Evidence map›Paper›PMID 41333412›Full record

ArticleResearch square2025

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, Panayotis K Thanos, Marco Lindeau, Álvaro Dowling, Rafaela Dowling, Jao Paulo Bergamaschi, Albert Pinhasov and 28 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Research square, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

38 authors.

Kenneth BlumDepartment of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel.
Alireza SharafshahCellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
Jag KhalsaDepartment of Medicine, University of Maryland, School of Medicine, Baltimore, MD., USA.
Kai-Uwe LewandrowskiDivision of Personalized Pain Therapy Research & Education, Center for Advanced Spine Care of Southern Arizona, Tucson, AZ., USA.
Panayotis K ThanosBehavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, USA.
Marco LindeauDivision of Clinical Neurology, The Blum Institute of Neurogenetics & Behavior, Austin, TX., USA.
Álvaro DowlingDivision of Clinical Neurology, The Blum Institute of Neurogenetics & Behavior, Austin, TX., USA.
Rafaela DowlingDivision of Clinical Neurology, The Blum Institute of Neurogenetics & Behavior, Austin, TX., USA.
Jao Paulo BergamaschiDivision of Clinical Neurology, The Blum Institute of Neurogenetics & Behavior, Austin, TX., USA.
Albert PinhasovDepartment of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel.
David BaronDivision of Addiction Research & Education, Center for Sports, Exercise, and Mental Health, Western University of Health Sciences, Pomona, CA., USA.
Catherine A DennenDepartment of Family Medicine, Jefferson Health Northeast, Philadelphia, PA, USA.
Joseph P MorganSubstance Use Disorders Institute University of Sciences, Philadelphia, PA, USA.
Igor ElmanDepartment of Psychiatry and Cambridge Health Alliance, Harvard Medical School, Cambridge, MA., USA.
Eliot L GardnerNeuropsychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Md., USA.
Mark S GoldDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Edward J ModestinoDepartment of Psychology, Curry College, Milton, MA, USA.
Fuehrlein BrianDepartment of Psychiatry, Yale University, New Haven, CT, USA.
Paul R CarneyDivision Pediatric Neurology, University of Missouri, School of Medicine, Columbia, MO, USA.
Rene CorteseDepartment of Child Health, Child Health Research Institute, School of Medicine, University of Missouri, Columbia, MO, USA.
Abadalla BowirratDepartment of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, Israel.
Keerthy SunderDepartment of Medicine, University of California, Riverside School of Medicine, Riverside, CA, USA.
Kavya MohankumarDivision of Clinical Neurology, The Blum Institute of Neurogenetics & Behavior, Austin, TX., USA.
Foojan ZeineAwareness Integration Institute, San Clemente, CA, USA.
Nicole JafariDivision of Personalized Medicine, Global Growth Institute, Inc., San Clemente, CA, USA.
Milan T MakaleDepartment of Radiation Oncology, University of California San Diego, La Jolla, CA, USA.
Debasis BagchiDepartment of Pharmaceutical Sciences, Texas Southern University College of Pharmacy, Houston, TX, USA.
Mauro CeccantiAlcohol Addiction Program, Latium Region Referral Center, Sapienza University of Rome, Roma, Italy.
Rossano K A FiorelliDepartment of General and Specialized Surgery, Gaffrée e Guinle Universitary Hospital (EBSERH), Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, RJ, Brazil.
Sérgio Luís SchimidtPrograma de Pós-Graduação em Neurologia, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
Daniel SippleM Health Fairview University of Minnesota Medical Center, Minneapolis, MN.,USA.
Alexander P L LewandrowskiDornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA., USA.
Gianni MatareDivision of Clinical Neurology, The Blum Institute of Neurogenetics & Behavior, Austin, TX., USA.
Shaurya MahajanDivision of Clinical Neurology, The Blum Institute of Neurogenetics & Behavior, Austin, TX., USA.
Yatharth MahajanDivision of Clinical Neurology, The Blum Institute of Neurogenetics & Behavior, Austin, TX., USA.
Chynna FliegelmanDivision of Clinical Neurology, The Blum Institute of Neurogenetics & Behavior, Austin, TX., USA.
Colin HannaDepartment of Psychology, University South Dekoda, Vermillion, SD., USA.
Rajendra D BadgaiyanDepartment of Psychiatry, Mt. Sinai University, School of Medicine, New York, NY., USA.

Funding

A Systematic Medical Approach to Reward Transformation (SMART) for Brain Health in Opioid Use DisorderR41MD012318 · NIMHD · VERSA INTEGRATED SOLUTIONS, INC. · PI BLUM, KENNETH, GONDRE-LEWIS, MARJORIE C · 2017 to 2017
$221k
NIMHD NIH HHS R41 MD012318
6 · The paper itself

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.

Indexed as

CannabisCannabis User DisorderCNR1 receptorGARSHyperdopaminergiaPro-dopamine regulation (KB220)

Identifiers

PMID41333412
PMCPMC12668167

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.