Psilocybin-facilitated Treatment for Cocaine Use

Individuals who are eligible to participate and provide informed consent will complete
baseline questionnaires and be randomly assigned in a double-blind manner to the Psilocybin
or Active Placebo group. The first MRI assessment will take place shortly thereafter using a
3T head-only Magnetic Resonance Imaging and Spectroscopy scanner (Magnetom Allegra, Siemens
medial Solutions, Malvern, PA), optimized for neuroimaging applications.

Preparation sessions (see below) and the drug administration session will take place in a
room at the Clinical Research Unit designed to be as comfortable, aesthetically pleasing
(i.e., living-room like), and safe (e.g., no furniture with sharp corners or glass objects)
as possible, with a directly adjacent, private restroom.

All participants will undergo four weekly preparation sessions of approximately 2 hours each.
The purpose of these sessions is to: 1) develop strong therapeutic alliance between the
participants and the guide (Dr. Hendricks) and secondary monitor (Dr. Cropsey); 2) establish
comfort and rapport between participants and the remainder of the research team; 3) discuss
participants' aspirations with regard to their drug administration experience (e.g., What do
participants hope to gain from their experience?); 4) discuss the treatment rationale and
putative mechanisms of action of psilocybin (e.g., insight and reorientation that boost
motivation to quit and abstinence self-efficacy, reduction of withdrawal/craving secondary to
mood improvement); 5) obtain a detailed personal history of the participant, with a focus on
those factors contributing to their current difficulties; 6) prepare participants for drug
administration, including a detailed account of all potential effects of the drug; 7) discuss
all aspects of the drug administration protocol (i.e., logistics and procedures), including
plans of action in the event that participants experience acute distress; and 8) administer
cognitive-behavioral treatment for cocaine use. Any participant who demonstrates significant
anxiety, discomfort, or unease regarding drug administration at the conclusion of the four
preparation sessions will be provided up to two additional preparation sessions. If these
sessions are unsuccessful at mitigating the participant's anxiety, discomfort, or unease, the
participant will be removed from the study.

Approximately one week after their final preparation session, participants will be instructed
to eat a low-fat breakfast prior to presenting for their drug administration session at 8:00
am, approximately 1 hour before drug administration. A urine sample will be collected to
verify drug-free status and participants will be encouraged to relax and reflect before drug
administration. The drug administration session will take place over the course of 8 hours.
The guide and secondary monitor will be present with participants throughout this session (at
least one individual will always be present with the participant, even during brief intervals
when the guide or monitor may be using the restroom). During this time, participants will be
encouraged to lie down, use an eye mask to block external visual distraction, and use
headphones through which a supportive music program will be played. Participants will be
instructed to focus their attention on their inner experiences throughout the session.

Any participant reporting significant distress will be provided reassurance verbally or
physically (e.g., with a supportive touch to the hand or shoulder). Although no contemporary
studies have reported the need for pharmacological intervention, in the event that
psychological distress is insufficiently managed with reassurance alone, medication will be
administered under the guidance of the study physician.

Blood pressure will be assessed at regular intervals via automatic blood pressure monitor
(e.g., pre-administration, and at 30, 60, 90, 120, 180, 240, 300, and 360 minutes
post-administration), and medication for the treatment of acute hypertension will be
administered should blood pressure exceed 190 systolic and 100 diastolic.

Sessions will be videotaped and reviewed to verify session procedures.

Seven hours after drug administration, when the major drug effects have subsided,
participants will complete questionnaires assessing their experience. Participants will then
be released into the care of a friend or family member oriented to be emotionally supportive
of the participant (as arranged during preparation sessions) and instructed not to drive an
automobile or engage in any other potentially dangerous activity for the remainder of the
day. Participants will be provided with the guide's pager number should they feel the need
for support that evening.

Within 2 days after the drug administration session, participants will meet with the guide
for approximately 2 hours to discuss and reflect on their experience. The guide will assess
for potential adverse effects at this time. The second MRI session will take place shortly
thereafter. Participants will then meet with the guide once per week over the next 4 weeks
with an emphasis on integration of their medication session experience in the context of
achieving abstinence from cocaine; continued cognitive-behavioral treatment for cocaine use
will be provided during these follow-up meetings.

Long-term assessment visits will take place 3 and 6 months after the final follow-up meeting.
A battery of measures will be delivered at these times. At the conclusion of the 6-month
assessment meeting, participants will be debriefed.

Inclusion Criteria:

- 25 years of age and older

- Score of at least 3 on the Severity of Dependence Scale

- Desire to cease cocaine use as indicated by a goal of complete cocaine abstinence on
the Thoughts about Abstinence questionnaire

- Ability to read/write in English

- No prior hallucinogen use or it will have been at least 3 years since their last use
of a hallucinogen

- Availability of 3 community observers to complete community observer forms via
telephone around baseline and follow-up assessments.

- Availability of a friend or family member into whose care the participant can be
released following their drug administration session.

- In good general health as assessed by detailed medical history and physical
examination

- Abstinence from cocaine for at least 7 days prior to experimental drug administration
as confirmed via urinalysis and no signs of intoxication on other drugs.

Exclusion Criteria:

- 24 years of age and younger

- Women who are pregnant or breast feeding

- Current psychiatric diagnoses other than substance abuse/dependence

- Current hypertension (exceeding 140 systolic and 90 diastolic at resting as described
below)

- Use of tricyclic antidepressants, lithium, Selective Serotonin Reuptake Inhibitors,
Monoamine Oxidase Inhibitors, haloperidol, St. John's Wort, or other antipsychotic
medications, mood stabilizers, or medications with serotonin activity

- History of any psychotic disorders

- History of bipolar I or II disorder

- First or second-degree relatives with any psychotic disorders, or bipolar I or II
disorders

- Current suicidal or homicidal ideation

- Planning to move from the Birmingham area in the next 6 months

- Contraindications of MRI (metallic objects in the body, claustrophobia, difficulty
with prior MRI)