A Double-Blind Trial of Psilocybin-Assisted Treatment of Alcohol Dependence

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.

Inclusion Criteria:

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.

Exclusion Criteria:

1. Medical conditions that would preclude safe participation in the trial (e.g., seizure
disorder, significantly impaired liver function, coronary artery disease, heart
failure, uncontrolled hypertension (above 165/95 mmHg at screening), history of
cerebrovascular accident, 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 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, or 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)

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).