Is CBD Effective for Psychosis? New Study Aims to Find Out

Up to 40% of individuals with psychosis do not respond to antipsychotic medications, and the vast majority of those who take them experience troubling side effects. Rapid and significant weight gain, increased blood glucose and cholesterol levels, and elevated blood pressure are common, contributing to an increased risk for diabetes and cardiovascular disease.

The search for safer, more effective treatments has been long and arduous. Hope surged in September 2024 when the US Food and Drug Administration (FDA) approved Cobenfy (xanomeline-trospium chloride), the first-in-class antipsychotic with a novel mechanism that targets trace amine-associated receptor 1 (TAAR1). 

The hope is the drug will effectively treat psychosis without the significant metabolic side effects of older antipsychotics. However, the jury is still out on whether it will live up to its promise in terms of efficacy and tolerability. 

But there is another compound that has existed in nature for millennia and is gaining renewed attention. Cannabidiol (CBD) is a nonpsychoactive component of cannabis and has shown promise in reducing psychotic symptoms in case reports and small studies for decades. 

To study CBD as a potential treatment for psychosis on a larger scale, researchers led by Philip McGuire, MD, professor of psychiatry at Oxford University in Oxford, United Kingdom, are launching the Stratification and Treatment in Early Psychosis (STEP) trial. Hailed by Nature Medicineas one of 11 studies that will shape medicine in 2025, STEP comprises three smaller trials and involves 1000 participants at 30 sites in Austria, Canada, Finland, Germany, Greece, Israel, Italy, the Netherlands, Spain, and Switzerland. 

Participants will receive Epidiolex, a concentrated formulation of CBD approved by the FDA in 2018 for the treatment of seizures associated with two rare forms of epilepsy: Lennox-Gastaut syndrome and Dravet syndrome. In 2020, the agency expanded the approval to include treatment of seizures linked to tuberous sclerosis. 

Although Epidiolex can cause adverse effects, including elevated liver enzymes, fatigue, and possible infections, investigators say that it is usually better tolerated than antipsychotic medications. 

Investigators plan to begin trial recruitment in April.

Small Studies, Mixed Results

CBD was first linked to reduced psychosis symptoms in the 1990s in a case report describing a woman with chronic psychosis who could not tolerate traditional antipsychotics owing to severe side effects. After taking 1500 mg of CBD for 4 weeks, she experienced a marked reduction in psychotic symptoms. 

In 2012, researchers published the first double-blind randomized clinical trial on the topic. A total of 42 inpatients with acute paranoid schizophrenia were randomly assigned on a 1:1 basis to receive 800 mg of CBD or amisulpride for 4 weeks. Although both groups had similar reductions in psychotic symptoms as measured by the Positive and Negative Symptom Scale (PANSS), CBD was associated with fewer adverse effects. 

In 2017, McGuire led a randomized controlled trial comparing 1000 mg of Epidiolex or placebo combined with participants’ existing antipsychotic medication for 6 weeks. The trial involved 88 participants at 11 sites in the UK, Romania, and Poland. 

At baseline, the distribution of Clinical Global Impression-Severity (CGI-S) scores were similar between the two treatment arms, with a majority of patients in both groups classified as having moderate-to-severe illness. 

By the end of treatment, the proportion of patients classified as moderate to severe decreased from 83.4% to 54.8% in the CBD group and from 79.6% to 63.6% in the placebo group. This corresponded with an increase in patients with mild to no illness from 16.7% to 45.2% in the CBD group, and from 20.5% to 36.4% in the placebo group (group differences in longitudinal change in CGI-S score P =.044).

The CBD group also showed greater reductions in overall treatment response, positive psychotic symptoms, and cognitive performance compared with the placebo group, although these differences were not statistically significant. 

More recently, McGuire and colleagues studied medical-grade CBD in individuals at high clinical risk for psychosis: those with attenuated psychotic symptoms and multiple risk factors. In this trial, 33 antipsychotic-naive participants were randomly assigned to receive either 600 mg CBD or placebo for 21 days. 

Compared with the placebo group, those treated with CBD had lower total scores on the Comprehensive Assessment of At-Risk Mental States scale (P =.012) and lower total PANSS score, although the difference was not significant. 

However, not all studies support CBD as a treatment for psychosis. A 6-week randomized controlled trial conducted in 2018 followed 36 stable patients with chronic schizophrenia taking a fixed dosage of 600 mg/d of oral CBD or placebo as an add-on to antipsychotic medication. 

Study participants were assessed for cognitive and psychotic symptoms, but researchers found no significant improvement in either outcome with CBD augmentation as measured by the PANSS. 

Three Trials in One

Mixed study results with small sample sizes such as these spurred McGuire to launch the STEP trial, which consists of three separate phase 3, placebo-controlled, double-blind randomized studies. The Wellcome Trust will provide $17.1 million for the study, and Jazz Pharmaceuticals, the manufacturer of Epidiolex, will provide the drug at no cost. 

Casual or occasional cannabis users will be accepted into the trial, McGuire noted, as its use is not unusual among individuals with psychosis. However, marijuana use will be carefully monitored. People who are pregnant are excluded from the study. 

The first trial, STEP-PROMOTE, will include 376 people across multiple countries who are at high risk for psychosis. Participants will receive CBD or placebo (no antipsychotic medication) for 104 weeks, with 11 scheduled visits to local study sites, followed by a monitoring period. 

“The question is whether CBD can halt the progression of psychosis in those patients before it reaches full-blown illness,” McGuire said. 

The second trial, STEP-ENHANCE, will include 250 participants in the UK and internationally with first-episode psychosis who continue to have symptoms despite receiving antipsychotic treatment. The 6-week trial will randomly assign participants to receive Epidiolex or placebo in a 1:1 ratio, with six assessments and a 3-month follow-up period.

Finally, STEP-ASSIST will focus on patients taking clozapine for psychosis who are still experiencing symptoms. Participants will receive either Epidiolex or placebo with clozapine for 12 weeks, with seven trial visits at their local hospital.

All participants will receive 1000 mg of Epidiolex, a dose McGuire said is optimal for its antipsychotic effects. They will be assessed before and after treatment using clinical, cognitive, neuroimaging, and blood-based measures to better understand the potential mechanisms behind the drug’s antipsychotic effects. 

As part of the STEP trial design, ethical guidelines require that Epidiolex be evaluated alongside antipsychotic medications in two of the trials. McGuire said that if the results are positive, the next step will be to test Epidiolex against placebo alone.

Store-Bought CBD vs Medical Grade

Smita Das, MD, PhD, former chair of the American Psychiatric Association’s Council on Addiction Psychiatry and associate clinical professor of psychiatry at Stanford University in California, said she is hopeful that the STEP trial’s large sample size will help clarify the promising signals from smaller studies in a larger trial. 

However, because nonmedical grade CBD is so widely available, there is concern that details of the study will lead other patients with psychosis to assume CBD could help their symptoms, said Das, who is not part of the STEP trial. 

Epidiolex, which will be used in the STEP trial, is a concentrated, pure, FDA-regulated form of CBD and does not contain delta-9-tetrahydrocannabinol (THC), which has been shown to cause psychosis.

If study results show that Epidiolex significantly improves outcomes for those with psychosis, she said, “patients will need to be taught to distinguish between store-bought CBD and medical-grade CBD,” which can only be prescribed by a physician. 

“The last thing I want for our patients is to go untreated. We do have an effective medication for our patients with psychosis, and that’s clozapine. I have seen it change lives,” Das said. 

Voicing Concern

Leslie Hulvershorn, MD, chair of the department of psychiatry at Indiana University School of Medicine, reinforced Das’s point about the importance of distinguishing between Epidiolex and other forms of CBD. 

“Trials like STEP are funded to use high-quality, medical-grade CBD preparations which are pure and expensive,” she told Medscape Medical News. “But most people purchase CBD at a local dispensary, and the composition can be very different.” 

In a recent Medscape commentary about cannabis for the treatment of psychiatric conditions, Hulvershorn pointed out that the cannabis plant is comprised of dozens of compounds — including THC — which must be studied separately. 

Hulvershorn noted that dispensaries lack any sort of oversight or regulatory process, so the formulations claiming to be CBD may include other ingredients, or low amounts of CBD. And at least one study showed that CBD formulations sold at some dispensaries contain THC. 

“There is no FDA to monitor these dispensaries and the compounds they sell,” Hulvershorn said. “So, if the STEP trial results are positive, people should not run to their dispensaries for CBD.”

McGuire said he understands these concerns, as well as potential concerns about the cost of Epidiolex, which can be expensive for those who are uninsured. “Cost is one of our considerations. For now, let’s just see if it works,” he said. 

Initial results of the STEP trial are expected by the end of 2025.

The STEP Trial will be funded by Wellcome. McGuire, Das, and Hulvershorn reported no relevant financial relationships.