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

Abstract

The endocannabinoids are a family of bioactive lipids that activate CB 1 cannabinoid receptors in the brain and exert intense emotional and cognitive effects. Here, we have examined the role of endocannabinoid signaling in psychotic states by measuring levels of the endocannabinoid anandamide in cerebrospinal fluid (CSF) of acute paranoid-type schizophrenic patients. We found that CSF anandamide levels are eight-fold higher in antipsychotic-naïve first-episode paranoid schizophrenics (n ¼ 47) than healthy controls (n ¼ 84), dementia patients (n ¼ 13) or affective disorder patients (n ¼ 22). Such an alteration is absent in schizophrenics treated with 'typical' antipsychotics (n ¼ 37), which antagonize dopamine D 2 -like receptors, but not in those treated with 'atypical' antipsychotics (n ¼ 34), which preferentially antagonize 5HT 2A receptors. Furthermore, we found that, in nonmedicated acute schizophrenics, CSF anandamide is negatively correlated with psychotic symptoms (r S ¼ À0.452, P ¼ 0.001). The results suggest that anandamide elevation in acute paranoid schizophrenia may reflect a compensatory adaptation to the disease state.

Endocannabinoids in Chronic Migraine: CSF Findings Suggest a System Failure

“…This was performed according to the method of Giuffrida and Piomelli (1998) adapted to CSF by Leweke et al (1999) and Giuffrida et al (2004), which involves separation of endocannabinoids by high-performance liquid chromatography (HPLC) and then quantification by gas chromatography/mass spectrometry (GS-MS). Fatty acyl chlorides in dichloromethane (10 mg/ml) were mixed with one equivalent of ethanolamine, and allowed to react for 15 min at 0-41C.…”

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

“…COMT genotypes may be relevant in this regard, as higher activation of phasic dopamine transmission, associated with the Val allele, is thought to be important in responding to experientially 'salient' stimuli, a mechanism that, in excess, may contribute to the formation of psychotic symptoms (Kapur, 2003). A reciprocal interaction between the endocannabinoid and dopamine system as suggested by Giuffrida et al (2004) may well explain how THC further reinforces this process. THC increases meso-limbic dopamine signaling in the acute phase (Voruganti et al, 2001).…”

“…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).…”

Cannabinoids Influence Lipid–Arachidonic Acid Pathways in Schizophrenia

“…Furthermore, D 9 -THC modulates the availability of free arachidonic acid, the precursor of endogenous cannabinoid (CB 1 ) ligands (eg anandamide). CB 1 receptors are expressed in basal ganglia, cortex, hippocampus and cerebellum, brain areas involved in the control of emotion, cognition, and motivation, all crucial in schizophrenia (Giuffrida et al, 2004). In the course of illness, the endocannabinoid system could play an adaptive role.…”

“…In the course of illness, the endocannabinoid system could play an adaptive role. During an initial 'protective' phase the demand for arachidonic acid precursors of anandamide seem to be increased, as anandamide seem to counterbalance psychotic symptoms being upregulated (Giuffrida et al, 2004;Glass, 2001). Longer lasting and sufficiently frequent exposure to D 9 -THC may cause an exhaustion of arachidonic acid reserves followed by downregulation of the endocannabinoid system, weakening of its protective power, and increasing severity of psychosis.…”