Feasibility of Psilocybin Combined with Psychological Support for Cocaine Use Disorder: A Randomized Controlled Pilot Trial

The primary objective is to evaluate the feasibility of administering a single 25mg dose of psilocybin combined with psychological support for the treatment of cocaine use disorder. This pilot study compares the intervention against 100mg of diphenhydramine to inform the design of future definitive trials. 3, 5.

Secondary objectives include the assessment of:

• Abstinence rates, measured via self-report Timeline Followback and urine drug test, including sustained abstinence and time to first relapse.
• Cocaine craving, mood, and anxiety levels.
• Functionality and quality of life.
• The psychedelic experience, treatment expectancy, and blinding efficacy.
• Safety parameters, including the frequency of adverse events and serious adverse events.
• Cardiovascular monitoring via electrocardiogram, blood pressure, and heart rate.
• Clinical laboratory assessments of full blood count, liver function tests, and urea and electrolytes.

The sponsor did not provide the total number of participants. The study population consists of male and female patients aged 21 to 65 years diagnosed with cocaine use disorder according to DSM-5 criteria. Inclusion requires a moderate or higher severity of the disorder, characterized by cocaine use on at least four separate days within the previous month and a score of $\ge$4 on the Severity of Dependence Scale. Eligible individuals must demonstrate a negative urine test for cocaine on the day preceding and the day of dosing. Participants must be able to provide informed written consent, speak English, and possess clinically acceptable electrocardiogram and laboratory findings. For females of childbearing potential, a negative pregnancy test is required, alongside a commitment to utilize approved contraception methods. Additionally, participants must have a designated friend or family member to ensure safe transport following administration.

This randomised, double-blind, controlled pilot feasibility trial is designed to evaluate the use of psilocybin combined with psychological support for the treatment of cocaine use disorder. Participants are assigned to receive either a single 25mg dose of psilocybin or a 100mg dose of diphenhydramine hydrochloride, which serves as a placebo, in a 1:1 ratio. The study protocol includes 6 sessions of psychological support. The research methodology aims to assess feasibility through recruitment methods, randomisation rates, adherence to follow-up, and reasons for dropout. Evaluation of secondary outcomes includes abstinence rates, cocaine craving, mood, functionality, and the nature of the psychedelic experience. Safety monitoring involves assessing adverse events, electrocardiogram findings, blood pressure, heart rate, and laboratory tests. The study process begins with a screening visit to assess eligibility, followed by a baseline visit and subsequent follow-up visits to monitor clinical and safety outcomes. Participant involvement concludes at the end-of-study visit.

The experimental medication, psilocybin (PEX010), is administered as a dry extract from Psilocybe cubensis (15-25:1) using methanol as an extraction solvent. This substance is provided in capsule form for oral administration. The protocol involves a single dose of 25 mg.

The comparator treatment consists of a placebo, identified as Nytol One-A-Night 50 mg Tablets, which contains diphenhydramine hydrochloride. This substance is administered in capsule form via the oral route at a dosage of 100 mg.

The study protocol for cocaine use disorder includes psychological support consisting of 6 sessions alongside the administration of the study substances.

The primary objective of this study is to evaluate the feasibility of psilocybin combined with psychological support for the treatment of cocaine use disorder. Feasibility will be assessed through recruitment methods, the rate of willingness to be randomised, randomisation, adherence to follow-up, and reasons for participant drop-out from treatment and follow-up.

Secondary efficacy outcomes include:

• The percentage of days abstinent, measured via Timeline Followback and urine analysis.
• Sustained abstinence and time to relapse.
• Cocaine craving assessed using the CCQ-Brief.
• Mood and anxiety levels evaluated by the DASS-21.
• Functionality measured through the Sheehan Disability Scale and EQ-5D-5L.
• The psychedelic experience assessed via the 5D-ASC and CEQ.
• Treatment expectancy measured by the SETS.
• Blinding assessment and meaning in life using the MLQ.

Safety assessment involves monitoring the number of adverse events and serious adverse events, ECG abnormalities, clinically significant changes in blood pressure and heart rate during dosing, and laboratory tests including full blood count, liver function tests, and urea and electrolytes.