Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia

TLDR

Cannabidiol, a non‑receptor‑activating component of marijuana, modestly inhibits anandamide degradation. The study aimed to evaluate the clinical relevance of cannabidiol’s effect on anandamide signaling by comparing it to amisulpride in acute schizophrenia. The authors conducted a double‑blind, randomized trial comparing cannabidiol to amisulpride in patients with acute schizophrenia. Both treatments were safe and improved symptoms, but cannabidiol had a superior side‑effect profile, increased serum anandamide, and its effect correlated with clinical improvement, suggesting that inhibiting anandamide deactivation may underlie its antipsychotic action.

Abstract

Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.