Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia
F. M. Leweke, D. Piomelli, F. Pahlisch, D. Muhl, C.W. Gerth, C. Hoyer, J. Klosterkötter, M. Hellmich and D. Koethe
- Translationnal Psychiatry, 2012, 2, e94
doi :10.1038/tp.2012.15; published online 20 March 2012
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.
The search for safe and effective drugs to treat schizophrenia is hindered by the complex nature of this disorder, which is known to involve multiple brain neurotransmitters.1 Among them are the endogenous cannabinoids, a family of lipid messengers that target the same cell surface receptors engaged by Δ9-tetrahydrocannabinol in marijuana.2 Because Δ9-tetrahydrocannabinol and other direct-acting cannabinoid agonists can induce psychotic symptoms both in healthy volunteers3, 4, 5 and schizophrenic patients,6, 7 it has been suggested that hyperactivity of the endocannabinoid system might contribute to psychotic states.8, 9 This idea has fueled two large-scale clinical trials with CB1-type cannabinoid receptor antagonists in schizophrenia, which yielded, however, negative results.10, 11 A diametrically opposite view — namely that certain components of the endocannabinoid system might have a protective role in schizophrenia — was suggested by studies with antipsychotic-naïve schizophrenic patients, in which it was found that the symptom intensity experienced by these subjects was negatively correlated with cerebrospinal levels of anandamide,12, 13 an endocannabinoid transmitter known to be involved in the regulation of pain, mood and cognition.14 Consistent with these clinical observations, animal experiments have shown that pharmacological blockade of anandamide degradation attenuates, rather than enhances, psychotic-like behaviors induced in rodents by amphetamine and phencyclidine.15, 16
Cannabidiol is a non-psychotropic component of marijuana that binds to CB1 receptors with only comparably very low affinity17, 18 and is devoid of overt cannabimimetic or pro-psychotic properties.17 Biochemical studies indicate that cannabidiol may enhance endogenous anandamide signaling indirectly, by inhibiting the intracellular degradation of anandamide catalyzed by the enzyme fatty acid amide hydrolase (FAAH).19 Furthermore, preliminary clinical case reports suggest that cannabidiol might exert antipsychotic effects in schizophrenic patients.20, 21, 22 In addition, experimental studies show that cannabidiol reduces psychosis-like effects of Δ9-tetrahydrocannabinol and synthetic analogs.22, 23