Computational GWAS Meta Meta Analysis Revealing Cross Talk Between Cannabis CNR1 and DRD2 Receptors Optimizing Long-Term Outcomes for Cannabis Use Disorder (CUD) By Enhancing Dopamine Homeostasis Promoting High-Quality Cannabis Medicinals.

This paper presents a shared perspective from scientists and clinicians seeking to harness the therapeutic potential of cannabis while addressing Cannabis Use Disorder (CUD) through reproducible scientific findings. Acute cannabis use may produce temporary well-being, but chronic use can create a "pseudo-feeling" of well-being, leading to tolerance, discomfort, and adverse effects. Rather than blocking CNR1 receptors, which may induce hypodopaminergia, we propose a pro-dopaminergic strategy using a natural nutraceutical formulation designed to enhance dopamine release and upregulate D2 receptor mRNA, thereby increasing D2 receptor density. Historically, low-potency cannabis (2-4% Δ9-THC) was not associated with major neuroanatomical, psychotic, or depressive outcomes. However, modern cannabis potency has risen dramatically, now exceeding 17% Δ9-THC on average, with concentrates reaching up to 97%, potentially increasing the risk of dopamine dysfunction and CUD. Computational analyses identified the drd2 gene as central to cannabis pharmacology. Meta and Meta-Meta analyses refined a Primary and Secondary Gene List, leading to 23 final genes, including DRD2, DRD1, BDNF, GNAT1, POU3F2, and SLC67A4. Significant miRNAs (hsa-miR-15a-5p, hsa-miR-16-5p) and transcription factors (SP1, REST, EGR1) were also revealed, highlighting dopaminergic pathway involvement. Additional systems biology results indicated heroin dependence as the highest-risk manifestation linked to these genes, and PGx analyses suggested DRD1, DRD2, BDNF, and OPRM1 as promising targets for future studies. Given the failure of CNR1 antagonists such as Rimonabant, we argue for an opposite approach: restoring dopamine balance through CNR1 stimulation rather than inhibition.