CBD and Early Psychosis: The Science Behind the Most Important Trials in a Generation

A major Phase 3 placebo-controlled trial at UC San Diego is asking whether CBD can do what 60 years of antipsychotic medications have largely failed to achieve — meaningfully improve cognition, reduce neuroinflammation, and address the full spectrum of early psychosis symptoms in adolescents and young adults. Simultaneously, Oxford University has launched the largest CBD and psychosis study in history. Here is the complete, deeply researched picture of what science currently knows — and where it is heading.

Psychosis: A Leading Cause of Disability With No Good Treatment for Two-Thirds of Symptoms

Psychotic disorders — including schizophrenia, schizoaffective disorder, schizotypal personality disorder, and first-episode psychosis — are among the most debilitating psychiatric conditions in the world. According to the World Health Organization, schizophrenia alone affects approximately 24 million people globally and is one of the leading causes of disability in young adults. In the United States, the condition typically emerges in adolescence or early adulthood — often between the ages of 16 and 30 — during precisely the years when education, career foundations, and social relationships are being established.

Antipsychotic medications have been the primary treatment for psychosis since the 1950s. While they are effective at reducing positive symptoms — hallucinations and delusions — they have made little meaningful progress against the conditions that most devastate patients’ lives: negative symptoms (social withdrawal, flat affect, loss of motivation), neurocognitive deficits (impaired memory, attention, and executive function), and functional disability. Up to 40% of patients discontinue antipsychotic medication within a year, often due to severe side effects including weight gain, metabolic disorders, sedation, and movement disorders. This is the treatment gap that makes new approaches like CBD so urgently important to study.

The UC San Diego CARE Trial: A Landmark Phase 3 Study

The most comprehensive CBD and early psychosis trial currently active in the United States is being conducted at the University of California, San Diego, within the CARE (Cognitive Assessment and Risk Evaluation) Early Psychosis Treatment Program. Led by Dr. Kristin Cadenhead and Dr. T. Dixon, and published in protocol form in the journal Trials (Springer Nature, 2023), the study is a Phase 3, double-blind, placebo-controlled, randomized superiority trial — the gold standard design in clinical research.

Study design and participants

Approximately 120 adolescents and young adults aged 16 to 30 in the early stages of psychosis are being randomized to either 1,000mg of CBD daily (as a pharmaceutical-grade oral solution) or a matching placebo for 8 weeks, as an adjunct to their existing antipsychotic treatment. Conditions included are schizotypal personality disorder, schizophrenia and schizoaffective disorders. The trial is sponsored by the CMCR (Center for Medicinal Cannabis Research) at UCSD and funded through its grants program. ClinicalTrials.gov Identifier: NCT04411225.

What the trial is measuring

What makes the UCSD trial exceptional is the breadth of its outcome measures. It is not simply asking whether CBD reduces psychotic symptoms — it is investigating CBD’s effects across five distinct domains simultaneously, with testing at baseline, midpoint (week 4), and endpoint (week 8):

1. Psychotic symptoms: Positive symptoms (hallucinations, delusions), negative symptoms (flat affect, social withdrawal, loss of motivation), and global functioning using validated clinical scales.

2. Neurocognition: Cognitive function assessments measuring memory, attention, processing speed, and executive function — the areas where antipsychotics largely fail.

3. Neuroinflammation and neurohormone biomarkers: Blood-based markers of inflammation and stress hormones, testing the hypothesis that CBD reduces pro-inflammatory signaling — a key mechanism implicated in the progression of psychotic disorders.

4. Eating behaviors and metabolic measures: Antipsychotic medications are notorious for causing hyperphagia (compulsive overeating) and severe metabolic abnormalities including weight gain and increased diabetes risk. The UCSD trial specifically tests whether CBD — through its known role in endocannabinoid modulation of appetite and reward — can reduce harmful eating behaviors and protect metabolic health.

5. Neurophysiological measures: Information processing and neural signal abnormalities, measured using neurophysiological paradigms that detect the specific brain processing deficits associated with early psychosis.

Full citation: Dixon T, Cadenhead KS. “Cannabidiol versus placebo as adjunctive treatment in early psychosis: study protocol for randomized controlled trial.” Trials, Springer Nature (2023). DOI: 10.1186/s13063-023-07789-w. PMC ID: PMC10691114. PubMed ID: 38037108.

Why this trial came about

The trial was not purely laboratory-driven. Anecdotally, patients already enrolled in the UCSD CARE Early Psychosis Program were self-administering CBD on their own and reporting subjective improvements in stress, anxiety, and their ability to cope with psychotic symptoms. Researchers saw this and recognized the urgent scientific need to rigorously test what patients were already experiencing informally — and to understand the mechanisms behind it.

The Oxford STEP Programme: The Largest CBD-Psychosis Study in History

Running parallel to the UCSD trial is the STEP (Stratification and Treatment in Early Psychosis) programme — the largest CBD and psychosis research initiative ever launched. Led by Professor Philip McGuire, Professor of Psychiatry at Oxford University, and funded by Wellcome with a £16.5 million grant, STEP involves 1,000 participants across 35 to 38 centers in 11 countries including the United States, Canada, Germany, Austria, Finland, Italy, Spain, Israel, Greece, the Netherlands, and Switzerland.

STEP comprises three separate sub-trials targeting different stages of psychosis: people at clinically high risk for psychosis who have not yet had a full episode, people with first-episode psychosis, and people with established psychosis that has not responded to conventional antipsychotic treatment. The CBD formulation used is Epidiolex (Jazz Pharmaceuticals) — the FDA-approved pharmaceutical-grade CBD already in clinical use for severe epilepsy — at 1,000mg daily for 6 weeks. The STEP-ENHANCE sub-trial (NCT06778564) specifically targets first-episode psychosis.

Nature Medicine named STEP one of the 11 studies that will shape medicine in 2025. Initial results are anticipated by end of 2025 or 2026. Professor McGuire said: “Cannabidiol is one of the most promising new treatments for people with psychosis. Many people with psychosis are open to trying cannabidiol and previous smaller-scale studies have indicated that it has beneficial effects. As well as treating psychosis that is already established, the study will also investigate whether cannabidiol can prevent the onset of psychosis in people at high risk of developing it.”

Source: University of Oxford Department of Psychiatry / Wellcome (February 2023). ClinicalTrials.gov: NCT06778564 (STEP-ENHANCE). https://www.ox.ac.uk/news/2023-02-16-major-trials-test-effectiveness-cannabidiol-psychosis

The Evidence Foundation: What Earlier Studies Showed

CBD vs. amisulpride: the 2012 Cologne trial (Leweke et al.)

In one of the most striking early studies, Leweke and colleagues at the University of Cologne conducted a randomized Phase 2 trial comparing CBD (up to 800mg/day) directly against amisulpride — a standard antipsychotic — over 4 weeks in 39 patients with acute schizophrenia. Both treatments produced highly significant and comparable improvements in psychotic symptoms. However, CBD produced significantly fewer side effects: no weight gain, no movement disorders, no elevated prolactin (which causes hormonal problems) compared to amisulpride. The researchers also found that CBD significantly increased serum anandamide levels, and this increase was directly correlated with the reduction in psychotic symptoms — providing the first human clinical evidence of CBD’s mechanism of action in psychosis.

Full citation: Leweke FM, Piomelli D, Pahlisch F, et al. “Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.” Translational Psychiatry (2012). DOI: 10.1038/tp.2012.15.

The 2018 McGuire landmark multicenter RCT

The largest completed clinical trial to date was published in the American Journal of Psychiatry (2018) by McGuire, Robson, Cubala, Vasile, Morrison, Barron, Taylor, and Wright — researchers at King’s College London, GW Pharmaceuticals, and centers in Poland and Romania. In a multicenter, double-blind, randomized controlled trial, 88 moderately ill patients with schizophrenia received CBD 1,000mg daily or placebo as an add-on to their existing antipsychotic medication for 6 weeks. The CBD group showed significantly greater improvements in positive psychotic symptoms (PANSS scale) compared to placebo (treatment difference: -1.4, 95% CI -2.5 to -0.2), and also showed significant improvement on the Global Clinical Impression scale. Crucially, CBD was associated with better patient and clinician ratings of mental state and overall function.

Full citation: McGuire P, Robson P, Cubala WJ, Vasile D, Morrison PD, Barron R, Taylor A, Wright S. “Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial.” American Journal of Psychiatry (2018). Vol. 175, pp. 225–231. DOI: 10.1176/appi.ajp.2017.17030325. PMC: PMC5887970.

Why early intervention matters: the staging insight

A critical finding that emerged from comparing the McGuire (2018) study with an earlier trial by Boggs and colleagues (2018, n=36, chronic schizophrenia) is that CBD appears more effective in earlier-stage illness. As a comprehensive review in Lancet Psychiatry (PMC6843725) concluded, younger patients in earlier stages of psychosis may benefit more from CBD treatment, “potentially because intervening early arrests pathophysiological processes before more severe or enduring neural changes take place.” This is precisely the rationale for both the UCSD CARE trial and the Oxford STEP programme targeting early and at-risk populations.

Why CBD Works Differently From Every Antipsychotic Ever Made

Every antipsychotic medication approved over the past 70 years — from haloperidol to clozapine to aripiprazole — works primarily by blocking dopamine D2 receptors. This blocks the dopamine overactivity that drives hallucinations and delusions. But the same mechanism causes the devastating side effects (movement disorders, metabolic syndrome, hormonal disruption) and does virtually nothing for the cognitive and negative symptoms that most impair daily functioning.

CBD works through an entirely different set of pathways. Research published in Schizophrenia Bulletin Open (Oxford Academic, 2022) and in a comprehensive Lancet Psychiatry review (PMC6843725) identifies four key mechanisms:

Anandamide upregulation: CBD inhibits FAAH (fatty acid amide hydrolase) — the enzyme that breaks down anandamide, the brain’s own endocannabinoid. By preserving anandamide, CBD appears to modulate the dopaminergic overactivity that underlies psychosis through an indirect, neuroprotective pathway rather than direct receptor blockade. Elevated anandamide in the cerebrospinal fluid of psychosis patients is inversely correlated with symptom severity — the more anandamide, the fewer symptoms. The 2012 Leweke trial confirmed that CBD increases serum anandamide, and this increase correlates with clinical improvement.

Anti-neuroinflammatory effects: Growing evidence implicates chronic neuroinflammation in the pathogenesis and progression of psychotic disorders. CBD has documented anti-inflammatory properties — suppressing inflammatory signaling in the medial temporal lobe and insula — brain regions directly involved in psychosis pathophysiology. The UCSD trial specifically measures pro-inflammatory biomarkers as a primary outcome.

5-HT1A and glutamate receptor activation: CBD acts on serotonin and glutamate receptor systems — two neurotransmitter systems that D2-blocking antipsychotics do not target — which may explain CBD’s potential benefits for negative symptoms and cognition that conventional medications miss.

Neuroprotection and neurogenesis: CBD has been shown to promote hippocampal neurogenesis and provide neuroprotection against excitotoxicity in animal models of psychosis — potentially arresting the progressive neural deterioration that characterizes untreated or inadequately treated early psychosis.

Citation: “Understanding the Potential Benefits of Cannabidiol for Patients With Schizophrenia.” Schizophrenia Bulletin Open, Oxford Academic (2022). DOI: 10.1093/schizbullopen/sgab053. AND: “Cannabidiol as a potential treatment for psychosis.” Lancet Psychiatry review. PMC ID: PMC6843725.

The Eating Behavior Dimension: A Uniquely Important Finding

One of the most distinctive aspects of the UCSD trial — and one that has received far too little public attention — is its investigation of CBD’s effects on eating behaviors and metabolic health in early psychosis patients.

Antipsychotic-induced weight gain and metabolic syndrome are among the most clinically significant side effects of current treatment. Many second-generation antipsychotics (olanzapine, clozapine, quetiapine) cause dramatic weight gain — often 20 to 30 pounds or more within months of starting treatment — through a combination of direct appetite stimulation (hyperphagia) and metabolic disruption. This metabolic syndrome dramatically increases long-term cardiovascular risk and is a major driver of medication non-adherence.

The endocannabinoid system plays a powerful regulatory role in eating behavior, appetite, reward, and metabolic function. The UCSD researchers hypothesize that CBD — by modulating endocannabinoid signaling without the appetite-stimulating effects of THC — may actually counteract the hyperphagia induced by antipsychotic medications and help protect metabolic health during early treatment. If confirmed, this would represent a profound clinical advance: not just improving psychotic symptoms, but also protecting the physical health of young patients who are especially vulnerable during their first years of treatment.

Additional Active Research

Beyond UCSD and Oxford, several other CBD and psychosis trials are active globally:

Denmark — Lone Baandrup / NCT04105231: A Phase 2 randomized trial comparing CBD directly against risperidone (an antipsychotic) in patients with non-affective psychosis and comorbid cannabis use. This trial also examines CBD’s effects on sleep quality and circadian rest-activity cycles in psychosis.

Germany — University of Cologne: Two completed Phase 2 randomized trials (NCT00309413 and NCT00628290) examining CBD versus placebo and CBD versus amisulpride in acute schizophrenic psychosis — providing foundational data that informed both the UCSD and Oxford trials.

STEP-ENHANCE (Oxford / NCT06778564): The first-episode psychosis sub-trial of the Oxford STEP programme, using 1,000mg Epidiolex daily for 6 weeks in a Phase 3 double-blind randomized controlled trial. This trial uses clinical, digital, cognitive, neuroimaging, and blood biomarker assessments — the most comprehensive measurement battery in any CBD-psychosis study to date.

Safety, Tolerability, and the Side Effect Advantage

One of the most consistently reported findings across all CBD and psychosis studies is CBD’s superior tolerability compared to antipsychotic medications. In the 2018 McGuire trial, CBD was not associated with movement disorders, prolactin elevation, or metabolic changes — the three most common and debilitating antipsychotic side effects. In the Leweke amisulpride comparison trial, CBD produced comparable symptom improvement with a markedly better side effect profile.

CBD does have known safety considerations at high doses: a 2025 FDA-reviewed trial found elevated liver enzymes in a subset of participants, and CBD can interact with medications metabolized by liver cytochrome P450 enzymes — a clinically relevant concern given that psychosis patients are by definition taking other medications. All active trials include hepatic monitoring protocols.

What This Means: Honest Context

It is essential to be clear about where the science stands. CBD is not an approved treatment for psychosis. The UCSD trial is still active and recruiting, and the Oxford STEP programme’s initial results are expected in 2025–2026 but have not yet been published. The existing evidence — while genuinely promising — comes primarily from relatively small Phase 2 trials. Large-scale Phase 3 data is precisely what is now being generated.

However, the convergence of evidence is striking: CBD works through mechanisms that are genuinely different from any existing antipsychotic, it has demonstrated effects on positive symptoms in the most rigorous completed trial, it appears more effective in early-stage illness, it has a dramatically better side effect profile than antipsychotic medications, and it may uniquely address the eating behaviors, metabolic dysfunction, cognition, and neuroinflammation that current treatments ignore. If the UCSD and Oxford trials confirm these benefits, CBD could represent the first genuinely new class of antipsychotic treatment in 70 years.

The Bottom Line

Psychotic disorders devastate the lives of young people at the moment they are just beginning. The UCSD CARE trial and the Oxford STEP programme represent the most serious, rigorous, and well-funded efforts in history to determine whether CBD can change that reality. At Tonify, we will follow these trials closely and report the results to our community as they emerge. The science of CBD and early psychosis is still being written — and the world is watching.

Full Sources & Citations

1. Dixon T, Cadenhead KS. “Cannabidiol versus placebo as adjunctive treatment in early psychosis: study protocol for randomized controlled trial.” Trials, Springer Nature (2023). DOI: 10.1186/s13063-023-07789-w. PMC: PMC10691114. PubMed: 38037108. https://pmc.ncbi.nlm.nih.gov/articles/PMC10691114/

2. Effects of Cannabidiol (CBD) Versus Placebo as an Adjunct to Treatment in Early Psychosis. Phase 3 RCT, UC San Diego CARE Program. ClinicalTrials.gov: NCT04411225. Sponsor: UCSD / CMCR. Ages 16–30. https://clinicaltrials.gov/study/NCT04411225

3. McGuire P, Robson P, Cubala WJ, et al. “Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial.” American Journal of Psychiatry (2018). Vol. 175, pp. 225–231. DOI: 10.1176/appi.ajp.2017.17030325. PMC: PMC5887970.

4. Leweke FM, Piomelli D, Pahlisch F, et al. “Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.” Translational Psychiatry (2012). DOI: 10.1038/tp.2012.15.

5. “Cannabidiol as a potential treatment for psychosis.” Lancet Psychiatry comprehensive review. PMC ID: PMC6843725. https://pmc.ncbi.nlm.nih.gov/articles/PMC6843725/

6. “Cannabidiol (CBD) as a novel treatment in the early phases of psychosis.” PMC ID: PMC9110455. https://pmc.ncbi.nlm.nih.gov/articles/PMC9110455/

7. “Understanding the Potential Benefits of Cannabidiol for Patients With Schizophrenia: A Narrative Review.” Schizophrenia Bulletin Open, Oxford Academic (2022). DOI: 10.1093/schizbullopen/sgab053. https://academic.oup.com/schizbullopen/article/3/1/sgab053/6445173

8. Oxford University STEP Programme — Major trials to test effectiveness of cannabidiol on psychosis. Funded by Wellcome (£16.5 million). University of Oxford Department of Psychiatry (February 2023). https://www.ox.ac.uk/news/2023-02-16-major-trials-test-effectiveness-cannabidiol-psychosis

9. STEP-ENHANCE Trial: Augmentation With Cannabidiol in First Episode Psychosis. Phase 3 RCT, University of Oxford. ClinicalTrials.gov: NCT06778564. https://clinicaltrials.gov/study/NCT06778564

10. Is CBD Effective for Psychosis? New Study Aims to Find Out. Medscape (February 2025). https://www.medscape.com/viewarticle/cbd-effective-psychosis-new-study-aims-find-out-2025a1000471

11. Is CBD the Future of Antipsychotic Drugs? Wellcome Foundation (February 2025). https://wellcome.org/news/cbd-future-antipsychotic-drugs-new-global-study-investigates

12. “The Potential of Cannabidiol as a Treatment for Psychosis and Addiction: Who Benefits Most? A Systematic Review.” Journal of Clinical Medicine (2019). MDPI. https://www.mdpi.com/2077-0383/8/7/1058

13. Cannabidiol for Treatment of Non-affective Psychosis and Cannabis Use. Phase 2 RCT, Denmark. ClinicalTrials.gov: NCT04105231. https://clinicaltrials.gov/study/NCT04105231

14. Nature Medicine: 11 studies that will shape medicine in 2025 (STEP trial featured). Nature Medicine, Springer Nature (2025).

15. UCSD Center for Medicinal Cannabis Research (CMCR): Effects of CBD vs Placebo in Early Psychosis. https://www.cmcr.ucsd.edu/index.php/?option=com_content&view=article&id=177/

16. “Understanding the Relationship Between Cannabidiol and Psychosis: Clinical Issues.” Psychiatric Times (2026). https://www.psychiatrictimes.com/view/understanding-relationship-between-cannabidiol-and-psychosis-clinical-issues

Disclaimer: This article is for informational and educational purposes only. The statements in this blog have not been evaluated by the Food and Drug Administration. Tonify products are not intended to diagnose, treat, cure, or prevent any disease. CBD is not approved for the treatment of psychosis, schizophrenia, or any related psychotic disorder. Anyone experiencing symptoms of psychosis should seek immediate evaluation from a qualified psychiatrist or mental health professional. Never discontinue prescribed antipsychotic medication without medical supervision.