Elevated endogenous cannabinoids in schizophrenia

Abstract

CA Corresponding Author à These authors contributed equally to this study EVIDENCE suggests that cannabinoid receptors, the pharmacologcial target of cannabis-derived drugs, and their accompanying system of endogenous activators may be dysfunctional in schizophrenia. To test this hypothesis, we examined whether endogenous cannabinoid concentrations in cerebrospinal¯uid of schizophrenic patients are altered compared to nonschizophrenic controls. Endogenous cannabinoids were puri®ed from cerebrospinal¯uid of 10 patients with schizophrenia and 11 non-schizophrenic controls by high-performance liquid chromatography, and quanti®ed by isotope dilution gas-chromatography/massspectrometry. Cerebrospinal concentrations of two endogenous cannabinoids (anandamide and palmitylethanolamide) were signi®cantly higher in schizophrenic patients than non-schizophrenic controls ( p , 0.05). By contrast, levels of 2-arachidonylglycerol, another endogenous cannabinoid lipid, were below detection in both groups. The ®ndings did not seem attributable to gender, age or medication. Elevated anandamide and palmitylethanolamide levels in cerebrospinal¯uid of schizophrenic patients may re¯ect an imbalance in endogenous cannabinoid signaling, which may contribute to the pathogenesis of schizophrenia. NeuroReport 10:1665±1669 # 1999 Lippincott Williams & Wilkins.

Cerebrospinal Anandamide Levels are Elevated in Acute Schizophrenia and are Inversely Correlated with Psychotic Symptoms

“…Second, the elevation in anandamide concentration was unlikely to be caused by a generalized alteration in lipid signaling, which is hypothesized to occur in schizophrenia (Horrobin 1998), because the levels of two closely related analogs of anandamide, OEA and PEA, were not increased in schizophrenics. It is noteworthy that we found that PEA levels in antipsychotic-naïve schizophrenics were lower than controls, thus correcting an earlier study from our lab, which reported elevated PEA levels in the CSF of a small set (n ¼ 11) of treated and untreated schizophrenics (Leweke et al, 1999b). Third, the elevation in CSF anandamide was apparently restricted to schizophrenia, because it was not found in patients affected by dementia or affective disorders.…”

“…The hypothesis that a dysfunction in endocannabinoid signaling may be associated with schizophrenia is further supported by studies showing that endocannabinoid levels in cerebrospinal fluid (CSF) (Leweke et al, 1999b) and plasma (Yao et al, 2002;De Marchi et al, 2003) as well as CB 1 receptor expression (Dean et al, 2001) are abnormal in schizophrenic patients. The interpretation of these results is obscured, however, by the small number of subjects involved, the interference of concurrent drug therapy, and the lack of systematic comparison with other mental disorders in which endocannabinoid signaling also might be dysregulated.…”

The Psychotomimetic Effects of Intravenous Delta-9-Tetrahydrocannabinol in Healthy Individuals: Implications for Psychosis

“…The findings of this study add to a growing body of literature from pharmacological (Jones, 1971;Leweke et al, 2000Leweke et al, , 1999bMcGuire et al, 1995), epidemiological (Andreasson et al, 1987(Andreasson et al, , 1988(Andreasson et al, , 1989Arseneault et al, 2002;McGuire et al, 1995;Zammit et al, 2002), genetic (Ujike et al, 2002), neurochemical (Leweke et al, 1999a), and postmortem (Dean et al, 2001) approaches, suggesting that the consumption of cannabinoids (exogenous) and/or brain cannabinoid dysfunction (endogenous) may contribute to the pathophysiology of psychosis and/or schizophrenia (Emrich et al, 1997;Schneider et al, 1998). Clearly, further work is needed to test these hypotheses.…”

An Experimental Study of Catechol-O-Methyltransferase Val158Met Moderation of Δ-9-Tetrahydrocannabinol-Induced Effects on Psychosis and Cognition

“…Similarly, exogenous cannabinoids like THC increase dopamine synthesis in rodents (Bloom, 1982;Maitre et al, 1970) and activation of dopamine D2 receptors triggers release of the endocannabinoid anandamide in the rat striatum . In addition, a study of endocannabinoid levels in cerebrospinal fluid found higher levels of anandamide in patients with schizophrenia compared to healthy controls (Giuffrida et al, 2004;Leweke et al, 1999). Prolonged exposure to cannabinoids in rodents resulted in dysregulation of the endocannabinoid system by desensitization of the CB1 receptor (Sim-Selley, 2003) and reduction of dopamine metabolism in the prefrontal cortex (Jentsch et al, 1998).…”