have been largely disappointing [9, 10]. 
3.1.3  The Use of Hallucinogens to Treat Addiction 
In the 1950s through early 1970s there was extensive research on the use of the prototypical classic 
hallucinogen LSD in the treatment of alcoholism (For reviews see [11-15]), with more limited research on LSD 
for the treatment of drug addiction [16, 17] and dipropyltryptamine (DPT) for alcohol dependence [18, 19].  At 
least a dozen trials included some form of control group [1, 20]. A recent meta-analysis [1] examined 6 
randomized trials (4 of which were fully double-blind) of LSD for alcohol dependence [21-26]. A total of 325 
participants received active treatment with LSD, and 211 received control treatment.  These studies all 
employed a single high-dose LSD session, and the vast majority of participants were male inpatient alcoholics.  
The studies were otherwise quite heterogeneous, with sample sizes varying from 20 to 176, LSD doses 
ranging from about 210 to 800 mcg, control conditions including placebo, low dose (25-50 mcg) LSD, 
ephedrine, and amphetamine, and great variability in preparation and debriefing of subjects and in the 
conditions during the LSD sessions.  At the first post-treatment follow-up (ranging from 1 month to 12 months) 
the odds ratio for improvement was 1.96, favoring LSD (95% confidence interval 1.36-2.84, Z = 3.59, p = 
.0003). Among the 5 studies reporting dichotomous outcomes, 59% of the LSD-treated participants were 
significantly improved, vs. 38% of the control participants (pooled benefit difference 16%, 95% confidence 
interval 8%-25%, p = .0003, number needed to treat = 6). Treatment effects decreased with the duration of 
follow-up, but remained significant at 6 months.  These effects were highly consistent across the 6 studies.  
These robust effects provide a strong rationale for resuming clinical investigation of classic hallucinogens for 
the treatment of alcoholism and other addictions.   With few exceptions, clinical research on hallucinogens was 
discontinued in the early 1970s, after enactment of the Controlled Substances Act placed all such compounds 
into the highly restrictive Schedule I class.   


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Ibogaine, a plant-derived hallucinogen with a complex pharmacological profile, later attracted interest when 
heroin addicts reported that they experienced a significantly attenuated withdrawal syndrome and 
subsequently lost the desire to use heroin after taking ibogaine.  Although initial preclinical and clinical results 
in the treatment of opioid withdrawal were encouraging, this line of research was eventually discontinued due 
to toxicity concerns [27].   
Finally, ketamine has been investigated in Russia as a potential treatment for both alcohol dependence and 
heroin dependence. Although ketamine is an NMDA receptor antagonist rather than a serotonergic 
hallucinogen, recent research reveals considerable overlap in the brain effects of these two classes of drugs 
[28]. In a controlled but non-randomized study, alcohol dependent subjects who volunteered to receive 
ketamine-assisted psychotherapy (ketamine 2.5 mg/kg IM, a dose producing prominent hallucinogen effects) 
showed significantly higher rates of abstinence at 1 year (73/111 = 65.8%) than those receiving usual care in 
the same facility (24/100 = 24%) [29]. In a randomized, double-blind trial (n = 70), heroin-dependent patients 
assigned to a single session of ketamine 2 mg/kg IM had significantly higher abstinence rates over 24 months 
of follow-up than those who received a lower, mildly psychoactive dose [30]. Both groups showed significant 
decreases in depression and anxiety which persisted for at least 6 months, but participants in the high-dose 
condition demonstrated greater and more enduring reductions in heroin craving. In a second study (n = 53), 
patients receiving 2 or 3 ketamine sessions had higher abstinence rates over 1 year of follow-up (50% 
continuous abstinence at 1 year) than those who received 1 session (22% continuous abstinence) [31]. Off-
label use of ketamine for alcohol dependence has been reported in the US, but quantitative outcome data are 
not available [32].  Ketamine also has been shown to produce rapid and robust antidepressant effects in 
patients with treatment-resistant major depression and bipolar depression [33-39]. 
3.1.4 Recent Clinical Trials of Psilocybin as Treatment for Various Conditions 
The past decade has seen a resurgence of interest in potential clinical applications of classic hallucinogens, 
particularly psilocybin.  The effect of varying doses of psilocybin (doses up to 0.3 mg/kg PO) on symptoms of 
obsessive compulsive disorder was tested in 9 subjects in a within-subjects design [40].  All doses tested 
produced significant decreases in OCD symptomatology, but there was no effect of dose or dose-by-time 
interaction.  Using a double-blind, cross-over design, Grob et al. administered psilocybin 0.2 mg/kg vs. placebo 
to 12 patients with anxiety related to advanced cancer [41]. Although significant treatment effects were not 
demonstrated in this pilot study, there were statistical trends suggesting a positive effect of psilocybin on mood.  
The low dose used may have limited efficacy in this study. Additional clinical trials are currently under way in 
cancer patients.  Currently, psilocybin is being investigated as an adjunct in smoking cessation treatment in an 
open-label pilot study at Johns Hopkins University [42].   
3.1.5 Safety of Classic Hallucinogens 
Extensive clinical research with the classic hallucinogens (LSD, psilocybin, DMT, mescaline) has 
established their relative safety within a clinical research setting when subjects are carefully screened, 
supervised, and followed up [43]. Although classic hallucinogens present significant dangers if misused or 
abused, they do not cause physical dependence, and full-blown psychological dependence appears to be 
relatively infrequent among users [44, 45].  Psilocybin, like other classic hallucinogens, is not reliably 
reinforcing in humans or in animal models used to study addiction potential [46].  Hallucinogen persisting 
perception disorder, though poorly understood, appears to be uncommon, even less so in research than 
illicit use settings, and more common following LSD use than use of other hallucinogens [47] (See Section 
4.1.3 for discussion of risks and Section 4.2.2 for protections against risks).    
3.1.6 Relationship of Sacramental Hallucinogen Use to Use of Other Substances 
Cross-sectional studies have consistently shown decreased rates of alcohol dependence among members of 
religions that use classic hallucinogens as a regular part of their practice, including the Native American 
Church, which uses the mescaline-containing peyote cactus as a sacrament [48], and both Brazilian [49, 50] 
and US [51] sects using ayahuasca (a botanical preparation which contains DMT and monoamine oxidase 
inhibitors that render DMT orally active). Although cultural norms within these religions likely contribute to such 
effects, the pattern suggests the possibility of a pharmacological effect as well.   


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3.1.7 How Might a Classic Hallucinogen Affect Drinking Behavior? 
A number of articles and chapters have reviewed the literature on the use of hallucinogens in the treatment of 
addictions [11-15], with the recent addition of two reviews that incorporate current research on the effects of 
classic hallucinogens more generally and discuss possible mechanisms of action [52, 53].  Here we provide a 
brief summary of the most important lines of evidence. 
3.1.7.1 Relevant Preclinical Research 
Although classic hallucinogens bind to many serotonin receptor subtypes and other receptors including D1 and 
D3 receptors [54], the psychoactive effects of all classic hallucinogens appear to depend primarily on their 
actions at 5HT2A receptors [28, 55].  Ketanserin, a 5HT2A antagonist, blocks most of the subjective effects of 
psilocybin in humans  [56].  Stimulation of 5HT2A receptors by 5HT2A agonists causes activation of sub-
populations of pyramidal cells in cerebral cortex by enhancing glutamatergic neurotransmission within 
intracortical networks, particularly those involving cortical layer V [57-60]. In mouse models, effects of 
hallucinogenic 5HT2A agonists are mediated by different intracellular signaling cascades from those activated 
by serotonin and non-hallucinogenic 5HT2A agonists [61-63]. The effects of LSD are mediated in part by 
pathways involving pertussis toxin-sensitive Gi/o proteins and Src, while the effects of lisuride (a non-
hallucinogenic 5HT2A agonist) do not depend on these pathways [61]. Moreno and colleagues demonstrated 
that the metabotropic glutamate mGlu2 receptor, which forms complexes with 5HT2A receptors, is necessary 
for the pharmacological and behavioral effects of hallucinogenic 5-HT2A agonists [64].  
Very little is known about persisting brain changes related to use of classic hallucinogens in treatment of 
addiction, but there are animal data suggesting directions for future research.  Administration of classic 
hallucinogens in rat models has been shown to induce down-regulation of 5HT2A receptors, particularly those 
in the anterior cingulate and frontomedial cortex, likely accounting for the rapid development and reversal of 
behavioral tolerance to most classic hallucinogens [65, 66].  This is interesting in relation to evidence that 
5HT2A receptors are upregulated with chronic alcohol exposure [67]. DOI and serotonin increase expression 
of glial cell line-derived neurotrophic factor (GDNF) mRNA in glioiblastoma cells by a 5HT2A-dependent 
mechanism [68].  Through its action on 5HT2A receptors, DOI has also been shown to increase levels of 
mRNA for brain-derived neurotrophic factor (BDNF) in rat parietal cortex and other neocortical regions, with 
decreases in the hippocampus and no change in piriform cortex [69]. These findings are relevant because 
levels of BDNF and GDNF are inversely related to alcohol consumption and conditioned place preference in 
animal models [70]. DOI activates intracellular signaling cascades associated with dendritic spine remodeling 
on rat pyramidal cells, and transiently increases the size of dendritic spines on cortical neurons [71].  At 
present there is no direct evidence as to whether any of these mechanisms mediates antiaddictive effects of 
classic hallucinogens.   
3.1.8 Neuroimaging Studies of Acute Effects of Classic Hallucinogens Human Brain Function 
PET, SPECT, and fMRI technologies have been applied to studies of the acute effects of classic 
hallucinogens, specifically psilocybin and ayahuasca (an herbal decoction containing dimethyltryptamine 
(DMT) and beta-carbolines including harmine, harmaline, and tetrahydroharmine).  The beta-carbolines are 
monoamine oxidase inhibitors that render DMT orally active, as well as having psychoactive effects 
themselves). In a PET study of effects of psilocybin (15-20 mg PO), Vollenweider and colleagues found that 
global cerebral glucose metabolism increased by 19.9% relative to baseline, with the largest increases in 
thalamus and frontomedial, frontolateral, anterior cingulate, and temporomedial cortices [72]. In a placebo-
controlled study by the same group, psilocybin 0.2 mg/kg produced increased glucose metabolism in the right 
anterior cingulate and right frontal operculum, with decreased metabolism in the right thalamus and left 
precentral cortex [73]. A placebo-controlled SPECT study of ayahuasca administration by Riba and colleagues 
demonstrated increased blood flow in the anterior insula bilaterally, in right anterior cingulate/frontomedial 
cortex, and in the left amygdala/parahippocampal gyrus [74].  In contrast, a recent fMRI study from Carhart-
Harris and colleagues using psilocybin 2mg administered intravenously, found that psilocybin administration 
was associated with decreases in regional cerebral blood flow and BOLD signal, with strongest effects in 
anterior cingulate cortex/medial prefrontal cortex, posterior cingulate cortex, and thalamus [75]. Psilocybin also 
decreased functional coupling between medial prefrontal cortex and posterior cingulate cortex. A secondary 
analysis of data from this study showed that during the acute effects of psilocybin there was increased 


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functional connectivity between two important brain networks: the default mode network, normally activated 
during internally oriented thinking, and the task-positive network, normally activated when attention is oriented 
toward external events or activities [76].  This could provide a biological explanation for the blurring of self-
other boundaries that is often a prominent feature of hallucinogen effects.   Another report from this group 
demonstrated that intravenous psilocybin increased activation in multiple brain regions in response to 
recollection of autobiographical events [77]. Clearly we are only beginning to understand the acute effects of 
classic hallucinogens on brain function.  In addition, there have been no neuroimaging studies of the persisting 
effects of classic hallucinogens. Since effects of some sort must persist beyond the period of acute intoxication 
for the treatment to have any clinical value, persisting brain effects are more directly relevant to therapeutic 
benefit than are acute brain effects.  
3.1.8.1 Can Administration of Classic Hallucinogens Precipitate or Facilitate Lasting Psychological 
Change? 
Although alcoholism is a disorder which frequently has a chronic or relapsing course [78], rapid, profound, and 
lasting behavior change can and does occur.  Over one hundred years ago William James described the 
phenomenon of sudden transformative change of a religious or spiritual nature [79], which was often 
accompanied by changes in behavior such as the abrupt onset of sobriety in alcoholics.  More recently, William 
R. Miller and others have elucidated the nature of what has been termed “quantum change” [80, 81]. Sudden 
and lasting behavior change can be triggered by an acute transformative experience that is frequently but not 
always described as spiritual in nature. Such experiences figure prominently in the AA literature [82].  In a large 
(n = 587) alcoholism treatment sample, reporting a recent “spiritual awakening” was associated with markedly 
increased rates of 12-month continuous abstinence (odds ration = 3.9) [83].  These experiences are not 
uncommon in the general population or among alcoholics [84].  However, there has never been a reliable way 
to elicit and apply such experiences to mobilize predictable change in a particular behavioral disorder such as 
alcohol dependence. 
Classic hallucinogens (primarily LSD) were studied extensively from the 1950s through the early 1970s in the 
treatment of alcohol and drug addiction as well as anxiety, depression, obsessive-compulsive disorder, and 
other conditions. Two contrasting models of treatment developed: the psycholytic and psychedelic models [15, 
85].  In psycholytic therapy, low to moderate doses of hallucinogens were administered, usually on many 
occasions over a period of months to years, to facilitate therapy based on traditional psychoanalytic principles 
[86, 87].  The psychedelic method used higher doses of LSD, administered once or on a few occasions, with 
the goal of inducing a “peak-psychedelic” experience [88, 89]. The psychedelic model held that such 
experiences often produced lasting change in habitual patterns of thought, emotional response, and behavior. 
Many of the studies from the 1960s, particularly those employing the psychedelic model, reported changes on 
measures of personality following hallucinogen administration [90-94].  
More recently, rigorous quantitative studies have demonstrated that psilocybin can occasion profoundly 
meaningful experiences that have significant lasting effects in normal volunteers [95-98].  In a double-blind 
study by Griffiths and colleagues, 22 out of 36 participants receiving a single high-dose psilocybin session met 
a priori criteria for a “complete mystical experience” (score of 0.6 or greater on 6 subscales of the Pahnke-
Richards Mystical Experience Questionnaire [97]). Fourteen months after the psilocybin session, 67% of 
participants rated it as one of the 5 most significant spiritual experiences of their lives, and 61% reported that 
the experience was associated with “moderate to extreme positive behavioral change,” as well as positive 
changes in attitudes, mood, and altruism [96]. These self-reports correlated with ratings by community 
observers who reported similar positive changes in participants. In a second study in which participants 
received a range of doses of psilocybin, 72% of volunteers reported a “complete mystical experience” at one of 
the highest two doses [98]. Persisting positive effects one month after the psilocybin session were found to be 
dose-related.   


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Based on these data, we have proposed a number of possible causal pathways that could lead to therapeutic 
effects of classic hallucinogens in the treatment of addiction (See Figure 1) [99].  Briefly, the effects of classic 
hallucinogens are expected to be highly dependent on environmental and subject factors (the “set and setting 
hypothesis”).  Acute brain effects may be measured at the level of the receptor, neuron, functional network, or 
patient-reported subjective 
experience.  Persisting 
effects likewise may be 
measured in terms of 
structural and functional 
brain changes as well as in 
psychological terms.  
Ultimately, to affect drinking 
behavior, this causal chain 
would need to lead to effects 
that directly affect drinking, 
such as decreased craving 
or enhanced self-efficacy or 
motivation. Is must be 
stressed that the specific 
mediators listed here are 
hypothesized based on what 
is known about the effects of 
classic hallucinogens and 
change processes in 
addiction, but have not been 
directly investigated in 
addiction treatment trials.  
The proposed study will 
examine the effects of 
psilocybin administration on 
several of these possible mediating variables. 
3.2 Innovation 
The proposed study brings together experienced researchers at the nexus of their areas of expertise to 
conduct a study that is highly innovative in several respects. The evidence summarized above, coming from 
several sources, provides a convincing rationale for reopening the question of whether a classic 
hallucinogen can improve treatment response among patients with alcohol dependence. Although this is not 
a novel question, it has not been investigated for 4 decades.  In spite of the accumulating data indicating 
that psilocybin has clinically relevant effects and is relatively safe under controlled conditions, our pilot 
study is the only trial that has ever has been conducted using psilocybin in the treatment of alcohol 
dependence. There have been no recent controlled trials using any drug in this class in the treatment of 
addiction.  The proposed study is highly innovative because classic hallucinogens have effects and 
mechanisms of action that are entirely distinct from any medications that are currently used in treatment of 
addiction. This study will be the first to use modern clinical trials technology to study the effects of a classic 
hallucinogen in alcohol dependent subjects, and the first controlled trial to use an established evidence-
based behavioral therapy in combination with hallucinogen administration in the treatment of addiction.  
This study will also be the first controlled trial to investigate whether putative change mechanisms are 
mobilized by administration of psilocybin to alcohol dependent patients.  More broadly, the administration of 
hallucinogens provides an attractive experimental model to study the phenomenon of quantum change, in 
which a single transformative experience can produce lasting and meaningful behavior change.  
3.3 Approach 
3.3.1 Design Overview 
Participant
Acute Brain Effects
Acute Psychological Effects
Direct effects 
on serotonin 
receptors
Secondary effects 
e.g. on glutamate 
receptors
“Quantum change” or “mystical-
type” experience, 
psychological insight
Enhanced Self-efficacy
Increased Motivation
Reduced Substance Use
Setting
Drug
Decreased Craving
Persisting Effects
Final Change Mechanisms
Improved Mood, 
Decreased Anxiety
Changes in 
Personality
Neuroplastic and 
Functional Changes
Changes in Beliefs 
and Values
Figure 1


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The proposed investigation is a multi-site (2-4 sites), double-blind, active-controlled trial (n = 180, 90 per 
group) contrasting the acute and persisting effects of psilocybin to those of diphenhydramine in the context 
of outpatient alcoholism treatment. During the double-blind phase, participants will receive psilocybin or 
diphenhydramine in two monthly sessions, with dose for the second session titrated base on response in 
the first session. Following completion of the double-blind phase of the protocol (at week 38, 34 weeks after 
randomization) all participants who meet interim safety criteria will be offered an additional session in which 
psilocybin will be administered, and participants will be followed for an additional 16 weeks. The drug will 
be administered during 8 hour sessions in an outpatient setting under close medical and psychiatric 
monitoring. The drug administration sessions will occur in the context of a behavioral intervention consisting 
of an extended version of Motivational Enhancement Therapy, (Motivational Enhancement Therapy and 
Taking Action, META), with the addition of standardized preparation before and debriefing and follow-up 
after the psilocybin administration sessions. Extensive screening and baseline assessment will be 
completed, including thorough safety screening and assessment of participant characteristics that could 
potentially moderate treatment response. Within-session and short-term persisting effects will be assessed. 
Drinking outcomes and changes in several potential mediators of treatment effect, including motivation, 
self-efficacy, craving, depression, anxiety, and spiritual dimensions of the experience, will be measured for 
50 weeks following initial administration of study medication (See Figure 2).  
 
Figure 2: Overview of study design 
 
 
 
 
Study period 
 
Week 
 
 
 
Treatment 
 
 
 
Assessment 
 
 
 
 
Period 1 
-4 to -1 
 
 
 
 
Screening 
 
 
 
Pre-treatment 
-1 to 0 
 
 
 
 
Baseline 
 
 
 
Period 2 
0 
 
 
1 (META) 
 
 
 
 
 
 Pre-Randomization 
1 
 
 
2 (META) 
 
 
 
 
 
 
 
2 
 
 
3 (PSI) 
 
 
 
 
 
 
 
3 
 
 
4 (PSI) 
 
 
 
 
 
 
 
4 
 
Psilocybin  
25mg/70kg 
5 (PSI) 
Diphenhydramine 
50 mg 
 
4 weeks 
 
 
 
 
 
 
 
 
 
 
4.1 
 
 
6 (PSI) 
 
 
 
 
 
 
 
5 
 
 
7 (META) 
 
 
5 weeks 
 
 
 
Period 3 
6 
 
 
8 (META) 
 
 
 
 
 
 
Double-blind 
7 
 
 
9 (PSI) 
 
 
 
 
 
 
Phase 
8 
 
Psilocybin  
25-40mg/70kg* 
10 (PS1) 
Diphenhydramine 
50-100 mg* 
 
8 weeks 
 
 
 
 
8.1 
 
 
11 (PSI) 
 
 
 
 
 
 
 
9 
 
 
12 (META) 
 
 
9 weeks 
 
 
 
 
10 
 
 
13 (META) 
 
 
 
 
 
 
 
12 
 
 
14 (META/PSI) 
 
12 weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
24 weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.3.2 Primary Outcome 
The primary outcome for the study, used to test hypothesis 2, is percent heavy drinking days as assessed 
by the Time-line Follow-back [100], during the 32 weeks following the first drug administration session. 
Secondary drinking outcomes will include percent days abstinent, drinks per drinking day, days to first 
drinking day, days to first heavy drinking day, and consequences of drinking (from the Short Inventory of 
Problems [101]).   
3.3.3 Preliminary Studies  
The UNM team has conducted an open-label pilot study of psilocybin for alcohol dependence, which is now 
nearing completion.  In the pilot study, participants receive two psilocybin sessions at 4 weeks and 8 weeks 
in the context of 12 weeks of psychosocial treatment.  The first dose of psilocybin is 0.3 mg/kg, and the 
second dose is 0.3 mg/kg or 0.4 mg/kg, depending on the effects of the first session.  Participants are 
assessed at baseline, 4 weeks (prior to first drug administration) 5 weeks (1 week after drug 
administration), 8 weeks (prior to second drug administration), 12 weeks, 24 weeks, and 36 weeks.   
3.3.3.1 Behavioral Interventions Used in UNM Pilot Study 
Behavioral interventions for alcoholism treatment require adaptation for use in combination with classic 
hallucinogens with the following issues in mind. It is crucial to provide a supportive context for hallucinogen 
administration sessions, including preparation before and debriefing after psilocybin administration. Proper 
preparation for a hallucinogen session is critical to establish a therapeutic “set” and to minimize the 
likelihood of adverse psychological reactions.  The debriefing process is intended to help the participant 
integrate and process the experience, and to assess for the presence of any adverse reactions that may 
require attention.  The ideal behavioral treatment for use in a trial of a hallucinogen administration protocol 
would be broadly effective and have the potential to work synergistically with the hypothesized mechanisms 
of action of the hallucinogen.  The length of the behavioral treatment should be appropriate to the duration 
of the pharmacotherapy.  
Based on these considerations, we developed a manualized 12-session behavioral intervention for use 
together with the two psilocybin administration sessions in the pilot study.  The behavioral intervention 
comprised 7 sessions of Motivational Enhancement Therapy (MET: a structured approach using the 
principles of Motivational Interviewing [102]), including 4 standard MET sessions and 3 booster sessions; 3 
preparation sessions; and 2 debriefing sessions (The MET sessions also provided some opportunity for 
debriefing). The MET content was based on procedures used previously in multisite trials [103, 104]. The 
second MET session provided an opportunity to focus specifically on the participant’s values (including 
spiritual values) and the discrepancy between values and behavior as motivation for change. Subsequent 
sessions followed up on the participant’s goals and change plan in relation to these values.  The 
preparation and debriefing procedures were based on those of the Johns Hopkins group [105] and those 
used in other prior hallucinogen administration studies [106-108].  Preparation and debriefing sessions 
were conducted by a study physician together with the MET therapist, while the MET sessions were 
normally conducted by the MET therapist alone.  
 
 
36 
 
 
 
 
 
36 weeks 
 
 
 
 
37 
 
 
15 (PSI) 
 
 
 
 
 
 
Period 4 
Open-label 
38 
 
Psilocybin  
25-40mg/70kg* 
16 (PSI) 
Psilocybin  
25mg/70kg 
 
38 weeks 
 
 
 
Extension phase 
38.1 
 
 
17 (PSI) 
 
 
 
 
 
 
 
39 
 
 
18 (META/PSI)  
 
 
39 weeks 
 
 
 
 
42 
 
 
19 (META/PSI)  
 
 
42 weeks 
 
 
 
 
54 
 
 
 
 
 
54 weeks 
 
 
 
*Dose titrated based on response in prior session, see section 3.3.8.1.3 
 
 


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Overall, this therapy model appeared to work well in the context of a 12-week, 2-session treatment model. 
The preparation and debriefing procedures appeared to be effective.  The MET seemed to function well to 
engage patients in treatment, to enhance their motivation for change prior to the first psilocybin session, 
and to elicit reasons for change and initial change plans. However, therapists reported that most 
participants were ready to take active steps toward change after the first psilocybin session, and felt that 
they would have benefitted from more action-oriented treatment. 
3.3.3.2 Pilot Study Results 
Figure 3 illustrates available pilot results by individual through week 8.  Participants were 6 men and 4 
women, mean age 40.1 (S.D. 10.3), who were concerned about their drinking but not interested in available 
treatment.  Participants had been alcohol dependent for a mean of 15.1 years (S.D. 11.5) and ranged in 
severity from mild to severe dependence with a mean of 5.0 dependence criteria (S.D. 1.2).   
Participants have tolerated psilocybin well in the pilot study. Transient mild headaches have been common 
during the 24 hours following psilocybin administration, as reported by Johnson et al. [109]. There have 
been no persisting adverse events that were considered related to the study treatments. Figure 3a shows 
mean scores on the Mystical Experience Questionnaire (MEQ) total score for the 10 participants receiving 
0.3 mg/kg in the first session and 5 participants receiving 0.4 mg/kg in the second session, as well as 
scores reported at similar doses in normal volunteers by Griffiths et al. [110]. On average, acute effects are 
lower in magnitude than those seen at comparable doses in normal volunteers.  Intensity of effects varied 
markedly from patient to patient, with MEQ scores ranging from .02 to .77 in the first session, and 
Hallucinogen Rating Scale (HRS) intensity scores ranging from 0 to 3.5. The mean score for the 0.4 mg/kg 
dose appears to be lower than that at 0.3 mg/kg. This is probably because the four participants with the 
strongest response in the first session did not receive 0.4 mg/kg in the second session. 
Results (n=9) for the month before and the two months after the first psilocybin session are shown in 
Figures 3b-3d. Participants showed modest change in drinking behavior during the first month of 
psychosocial treatment.  However, drinking days and heavy drinking days decreased significantly during the 
month following the first psilocybin session.  Changes in drinking were accompanied by modest significant 
increases in self-efficacy (AASE confidence scale) following the psilocybin session.  Importantly, the 
magnitude of the effects reported during the first psilocybin session (at week 4) is strongly correlated with 
changes in craving and self-efficacy in the week following the session, and with changes in drinking in the 
month following the session.  In addition, changes in craving and self-efficacy at week 5 are correlated with 
changes in drinking during weeks 5-8 relative to weeks 1-4.  


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Figure 3a. MEQ Total Score
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Alcoholic  (current study)      Normal*
0.3mg/kg (n=10)
0.4mg/kg (n=6)
.29mg/kg
.43mg/kg
*Griffiths et al. 2011
max 0.77
max 0.92
min .0.02
min .0.01
Figure 3b. Percent drinking days and 
Percent heavy drinking days
0
5
10
15
20
25
30
35
40
45
Baseline
Month 1 
(before S1)
Month 2   
(after S1)
Month 3
Drinking days
Heavy drinking days
*
*
*
*
* Different from baseline and 
Month 1, all p < .05
Except month 1 vs. month 3 
percent heavy drinking days, p = 
Figure 3c. Self-Efficacy (AASE Confidence)
0
10
20
30
40
50
60
pre-treatment
Month 1 (before S1)
1 week after S1
4 weeks after S1
*
#
* Different from baseline (p = .019)  and Month 1 (p = .008) 
# Different from Month 1 (p = .085)
Figure 3d. Correlations with intensity of 1st session
Pearson’s r 
(n = 9)
Change in 
PACS
(wk 5-wk 4)
Change in 
AASE conf.
(wk 5-wk 4)
Change in 
PDD
(wk 8-wk 4)
Change in 
PHDD
(wk 8-wk 4)
MEQ total 
(wk 4)
r  = -.810
p = .008
r  = .762
p = .017
r =-.884
p = .002
r = -.823
p = .006
HRS Intensity 
Scale (wk 4)
r  = -.823
p = .006
r  = .753
p = .019
r = -.834
p = .005
r = -.762
p = .017
HRS item 98
(wk 4)
r  = -.862
p = .003
r  = .803
p = .009
r = -.826
p = .006
r = -.711
p = .032
Change in 
PACS
(wk 5-wk 4)
r  = .762
p = .017
r  = .726
p = .027
Change in 
AASE conf.
(wk 5 – wk 4)
r  = -.611
p = .081
r  = -.494
p = .177
 
3.3.4 Recruitment, Pre-screening, and Informed Consent 
Participants will be recruited from the community using advertisements in local media and flyers, a 
methodology we have used successfully in many prior studies.  Recruitment will use a combination of the 
following methods:  1) Advertising in local print media; 2) Advertising in electronic media such as Craigslist; 3) 
Flyers placed in community locations where this is permitted.  Those who are interested will be pre-screened 
using an IRB-approved pre-screening form including basic demographic data and questions related to 
inclusion and exclusion criteria.  Those who pass pre-screening will be scheduled for a screening visit.  
Informed consent will be conducted by a trained investigator who is knowledgeable about the effects of 
hallucinogens as well as all aspects of the protocol.  Details of the informed consent process are described 
in Section 4. 
3.3.5 Randomization and Blinding 
Randomization will be performed as close as possible to the first drug administration session (on the 
morning of the session if possible) in order to restrict the intent-to-treat sample to patients who actually 
receive study medication.  The randomization will be stratified by site and will consist of balanced varied 
size blocks within strata to ensure relative equality of assignment across treatment groups. The block sizes 
will not be revealed to participating investigators and will be randomly selected from a small number of 
different block sizes to help reduce the likelihood of an investigator predicting the next treatment 
assignment. The study statistician will generate the randomization scheme for each site, and the study 
pharmacist will assign treatment sequentially according the sequence for each site.  


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3.3.6 Study Participants 
Participants will be recruited from the community through advertising and referral, according to recruitment 
plans to be developed locally at each site. 
3.3.6.1 Inclusion Criteria 
Participants will be: 
1) Males and females age 25-65 with SCID (DSM-IV) diagnosis of alcohol dependence who 
2) Want to stop or decrease their drinking  
3) Are not participating in any formal treatment for alcohol dependence (12-step meetings are not 
considered treatment)  
4) Are able to provide voluntary informed consent  
5) Have at least 4 heavy drinking days in the past 30 days  
6) If female of childbearing potential, are willing to use approved form of contraception# from screening 
until after the psilocybin administration sessions  
7) Have a family member or friend who can pick them up and stay with them overnight after the 
psilocybin administration sessions  
8) Are able to provide adequate locator information.  
3.3.6.2 Exclusion Criteria  
Participants will be excluded if they have: 
1) Medical conditions that would preclude safe participation in the trial (e.g., seizure disorder, 
significantly impaired liver function*, coronary artery disease, history of arrhythmia, heart failure, 
uncontrolled hypertension (above 165/95 mmHg at screening), history of cerebrovascular 
accident, severe asthma^, hyperthyroidism, narrow-angle glaucoma, stenosing peptic ulcer, 
pyloroduodenal obstruction, symptomatic prostatic hypertrophy, or bladder-neck obstruction)  
2) Exclusionary psychiatric conditions (schizophrenia, schizoaffective disorder, bipolar disorder, 
current major depressive episode, current post-traumatic stress disorder, current suicidality or 
history of medically serious suicide attempt)  
3) Cognitive impairment (Folstein Mini Mental State Exam [111] score < 26) 
4) A family history of schizophrenia or schizoaffective disorder (first or second degree relatives), or 
bipolar disorder type 1 (first degree relatives)  
5) History of hallucinogen use disorder, any use in the past 1 year, or >25 lifetime uses;  
6) Cocaine, psychostimulant, opioid, or cannabis dependence (past 12 months)  
7) Current non-medical use of cocaine, psychostimulants, or opioids (past 30 days) 
8) Significant alcohol withdrawal (CIWA-Ar score greater than 7. Patients presenting at screening in 
withdrawal may be referred for detoxification and reassessed within 30 days)  
9) Serious ECG abnormalities (e.g., evidence of ischemia, myocardial infarction, QTc prolongation 
(QTc > 0.45 seconds for men, QTc > 0.47 seconds for women)) 
10) Serious abnormalities of complete blood count or chemistries   
11) Active legal problems with the potential to result in incarceration  
12) Pregnancy or lactation   
13) Need to take medication with significant potential to interact with study medications (e.g., 
antidepressants, antipsychotics, psychostimulants, treatments for addictions, other dopaminergic 
or serotonergic agents, lithium, anticonvulsants).   
14) Allergy or hypersensitivity to psilocybin or diphenhydramine.  
15) High risk of adverse emotional or behavioral reaction based on investigator’s clinical evaluation 
(e.g., evidence of serious personality disorder, antisocial behavior, serious current stressors, 
lack of meaningful social support). 
Participants with elevated blood pressure on screening (i.e., reading above 140/90 mmHg but no higher 
than 165/95 mmHg) who otherwise qualify for the study may be provisionally included and referred to their 
primary care provider for management of hypertension. For all participants, vital signs will be measured at 
all assessment visits, and may be monitored at therapy visits at the discretion of the study physician. 


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Participants will receive study medication only if blood pressure is less than or equal to 140 systolic, 90 
diastolic at safety screening on the day of the drug administration sessions. Participants with a blood 
pressure reading greater than 165/95 at screening will be excluded from the study. 
Participants with a BMI exceeding 35 at screening who otherwise qualify for the study will be administered 
a dose of study medication that corresponds to the body weight that would yield a BMI of 35 for their height. 
#Acceptable methods of contraception include oral contraceptives, barrier with spermicide, IUD, 
levonorgestrel implant (Norplant), medroxyprogesterone acetate (Depo provera), surgical sterilization, 
contraceptive patch, vaginal contraceptive ring, and complete abstinence (not having sex). 
*Significantly impaired liver function is defined as 1)  Alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) > 5 × upper limit of normal (ULN); 2) ALT or AST > 3 × ULN with concomitant total 
bilirubin > 2.0 × ULN; or 3) ALT or AST ≥ 3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia.  
^Severe asthma is defined as asthma diagnosis along with any of the following: 1) an active or chronic 
cough, 2) current respiratory infection 3) current difficulty breathing 4) asthma-related emergency room 
visit, hospitalization, or oral, intravenous, or intramuscular steroidal treatment within the past 6 months. 
Participants with asthma diagnosis that are included in the study and are currently using an inhaler will be 
asked to bring their inhaler to the medication sessions.  
3.3.7 Sites 
Up to 4 sites will participate in the trial. Sites will be selected on the basis of experience with administration of 
classic hallucinogens, other clinical trial experience, available staff, available facilities, regulatory approvals, 
and institutional support.   
3.3.8 Study Treatments 
3.3.8.1 Pharmacologic Interventions 
3.3.8.1.1 Psilocybin 
Psilocybin has some advantages over other classic hallucinogens.  Recent human studies with psilocybin 
confirm the relatively benign safety profile [40, 41, 97, 112].  Its duration of action (approximately 6 hours) is 
intermediate between that of LSD or mescaline and that of DMT. This duration makes it practical to 
administer during a session lasting no more than 8 hours, but, unlike DMT, allows ample time for the 
experience to be integrated into normal consciousness.  Unlike DMT, it can be administered orally.  
Psilocybin will be obtained from a laboratory capable of producing psilocybin meeting CMC requirements 
for use under IND 113080. Study drug will only be used in patients following acceptable testing results after 
shipment to the site. Psilocybin will be stored according to state and federal regulatory requirements for 
handling of a schedule I drug. The appropriate schedule I research licenses will be obtained at each 
institution. 
3.3.8.1.2 Diphenhydramine 
It is difficult to create a suitable blind when the active treatment elicits a powerful subjective effect.  The 
purpose of a psychoactive control medication is to create uncertainty as to which medication was 
administered, and to minimize disappointment due to not receiving active medication. Niacin has been used 
in some studies because it causes flushing but is essentially a placebo [106, 113]. Griffiths and colleagues 
have used methylphenidate as a psychoactive control [97].  
We propose to use diphenhydramine in the dose range of 50-100 mg as the control condition. In this dose 
range, diphenhydramine has noticeable subjective effects [114], and could possibly be mistaken for 
psilocybin by psychedelic-naive participants. Diphenhydramine also has a high index of safety and very low 
abuse potential [115-118]. There is no evidence that it is effective in the treatment of alcohol dependence.  
3.3.8.1.3 Dosing and Administration of Study Medications 


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Setting. The psilocybin sessions will take place in outpatient facilities that are appropriate for hallucinogen 
administration sessions. To the extent possible, the room used for the session will be specially prepared for 
the sessions to provide a warm and home-like rather than a stark clinical quality because of the large 
influence that setting can have on the subjective effects of hallucinogens. Each site will have detailed SOPs 
in place for managing medical or psychiatric emergencies should any occur. 
Safety Screening on the Day of Drug Administration Sessions. Participants will be required to attempt to 
remain abstinent during the week preceding the drug administration sessions.  On the morning of the 
psilocybin session, participants must have a negative breathalyzer reading, drug screen must be negative for 
all non-prescribed tested drugs of abuse except for marijuana, CIWA–Ar score must be less than 8, and vital 
signs must be within normal limits (afebrile, blood pressure less than or equal to 140 systolic, 90 diastolic, 
resting pulse less than 100). Female participants of childbearing potential must also have a negative urine 
pregnancy test.  
 
Dosing of Study Medications. Individualized doses of psilocybin will be prepared by the site pharmacist 
using an analytical balance. Medication will be placed in an opaque gelatin capsule prior to administration, 
with the balance of the capsule volume filled with microcrystalline cellulose.   
Although the optimal dose of psilocybin in the treatment of alcohol dependence is unknown, several 
arguments suggest that strong effects are likely to be predictive of therapeutic benefit.  The controlled trials 
of LSD for alcohol dependence used relatively high doses of LSD (median dose 500 mcg [1]) which 
typically produce very strong effects.  The “peak-psychedelic” experience was widely believed to be the 
active ingredient in LSD therapy for alcoholism. In published work with normal volunteers Griffiths et al. 
reported that that highest dose used (30 mg/70 kg) produced the strongest effects and the highest 
frequency of “complete mystical experience” based on their scores on the Pahnke-Richards Mystical 
Experience Questionnaire [97, 110].  The degree of mystical experience predicted spiritual significance and 
personal meaningfulness at 14 mo [119]. Participants who had a “complete mystical experience” had 
significant persistent (14 mo.) increase in the personality dimension of “openness” [120]. The 0.43 mg/kg dose 
was generally well-tolerated, although fear, anxiety, and dysphoria were common side effects, and 6/36 
participants undergoing a single session at this dose reported mild, transient paranoia or ideas of reference 
at some point during the session [97].  None of the volunteers reported persisting adverse effects or rated 
the session as having decreased their well-being or satisfaction with life.  
There are reasons to believe that higher doses of psilocybin may be needed to achieve strong effects in 
some alcoholics than the doses that reliably produce such effects in normal volunteers. In our pilot work 
doses of psilocybin 0.3 mg/kg and 0.4 mg/kg have been well-tolerated in alcohol dependent participants, 
but responses demonstrated that some alcohol dependent subjects have less pronounced response to 
psilocybin than those reported by normal volunteers, although others have strong reactions typical of non-
alcoholic individuals. This is consistent with observations beginning in the 1950s that alcoholics tended to 
show greater tolerance to the effects of LSD [107].   
To maximize the probability that participants treated with psilocybin will have strong and meaningful 
experiences while minimizing the chance of significant psychological distress or other adverse events, we 
propose to titrate the dose of study medications in the second session based on the response in the first 
session.  In the first session, participants in the psilocybin group will receive a moderately high dose of 25 
mg/70 kg.  For the second session, the dose will be titrated within a range of 25-40 mg/70 kg, depending on 
the participant’s response in the prior session. The dose will be increased if the participant tolerated the 25 
mg/70kg dose well (no clinically significant adverse psychiatric or medical effects) and is willing to increase 
the dose.  The dose will be increased to 30 mg/70kg if the participant had reported strong subjective 
response to the first session, as evidenced by a total score on the MEQ ≥ 0.6.  The dose will be increased 
to 40 mg/70 kg only if the participant a) had a relatively mild response to 25 mg/70 kg (MEQ total score < 
0.6) and b) the therapists and participant agree that increasing the dose to 40mg/70kg will be safe and will 
maximize likelihood of clinical benefit. The dose may be held at 25 mg/70 kg if the participant is not willing 
to increase the dose.  The second session will be canceled if the participant is not willing to undergo a 
second session, or if he or she experienced clinically significant adverse psychiatric or medical adverse 


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events related to the first session. Figure 4 illustrates the dosing algorithm.  The first and second decision 
points (whether to conduct the second session and whether to increase the dose) will be determined by the 
study clinicians in collaboration with the participant.  The third decision point (how much to increase the 
dose will be determined by the total score of the Mystical Experience Questionnaire (MEQ), scored by a 
trained research staff member not participating in the study treatment. 
In the control condition, the dose of diphenhydramine will be 50 mg in the first session.  In the second 
session the dose will be increased to 100 mg if the participant tolerated the 50 mg dose well (no clinically 
significant adverse psychiatric or medical effects) and is willing to increase the dose. If the participant has 
no clinically significant adverse psychiatric or medical effects but is unwilling to increase the dose, the dose 
will be held at 50 mg. If the participant is not willing to undergo a second session or experienced clinically 
significant adverse psychiatric or medical effects related to the first session, the second session will be 
canceled.  Participants who decline to participate in the second medication session of the double-blind 
phase, but otherwise complete the double-blind phase of the trial, and did not experience clinically 
significant adverse psychiatric or medical effects related to the first medication session, may participate in 
the third, open-label medication session.  
Did the participant experience clinically 
significant adverse psychiatric or 
medical effects in the first session, or is 
he/she unwilling to undergo a second 
session? 
Cancel second session.
Is the participant willing to 
increase the dose?
Second session dose:
Psilocybin 25 mg/70 kg vs.
Diphenhydramine 50 mg.
Is the MEQ total score < 0.6
AND
Baseline QTc < 0.43 seconds if male, < 0.45 
seconds if female?
Second session dose:
Psilocybin 40 mg/70 kg vs.
Diphenhydramine 100 mg. 
Second session dose: 
Psilocybin 30 mg/70 kg vs.
Diphenhydramine 100 mg. 
Figure 4: Dose Determination for Second Drug Adminstration Session
 
Prior to the third session, ECG will be repeated. The dose will again be capped at 30 mg/70 kg if QTc >0.43 
seconds or  >0.45 seconds for men and women, respectively. The session will be canceled if QTc >0.45 
seconds or 0.47 seconds for men and women respectively. Otherwise, in the third session, participants in 
the diphenhydramine group will receive psilocybin 25 mg/70 kg, and participants in the psilocybin group will 
receive the same dose they received in the second session, unless they request a lower dose, in which 
case they will receive a dose of 25 mg/70kg.  


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The pharmacologic treatment will be terminated after the first or second session if adverse events during or 
after the session suggest that another session would pose significant risk, if there are any significant 
persisting negative effects from the first session, or if the participant does not wish to complete an 
additional session. If pharmacologic treatment is terminated, the participant still will complete the 
psychosocial treatment. 
Monitoring and Safety Procedures. As psilocybin use is associated with a small risk of emesis, participants 
will be instructed to have only a light breakfast on the morning of the psilocybin administration sessions, at 
least an hour before the beginning of the session. Participants will complete assessments including 
confirmation of medical stability and drug- and alcohol-free status. (If the participant has CIWA-Ar score of 
7 or greater, need for detoxification will be assessed and the patient will be referred for treatment if 
indicated).  They will then ingest the capsule containing the study medication, followed by approximately 4 
ounces of water. Participants will remain under observation for at least 8 hours following psilocybin 
administration (maximal effects are expected to occur at approximately 2-3 hours).  Two therapists will be 
present throughout all psilocybin administration sessions (except for breaks, which will be taken one at a 
time). Interaction with the participants will be supportive and non-directive. Vital signs will be monitored by 
study staff at 30 minute intervals for three hours, and then hourly.  At the time of vital sign measurement, 
the therapists will also check in with briefly with participants and complete a brief Monitor Rating 
Questionnaire. Management of hypertension will be as follows. If BP is greater than or equal to 180 systolic 
or 100 diastolic, subjects will be assessed for discomfort that may be causing the BP elevation, e.g. anxiety, 
headache/pain, or alcohol withdrawal. These symptoms should be addressed/medicated, and BP will be 
reassessed at 15 minute intervals until below 180/100.  If patient has >2 BP readings of 200/110 or higher, 
then the BP will be treated directly. At this time, the patient should specifically be assessed for new chest 
pain, shortness of breath, or focal weakness, in which case the subject will need more urgent medical 
attention. The following medications will be available for administration by the study physician if needed to 
treat hypertension (captopril 25 mg orally/sublingually, clonidine 0.1 mg orally, or hydralazine 10 mg orally). 
In the event that a subject experiences distressing anxious or psychotic symptoms during the experimental 
or control session, the clinical personnel in attendance will initiate verbal communication designed to 
reorient and reassure the subject.  If that does not effectively alleviate the signs of an anxious or psychotic 
reaction, diazepam 5-10 mg, orally, or lorazapam 1 mg, intramuscularly, will be administered to lower 
anxiety.  Only if that is ineffective or if the participant presents a danger to self or others will an 
antipsychotic be administered, olanzapine 5-10 mg, given either orally or intramuscularly. For headache or 
pain, Tylenol 500-1000 mg and/or Ibuprofen 600 mg-800 mg may be administered once orally.  
Beginning 7 hours following drug administration, participants will complete questionnaires and 
assessments, and a study therapist will complete a brief clinical assessment, including mental status exam, 
recorded in the progress note.  The mental status exam includes the following: 
o Appearance  
o Behavior 
o Speech 
o Thought process (ask specifically about persisting hallucinations) 
o Thought content (ask specifically about delusional material, suicidality, homicidality) 
o Affect and mood 
o Cognitive function 
o Judgment and insight 
If there are no residual effects posing significant risk, the participant will be escorted home at the end of the 
session by a family member or friend, who will stay with the participant overnight.  A study clinician will be 
available to participants by pager or phone at all times during study participation. If the clinical assessment 
reveals evidence of any residual effects that could pose a risk to the patient or others (e.g., suicidal 
thoughts, psychotic symptoms), the therapists will stay with the participant until the symptoms resolve or it 
is determined that further treatment is required.  In the latter case, the participant may be taken to the 
psychiatric emergency service for further assessment, observation, or even psychiatric admission if 
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3.3.8.2 Behavioral interventions 
For the current randomized trial we propose to keep the psychosocial treatment procedures very similar to 
those used in the pilot and described in the therapy manual.  Figure 2 illustrates how the behavioral 
interventions interface each other and with the three drug administration sessions. For simplicity, the 
behavioral interventions that have to do with the drug administration sessions will be referred to as 
Preparation, Support, and Integration (PSI).  The alcohol therapy component consists of Motivational 
Enhancement Therapy (MET) followed by cognitive behavioral therapy sessions including implementation 
of specific strategies for change during the later sessions.  To distinguish it from more typical MET 
approaches, this therapy will be called Motivational Enhancement and Taking Action (META).  
 
As in the pilot study, the therapy will be conducted by a team of two therapists, one responsible for the 
alcohol-specific treatment (META), the other responsible for the hallucinogen-specific treatment (PSI). The 
two therapists forming a dyad should be of opposite genders if possible, and should never be both of the 
gender opposite that of the patient.  The META therapist may conduct the META sessions alone, and will 
also attend the PSI sessions facilitated primarily by the PSI therapist.  The PSI therapist may conduct 
preparation and debriefing sessions alone if necessary, but both therapists must attend the drug 
administration sessions.  In the event that in person visits are not possible, therapy visits may be held via 
phone or WebEx. Substitutes for drug administration sessions may be used only if they have had at least 
two meetings with the participant prior to the session. The separation of roles is intended to maintain clarity 
about the purpose of the sessions, while the attendance of the META therapist at PSI sessions allows the 
two components to function as an integrated whole.  A practical advantage to the separation of roles is that 
each therapist only needs to have a high degree of expertise in his or her respective area.   
3.3.8.2.1 Motivational Enhancement and Taking Action (META) 
The META content will be based on procedures used in the UNM pilot study, which are largely based on 
materials used previously in multisite trials [103, 104, 121]. Because the number of sessions indicated is 
greater than the 3-4 sessions typically used in MET, and because of the relatively high motivation for 
change seen in many of the pilot study participants, the META manual developed for this protocol will 
include greater emphasis on exploration of a patient’s goals for change and the development and 
implementation of specific strategies to meet those change goals.  
The goal of the first session is for the therapist to use open motivational interviewing to elicit and clarify 
the patient’s intrinsic motivation for change.  During this session, therapists will also offer feedback from the 
baseline assessment, specifically focusing on drinking percentile relative to population norms, 
consequences of drinking, and motivation for change. The focus of the second session will be on exploring 
the patient’s values (including spiritual values) and the discrepancy between values and behavior as 
motivation for change.  
The two subsequent META sessions (sessions 3 and 4) will follow up on the patient’s goals for 
change and experiences during the first medication session in relation to the key values identified during 
META session two. The focus of these sessions is also for the therapist and patient to negotiate a specific 
treatment plan for the remaining sessions. Using the structure of the behavioral STORC model (situation, 
thoughts, organic patterns, response, and consequences), therapists will work with patients to identify 
specific components of STORC sequences in which the patient seems to be encountering difficulties.  At 
each step in the STORC cycle there are usually a number of things that can be done to promote change.  
For each change goal a patient identifies, therapists will offer a menu of options for strategies potentially 
useful in facilitating change (e.g., the Situational Factors Menu will include modules on how to identify problem 
situations, monitoring urges, ways to change your environment, how to ask others for help, and how to 
surround yourself with support; the Organic Patterns Menu will include modules on exercise, mindfulness 
practice, sleep hygiene, and nutrition).   
In contrast to the first four sessions which are highly structured in that all patients receive similar 
content on feedback, values exercise, and structuring a treatment plan, the remaining sessions will be 
individualized to the unique needs of each patient.  Specific pull-out teaching modules with worksheets--to be 


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completed during and between sessions--will offer structure for therapists in the delivery of this portion of 
the intervention. This will allow therapists to use flexible discretion as to the content of these sessions as the 
needs of the patient evolve. Activities that may be used during these sessions will include 12-step or other 
self-help involvement, mindfulness practice, exercise, changes in social network, cognitive behavioral self-
help, alternative sources of positive reinforcement that do not involve substance use, or further formal 
alcohol treatment. The plan for change will be revisited and revised as needed during each session, and 
therapists will reinforce progress and revise the plan as needed in collaboration with the patient.  
Consistent with the MI style, these remaining sessions are also intended to be a time to re-engage the patient, 
continue discussions on experiences and feelings resulting from the medication sessions, support continuing 
efforts, and address any barriers to goal achievement. 
3.3.8.2.2 Preparation, Support, and Integration (PSI) 
These procedures will be very similar to those defined in the manual used in the UNM pilot study.  
 
Preparation sessions. There are two preparation sessions before the first drug administration session, and 
one before the second drug administration session. The primary goals for the first preparation session are 
to provide an overview of the process and rationale of the study intervention; to allow the clinicians to 
gather information about the participant’s history, current situation, personality, and values; and to facilitate 
the development of rapport between the participant and the clinicians. The second session includes a 
review of motivation and expectations for the study; detailed information about the possible physiological 
and psychological effects of study medication; advice as to how to deal with dysphoric reactions to study 
medication, should they occur; identification of any personally meaningful items that the participant will 
bring to the session (e.g., images, family photographs, objects of personal or religious significance); 
discussion of ground rules for the session; and addressing questions, concerns, hopes, and fears related to 
the medication-assisted treatment.  In the third preparation session, each topic is revisited, plans are 
revised based on the experience in the prior drug administration sessions, and the therapists and 
participant decide on the dose of medication to be used in the second drug administration session. 
Drug Administration Sessions. Beyond the monitoring procedures described above, the interventions 
employed during the drug administration sessions are intended to help the participant use the session as 
productively as possible, rather than to provide directive therapy.  Participants wear eyeshades and listen to 
a standardized program of music through headphones during most of the session. Brief check-ins are used 
to assess the participant’s mental state.  Therapists may provide reassurance, support, grounding, and 
redirection as needed.  Participants are encouraged to focus on their internal experience as much as 
possible, and to “trust, let go, and be open” to the experience rather than try to direct or control it. Once the 
drug effects have largely subsided (after 5-6 hours) participants may spend increasing amounts of time 
interacting with the therapists and discussing the content and meaning of the experience.  Participants are 
asked to write down an account of the experience during the evening after the experience, for discussion at 
subsequent debriefing sessions.   
Debriefing Sessions. A debriefing session is scheduled the day after each drug administration session. The 
basic content of these sessions includes open-ended inquiry concerning the drug administration session 
and invitation to reflect on the experience.  Participants are invited to consider the meaning and 
implications of the experience, including any changes in views of self, relationships, values, and spirituality. 
Using the motivational interviewing style, therapists will elicit discussion of how the session has affected the 
participant’s relationship to alcohol and desire to change drinking behavior. Safety assessment will also be 
completed (mental status exam and follow-up on any adverse events). 
3.3.8.2.3 Therapist Selection, Training, Supervision, and Fidelity Monitoring 
It is important to specify the content of behavioral treatments in pharmacologic trials, and to ensure fidelity 
to the specified content.  This is particularly important in studies of classic hallucinogens, since it is 
expected that the therapeutic benefits of the medication could be moderated by non-pharmacologic 
components of the treatment.  We have adapted the procedures used in the COMBINE trial, streamlining 
them to some extent because the behavioral treatments are not being manipulated experimentally in the 


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current study, serving rather as the platform for the pharmacologic interventions. All sessions will be audio-
recorded if possible. Checklists and rating forms for all components of the therapy will be developed based 
on those used in COMBINE.  These will serve three purposes: to provide guidance to therapists in 
conducting sessions and allow them to document their self-assessed adherence; to provide material for 
supervision at the local level; and to provide material for formal fidelity monitoring, which will be done 
centrally at UNM.   
Therapist Qualifications. Both the META and PSI therapists must have at least a master’s degree in a 
related field or be pursuing a master’s degree. At least of one or both of the META and PSI therapists must 
be a licensed physician (MD) for all sessions.  
Training and Certification. Overlapping training requirements and procedures are established for the PSI 
therapists and the META therapists.  Therapists in both roles will be required to read the entire therapy 
manual (covering both PSI and META procedures). Both will be required to attend a 2-day basic training in 
motivational interviewing and a 1-day basic training on hallucinogen-assisted therapy (unless they have 
already attended such trainings).  In addition, the PSI therapists will attend an additional 1-day training 
covering the specific manualized approach used in this trial.  Similarly the META therapists will receive an 
additional 2 days of training in the META intervention used in the current trial.  In order to receive 
provisional certification for the type of treatment they will be conducting (META or PSI), therapists will be 
required to complete one case with a simulated patient (staff member or actor), and receive satisfactory 
ratings from the Fidelity Monitor for their type of treatment.  Up to two additional training cases may be 
completed if the first one is not satisfactory. Following provisional certification, therapists may begin seeing 
patients in the training/pilot phase (see Section 3.3.8.2.4 below) or main trial participants.  The first case 
will be rated in its entirety by the Fidelity Monitor, and therapist will receive full certification following 
satisfactory completion of the first case. 
Supervision. Supervision will be conducted locally, and will be the responsibility of a designated lead PSI 
therapist and lead META therapist at each site.  Study clinicians will use session checklists to document 
adherence to the model. Cases will be discussed in weekly group supervision including all active therapists 
at the site.  The lead therapists will review one META and one PSI session per case for each additional 
therapist at the site, score them using session checklists, and provide feedback to the therapists.  The 
Fidelity Monitor will have monthly conference calls with the lead therapists, and will periodically review 
session tapes (including those of the lead therapists) as needed.  Patterns of unsatisfactory performance 
will result in a warning from the Fidelity Monitor, and the Supervisor will implement a performance 
improvement plan.  Persistent or serious deviation from the prescribed treatment model may result in 
removal of the therapist from the trial until the therapist completes a remedial training plan and 
demonstrates competence with simulated patients. All session recordings will remain available for further 
coding and/or qualitative analysis. 
3.3.8.2.4 Training/Pilot Phase 
At each site, at least 4 participants will be treated in a training/pilot phase prior to recruitment of participants in 
the main trial.  These cases will be randomly assigned to one of the two treatments in blocks of 4, independent 
of the main trial. Therapists and participants will be blinded to treatment assignment. Pilot participants will be 
included in the main trial sample if 1: Therapy fidelity ratings are adequate, and 2: No protocol modifications 
are made that would invalidate their inclusion.  
3.3.9 Concomitant Therapy 
Participants should not be actively engaged in other forms of addiction treatment during the treatment phase of 
the study.  Ongoing counseling or therapy for conditions other than substance use disorders is permitted.  Most 
psychotropic medications are excluded until after the double-blind drug administration sessions.  Excluded 
medications include antidepressants, antipsychotics, psychostimulants, pharmacologic treatments for 
addictions, other dopaminergic or serotonergic agents, lithium, and anticonvulsants. Other concomitant 
medications will be reviewed during the screening medical assessment, and a study physician-investigator will 
determine whether the participant should continue the medication, temporarily discontinue it, or be excluded 
from the study.  If excluded medication is started or resumed during the double-blind follow-up period (i.e, 


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during weeks 9-38) and the participant is interested in completing in the open-label session, the study 
physician will consider whether it is clinically appropriate to taper the medication in preparation for the open-
label session, consulting with the participant’s prescriber as needed. Examples of possibly appropriate 
situations include psychostimulant treatment of ADHD or antidepressants for mild depression or anxiety 
disorder. If the risks of a taper are deemed acceptable and the participant agrees, the medications may be 
tapered by the participant’s prescriber as clinically appropriate. The excluded medications must be completely 
discontinued for 5 half-lives or one week, whichever is greater, prior to the open-label medication session. 
3.3.10 
Measures 
Measures are listed in Table 1 below, organized by domain. 
 
Table 1.  Assessment 
Schedule 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessments by Visit 
Scr. BL W04 W05 W08 W09 W12 W24 W36 W38 W39 W42 W54 
Medical 
evaluation 
History and physical,  liver 
function tests, complete 
blood count, Chem 7, U/A, 
serum pregnancy test, height 
and weight, medical history 
intake form 
550’ 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
5’ 
 
 
 
 
 
 
 
5’ 
 
 
 
 
Concomitant meds, 
menstrual calendar 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
Urine pregnancy test 
 
 
5’ 
 
5’ 
 
 
 
 
5’ 
 
 
 
Psychiatric 
and SUD 
assessment 
Structured Clinical Interview 
for DSM-IV (SCID), Family 
History Questionnaire, 
Folstein MMSE 
75’ 
 
 
 
 
 
 
 
 
 
 
 
 
Other baseline 
characteristics 
Attentional Resource 
Allocation Scale, Treatment 
Goal Form, Demographics 
Form, Locator Form 
 
15’ 
 
 
 
 
 
 
 
 
 
 
 
Withdrawal 
CIWA-Ar 
5’ 
 
5’ 
 
5’ 
 
 
 
 
5’ 
 
 
 
Substance use 
and 
consequences 
Time-line Follow-back, BAC  
30’ 
10’ 
10’ 
 
10’ 
 
10’ 
10’ 
10’ 
10’ 
 
10’ 
10’ 
Hair/ Nail sample for ethyl 
glucuronide 
 
 
 
 
 
 
 
5’ 
 
 
 
 
 
Urine Drug Screen 
5’ 
 
5’ 
 
5’ 
 
5’ 
5’ 
5’ 
5’ 
 
5’ 
5’ 
Short Inventory of Problems 
(past 3 months)  
 
5’ 
 
 
 
 
5’ 
5’ 
5’ 
 
 
 
5’ 
Acute 
Hallucinogen 
Effects 
5D-ASC, HRS, SCQ, Monitor 
Rating Scale, Mysticism 
scale, guesses of medication 
received, MUSE 
questionnaire 
 
 
30’ 
 
30’ 
 
 
 
 
30’ 
 
 
 
Persisting 
Effects 
Mysticism Scale (lifetime), 
Spiritual Transcendence 
Scale, Persisting Effects 
Questionnaire (follow-up 
 
90’ 
 
 
 
 
 
 
90’ 
 
 
 
90’ 


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only), BMMRS, NEO-PI-3, 
Schwartz Value Survey 
Motivation 
Readiness rulers  
 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
Self-efficacy Alcohol Abstinence Self-
efficacy Scale  
 
10’ 
10’ 
10’ 
10’ 
10’ 
10’ 
10’ 
10’ 
10’ 
10’ 
10’ 
10’ 
Craving 
Penn Alcohol Craving Scale  
 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
Self-
Compassion 
Self-Compassion Scale 
(Short Form) 
 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
5 
Mood/ Anxiety Ham-D, Ham-A  
 
20’ 
20’ 
20’ 
20’ 
20’ 
20’ 
20’ 
20’ 
20’ 
20’ 
20’ 
20’ 
Safety 
Adverse Events Case Report 
Form 
 
 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
Vital Signs and weight 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
5” 
5’ 
5’ 
5’ 
5’ 
5’ 
5’ 
Visual Analog Scales for 
abuse potential 
 
 
 
 
 
 
5’ 
5’ 
5’ 
 
 
5’ 
5’ 
Tx satisfact. Visual Analog Scales 
 
 
 
 
 
 
5’ 
 
 
 
 
5’ 
 
   Assessment Length 185’ 175’ 110’ 55’ 110’ 55’ 
85’ 
85’ 170’ 110’ 55’ 
75’ 170’ 
3.3.10.1 
Medical Evaluation 
Medical screening will consist of medical history and physical, ECG, liver function tests, complete blood 
count, Chem 7, U/A, serum pregnancy test, height, and weight. Labs may be repeated if needed to ensure 
safety. Concomitant medications will be recorded at screening and updated at each visit. Women of 
childbearing potential will complete a menstrual calendar at each assessment visit, and urine pregnancy 
tests will be completed prior to each drug administration session.  Vital signs will be measured at each 
assessment visit, and during the psilocybin sessions (q 30 minutes for 2 hours, then hourly to 6 hours post 
administration).  
3.3.10.2 
Psychiatric and Substance Use Disorder Assessment 
For Axis I diagnoses we will use the Structured Clinical Interview for DSM-IV (SCID), a structured interview 
which yields DSM-IV diagnoses for Axis I disorders including substance abuse and dependence diagnoses 
[122].  To allow DSM-5 substance use disorder diagnoses to be made as well, an item will be added for the 
DSM-5 craving criterion. Excellent inter-rater reliability of the DSM-III-R version of the SCID has been 
reported for schizophrenia, major depression, and substance use disorders (kappas ranging from 0.85 to 
0.96), with adequate to excellent reliability for other mood and anxiety disorders, with the exception of 
obsessive-compulsive disorder [122]. . Family history of addiction and exclusionary psychiatric disorders 
will be recorded using a Family History Interview. The Folstein Mini–Mental State Examination [111] will be 
used to screen for cognitive impairment. A score below 26 will exclude subjects from the study. 
3.3.10.3 
Alcohol Withdrawal 
The Clinical Institute Withdrawal Scale—Alcohol, revised (CIWA-Ar) [123] will be used to assess alcohol 
withdrawal at screening and before the psilocybin sessions.  
3.3.10.4 
Substance Use 
3.3.10.4.1 Self-report  
The Time-line Follow-back (TLFB) [124, 125] procedure will be used to assess drug use behavior at 
baseline and follow-up visits.  The TLFB is a semi-structured interview that provides estimates of the daily 
quantity, frequency, and pattern of drug use during a specified time period.  It uses a calendar prompt and 
number of other memory aids (e.g., holidays, payday, and other personally relevant dates) to facilitate 
accurate recall of drug use during the target period.  The TLFB has shown adequate to excellent reliability 
and validity over a wide range of research and clinical contexts [100, 126, 127]. It is estimated that the 


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TLFB assessment will take 10-30 minutes to complete, depending on the length of the assessment period 
and the patterns of alcohol and drug use. Non-study treatment and 12-step attendance will also be 
recorded on the TLFB form.  
3.3.10.4.2 Objective Measures of Alcohol and Drug Use  
Hair/ nail analysis for Ethyl glucuronide (HEtG) Hair/nail samples will be obtained at 24 weeks (20 weeks 
after the first drug administration session). HEtG is a sensitive and specific measure of recent alcohol 
consumption, with a cut-off of 27 pg/ng detecting heavy drinking (≥ 60g alcohol/day) at sensitivity of .92 and 
specificity of .96 [128, 129].  A 3 cm proximal sample of hair (scalp hair if possible) representing a 3-month 
history of alcohol use will be obtained at week 24 (20 weeks after the first drug administration session).  If 
participants do not have sufficient hair, then fingernails (2 mm from each of 10 fingernails) may be used as 
an alternative.  Samples will be analyzed quantitatively using a liquid chromatography–tandem mass 
spectrometry (LC-MS/MS) method. Results may be used categorically. 
Breath Alcohol Concentration (BAC) will be measured using the Alcosensor III ® or a similar device, which 
will be calibrated monthly. 
  
Urine Drug Screen (UDS) We will use the Alere™ iCup ® or similar chromatographic immunoassay to test 
for use of marijuana, cocaine, opiates, and methamphetamine. 
3.3.10.5 
Substance Use Consequences 
The Short Inventory of Problems (SIP-2R) [101], past 3 month version, will be used to measure 
consequences of alcohol use. The SIP-2R is a 15-item measure that assesses five domains of alcohol-
related consequences: (1) social, (2) intrapersonal, (3) interpersonal, (4) impulse control, and (5) physical. 
Derived from the 50-item Drinkers Inventory of Consequences (DrInC), the SIP-2R has excellent reliability 
and validity.  
3.3.10.6 
Acute and Persisting Hallucinogen Effects 
3.3.10.6.1 Acute Hallucinogen Effects 
5-Dimensional Altered States of Consciousness Scale (5D-ASC) [130] will be used to quantify acute 
hallucinogen effects.  This scale has 94 items using the visual analog scale format, yielding 5 primary 
dimensions. The primary dimensions are “oceanic boundlessness,” “anxious ego-disintegration,” “visionary 
restructuralization,” “acoustic alterations,” and “altered vigilance.”  
The Hallucinogen Rating Scale (HRS), developed and validated at the University of New Mexico by Rick 
Strassman et al. (1994) in studies of intravenous DMT and validated in ayahuasca users [131], will also be 
administered following each drug administration session.  It is being used by the Hopkins and Tucson 
groups in their psilocybin research, and has been used to assess effects of a wide variety of psychoactive 
drugs including MDE, methamphetamine, psilocybin, ibogaine, MDMA, ayahuasca, methylphenidate, d-
amphetamine, ketamine and mCPP.  This 99-item scale has 6 subscales: intensity, somaesthesia, affect, 
perception, cognition, and volition.  
The Mysticism Scale will be used to assess “mystical” dimensions of the hallucinogen experience.  This 32-
item, 3-factor questionnaire has been used in studies of non-drug-induced mystical experiences [132], and 
has also been used in the psilocybin work of Griffiths et al. (2006).   
The States of Consciousness Questionnaire (SCQ) will also be administered. This 100-item questionnaire 
has been used extensively to measure mystical-type states of consciousness in hallucinogen administration 
experiments [97, 113, 133-135].  This scale contains the 43 items of the Pahnke-Richards Mystical 
Experience Questionnaire (MEQ) [97]. 
A 20-item Monitor Rating Scale [97] will be completed by both therapists at intervals during the psilocybin 
sessions (every 30 minutes for the first 2 hours, then hourly) to provide objective ratings of participants’ 
behavior and affect during the session. 


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A novel Music and Sound Experience (MUSE) questionnaire will be administered at the end of each 
medication session. The questionnaire contains 20 items that assess the impact the music and sounds 
played during the medication session had on the quality of the participant’s experience. 
3.3.10.6.2 Persisting Hallucinogen effects 
The Persisting Effects Scale [97] is based in large part on items used by Pahnke (1963; 1969), and 
includes subscales related to positive and negative changes in attitudes, mood, social functioning, and 
behavior.   
The Mysticism Scale (lifetime version) and the ASPIRES Spiritual Transcendence Scale will also be used 
as measures of persisting effects.  The Spiritual Transcendence Scale is a scale addressing the individual’s 
sense of connectedness and meaning [136].  The scale yields a total score and three empirically derived 
factor scores: prayer fulfillment, universality, and connectedness.  We will use the 13-item short form.   
The Brief Multidimensional Measure of Religiousness/Spirituality (BMMRS) [137] will be used as a broad 
measure of multiple domains of spirituality. 
The NEO Personality Inventory 3 (NEO-PI-3) [138] will be used to assess personality at baseline, 12, and 
36 weeks as a recently published study has shown that psilocybin administration can cause significant 
persisting increases in the personality dimension of “openness” [120]. The NEO-PI-3 is an updated version 
of the NEO-PI-R [139]. The NEO inventories measure the personality dimensions of the 5-factor model: 
neuroticism, extraversion, openness, agreeableness, and conscientiousness, with 6 “facets” within each 
factor.   
The Schwartz Value Survey [140] will be used to assess participants’ values and possible shifts in relation 
to treatment.  This instrument includes 57 items organized into 10 cross-culturally valid dimensions of 
value: self-direction, stimulation, hedonism, achievement, power, security, conformity, tradition, 
benevolence, and universalism [141]. 
3.3.10.7 
Potential Mediators of Therapeutic Effect  
3.3.10.7.1 Motivation 
Readiness Rulers will be used as to measure motivation in the course of the trial, [142]. This simple 
measure comprises Likert-scale ratings of the participant’s perception of the importance of change in 
drinking, confidence of ability to change, and readiness for change. Commitment to the goal of abstinence 
will be added as a fourth item.  
3.3.10.7.2 Self-efficacy 
The Alcohol Abstinence Self-Efficacy Scale (AASE) [143] is a self-report questionnaire which has been 
used widely in the alcohol treatment research, both as a predictor of outcome and as a client-treatment 
matching variable [144, 145]. Item content of the AASE-C subscale asks the respondent to rate the 
confidence they have to avoid drinking in different situations.  In time-ordered analyses, a relationship has 
been demonstrated between the AASE-C  and AA behaviors and drinking, both at 6 months [146] and 3 
years after completing outpatient treatment [147].   
3.3.10.7.3 Alcohol craving 
The Penn Alcohol Craving Scale [148] will be used to assess craving. This scale has 5 Likert-scaled items 
with excellent internal consistency and evidence of predictive, construct, and discriminant validity. 
3.3.10.7.4 Self-compassion 
Self-compassion is a construct, derived from Buddhist psychology, which denotes a kind and non-
judgmental attitude toward oneself [149]. A reliable and valid 12-item form of the Self-Compassion Scale 
[150] will be used as measure of self-compassion. 
3.3.10.7.5 Mood and Anxiety 
The Hamilton Anxiety (Ham-A) [151] and Depression (Ham-D) (17-item) [152] scales will be used as measures 
of depression and anxiety at baseline and at each follow-up visit. 


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3.3.10.7.6 Treatment Satisfaction 
Visual Analog Scales will be used to assess participants overall satisfaction with study treatment (separate 
scales for satisfaction and usefulness). 
3.3.10.8 
Potential Moderators of Acute and Persistent Effects of Psilocybin 
In addition to the participant characteristics measured above, the following measures will be obtained at 
baseline. 
3.3.10.8.1 Dissociation and Absorption 
The Attentional Resource Allocation Scale (ARAS) [153] will be used as measure of dissociation and 
absorption.  This questionnaire is derived from factor analyses of two large samples administered both the 
a composite of the Tellegen Absorption Scale (a 34-item measure of absorption) [154] and the Dissociative 
Experiences Scale (a 28-item self-report questionnaire) [155] (items of both scales were Likert-scaled in 
this study).  Exploratory and confirmatory factor analyses yielded 15 items loading on three highly 
intercorrelated factors: imaginative involvement, dissociative amnesia, and attentional dissociation.  The 
single factor model also produced acceptable (but statistically inferior) fit indices.  
 
3.3.10.8.2 Thoughts About Abstinence 
Using the form that was used in the COMBINE trial [156], participants will be asked to endorse one of 
seven treatment goals which can be categorized as: 1) total abstinence; 2) conditional abstinence; and 3) 
moderation.  
3.3.10.8.3 Demographics form 
A standard Demographics form will be used to capture information such as ethnicity, education, and 
employment. 
3.3.10.9 
Safety Assessment 
Adverse events (AEs), when present, will be collected on an AE Case Report Form at the end of the psilocybin 
sessions and at all subsequent visits. The form will include an assessment of clinical significance and study 
relatedness.  Serious Adverse Events (SAEs) will be documented on an additional SAE form. These CRFs will 
be based on those used in recent NIDA Clinical Trials Network trials.   Vital signs will be obtained at each visit 
and measured frequently during psilocybin sessions: every half hour for the first 2 hours, then hourly for a 
total of 8 hours, with more frequent readings as needed (See Therapy Manual). To further assess abuse 
potential, visual analog scales will be used to assess abuse potential.  Scales will include desire to use the 
study medication again, desire to use the study medication again for pleasurable intoxication (“to get high”), 
and craving for the study medication. 
3.3.10.10 Therapist and Participant Guesses of Treatment Assignment 
In order to assess the integrity of the blind, following each drug administration session participants and 
therapists will be asked to guess 1) what medication was administered (psilocybin or diphenhydramine), 
and 2) degree of confidence in this guess.  
3.3.10.11 Locator form 
A standard locator form will be used to collect information on contact who can help locate participants in 
case they change address and/or phone numbers.  Ideally at least 3 independent contacts will be identified. 
3.3.11 
Data Management and Procedures 
Raw data in case report forms (CRFs) will be reviewed for completeness and accuracy at each visit.  CRFs 
and source documents will be stored in locked cabinets in an office which will be locked when the office is 
not in use.  Identifying data (e.g., consent) will be stored in separate locked cabinets.  Data will also be 
entered into “Research Electronic Data Capture” (REDCap™) hosted at each participating site. At the 
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Data will be kept for at least 5 years following completion of the study.  No PHI data will be kept unless 
subjects sign the informed consent form. PHI data of individuals who do not sign an informed consent form 
will be destroyed.  Visits may be conducted in-person or via phone and data will be entered either by direct 
electronic data capture (e.g., tablet computers) by a research assistant or by the participant, or by 
independent double entry into an encrypted REDCap™ database located on a server and accessible only 
to approved staff study through a password-protected computer.  The study database will be set up not to 
accept out-of-range values.   
3.3.12 
Statistical analysis and power 
A full description of the planned analyses for this trial can be found in the Statistical Analysis Plan (SAP) 
3.3.12.1 
Preliminary analyses 
In addition to the assessment of the distributional properties of key measures at baseline and follow-up, we 
will evaluate the nature and pattern of missing data and assess treatment group equivalency at baseline on 
primary substance use measures and patient characteristics that are central to study aims.  
Self-selection and Attrition. Baseline measures of substance use and other relevant characteristics will be 
used to compare eligible prospects who do and do not drop out prior to randomization and receiving study 
medication. Contingent on the scale of measurement of the comparison variable, unprotected t-tests and Chi 
Squares will be done to compare these groups. Two strategies will be used to examine the impact of post-
randomization attrition on study internal validity, and both strategies will employ hierarchical linear modeling 
(HLM) with binary outcomes depicting attrition status (yes/no) jointly at post-medication session visits 
(Bernoulli function). First, we will examine attrition by group assignment. Here, the HLM will identify both the 
main effect of group assignment on later attrition as well as the potential for a group-by-time attrition effect. 
Second, group equivalency on factors potentially predictive of future drinking will be evaluated with t-tests 
using baseline drinking intensity and other characteristics as dependent measures.  
3.3.12.2 
Aim 1 (to characterize the acute effects of PO psilocybin 25 mg/70kg, 30mg/70kg, and 40 
mg/kg in alcohol dependent patients)  
3.3.12.2.1 Outcome measures 
The primary safety measures will be changes in vital signs, psychological or other clinically significant 
adverse events, and serious adverse events using the FDA definition.  The primary measure of 
hallucinogen effect is the 5-Dimensional Altered States of Consciousness Scale (5D-ASC) [130]. Secondary 
outcomes the Intensity score and other subscales from the Hallucinogen Rating Scale (HRS) [157], the 
Mysticism scale [132], the Mystical Experience Questionnaire [97], abuse potential visual analog scales, 
and within-session Monitor Rating Scale Scores. 
3.3.12.2.2 Method 
Tolerability. Adverse events will be tabulated.  The primary safety measures will be changes in vital signs, 
psychological or other clinically significant adverse events, and serious adverse events using the FDA 
definition.  Blood pressure and ratings will be contrasted by group using t-tests.  AEs will be MedRA coded 
and groups contrasted using Chi squared or Fisher’s exact test. All tests will be unprotected against inflated 
Type I error thus providing the most liberal estimate for potential safety concerns. 
Psychoactivity. Scores from the HRS and other scales (mean, SD, median, range) will be computed and 
reported.  Scores will be contrasted by group using t-tests for independent samples.  Mean scores will be 
compared descriptively to means reported in other studies, particularly Griffiths et al. [97, 110]. 
3.3.12.3 
Aim 2 (To evaluate the effect of psilocybin treatment on drinking outcomes for 32 weeks after 
the first administration, relative to diphenhydramine control) 
3.3.12.3.1 Outcome measures 
The primary drinking outcome for hypothesis 2 is percent heavy drinking days during weeks 5-36 (the 32 
weeks following the first drug administration session) as assessed by the Time-line Follow-back [100]. 
Other drinking variables will serve as secondary outcomes, including percent days abstinent, drinks per 


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drinking day, days to first drinking day, days to first heavy drinking day, and consequences of drinking (from 
the Short Inventory of Problems [101]).   
3.3.12.3.2 Method 
For PHDD we will employ a MMRM including fixed, categorical effects of treatment, assessment, and site; 
site-by-treatment and treatment-by-assessment interactions; the continuous, a fixed covariate (week 1-4 
PHDD); and using monthly values of PHDD (weeks 5-8, 9-12, 13-16, 17-20, 21-24, 25-28, 29-32, 32-36) as 
the dependent measure. Site and the site-by-treatment interaction will be removed from the final model if not 
significant at the p < 0.05 level. Secondary drinking measures with a continuous scale of measurement, i.e., 
PDA and DPDD, will be tested in a similar fashion and for days to first drinking day and days to first heavy 
drinking day (5 or more standard drinks for a man, 4 or more standard drinks for a woman). Cox survival 
analysis will be used. Measures of effect size will be calculated for all planned between-group contrasts 
(Hedges d) and the Q statistic will be calculated to assess the homogeneity of effect across the primary and 
secondary outcome measures of drinking. 
3.3.12.4 
Aim 3 (To test whether or not characteristics of the drug administration session experiences 
mediate effects of psilocybin on short term (1 week) persisting effects and post-session drinking 
behavior). 
3.3.12.4.1 Measures 
The three main dimensions of the 5D-ASC (“oceanic boundlessness,” “anxious ego-disintegration,” “visionary 
restructuralization,”) and the total score from the MEQ will be used as independent measures of acute drug 
effects.  Short term (1-week post-session) effects will be the as follows: for craving, the primary measure is 
the total score from The Penn Alcohol Craving Scale [148]; for self-efficacy, Abstinence Confidence from 
the Alcohol Abstinence Self-efficacy Scale [143]); and for motivation the “readiness” score from the 
Readiness Rulers [142].  Drinking outcomes will be those specified for Specific Aim 2. 
3.3.12.4.2 Method 
Tests of statistical mediation will use a product-of-coefficients approach with a bootstrapping procedure. This 
choice provides the most powerful test of mediation with smaller samples and does not assume normality in 
the distribution of (a’b’) product terms (Preacher and Hayes, 2008; Hayes, 2009).  HLM will be applied to 
identify the a and b parameter estimates for the between-group contrast (treatment assignment psilocybin 
versus control; df = 1), and baseline values of the dependent variable will be entered in level 2.   
3.3.12.5 
Aim 4 (To evaluate the explanatory value of changes in alcohol craving, self-efficacy, 
motivation, and other psychological domains in accounting for the observed experimental effect 
of psilocybin relative to diphenhydramine control)  
3.3.12.5.1 Measures 
For craving, the primary measure is the total score from The Penn Alcohol Craving Scale [148]; for self-
efficacy, Abstinence Confidence from the Alcohol Abstinence Self-efficacy Scale [143]); and for motivation 
the “readiness” score from the Readiness Rulers [142].  Additional secondary measures are defined for 
depression (Hamilton Depression Scale score [152]) and  anxiety (Hamilton Anxiety Scale score).  Drinking 
outcomes will be those specified for Specific Aim 2. 
3.3.12.5.2 Method  
Statistical procedures described for Aim 3 will be used to determine if the proposed mediators account for the 
effectiveness of the psilocybin administration.  Changes in proposed primary and secondary mediators will be 
assessed at weeks 5 and 9 (1 week following drug administration) and drinking outcome (PHDD) will be 
assessed at weeks 8 and 12 (4 weeks post drug administration).  No protection for inflated Type I error will be 
applied to the testing of the three primary mediators, i.e., Penn Alcohol Craving Scale, and Abstinence Self-
efficacy from the AASE, and Readiness from the Readiness Rulers. Performance site and the site by treatment 
group interaction terms will not be entered into the model. 


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3.3.12.6 
Aim 5 (To evaluate pre-post changes in drinking in participants after they receive psilocybin in 
the third session)   
3.3.12.6.1 Measures  
The primary drinking outcome for hypothesis 5 is percent heavy drinking days during weeks 39-54 (the 32 
weeks following the first drug administration session) as assessed by the Time-line Follow-back [100]. 
Other drinking variables will serve as secondary outcomes, including percent days abstinent, drinks per 
drinking day, days to first drinking day, days to first heavy drinking day, and consequences of drinking (from 
the Short Inventory of Problems [101]). 
3.3.12.6.2 Method 
Methods for Aim 5 will parallel those used in Aim 2, except that only participants in the control group will be 
included in this analysis, so treatment and site-by-treatment interactions will be omitted from the model, with 
the time effect being of principal interest.  PHDD will be centered at week 42. 
3.3.12.7 
Statistical power 
Power analysis is based on the primary outcome analysis contrasting the psilocybin group with the control 
group with respect to percent heavy drinking days in months 1-8 post pharmacologic treatment (Aim 2). With a 
total sample size of n = 180 (90 assigned to psilocybin and 90 to control), and 5% attrition (realistic 
because useable data require only 1 month follow-up in participants who have already participated for 1 
month, N = 171) our power analysis was based on the assumption that four predictors would be in the 
regression-based HLM model.  We estimate that the study has power of 0.8 to detect an effect of size f2 = 
.065, with alpha = 0.05 (2-tailed) and no correction for multiple comparisons.  This effect is comparable to 
that of naltrexone [9, 158, 159], and smaller than those observed in some recent trials of other promising 
medications [160-162].  Regardless of the statistical significance of these changes, standardized and non-
standardized effect sizes will be computed for primary and secondary outcome variables. The addition of an 
open-label optional third dosing does not affect the required sample size for Aim 2 (primary outcome), but 
approximately doubles the sample size for Aim 1 and allows for the addition of Aim 5.   
3.3.12.8 
Ancillary analyses 
Additional ancillary interim analyses will be performed on blinded, de-identified data by Ms. Gabrielle Agin-
Liebes as part of her doctoral dissertation. Ms. Agin-Liebes is completing her training toward a PhD in 
clinical psychology at Palo Alto University (PAU), and is a member of PAU’s Early Intervention Clinic clinical 
research laboratory, which provides and evaluates evidence-based treatments to prevent trauma-related 
problems in recently traumatized individuals. As part of this research laboratory, Ms. Agin-Liebes is 
examining the effects of trait self-compassion on trauma-related guilt cognitions. Blinded, de-identified 
scores on the SCQ, Self-Compassion Scale Short-Form (SCS-SF), and number of self-reported drinking 
days will be shared with Ms. Agin-Liebes to allow her to assess the following aims: 
Aim 1) To examine the relationships between self-reported drinking days and self-compassion in the 
context of a psilocybin-facilitated MET program following two drug administration sessions (either psilocybin 
or placebo), Aim 2a) To examine within-person, pre-post intervention changes in self-reported drinking days 
in the context of a medication-facilitated MET program, Aim 2b) To examine within-person, pre-post 
intervention changes in self-reported self-compassion in the context of a medication-facilitated MET 
program, Aim 2c) To examine whether these within-person, pre-post intervention changes in self-reported 
drinking days are greater in participants that score above the median on the SCQ than the than those with 
SCQ scores below the median score, Aim 2d) To examine whether these within-person, pre-post 
intervention changes in self-compassion are greater in the in participants that score above the median on 
the SCQ than the than those with SCQ scores below the median score, and Aim 3) To examine whether 
SCS-SF scores mediate the relationship between SCQ scores and drinking behavior. 
3.3.13 
Study Milestones  
We propose to implement the study in three stages, with interim analyses and DSMB review after the first 
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Stage 1: Following final protocol approval by all necessary authorities and procurement of necessary 
funding, staff will be trained, at least 4 pilot/training participants per site will be treated, and 20 participants 
will be randomized into the main trial across two sites (UNM and NYU, 10 per site). At the end of this stage, 
feasibility and tolerability will be assessed, and necessary protocol modifications may be made.  
Stage 2: An additional 80 participants will be randomized, with the possible addition of one or two additional 
sites to enhance recruitment capacity. At the end of this stage, interim checks of attrition rates and the 
assumed error standard deviation σ for the primary outcome measure will be conducted to assess the 
adequacy of the projected study sample size. This check will be performed by an unblinded statistician, 
who will estimate the primary model, and report back on error variance and drop-out rates. Additional 
necessary protocol modifications may be made, and final sample size will be determined.  In addition, 
safety interim looks will be performed (without formal statistical testing) at the regular DSMB meetings or 
unscheduled times per the DSMB’s request. Although at this time we are not planning a formal statistical 
interim analysis for efficacy or futility, such an interim analysis can be performed if requested by the DSMB 
or the sponsor.  
Stage 3: Assuming 180 participants are required, the 80 remaining participants will be randomized, with an 
additional 9 months to complete treatment and assessment of the final participants. 
3.3.14 
Regulatory Considerations 
3.3.14.1 
Statement of Compliance 
This trial will be conducted in compliance with the appropriate protocol, current Good Clinical Practice 
(GCP), the principles of the Declaration of Helsinki, and all other applicable regulatory requirements. 
Participating sites must obtain written approval of the study protocol, informed consent form, other 
supporting documents, and any advertising for participant recruitment from their local institutional review 
board (IRB) in order to participate in the study. Prior to study initiation, the protocol and the informed 
consent documents will be reviewed and approved by an appropriate Ethics Review Committee (ERC) or 
IRB. Any amendments to the protocol or consent materials must be approved before they are implemented. 
Annual progress reports and local Serious Adverse Event (SAE) reports will be submitted to each IRB, 
according to its usual procedures. 
3.3.14.2 
Necessary approvals 
Human trials with Schedule I substances pose special challenges. The UNM site has already obtained an 
IND to study the use of psilocybin in the treatment of alcohol dependence, and has Schedule 1 DEA license 
and board of pharmacy approval to store, dispense, and administer psilocybin at UNM. The NYU site has 
an active Schedule I license to dispense psilocybin in the treatment of anxiety associated with cancer and 
will amend their Schedule 1 license for the purposes of this trial.  The trial will not begin until the following 
have been achieved. 1) The existing UNM IND (#113080) will be amended to include the new protocol and 
the NYU site; 2) The existing DEA Schedule 1 licenses will be amended to include the new protocol; 3) any 
necessary local requirements, including Board of Pharmacy Schedule 1 permits, if necessary, will be 
obtained.  Any additional sites will also satisfy these requirements prior to beginning participation in the 
study. 
3.3.14.3 
Regulatory Files 
The regulatory files should contain all required regulatory documents, study-specific documents, and all 
important communications. Regulatory files will be checked at each participating site for the regulatory 
documents compliance prior to study initiation, throughout the study, as well as at the study closure. 
3.3.14.4 
Health Insurance Portability and Accountability Act (HIPAA) 
Study sites may be required by their institutions to obtain authorization from participants for use of 
protected health information. Sites will be responsible for communicating with their IRBs or Privacy Boards 
and obtaining the appropriate approvals or waivers to be in regulatory compliance. 
3.3.14.5 
Financial Disclosure 


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All investigators will comply with the requirements of 42 CFR Part 50, Subpart F to ensure that the design, 
conduct, and reporting of the research will not be biased by any conflicting financial interest. Everyone with 
decision-making responsibilities regarding the protocol will have an up-to-date signed financial disclosure 
form on file. 
3.3.14.6 
Clinical Monitoring 
Site staff will be required to  audit source documentation, including informed consent forms and HIPAA 
forms, regulatory documents and case report forms on a biannual basis. Site staff will be responsible for 
local quality assurance and will verify that study procedures are properly followed and that site staff are 
trained and able to conduct the protocol appropriately. If the site staff’s review of study documentation 
indicates that additional training of study personnel is needed, this will be arranged as per the PI. Study 
team members will review each other’s data for completeness, accuracy, and fidelity to the protocol.   
3.3.14.7 
Study Documentation 
Study documentation includes all case report forms, data correction forms, workbooks, source documents, 
monitoring logs and appointment schedules, sponsor-investigator correspondence, and signed protocol and 
amendments, Ethics Review Committee or Institutional Review Board correspondence, approved consent 
form, and signed participant consent forms. Source documents include all recordings of observations or 
notations of clinical activities and all reports and records necessary for the evaluation and reconstruction of 
the clinical research study. Whenever possible, the original recording of an observation should be retained 
as the source document; however, a photocopy is acceptable provided that it is a clear, legible, and an 
exact duplication of the original document. 
3.3.15 
Compensation to Participants  
Participants will be reimbursed $50 for the screening visit, baseline visit, and each comprehensive visit 
(weeks 4, 8, 12, 24, 36, 38, 42 and 54), and $20 for the interim visits 1 week after each drug administration 
session (weeks 5, 9 and 39).  Participants completing all of the assessments would therefore receive a total 
of $560.   
4. HUMAN SUBJECTS PROTECTIONS 
4.1 Risks to Human Subjects 
4.1.1 Human Subjects Involvement and Characteristics.   
4.1.1.1 Participants 
Subjects will be women and men, age 25 to 65 with DSM-IV alcohol dependence, recruited from the 
community through advertisements at 2-4 sites.  Participants will meet the inclusion and exclusion criteria listed 
in Section 3.3.6 of the protocol. Recruitment will continue until up to approximately 180 participants are 
randomized.  
4.1.1.2 Study treatments 
The proposed investigation is a multi-site, double-blind active-controlled trial (n = 180, 90 per group) 
contrasting the acute and persisting effects of psilocybin to those of diphenhydramine in the context of 
outpatient alcoholism treatment. The total duration of psychosocial treatment in the double blind period will 
be 12 weeks, and double-blind drug-administration sessions will occur after 4 and 8 weeks. The first 
psilocybin session will employ a moderately high dose of psilocybin (25 mg/70 kg). The dose may be 
increased in the second session to 30 mg/70 kg or 40 mg/70 kg, depending on response in prior sessions. 
The dose of diphenhydramine will start at 50 mg, and may be increased to 100 mg in the second session if 
50 mg is well tolerated in the first session. Following completion of the double-blind period (34 weeks after 
randomization) all participants who meet interim safety criteria will be offered an additional session in which 
psilocybin will be administered. Drug administration will occur during 8-hour sessions conducted in an 
outpatient setting under close medical and psychiatric monitoring by two trained monitors. Psychosocial 
treatment will occur in the context of a behavioral intervention incorporating a modified version of the 


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Motivational Enhancement Therapy (Called Motivational Enhancement and Taking Action, META) [103] as 
well as preparation before and debriefing after the psilocybin session.   
Procedures for minimizing COVID-19 risk among participants and study team members during required in-
person visits (including routine temperature checks, use of personal protective equipment, symptom checks, 
etc.) are outlined in the COVID Safety Procedures SOP (etc-research-01\EtOH-14-00614\4. Study 
Documentation\3. SOPs\ SOP_14-00614_COVIDSafety_Procedures_V2_09.01.2020.docx). 
4.1.2 Sources of Materials   
Materials obtained from participants will include samples of blood, urine, hair, fingernails, and breath.  Data will 
be collected through use of interviews, questionnaires, physical examination, and laboratory tests.  These data 
will include measures of medical health (medical evaluation), alcohol withdrawal, psychiatric diagnosis 
including drug and alcohol use disorders, substance use, alcohol consequences, motivation, self-efficacy, 
craving, mood and anxiety, acute effects of psilocybin administration, persisting effects of psilocybin 
administration, and safety.  These materials and data will be obtained specifically for research purposes  
4.1.3 Potential Risks 
4.1.3.1  Risks of experimental medications 
4.1.3.1.1 Psilocybin 
The test article used in the proposed study is psilocybin.  In this study psilocybin will be used as the putatively 
active treatment.  Psilocybin is a Schedule 1 substance with no currently accepted medical use.  However, it 
has been used safely in numerous previous human studies, both in the US and abroad.  In carefully conducted 
clinical research settings, with careful screening, preparation and support, the risks of psilocybin administration 
appear to be low [40, 41, 43, 97, 105]. Classic hallucinogens including psilocybin  have the lowest 
physiological toxicity of all well-known drugs of abuse [163].  A recent analysis by the Independent Scientific 
Committee on Drugs in the UK found that individual and societal harms associated with use of psilocybin 
mushrooms were the lowest of any of the 20 drugs assessed [6]. However, there are some rare but potentially 
serious effects that require attention.  With each exposure to psilocybin there is an additional chance that 
study participants may experience adverse events. 
• 
Experiences with hallucinogens provoke a variety of positive and negative emotional responses in the 
hours to weeks following the acute drug experience, which can be unsettling.  Anxiety and dysphoria 
are common during psilocybin intoxication.  These symptoms can be distressing, and were the 
predominant emotional state in 4/36 sessions at 0.43 mg/kg reported by Griffiths et al. (2006). These 
symptoms generally respond well to reassurance.  Anxiety rarely can escalate to panic.  
• 
Increased blood pressure and heart rate during intoxication (mean increase of approximately 20 mm Hg 
systolic, 12 mm Hg diastolic, mean increase in pulse of approximately 10 bpm in Griffiths et al., 2006).  
This side effect is common, but unlikely to be clinically significant with careful screening for 
hypertension and cardiovascular disease. 
• 
Serotonin syndrome is possible if psilocybin is used in combination with other serotonergic drugs.  
Individuals known to be taking such drugs will be excluded from the study.  This adverse event is 
expected to be very uncommon.   
• 
Transient psychotic symptoms (delusions, paranoia, hallucinations) have been reported during 
psilocybin intoxication. We are unaware of any reports of persistent psychotic symptoms associated 
with the use of psilocybin, but such symptoms have been reported following use of LSD [43, 164].  
Individuals with history of psychosis or vulnerability (e.g., family history) are thought to be at higher risk 
for psychotic reactions to hallucinogens, but we cannot rule out a very small risk of such reactions to 
psilocybin in normal individuals. 
• 
Secondary analyses of a pharmacokinetic study [165] revealed an association between psilocybin level 
increase in QTc (See Investigator Brochure v2.).  at psilocin concentrations above 31.1 ng/ml. 
• 
Hallucinogen persisting perception disorder can be caused by hallucinogen use.  The incidence of this 
disorder is thought to be very low, and associated primarily with use of LSD [47].   


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• 
Headaches are common following psilocybin administration [109].  These headaches are not severe, 
resolve within a day, and appear to respond to over-the-counter pain medications.  
• 
Psilocybin, like other classic hallucinogens, is not reliably reinforcing in humans or in animal models 
used to study addiction potential [46].  However, psilocybin is an abusable drug.  It is theoretically 
possible that a participant could develop a pattern of psilocybin misuse due to his/her experience in the 
trial, although this has not been reported in previous studies in which psilocybin or other classic 
hallucinogens have been administered to humans.  
Although there is considerable clinical experience with psilocybin over more than 50 years, it has not been 
used in controlled trials with alcohol dependent subjects.  There is, however, a large literature dating from the 
1950s through the early 1970s, including over 1000 subjects, on the use of LSD in the treatment of alcoholism 
[1, 11-15, 21-26].  Few safety issues were noted in these studies.   
4.1.3.1.2 Diphenhydramine 
Diphenhydramine is used as an active control medication in this study.  Diphenhydramine is a H1 antagonist 
(antihistamine) which is available over the counter and by prescription for treatment of insomnia, allergic 
reactions, parkinsonism, and motion sickness.  It has been safely administered in doses up to 400 mg PO 
[114-116, 166]. Reported side effects and adverse events associated with diphenhydramine include the 
following (from package insert [167]). 
• 
General: Urticaria, drug rash, anaphylactic shock, photosensitivity, excessive perspiration, chills, 
dryness of mouth, nose and throat. 
• 
Cardiovascular System: Hypotension, headache, palpitations, tachycardia, extrasystoles. 
• 
Hematologic System: Hemolytic anemia, thrombocytopenia, agranulocytosis. 
• 
Nervous System: Sedation, sleepiness, dizziness, disturbed coordination, fatigue, confusion, 
restlessness, excitation, nervousness, tremor, irritability, insomnia, euphoria, paresthesia, blurred 
vision, diplopia, vertigo, tinnitus, acute labyrinthitis, neuritis, convulsions. 
• 
GI System: Epigastric distress, anorexia, nausea, vomiting, diarrhea, constipation. 
• 
GU System: Urinary frequency, difficult urination, urinary retention, early menses. 
• 
Respiratory System: Thickening of bronchial secretions, tightness of chest and wheezing, nasal 
stuffiness. 
4.1.3.1.3 Adjunctive medications 
With the exception of acetaminophen and ibuprofen, use of these medications is expected to occur 
uncommonly if at all in this study.  
• 
For treatment of severe hypertension: captopril 25mg orally or sublingually; clonidine Orally, initial 
0.1mg; may be followed by additional doses of 0.1 mg every hour, if necessary, to a maximum total 
dose of 0.7 mg. Hydralazine orally, 10mg once. Common side effects include headache, 
lightheadedness, dizziness, flushing, orthostatic hypotension, and reflex tachycardia. Uncommon but 
serious reactions include severe hypotension, paradoxical bradycardia angioedema and allergic 
reactions. 
• 
For severe anxiety: Diazepam 5-10 mg orally or Lorazepam 1 mg intramuscularly. The most common 
effects of benzodiazepines are sedation, dizziness, weakness, and unsteadiness.  Rare but serious 
adverse events that could occur with a single administration include respiratory depression, apnea, and 
anaphylaxis. 
• 
Olanzapine 5-10 mg orally or intramuscularly for psychotic symptoms (delusions, hallucinations, 
disorganized behavior) that pose a significant danger. Common side effects of olanzapine possible with 
one or two doses are somnolence, dizziness, hypotension, akathisia, extrapyramidal symptoms, dry 
mouth, tremor, nausea, and vomiting.  Rare but serious side effects include seizures, neuroleptic 
malignant syndrome and tardive dyskinesia, (the latter two are extremely unlikely with one or two small 
doses). The risk of hypotension is increased when intramuscular olanzapine is given in combination 
with benzodiazepines, so intramuscular olanzapine will not be given if diazepam has already been 
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• 
For headache or pain: Acetominophen 500-1000 mg orally q4 hours prn pain/headache and/or 
Ibuprofen 600 mg-800 mg orally x q8 prn pain/headache.  Common side effects include nausea, 
stomach discomfort. 
4.1.3.1.4 Risk in pregnancy and lactation   
Risks of psilocybin in pregnancy and lactation are unknown.  Diphenhydramine is Pregnancy Category B 
Benzodiazepines are pregnancy category D, with evidence of fetal risk.  Use during lactation is considered 
possibly unsafe.  Olanzapine is pregnancy category C, not for use in nursing.  Captopril is pregnancy category 
D, evidence of fetal toxicity. Hydralazine and clonidine are pregnancy category C. 
4.1.3.2 Risks of psychosocial treatments 
There are no known specific risks to META or the preparation and debriefing sessions used in the proposed 
trial.  Non-specific risks include discomfort with sharing personal information, and the risk of therapist 
misconduct.  These risks are judged to be very minor. 
4.1.3.3 Risks of blood draws.  
For most people, needle punctures for blood draws do not cause any serious problems.  However, they may 
cause bleeding, bruising, discomfort, infections and/or pain at the needle site, or dizziness. 
4.1.3.4 Risks of assessment procedures  
There are no known psychological risks associated with the questionnaires used in the study, all of which have 
been used extensively in clinical populations.  It is possible that discussion of substance use and psychiatric 
symptoms may cause emotional discomfort in some participants.  To minimize such discomfort, the following 
steps will be taken.  The consent form will fully inform the participants about the nature of the information to be 
disclosed in the protocol, and the participants will be informed in the consent form that they can refuse to 
answer any questions or withdraw from the study at any time.  Participants will be informed that all information 
is confidential.  The steps taken to guard confidentiality, as well as the limits to confidentiality, will be 
described.  One of the investigators of the project will be available to meet with any participant who becomes 
distressed about any aspect of the protocol and wishes to discuss this.   
4.1.3.5 Risks to confidentiality and potential legal consequences.   
Information from this study may be submitted to the U.S. Food and Drug Administration (FDA).  Medical 
records which identify subjects and the consent form signed by subjects may be inspected by the FDA and the 
local Institutional Review Board.  Because of the need to release information to these parties, absolute 
confidentiality cannot be guaranteed.  The results of this research project may be presented at meetings or in 
publications.  However, the identity of individual subjects will not be disclosed in those presentations.  
Additionally, with the participant’s permission, their information may be disclosed to a contact such as a friend 
or family member that they identify in a written release specifying what information may be shared with whom. 
4.1.3.6 Risks and benefits of alternative treatments. 
Standard of care for outpatient treatment of alcohol dependence is pharmacotherapy with medication 
monitoring and/or evidence-based psychosocial treatment (individual and/or group therapy).  The FDA-
approved treatments for alcohol dependence are disulfiram (Antabuse), naltrexone (ReVia and Vivitrol) and 
acamprosate (Campral).  Common side effects of disulfiram include the disulfiram-alcohol reaction, rash, 
peripheral neuropathy, drowsiness, impotence, headache, acne, and metallic taste.  Serious reactions include 
respiratory depression, cardiovascular collapse, arrhythmias, acute MI, congestive heart failure, seizures, 
coma, psychosis, optic neuritis, and hepatitis.  All but the last three are potential consequences of a severe 
disulfiram-alcohol reaction.  Common side effects of naltrexone include insomnia, nausea, vomiting, anxiety, 
headache, abdominal pain, muscle aches, rash, dizziness, fatigue, somnolence, anorexia, constipation, liver 
dysfunction, and chills.  Serious reactions include suicidality, depression, precipitated opiate withdrawal 
syndrome, hypersensitivity reaction, and hepatotoxicity.  Common side effects of acamprosate include 
diarrhea, insomnia, anxiety, depression, asthenia, nausea, pruritus, and dizziness.  Serious reactions include 
suicidality and depression.   Evidence-based psychosocial treatments for alcohol dependence include methods 
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behavioral approaches, 12-step facilitation therapies, approaches involving the spouse and family, and 
standardized counseling approaches incorporating elements of these various approaches.   
4.2 Adequacy of Protection Against Risks 
4.2.1 Recruitment and Informed Consent 
4.2.1.1 Recruitment 
Patients will be recruited from the community through advertisements in local media.   
4.2.1.2 Pre-Screening 
An IRB-approved pre-screening form will be used by study staff to pre-screen individuals expressing interest in 
the study, to assess whether they are likely to qualify for the study.  Interested participants who pass the pre-
screening will be referred for informed consent.  No PHI data will be kept unless subjects sign the informed 
consent form. PHI data of individuals who do not sign an informed consent form will be destroyed.  The only 
information that will be retained from the pre-screening form for individuals that do not pass the pre-
screening is the reason they were excluded, the date of the pre-screening, and where they learned about 
the study. 
4.2.1.3 Informed consent process and document 
Interested patients will be provided with an informed consent form, approved by the local site’s Institutional 
Review Board and including all pertinent details of the study including description of the following: the 
assessment interview and questionnaires; the follow-up interviews; description of experimental treatment; risks 
and benefits of study procedures; alternatives to participation in the study; confidentiality; emergency treatment 
and compensation for injury; payment for participation; a statement that patients will be informed of any new 
findings affecting the risks or benefits of the study; a statement that participation is voluntary and that the 
patient may withdraw at any time; and information about whom to contact with questions or in case of 
emergency. The consent form will also include a section that allows participants to decide if they would like to 
participate in any potential future studies related to this study.  The consent form will also include assurances 
of confidentiality and a statement that participation is entirely voluntary, that the decision to participate will in no 
way influence other aspects of the patient’s treatment or involvement in the main trial, and that the participant 
is free to withdraw participation at any time. Prior to signing the informed consent document, patients will be 
required to pass an informed consent quiz (10 items, passing score 90% or above) covering key elements of 
the study.  Patients who score less than 90% on the informed consent quiz will be counseled further and will 
have up to a total of 3 chances to pass the quiz.  Patients indicate their consent to participate in the study by 
signing and returning the informed consent form.   
4.2.2 Protection Against Risk 
4.2.2.1 Management of risk due to study treatments 
Risks of hallucinogen administration are thought to be minimized by a) careful screening of participants, b) 
extensive preparation, c) establishment of rapport and trust between participants and monitors, d) presence of 
two monitors during the psilocybin sessions, e) a safe and reassuring physical environment, f) careful planning 
for unusual but potentially serious adverse reactions, and g) debriefing and follow-up for possible residual 
adverse effects [105].  These principles are incorporated into our protocol as follows.   
a. Subject selection: Exclusion criteria are designed to exclude patients who would be at elevated risk for 
adverse events due to psilocybin. These criteria are listed in Section 3 above, and include both medical 
exclusions and psychiatric exclusions for serious psychopathology, history of violent or suicidal behavior, and 
family history of psychosis or suicide.    
b. Subject preparation:  In addition to the information and discussion provided in the informed consent process, 
participants will spend a total of 6 hours in 4 sessions: two 1-hour META sessions, and two preparation 
sessions (4 hours total) including both the PSI therapist and the META therapist.  Both of the clinicians will be 
present during the psilocybin sessions. Preparation will include 1) open-ended questions to establish rapport, 
learn about the participant’s history, belief system, and values, assess motivation and expectations for the 


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study, and discuss any previous experience with hallucinogens; 2) detailed information about the physiological 
and psychological effects of psilocybin; 3) emphasis that the purpose of the psilocybin sessions is to facilitate 
behavior change, and discussion of how this could work; 4)  advice as to how to deal with dysphoric reactions 
to psilocybin, should they occur; 5) identification of any personally meaningful items that the participant will 
bring to the session (e.g., photographs, images, objects of personal or religious significance); and 6) 
discussion of ground rules for the session.   
c. Establishment of rapport and trust: The extensive contact between the participant and therapists prior to the 
psilocybin sessions is intended to build rapport and trust during the psilocybin sessions.   
d. Support during psilocybin sessions:  Because this study involves use of psilocybin in a clinical population as 
part of an intervention intended to be therapeutic, the two study therapists will serve as the monitors who will 
attend the patient during the psilocybin sessions. At least one of these therapists will be a licensed clinician.   
e. Physical environment:  The psilocybin session will take place in outpatient facilities that are appropriate 
for hallucinogen administration sessions. To the extent possible, the room used for the session will be 
specially prepared for the sessions to provide a warm and home-like rather than a stark clinical quality 
because of the large influence that setting can have on the subjective effects of hallucinogens. Each site 
will have detailed SOPs in place for managing medical or psychiatric emergencies should any occur.  
f. Planning for emergencies:  Each of the research sites has established practices for managing medical and 
psychiatric emergencies, and the study staff will continue to utilize these procedures. Staff will be responsible 
for monitoring participants for possible clinical deterioration or other problems, and for implementing 
appropriate courses of action. Acute adverse reactions to psilocybin initially will be managed by increasing 
psychological support (“talking down”). Medications will be available for administration if needed to treat 
hypertension (sublingual captopril 25 mg orally/sublingually, clonidine 0.1 mg PO, and hydralazine 10 mg PO), 
anxiety (diazepam 5-10 mg PO, or lorazepam 1 mg IM), or acute psychosis posing a danger to the participant 
or others (olanzapine 5-10 mg PO or IM).  Referral for emergency treatment and/or hospitalization will be 
available at each site. A study clinician will be available by pager or phone at all times during study 
participation.  
g.  Debriefing and Follow-up:  Debriefing sessions, approximately 2 hours long and conducted by the PSI 
therapist and the META therapist on the day after the psilocybin sessions, consist of the following elements: 
1) open-ended inquiry concerning the psilocybin session (and what has happened since); 2) invitation to 
reflect on the experience; 3) discussion of what has changed as a result of the session; 4) discussion of 
how the session has affected the participant’s relationship to alcohol; and 5) assessment of mental status.  
Additional META sessions and booster sessions (two 1-hour sessions following the first debriefing session, 
and three 1-hour sessions following the second debriefing session) will allow further opportunity to process 
the experience. 
4.2.2.2 Minimization of risk to confidentiality 
Confidentiality of research material will be ensured by storing the research materials in locked cabinets in NYU 
space within the A, C-D, and H buildings of Bellevue Hospital Center.  Material will be available only to project 
staff, and only as needed.  All project staff will be thoroughly trained in issues relating to confidentiality.  
Participants will be identified in case report forms (CRFs) by initials and an identification code.  Data will be 
entered into REDCap™, a program designed specifically to protect patient privacy and confidentiality (see 
section 3.3.11). Published reports will be based on group data; no individual data will be reported.  As a further 
protection to confidentiality, we will request a Confidentiality Certificate from the Department of Health and 
Human Services (DHHS).  With this Certificate, the investigators cannot be forced (for example by court order 
or subpoena) to disclose research information that may identify individual patients in any Federal, State, or 
local civil, criminal, administrative, legislative, or other proceedings.  Disclosure will be necessary, however, 
upon request of DHHS for audit or program evaluation purposes.  DHHS ensures confidentiality of requested 
data.  Participants will be notified in the informed consent that the Certificate of Confidentiality does not prevent 
them or a member of their family from voluntarily releasing information about themselves and their involvement 
in the research. If an insurer, employer or other person obtains their written consent to receive research 
information, then the researcher may not use the Certificate to withhold that information. Participants will also 


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be informed that the Certificate of Confidentiality does not prevent the researchers from disclosing voluntarily, 
without their consent, information that would identify them as a participant of the research project under the 
following circumstances:   the present danger of child abuse, suicide, and/or homicide. In addition to current 
measures, the present study will comply with the Health Insurance Portability and Accountability Act of 1996. 
Records related to this study will not be released to third parties.    
4.3 Potential Benefits of the Proposed Research to Human Subjects and Others  
4.3.1 Potential Benefits to Participants  
Participants may or may not experience clinical benefit from this study.  There is equipoise regarding the 
effects of the experimental drug used in this study.  Aspects of study participation likely to be beneficial include 
free medical and psychiatric evaluations, the attention and support or of participating in a clinical trial, and a 
course of an evidence-based psychosocial treatment for alcohol dependence.  
4.3.2 Potential Benefits to Others.   
Knowledge gained through this study may aid the development of more effective treatments for individuals with 
alcohol dependence and other addictive disorders.   
4.3.3 Risk Benefit Assessment 
Risks to individual participants appear to be balanced by the likely benefits of study participation, and 
outweighed by the potential benefits to others.   
4.4 Importance of the Knowledge to be Gained 
There is an urgent need to develop more effective methods to help people who suffer from addictions and 
other forms of loss of behavioral control (e.g., overeating).  The knowledge gained through this study could 
point the way to an entirely new treatment for alcohol dependence, and may also yield important gains in 
understanding of the psychological processes that underlie behavior change. As indicated above, these 
potential benefits (in addition to the potential benefits to individual participants) appear to justify the risks to 
individual participants.    
4.5 Data and Safety Monitoring Plan 
4.5.1 General Considerations   
Although the safety profile of psilocybin in clinical research is well established, our pilot study is the only 
controlled trial to date using psilocybin in an alcohol dependent population (although there are more than thirty 
published studies reporting on the use of LSD in the treatment of alcohol dependence). The data and safety 
monitoring plan is therefore designed both to ensure that the risks of medications and study-related procedures 
are minimized for patients, and to minimize any doubt that there are adequate safeguards in place to minimize 
this risk.     
4.5.2 Institutional Review Board (IRB)   
All study procedures will be approved by the local IRB at each participating site.  
4.5.3 Data and Safety Monitoring Board  
A Data and Safety Monitoring Board (DSMB) will be established, comprising three to five individuals appointed 
by the Heffter Research Institute.  This committee will meet (in person or by teleconference) prior to enrollment 
of the first participant in the double blind and at least annually thereafter, including meetings after enrollment of 
the first 10 participants, and upon completion of stage 1 and stage 2 of the trial.  At its meetings the Board will 
• 
review protocol violations and deviations to assess adequacy of study 
• 
ensure documentation of informed consent  
• 
review enrollment and retention 
• 
review IND information 
• 
discuss investigator or key personnel changes 


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• 
review completeness and quality of data collection forms 
• 
evaluate the aggregate analysis of adverse events/serious adverse events 
• 
review confidentiality 
• 
review interim analyses conducted at completion of stage 1 and stage 2 of the trial. 
Following each meeting, the board will provide the PI with a report including a recommendation to continue the 
study unchanged, continue with modifications of the protocol and/or the consent form to protect participant 
safety, or terminate the study.   
4.5.4 Procedures for Monitoring and Reporting Adverse Events.  
The study staff will be trained to monitor for and report adverse events and Serious Adverse Events. Adverse 
events (AEs), when present, will be collected on an AE case report form at the end of the first psilocybin 
session and at all subsequent visits. The form will include an assessment of clinical significance and study 
relatedness.  Serious Adverse Events (SAEs) will be documented on a separate SAE form.  AEs will be 
reported in accordance with federal law and policies the IRB requirements.  Reporting procedures vary 
depending on the severity of the AE.  
4.5.4.1 Safety reporting to the FDA  
Safety reporting will follow 21CFR312.32.  Site investigators will notify the Lead Investigator of any SAEs within 
24 hours of becoming aware of the event. The Sponsor will notify the FDA regarding any suspected adverse 
reaction associated with the use of the drug that is both serious and unexpected. The sponsor will also notify 
the FDA of findings from other human, animal, or in vitro studies that suggest increased risk to humans, or any 
pattern of increase in the rate of adverse events over what is expected.  Each notification will be made as soon 
as possible and no greater than 15 calendar days after the initial receipt of the information.  Each written 
notification will be submitted on an FDA Form 3500A.  The Principal Investigator will also notify the FDA of any 
unexpected fatal or life-threatening experience associated with the use of the drug as soon as possible but no 
later than 7 calendar days after the initial receipt of the information. 
4.5.4.2 Other reporting to FDA 
On an annual basis as part of the update to the study IND, the Principal Investigator will submit to the FDA: 
A summary of all IND safety reports submitted during the past year. 
A list of all subjects who died during the participation in the investigation, listing cause of death for each. 
A list of subjects who dropped out during the course of the investigation in association with any adverse 
experience, whether or not thought to be drug related. 
4.5.4.3 Stopping Rules for Study 
Stopping rules will be put in place if 1) there are untoward and concerning levels of Adverse Event (AE) or 
Serious Adverse Event (SAE) outcomes attributable to psilocybin, or 2) there is a  significant worsening of 
drinking behavior or consequences in the psilocybin group. The methodology that will be used for both of the 2 
rules above will be as follows: interim analyses will be performed in the aggregate (psilocybin and control 
groups combined) for both AEs/SAEs and drinking clinical outcomes, and these results will be reviewed by the 
DSMB. If the aggregate analyses reveal either concerning levels of AEs/SAEs or worsening drinking 
outcomes, then an unblinded statistician will analyze the data to determine (as best as possible from the data) 
if the concerning AEs/SAEs and/or the worsening drinking outcomes are significantly due to the psilocybin 
group compared to the placebo. If the DSMB finds it is likely the psilocybin group is contributing to negative 
outcomes, they will consider solutions including protocol changes or potentially stopping the study.    
 


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