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American Journal of Psychiatry: 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.

Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug


Anxiolytic effect of cannabidiol

The anxiolytic properties of CBD has been demonstrated by several pre-clinical studies that employed different paradigms such as the conditioned emotional response (21), the Vogel conflict test (22) and the elevated plus-maze (23,24). In the later study (24), the effective doses of CBD ranged from 2.5 to 10 mg/kg, and the drug produced an inverted U-shaped dose-response curve, the higher doses being no longer effective in rats. This could explain the negative results obtained with high doses of CBD (above 100 mg/kg) in a previous study employing the Geller-Seifter conflict test (25).

To evaluate a possible anxiolytic effect of CBD in humans, a double-blind study was conducted on healthy volunteers submitted to a simulation of the public speaking test. CBD (300 mg, po) was compared to ipsapirone (5 mg), diazepam (10 mg) or placebo. The results showed that both CBD and the two other anxiolytic compounds attenuated the anxiety induced by the test (26). The anxiolytic-like effect of CBD in healthy volunteers was also observed in a more recent double-blind study that investigated its effects on regional cerebral blood flow by single-photon emission computed tomography. Because the procedure, by itself, can be interpreted as an anxiogenic situation, it permits the evaluation of anxiolytic drugs. CBD induced a clear anxiolytic effect and a pattern of cerebral activity compatible with an anxiolytic activity (27). Therefore, similar to the data obtained in animal models, results from studies on healthy volunteers have strongly suggested an anxiolytic-like effect of CBD.


Safety studies

Safety studies of CBD were required before human tests. CBD was extensively investigated in laboratory animals to detect possible side or toxic effects (17). Acute CBD administration by the oral, inhalatory or intravenous route did not induce any significant toxic effect in humans (38). In addition, chronic administration of CBD for 30 days to healthy volunteers, at daily doses ranging from 10 to 400 mg, failed to induce any significant alteration in neurological, psychiatric or clinical exams (17). Finally, in patients suffering from Huntington's disease, daily doses of CBD (700 mg) for 6 weeks did not induce any toxicity (39). Therefore, confirming results from animal studies, the available clinical data suggest that CBD can be safely administered over a wide dose range.


On view of the safe profile of CBD administration in humans and in laboratory animals, we decided to perform open-label clinical trials in a reduced number of patients. In 1995, CBD was tested in a case study with a 19-year-old schizophrenic female patient who presented serious side effects after treatment with conventional antipsychotics (47). Following a wash-out period of 4 days this patient received increasing oral doses of CBD dissolved in oil, reaching 1500 mg/day, for 4 weeks. After this period, CBD administration was interrupted and placebo was administered for 4 days. Finally, the treatment was shifted to increasing doses of haloperidol that reached 12.5 mg/day. The psychiatric interviews were video-recorded and the symptoms were assessed by a blinded-psychiatrist using the Brief Psychiatric Rating Scale (BPRS). A significant improvement was observed during CBD treatment, while a worsening was observed when the administration was interrupted. The improvement obtained with CBD was not increased by haloperidol (Figure 3, patient A). Further supporting the safe profile of CBD, no side effects were observed, as assessed by the Ugvalg for Kliniske Undersgelser (UKU) scale (47).


More recently, CBD was administered to three 22- or 23-year-old male patients with a diagnosis of schizophrenia who had not responded to typical antipsychotic drugs (48). They received placebo for 5 days in the hospital followed by CBD from the 6th to the 35th day. After this period, they received placebo for an additional 5 days, followed by olanzapine for at least 15 days. The dose of CBD was increased from 40 up to 1280 mg/day. The patients were assessed by two psychiatrists, who were blind to the doses administered, using the BPRS and UKU scales. No side effects were observed during CBD treatment, even at the higher dose of 1280 mg/day. A partial improvement was observed in one patient (Figure 3, patient B) while slight or no improvement was observed in the other two (Figure 3, patients C and D). However, the patients (C and D) were considered to be refractory, since they did not even respond to clozapine, a fact that may explain the lack of CBD effectiveness (48). Figure 3shows the results obtained with the 4 schizophrenic patients treated so far with CBD. These studies suggest, therefore, that CBD has an antipsychotic-like profile in healthy volunteers and may possess antipsychotic properties in schizophrenic patients, but not in the resistant ones.

Confirming this suggestion, a preliminary report from a 4-week, double-blind controlled clinical trial, using an adequate number of patients and comparing the effects of CBD with amisulpride in acute schizophrenic and schizophreniform psychosis, showed that CBD significantly reduced acute psychotic symptoms after 2 and 4 weeks of treatment when compared to baseline. In this trial CBD did not differ from amisulpride except for a lower incidence of side effects (49).

In conclusion, results from pre-clinical and clinical studies suggest that CBD is an effective, safe and well-tolerated alternative treatment for schizophrenic patients. Future trials of this cannabinoid in other psychotic conditions such as bipolar disorder (50) and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly needed.