A Double‑Blind Randomized Controlled Trial of Oral Cannabidiol Augmentation of Antipsychotic Therapy in First‑Episode Psychosis

The primary objective is to assess whether adjunctive cannabidiol administered for six weeks produces greater overall symptomatic improvement compared with placebo when added to standard antipsychotic therapy in individuals experiencing First Episode Psychosis. Demonstrating superior symptom reduction would support the therapeutic value of cannabidiol as an augmentative agent in early psychotic illness.

Secondary objectives address efficacy, safety, functional, and biomarker outcomes during the 6‑week intervention and over a subsequent 12‑month follow‑up.

• During the 6‑week intervention: evaluate changes from baseline in (i) severity of attenuated psychotic symptoms and remission status, (ii) depressive and anxiety symptom severity, (iii) health‑related quality of life, (iv) overall functioning, (v) discontinuation rate for any reason, (vi) severity and incidence of adverse events, (vii) general mental‑health symptomatology, (viii) cognitive performance, and (ix) selected biomarker levels.
• During the 12‑month follow‑up: assess long‑term change from baseline in (i) attenuated psychotic symptom severity and remission, (ii) quality of life, (iii) functional level, and (iv) general mental‑health symptomatology.
• Biomarker analyses: determine biomarker alterations associated with symptomatic improvement and identify clinical, demographic, and biological predictors of outcome at one year.

The trial enrolled 102 individuals diagnosed with First Episode Psychosis (FEP) who were between 16 and 40 years of age; both female and male participants were eligible. All participants were required to be receiving an antipsychotic medication for a minimum of three weeks and no more than sixteen weeks, at a dose considered the minimum effective according to modified Maudsley guidelines, and to be judged by the treating clinician as a non‑responder to that treatment. Inclusion required a DSM‑5 diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder confirmed by SCID‑5‑RV, a compliance score of 4 or higher on the Clinician Rating Scale, and the absence of symptomatic remission per modified Andreasen criteria. Participants of child‑bearing potential had to use highly effective contraception throughout the study and for three months after the last dose. Optional participation in MRI scanning was limited to individuals without contraindicating implants or other exclusions. Subjects were required to provide written informed consent (or assent) and to demonstrate the ability and willingness to comply with all trial procedures.

The STEP‑ENHANCE trial is a multicentre, phase 5, parallel‑group study employing a First Episode Psychosis population and investigating adjunctive oral cannabidiol (1000 mg daily) versus a matching placebo oral solution in a randomized (1:1), double‑blind, placebo‑controlled design. After an initial screening visit to confirm eligibility, participants undergo a baseline assessment during which randomization occurs and the investigational product is initiated in addition to their existing antipsychotic regimen. Subsequent study visits are scheduled at weeks 2, 4 and 6 to monitor symptom change (primary outcome: change in total PANSS score), safety parameters, adherence, and to collect secondary efficacy and biomarker data. The week‑6 visit serves as the end‑of‑treatment assessment, after which a short safety follow‑up (e.g., week 8) may be performed to capture delayed adverse events. Participant involvement therefore spans approximately six weeks of double‑blind treatment with an additional brief follow‑up period. Early termination may occur if a participant experiences a serious adverse event, develops pregnancy, exhibits non‑compliance with study medication or visits, requires a clinically unacceptable modification of antipsychotic therapy, or withdraws consent. All procedures are conducted in accordance with Good Clinical Practice and relevant regulatory guidelines.

The investigational product is a pharmaceutical preparation of cannabidiol supplied as an oral dosage form containing 1000 mg of the active substance per administration. The product is taken by the oral route and is administered in conjunction with each participant’s ongoing antipsychotic therapy for a treatment period of six weeks.

The comparator is a matching placebo oral solution formulated with beta‑carotene. The placebo contains no active pharmaceutical ingredient, has no marketing authorisation, and is manufactured under good manufacturing practice (GMP) conditions exclusively for use in this clinical trial.

Both study medications are provided in identical containers to preserve blinding. Dosing is recorded in the participant’s study diary, and compliance is assessed through pill count at each scheduled visit, as well as by review of the diary entries. Administration is performed under supervision when feasible, and any missed doses are documented according to protocol‑specified procedures.

The primary efficacy assessment is the change from baseline in the total PANSS score after 6 weeks of adjunctive cannabidiol or placebo treatment. Assessments are performed at baseline and at the end of the 6‑week treatment period.

Secondary efficacy parameters include the PANSS, the Calgary Depression Scale for Schizophrenia (CDSS), the Hamilton Anxiety Rating Scale (HAM‑A), the Overall Anxiety Severity and Impairment Scale (OASIS), the WHOQOL‑BREF, the EQ‑5D‑3L, the Social and Occupational Functioning Assessment Scale (SOFAS), the Functional Recovery Outcomes in General Schizophrenia (FROGS), all‑cause discontinuation, the Glasgow Antipsychotic Side‑Effect Scale (GASS), adverse event reporting, the Clinical Global Impression – Severity (CGI‑S) and – Improvement (CGI‑I) scales, the Patient‑Reported Global Impression of Improvement (PGI‑I) and Severity (PGI‑S), and the PsyCog Battery. These measures are collected at baseline, at week 6, and during a long‑term follow‑up period.

Exploratory biomarker assessments encompass genomics, proteomics, inflammatory markers, metabolomics, redox status, microbiome analysis, and neuroimaging (MRI/MRS). Biological samples are obtained at baseline and at designated follow‑up visits, with neuroimaging performed at eligible sites.

All efficacy endpoints are analyzed using validated scoring algorithms for the respective instruments. Changes from baseline are compared between the cannabidiol and placebo arms using appropriate statistical models for continuous and categorical outcomes.