Anandamide levels in cerebrospinal fluid of first-episode schizophrenic patients: Impact of cannabis use

F Markus Leweke,Andrea Giuffrida,Dagmar Koethe,Daniela Schreiber,Brit M Nolden,Laura Kranaster,Miriam A Neatby,Miriam Schneider,Christoph W Gerth,Martin Hellmich,Joachim Klosterkötter,Daniele Piomelli

doi:10.1016/j.schres.2007.04.025

Abstract

BackgroundPrevious studies have shown that cerebrospinal fluid (CSF) from schizophrenic patients contains significantly higher levels of the endogenous cannabinoid anandamide than does CSF from healthy volunteers. Moreover, CSF anandamide levels correlated inversely with psychotic symptoms, suggesting that anandamide release in the central nervous system (CNS) may serve as an adaptive mechanism countering neurotransmitter abnormalities in acute psychoses. In the present study we examined whether cannabis use may alter such a mechanism. MethodsWe used liquid chromatography/mass spectrometry (LC/MS) to measure anandamide levels in serum and CSF from first-episode, antipsychotic-naïve schizophrenics (n=47) and healthy volunteers (n=81). Based on reported patterns of cannabis use and urine Δ9-tetrahydrocannabinol (Δ9-THC) tests, each subject group was further divided into two subgroups: ‘low-frequency’ and ‘high-frequency’ cannabis users (lifetime use ≤5 times and >20 times, respectively). Serum Δ9-THC was investigated to determine acute use and three patients were excluded from the analysis due to detectable Δ9-THC levels in serum. ResultsSchizophrenic low-frequency cannabis users (n=25) exhibited >10-fold higher CSF anandamide levels than did schizophrenic high-frequency users (n=19, p=0.008), healthy low-frequency (n=55, p<0.001) or high-frequency users (n=26, p<0.001). In contrast, no significant differences in serum anandamide levels were found among the four subgroups. CSF anandamide levels and disease symptoms were negatively correlated in both user groups. ConclusionsThe results indicate that frequent cannabis exposure may down-regulate anandamide signaling in the CNS of schizophrenic patients, but not of healthy individuals. Thus, our findings suggest that alterations in endocannabinoid signaling might be an important component of the mechanism through which cannabis impacts mental health.

Highlights

Cannabis use is highly prevalent among schizophrenic patients (Kovasznay et al, 1997) and is considered a risk factor for development (Andreasson et al, 1987; Arseneault et al, 2002; Henquet et al, 2005; van Os et al, 2002; Zammit et al, 2002) and relapse of psychotic symptoms and schizophrenia in vulnerable subjects (Linszen et al, 1994; Veen et al, 2004)
cerebrospinal fluid (CSF) anandamide levels were markedly altered in one of the schizophrenic patients subgroups: patients who reported low frequency cannabis use exhibited N10-fold higher CSF anandamide levels than did healthy lowfrequency users (p b 0.001), or healthy high-frequency users (p b 0.001) as well as schizophrenic high-frequency users (p = 0.008)
We have shown that CSF levels of the endocannabinoid anandamide are markedly higher in first-episode antipsychotic-naïve schizophrenic patients than in age-and gender-matched healthy volunteers (Giuffrida et al, 2004)

Summary

Introduction

Cannabis use is highly prevalent among schizophrenic patients (Kovasznay et al, 1997) and is considered a risk factor for development (Andreasson et al, 1987; Arseneault et al, 2002; Henquet et al, 2005; van Os et al, 2002; Zammit et al, 2002) and relapse of psychotic symptoms and schizophrenia in vulnerable subjects (Linszen et al, 1994; Veen et al, 2004). Biochemical analyses have focused on the impact of schizophrenia on serum and CSF levels of endocannabinoid mediators such as anandamide (De Marchi et al, 2003; Giuffrida et al, 2004; Leweke et al, 1999a). These studies concord in suggesting that anandamide signaling may be hyperactive in schizophrenic patients.

Methods

Results

Conclusion