In a randomized, double-blind, placebo-controlled crossover trial published in Neuropsychopharmacology (2025), Chesney and colleagues examined whether cannabidiol (CBD) could mitigate the acute adverse effects of cannabis in people with schizophrenia or schizoaffective disorder who also had a cannabis use disorder.
This study was a randomized, double-blind, placebo-controlled, cross-over trial conducted at the NIHR Clinical Research Facility at King’s College London. Thirty clinically stable individuals who regularly use cannabis participated. Each participant received either 1000 mg of oral CBD or a placebo, administered three hours before they inhaled vaporized cannabis containing between 20 and 60 mg of THC. The primary cognitive outcome was delayed verbal recall, assessed using the Hopkins Verbal Learning Test–Revised. Psychotic-like effects were measured using the Positive subscale of the PANSS.
The study found that CBD pretreatment unexpectedly worsened, rather than improved, cannabis-induced cognitive impairment. Participants recalled an average of 3.5 words after cannabis when pretreated with CBD compared with 4.8 words after placebo, a mean difference of –1.3 that was statistically significant (p = 0.001). Psychotic symptoms also increased more following cannabis when participants had received CBD, with PANSS Positive scores rising by 5.0 points after CBD versus 2.9 after placebo, a difference of 2.2 points (p = 0.01), driven particularly by greater conceptual disorganization and suspiciousness or persecution. Pharmacokinetic analyses indicated that CBD did not alter THC or 11-hydroxy-THC levels, ruling out metabolic interaction; however, higher CBD plasma concentrations were associated with worse verbal recall (r = –0.27, p = 0.038) and higher PANSS Positive scores (r = 0.43, p = 0.018), suggesting a pharmacodynamic mechanism. Two participants experienced adverse reactions attributed to CBD, including one brief psychotic episode characterized by persecutory delusions and one case of severe hypertension (224/78 mmHg), both of which resolved without lasting effects.
The findings indicate that high-dose oral CBD at 1000 mg did not protect schizophrenia patients with cannabis use disorder from the cognitive or psychotic effects of cannabis and may, in fact, exacerbate both, a result that runs counter to expectations and to earlier studies in healthy volunteers in which CBD sometimes attenuated THC-related adverse effects. The authors suggest that underlying differences in endocannabinoid signaling or mitochondrial function in schizophrenia or in chronic cannabis users may alter CBD’s pharmacodynamic profile, potentially reversing the effects observed in other populations. Importantly, these results do not challenge CBD’s broader therapeutic potential as an antipsychotic agent in schizophrenia but do imply that it should not be relied upon to lessen or counteract the acute effects of cannabis in individuals who use both substances.
Table 1.
| Aspect |
Key Point |
| Population |
Schizophrenia/schizoaffective disorder with comorbid cannabis use disorder |
| Intervention |
1000 mg oral CBD 3h before THC (20–60 mg) |
| Outcome |
Increased THC-induced cognitive and psychotic effects |
| Mechanism |
Likely pharmacodynamic, not due to THC metabolism |
| Safety |
Generally well tolerated; rare acute psychiatric or BP events |
| Clinical Implication |
CBD should not be used to prevent cannabis-related symptom exacerbation in this group |
Overall, the study suggests that CBD does not protect against the psychotomimetic or cognitive effects of THC in this population, highlighting the need for caution when co-prescribing or recommending CBD products to schizophrenia patients who use cannabis. Further research is required to determine whether CBD may have different effects in schizophrenia patients who do not use cannabis, whether alternative dosing or timing strategies could yield protective benefits, and which underlying mechanisms—such as CB1 receptor modulation or mitochondrial dysfunction—might explain the unexpected worsening of outcomes observed here.
Reference:
Reference: Chesney E et al. Neuropsychopharmacol. 50;1759–1767:2025. Abstract
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