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

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 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review 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Medicinals Kenneth Blum, Alireza Sharafshah, Jag Khalsa, Kai-Uwe Lewandrowski, and 34 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8140327/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract 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. Cannabis Cannabis User Disorder Hyperdopaminergia CNR1 receptor GARS Pro-dopamine regulation (KB220) Full Text Additional Declarations The authors declare potential competing interests as follows: KB is the inventor and patent holder of GARS and pro-dopamine regulators. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8140327","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":546642456,"identity":"dd2084c9-1669-4c8a-b08e-1717a37bbf2c","order_by":0,"name":"Kenneth 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CNR1 and DRD2 Receptors Optimizing Long-Term Outcomes for Cannabis Use Disorder (CUD) By Enhancing Dopamine Homeostasis Promoting High-Quality Cannabis Medicinals\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[{"identity":"14891f8e-eb78-4863-864d-9a39c99b422c","identifier":"10.13039/100000002","name":"National Institutes of Health","awardNumber":"R41 MD012318","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Division of Clinical Neurology, The Blum Institute of Neurogenetics \u0026 Behavior, Austin, TX., 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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.\u003c/p\u003e\n\u003cp\u003eHistorically, 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.\u003c/p\u003e\n\u003cp\u003eGiven the failure of CNR1 antagonists such as Rimonabant, we argue for an opposite approach: restoring dopamine balance through CNR1 stimulation rather than inhibition.\u003c/p\u003e","manuscriptTitle":"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","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-19 06:22:06","doi":"10.21203/rs.3.rs-8140327/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a3b35d2f-b40a-481e-a70f-bd7752c5d5b5","owner":[],"postedDate":"November 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-19T06:22:07+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-19 06:22:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8140327","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8140327","identity":"rs-8140327","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}