The Diagnostic and Statistical Manual of Mental Disorders (DSM 5), alcohol use disorder including alcohol abuse and alcohol dependence (AD) defined as a psychiatric dysfunction, marked by compulsive drinking, leading to pathological alcohol seeking behavior.^[1] Alcohol abuse corrodes the security of health, job, and family.^[2,3] Moreover, the morbidity and mortality that result from AD, adversely impacts individuals and society, contributing to the global burden of disease.^[4]

Persistence of AD in humans through the millennia may have come from the driving force of positive reinforcement mechanisms that stimulates reward pathways of the brain, which involve the endocannabinoid system (ECS).^[5] Studies have shown that the ECS regulates dopamine reward circuits, which play an important role in the reward processes involved in substance dependence^[6,7] and facilitate vulnerability to the progression of addiction.^[8] The ECS is composed of cannabinoid receptors as well as enzymes that synthesize, degrade, and transport endocannabinoids (endogenous cannabinoids).^[9] The cannabinoid receptors, CB1 and CB2 are encoded by cannabinoid receptor 1 (CNR1) and cannabinoid receptor 2 (CNR2) genes, respectively. CNR2 is found at the brain periphery and appears to have an immune function.^[10]CNR1 is expressed at high levels in brain regions that act on drug reward and drug memories,^[11] which include the hippocampus, striatum, and cerebral cortex.^[12] The machinery of drug rewards and memories lead to risks of psychiatric disorders that include substance abuse which involves the ECS.^[13] Activating the same reward pathways in the brain are cannabinoids, chemical substances that attach to the cannabinoid receptors of the brain and elicit pharmacological effects similar to marijuana (cannabis).^[14] It has been shown that delta-9-tetrahydrocannabinol and alcohol share similar behavioral profiles where at low and high doses, both induce euphoria/motor incoordination and sedation, respectively.^[15] delta-9-tetrahydrocannabinol is mediated by CB1, encoded by the CNR1 gene, which maps to chromosome 6q14-q15. CB1/CNR1 displays at least 4 exons that spans 25 kb and produces several transcripts. Common single-nucleotide polymorphisms (SNPs) account for as much as 30% of the variance in AD.^[16] Various locations of CNR1 SNPs point to the silent rs1049353 found in the coding region involving a substitution of “G” to “A” at nucleotide position 1359 in codon 435 (threonine). The rs806379 SNP (A/T) is located in intron 2 of the CNR1 gene (–385 to exon 3 alternate transcript initiation site). The rs2023239 and rs1535255 SNPs are non-coding intron variants in the 3 prime untranslated region.

These CNR1 SNPs were found to be associated with polysubstance abuse.^[17] A study showed that C allele carriers of rs2023239 had elevated cravings in response to alcohol-associated cues.^[18] However, the association of rs1049353 with alcohol and drug dependence elicited variable results from different studies.^[10,19–22] A nicotine study found that the T allele on rs806379 reduced mRNA expression resulting in less mRNA activity,^[23] which agreed with an earlier haplotype study involving rs2023239, rs806379 and rs1535255.^[24] Yet, examinations of these SNPs for their associations with development of AD^[25] have produced inconsistent outcomes, that ranged from reduced to increased risks. Hence, using the Population Intervention Comparators Outcome approach, we performed this meta-analysis to realize our objectives of obtaining less ambiguous and better estimates of associations. Here, we examined SNPs that might provide clues of the roles of their proteins in the neuro-metabolic pathways, fostering better understanding of risk biomarkers in AD.