Drug and Alcohol Dependence 65 (2002) 221–224 Association of a CB1 Cannabinoid Receptor Gene (CNR1 ) polymorphism with severe alcohol dependence Lutz G. Schmidt a, *, Jerzy Samochowiec a,b,c , Ulrich Finckh d , Ewa Fiszer-Piosik b , Jan Horodnicki b , B. Wendel e , Hans Rommelspacher c , Margret R. Hoehe e a Department of Psychiatry, Uniersity of Mainz, Untere Zahlbacher Straße 8, D-55131 Mainz, Germany b Department of Psychiatry, Pomeranian Academy of Medicine, Broniewskiego 226, Pl -71 -460 Szczecin, Poland c Department of Clinical Neurobiology Uniersity Hospital Benjamin Franklin, Free Uniersity of Berlin, Ulmenallee 32, D-14050 Berlin Germany d Department of Human Genetics, Uniersity Hospital Eppendorf, Butenfeld 42, D-22529 Hamburg, Germany e Genome Research, Max – Delbru ¨ck -Center for Molecular Medicine, Robert Ro ¨ssle -Strasse 10, D-13092 Berlin, Germany Received 13 June 2000; accepted 27 April 2001 Abstract Due to the involvement of the endogenous cannabinoid system in brain reward mechanisms a silent polymorphism (1359G/A; Thr453Thr) in the single coding exon of the CB1 human cannabinoid receptor gene (CNR1 ) was analysed in 121 severely affected Caucasian alcoholics and 136 most likely non-alcoholic controls. The observed frequency of the A allele was 31.2% for controls and 42.1% for alcoholics with severe withdrawal syndromes (P =0.010). Post-hoc exploration indicated that this allelic association resulted from an excess of the homozygous A/A genotype in patients with a history of alcohol delirium (P =0.031, DF 2), suggesting an increased risk of delirium (OR =2.45, 95% CI 1.14 – 5.25). This finding suggests that the homozygous genotype CNR1 1359A/A confers vulnerability to alcohol withdrawal delirium. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: CB1 Cannabinoid receptor gene (CNR1 ); Alcoholism; Alcohol withdrawal; Alcohol seizures; Genetics www.elsevier.com/locate/drugalcdep 1. Introduction Alcohol dependence is a clinically and etiologically heterogeneous syndrome caused by a complex interac- tion of genetic and environmental factors (Merikangas, 1990). A high genetic load is expected in severely af- fected alcohol-dependent subjects (Lander and Schork, 1994) and as a consequence, alcoholics who display severe withdrawal symptoms are suitable for the genetic dissection of the complex genetic disposition to alcohol dependence (Noble et al., 2000). Abnormalities in various neurotransmitter functions have been considered as the basis for withdrawal symp- toms (Glue and Nutt, 1990), and genetic variants of the dopamine, serotonin, GABA, glutamate and opioid systems have been investigated in terms of how they might contribute to withdrawal vulnerability (Schmidt and Sander, 2000). The recently identified endogenous cannabinoid system (Devane et al., 1992) — character- ized by the cloning (Matsuda et al., 1990) and mapping of the CB1 brain receptor gene (CNR1 ) (Hoehe et al., 1991)—was also shown to be part of the mesocorticol- imbic reward pathway (Tanda et al., 2000). It has been demonstrated that the neurophysiological and patho- logical effects of chronic ethanol consumption might also be mediated through the endogenous cannabinoid system (Hungund and Basavarajappa, 2000a). Evidence for distinct differences in the binding characteristics of CB1 in the brain of mice selected for their differences in voluntary ethanol consumption (Hungund and Basavarajappa, 2000b) when combined with studies reporting genetic variants of CNR1 associated with alcohol and drug addiction (Johnson et al., 1997), * Corresponding author. Tel.: +49-6131-177335; fax: +49-6131- 229974. E-mail address: schmidt@psychiatrie.klinik.uni-mainz.de (L.G. Schmidt). 0376-8716/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII:S0376-8716(01)00164-8