The Endocannabinoid System in Schizophrenia - a Mechanistically New Approach to its Pathophysiology and Treatment

BACKGROUND: There is urgent need for an improved understanding of pathomechanisms of schizophrenia to enable improved new pharmacological treatments. We initially identified one of the two major endocannabinoids, anandamide, as a counterbalancing if not protective factor in paranoid schizophrenia. Most recently, we reported that increasing levels of anandamide by blocking its metabolization by cannabidiol (CBD) significantly ameliorates psychotic symptoms in acute schizophrenia (Leweke et al., Transl Psychiatry 2012). Here, we report on the results of the first clinical trial comparing CBD vs. placebo in acutely exacerbated, first-break paranoid schizophrenia patients. METHODS: We performed a randomized, double-blind, placebo-controlled, cross-over clinical trial in acute, antipsychotic- naive, first-break paranoid schizophrenia patients, fulfilling diagnostic criteria of DSM-IV. 29 patients were treated after written informed consent with either CBD or placebo for 14 days and than switched to the corresponding cross-over condition. Additional patients to gain a total of 18 patients treated per protocol replaced dropouts. Serum was taken at baseline and on days 14 and 28. In addition, 14 patients provided cerebrospinal fluid (CSF) at baseline and day 28 for biomarker investigations. RESULTS: CBD significantly improved psychotic symptoms in the CBDplacebo condition during the first 14 days of treatment when compared to baseline. A MMRM analysis of all randomized patients (n = 29) yielded a mean improvement of 2.4 points (standard error 3.0) on PAN SS total in favor of CBD (vs. placebo), albeit not statistically significant. Only one patient on sequence CBD-placebo terminated treatment early (last seen at visit 3) whereas 10 patients terminated early on sequence placebo- CBD. The most frequent reason given was worsening of symptoms (5/11 patients). In addition, CBD was detectable in serum of almost all patients in the CBD-placebo group. Side-effects of CBD were on the level of placebo. CONCLUSION: Although limited by design issues, duration of treatment, carry-over effects, and relevant placebo-response rates, this is the second study to provide evidence for antipsychotic properties of CBD accompanied by a superior side-effect profile. Future placebo-controlled parallel-group trials studying the antipsychotic properties of CBD in acute schizophrenia are necessary to provide further evidence for its efficacy in the treatment of this devastating disease.