MODULATION OF THE ENDOCANNABINOID SYSTEM AS A POTENTIAL NEW TARGET IN THE TREATMENT OF SCHIZOPHRENIA

BACKGROUND:

New pharmacological targets for the treatment of schizophrenia are urgently required. 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, a purified phytocannabinoid, significantly ameliorates psychotic symptoms in acute schizophrenia.

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 cannabidiol (600 mg per day) 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.

RESULTS:

Cannabidiol significantly improved psychotic symptoms in the cannabidiol-placebo 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 PANSS total in favor of cannabidiol (vs. placebo), albeit not statistically significant. Only one patient on sequence cannabidiol-placebo terminated treatment early (last seen at visit 3) whereas 10 patients terminated early on sequence placebo- cannabidiol. The most frequent reason given was worsening of symptoms (5/11 patients). In addition, cannabidiol was detectable in serum of almost all patients in the cannabidiol-placebo group. Side-effects of cannabidiol were on the level of placebo.

CONCLUSION:

Although limited by design issues (cross-over), duration of treatment (14 days), carry-over effects (serum levels of cannabidiol), and relevant placebo-response rates, this is the second study to provide evidence for antipsychotic properties of cannabidiol accompanied by a superior side-effect profile. Future placebo-controlled parallel-group trials studying the antipsychotic properties of cannabidiol in acute schizophrenia are necessary to provide further evidence for its efficacy in the treatment of this devastating disease.