Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia : A Multicenter Randomized Controlled Trial
Research in both animals and humans indicates that cannabidiol (CBD) has antipsychotic properties. The authors assessed the safety and effectiveness of CBD in patients with schizophrenia.
In an exploratory double-blind parallel-group trial, patients with schizophrenia were randomized in a 1:1 ratio to receive CBD (1000 mg/day; N=43) or placebo (N=45) alongside their existing antipsychotic medication. Participants were assessed before and after treatment using the Positive and Negative Syndrome Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia (BACS), the Global Assessment of Functioning scale (GAF), and the improvement and severity scales of the Clinical Global Impressions Scale (CGI-I and CGI-S).
After 6 weeks of treatment, compared with the placebo group, the CBD group had lower levels of positive psychotic symptoms (PANSS: treatment difference=−1.4, 95% CI=−2.5, −0.2) and were more likely to have been rated as improved (CGI-I: treatment difference=−0.5, 95% CI=−0.8, −0.1) and as not severely unwell (CGI-S: treatment difference=−0.3, 95% CI=−0.5, 0.0) by the treating clinician. Patients who received CBD also showed greater improvements that fell short of statistical significance in cognitive performance (BACS: treatment difference=1.31, 95% CI=−0.10, 2.72) and in overall functioning (GAF: treatment difference=3.0, 95% CI=−0.4, 6.4). CBD was well tolerated, and rates of adverse events were similar between the CBD and placebo groups.
These findings suggest that CBD has beneficial effects in patients with schizophrenia. As CBD’s effects do not appear to depend on dopamine receptor antagonism, this agent may represent a new class of treatment for the disorder.
Antipsychotic drugs, the first-line treatment for schizophrenia, act through the antagonism of central dopamine D2 receptors (1). Although they are effective in most patients, therapeutic response is poor in up to one-third of patients (2); this may reflect an absence of elevated dopamine function in this subgroup (3). In patients who respond to antipsychotics, the beneficial effects are mainly on positive psychotic symptoms: antipsychotics have relatively little impact on negative symptoms and cognitive impairments (4). This may be because, in contrast to positive symptoms, these features of schizophrenia are not driven by elevated dopamine function (2). Compounds whose molecular mechanism of action differs from that of antipsychotic drugs might therefore improve the treatment of schizophrenia.
The two most abundant cannabinoids in Cannabis sativa are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Different forms of cannabis vary in the relative proportions of THC and CBD, and the risk of psychotic symptoms and impaired cognitive functioning following cannabis use is lower with cannabis preparations that have a relatively high CBD content (5). In healthy volunteers, pretreatment with CBD attenuates both the experimental induction of psychotic symptoms by THC (6, 7) and the adverse effects of THC on cognitive performance (8–10). The mechanism of action of CBD is unclear, but it does not appear to involve the direct antagonism of dopamine receptors (11).
The first evidence that CBD might be useful in treating schizophrenia came from a case report in which it was found to improve symptoms in a patient who had not responded to haloperidol (12).
CBD has also been reported to reduce psychotic symptoms in patients with Parkinson’s disease (13). The only previous trial of CBD in schizophrenia compared CBD against amisulpride in patients with an acute exacerbation of schizophrenia symptoms (14). After 4 weeks of treatment, both drugs had reduced ratings on the Positive and Negative Syndrome Scale (PANSS) to a similar extent, but CBD was associated with fewer adverse effects.
The aim of the present study was to explore the safety and effectiveness of CBD as an adjunctive treatment in schizophrenia. In a randomized double-blind trial, patients who had been partially responsive to antipsychotic medication received either CBD or placebo as an add-on treatment for 6 weeks. We examined the effects of CBD on positive and negative psychotic symptoms, cognitive performance, level of functioning, and the treating psychiatrist’s overall clinical impression.