The receptors for tetrahydrocannabinol, the active ingredient of marijuana, have been identified. A microsatellite polymorphism (AAT)n at the cannabinoid CB1 (brain) receptor gene (CNR1) consists of 9 alleles. Since the cannabinoid system is part of the reward pathway we examined the hypothesis that genetic variants of the CNR1 gene might be associated with susceptibility to alcohol or drug dependence. The study consisted of 92 subjects on an Addiction Treatment Unit (ATU) and 114 controls. All were non-Hispanic Caucasians. The ATU subjects were screened for all types of substance dependence using the Diagnostic Interview Schedule (DIS), and for a variety of substance abuse symptoms using the Addiction Severity Index (ASI). Since inspection of the distribution of alleles in controls vs i.v. drug use showed a decrease in the frequency of the 4 allele, and the < 4 alleles were rare, the alleles were divided into two groups, < 5 and < or = 5, and three genotypes < 5/< 5, heterozygotes, and > or =/> or = 5. When all variables were subjected to factor analysis, factor 1 showed a clustering of drug dependence variables and factor 2 of alcohol dependence variables. By ANOVA only factor 1 showed significant differences by genotype consistent with a model where homozygosity for the > or = 5 repeat alleles showed the greatest effect. The number of i.v. drugs used was significantly greater for those carrying the > or =/> or = 5 genotype than for other genotypes (P = 0.005). The association with specific types of drug dependence was greatest for cocaine, amphetamine, and cannabis dependence. The results are consistent with a role of cannabinoid receptors in the modulation of dopamine and cannabinoid reward pathways. Independent studies should be designed to further confirm the hypothesis that cannabinoid receptors may contribute to the susceptibility to drug abuse.