Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia

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.

Figure 1

Participant flow; analysis sets: VfS, valid for safety; mITT, modified intention-to-treat and PP, per protocol.

Figure 2

Changes from baseline in Positive and Negative Symptoms Scale (PANSS) scores determined using mixed effects repeated measures model analysis (adjusted for baseline). (a) PANSS total score. (b) PANSS-positive score. (c) PANSS-negative score. (d) PANSS general score. Data show predicted means and s.e. at each weak. Statistical significance is calculated between groups (^†P⩽0.05, ^††P⩽0.01 and ^†††P⩽0.001) and vs baseline (that is, 0; ^*CBD, ^#AMI; ^***/###P⩽0.05, ^**/##P⩽0.01, ^*/#P⩽0.001).

Figure 3

Changes from baseline in side effects determined using mixed effects repeated measures model analysis (adjusted for baseline). (a) Extrapyramidal Symptom Scale (EPS). (b) Weight gain. (c) Prolactin. Data show predicted means and s.e. at each weak. Statistical significance is calculated between groups (^†P⩽0.05, ^††P⩽0.01 and ^†††P⩽0.001) and vs baseline (that is, 0; ^*CBD, ^#AMI; ^***/###P⩽0.05, ^**/##P⩽0.01, ^*/#P⩽0.001).

Figure 4

Changes from baseline in fatty acid amide hydrolase substrates determined using mixed effects repeated measures model analysis (adjusted for baseline). (a) Anandamide (AEA) in serum. (b) Oleoylethanolamide (OEA) in serum. (c) Palmitoylethanolamide (PEA) in serum. Data show predicted means and s.e. at each weak. Statistical significance is calculated between groups (^†P⩽0.05, ^††P⩽0.01 and ^†††P⩽0.001) and vs baseline (that is, 0; ^*CBD, ^#AMI; ^***/###P⩽0.05, ^**/##P⩽0.01, ^*/#P⩽0.001).

Figure 5

Association of change in anandamide in serum and change in the Positive and Negative Symptoms Scale total score in patients treated and observed per protocol. (a) Individual changes of patients treated with cannabidiol (n=14). (b) Individual changes of patients treated with amisulpride (n=8). P-values are from the Wilcoxon signed rank test of the null hypothesis that the distribution of slope is symmetric about zero.