Efficacy of Cannabidiol and Risperidone in Treating Non-Affective Psychosis and Cannabis Use: A Randomized Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of cannabidiol (CBD) in the treatment of non-affective **psychosis**. This is clinically relevant as it explores a potential therapeutic option for managing symptoms associated with psychosis, which can significantly impact patient quality of life and functional outcomes.

Secondary objectives include examining how CBD affects the use of **cannabis**, cessation, and related behaviors. Understanding these effects is important for developing comprehensive treatment strategies for individuals with a history of cannabis use, which is often comorbid with psychotic disorders.

The clinical trial focuses on evaluating the efficacy of **cannabidiol (CBD)** for the treatment of psychosis, specifically targeting individuals with a history of **lifetime cannabis use** and **non-affective psychosis**. The study population includes both male and female participants aged 18 to 45 years. Participants are required to have an ICD-10 diagnosis of schizophrenia, paranoid psychosis, acute or intermittent psychotic disorder, schizoaffective psychosis, other or unspecified nonorganic psychotic disorder, or cannabis-induced psychotic disorder. Additionally, they must have a PANSS score of 60 or higher, with a score of 4 or more on at least two PANSS-Positive subscale items. Female participants of childbearing potential are required to use an appropriate method of contraception. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of **cannabidiol** (CBD) in the treatment of non-affective psychosis and lifetime cannabis use. This study is structured as a randomized, double-blind, controlled trial, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thus minimizing bias. The trial is expected to run from April 1, 2021, to December 31, 2025, with participant involvement lasting up to 7 days, depending on the treatment period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as an ICD-10 diagnosis of schizophrenia, paranoid psychosis, or cannabis-induced psychotic disorder, among others. The primary endpoint is the severity of psychotic symptoms, while secondary endpoints include the frequency and quantity of cannabis use, total symptom severity, and psychosocial functioning. Follow-up visits will monitor these endpoints and ensure adherence to the study protocol.

The trial involves the administration of Epidyolex 100 mg/ml oral solution, **risperidone** film-coated tablets, and their respective placebos. The maximum daily dose for Epidyolex is 600 mg, with a total dose not exceeding 29,400 mg over the treatment period. For risperidone, the maximum daily dose is 4 mg, with a total dose not exceeding 196 mg. Participants may be withdrawn from the study if they experience adverse effects, fail to comply with the study protocol, or choose to withdraw consent.

The clinical trial involves the administration of **Epidyolex 100 mg/ml oral solution**, which contains the active substance **cannabidiol**. This experimental medication is provided in the form of an oral solution and is administered orally. The maximum daily dose is 600 mg, with a total maximum dose of 29,400 mg over a treatment period of up to 7 days. The solution is manufactured by Jazz Pharmaceuticals Ireland Ltd and is classified under the ATC code N03AX24. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to the experimental medication, a **placebo** matching the Epidyolex oral solution is used as a comparator in the study. The placebo is designed to mimic the appearance and administration route of the active treatment but contains no active substance. This ensures the blinding of participants and investigators to treatment allocation, maintaining the integrity of the trial results.

The study also includes the administration of **Risperidon "Krka", film-coated tablets**, which contain the active substance **risperidone**. These tablets are administered orally, with a maximum daily dose of 4 mg and a total maximum dose of 196 mg over a 7-day treatment period. The tablets are produced by KRKA Sverige AB and are classified under the ATC code N05AX08. As with the other treatments, participant adherence to the dosing regimen will be closely monitored.

A **placebo** corresponding to the Risperidon tablets is also utilized in the trial. This placebo is designed to match the film-coated tablets in appearance and administration route, ensuring the blinding of the study. The use of placebos in this trial is critical for evaluating the efficacy of the active treatments against a control group.

The efficacy of cannabidiol (CBD) for the treatment of non-affective psychosis and cannabis use will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the **severity of psychotic symptoms**. Secondary endpoints include the frequency and quantity of cannabis use, cannabis cessation for current users, total symptom severity, symptom response and remission, global severity of illness, psychosocial functioning, neurocognitive functioning, subjective well-being, circadian sleep-wake cycle, subjective sleep quality, objective sleep evaluation, and metabolomics.

These efficacy parameters will be measured using validated scales and patient-reported outcomes. The Positive and Negative Syndrome Scale (PANSS) will be utilized to assess psychotic symptoms, with inclusion criteria requiring a PANSS score of ≥ 60 and a score of ≥ 4 on at least two PANSS-Positive subscale items. The frequency and quantity of cannabis use will be self-reported by participants, detailing days of use per week and the amount used. Cannabis cessation will be defined as no use during the past two weeks, as self-reported by participants.

The trial is designed to explore and confirm the therapeutic potential of CBD, with an estimated end date of December 31, 2025. The study will include participants aged 18-45 years with specific ICD-10 diagnoses related to psychosis and cannabis use. Female participants of childbearing potential are required to use appropriate contraception methods. The trial will employ a rigorous methodology to ensure the accurate collection and analysis of efficacy data, contributing to the understanding of CBD's role in treating psychosis and cannabis use disorders.