Effects of Cannabidiol on Psychiatric Symptoms, Cognition, and Cannabis Consumption in Cannabis Users With Recent-Onset Psychosis

This is a double-blind, randomized, placebo-controlled trial, evaluating the effects of a
12-week treatment course with CBD on psychiatric symptoms, cognition, and cannabis
consumption in regular cannabis users with recent-onset psychosis. The study will be
conducted at the Maryland Psychiatric Research Center (University of Maryland School of
Medicine) and associated Early Intervention Programs in Baltimore, at the Sheppard Pratt
Health System in Baltimore, and at the Psychosis Clinic of the University of California Los
Angeles.

The daily dose of CBD is 600 mg (p.o.), administered as adjunct medication. Any
non-exclusionary antipsychotic, antidepressant, anxiolytic, or other medication prescribed
prior to the trial will be continued. Participants may, but do not have to be taking
conventional antipsychotic medication.

The study will include 84 regular cannabis users with a schizophrenia-spectrum disorder who
experienced their first psychotic episode within the last 5 years (90). Participants will be
randomized 1:1 to either the CBD or the placebo group.

Outcome measures include psychiatric symptoms, cognition, global functioning, and drug use,
and will be assessed at baseline, and every 3 or 6 weeks thereafter (depending on the
measure), until the end of treatment at 12 weeks. Outcome will be assessed again at a 3-month
follow-up.

Inclusion Criteria:

- DSM-5 diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder,
and other specified or unspecified schizophrenia spectrum and other psychotic
disorder.

- Experienced a first psychotic episode within the last 5 years.

- Self-reported cannabis use at least twice/week for at least the last 4 weeks.

- THCCOOH serum levels of ≥ 5 ng/mL.

- Total score ≥45 on the 18-item version of the Brief Psychiatric Rating Scale.

- Able to give written informed consent.

- Normal or corrected to normal vision.

- If medicated, no change in psychiatric medication within the preceding 4 weeks, with
no foreseeable changes.

Exclusion Criteria:

- DSM-5 diagnosis of Substance Use Disorder other that cannabis or nicotine within the
last year (recreational use is not exclusionary).

- Currently undergoing active treatment for Cannabis Use Disorder other than low-level
(once/week or less) psychosocial intervention.

- Uncontrolled hypertension (resting systolic BP above 150 or diastolic above 95 mm Hg).

- Cardiovascular disease, such as history of myocardial infarction and ischemia, heart
failure, angina, severe arrhythmias, or EKG abnormalities (Wolf-Parkinson-White
syndrome, Complete left bundle branch block, PR interval <120 ms or >200 ms, Prolonged
QT interval (corrected) >500 ms, Cardiac arrhythmias as defined by PACs >3 per min or
PVCs >1 per min).

- History of or current neurological illness, such as stroke, seizure disorders,
neurodegenerative diseases, or organic brain syndrome.

- Intellectual disability.

- Pregnant or lactating.

- Diabetes.

- Significant kidney or liver impairment.

- Any chronic or severe infectious disease, including HIV and hepatitis.

- Cancer.

- Use of any barbiturates, diazepam, diltiazem, verapamil, protease inhibitors, any
anticonvulsant medications (including valproate/valproic acid, lamotrigine,
carbamazepine, and clobazam), glipizide, glyburide, warfarin, and cyclophosphamide/
ifosfamide, due to potential interaction with CBD at the metabolic level.

- Suicidal ideation currently or within last 6 months (score of >/= 3 on the Columbia
Suicide Severity Rating Scale).

- Less than the lower limit of normal hemoglobin and hematocrit at screening.

- Elevated transaminase levels >3 times the ULN, accompanied by elevations in bilirubin
>2 times the ULN.