Cannabigerol (CBG) is a non-psychoactive cannabinoid and minor constituent of cannabis.[1][2][3][4][5] It is one of more than 120 identified cannabinoids found in the plant genus Cannabis.[6][7] The compound is the decarboxylated form of cannabigerolic acid (CBGA), the parent molecule from which other cannabinoids are biosynthesized.[2][8]

Cannabigerol
Clinical data
Other namesCBG
ATC code
  • None
Legal status
Legal status
  • US: Unscheduled
Identifiers
  • 2-[(2E)-3,7-Dimethylocta-2,6-dienyl]-5-pentyl-benzene-1,3-diol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.346.098 Edit this at Wikidata
Chemical and physical data
FormulaC21H32O2
Molar mass316.485 g·mol−1
3D model (JSmol)
  • Oc1cc(cc(O)c1C/C=C(\C)CC\C=C(/C)C)CCCCC
  • InChI=1S/C21H32O2/c1-5-6-7-11-18-14-20(22)19(21(23)15-18)13-12-17(4)10-8-9-16(2)3/h9,12,14-15,22-23H,5-8,10-11,13H2,1-4H3/b17-12+ checkY
  • Key:QXACEHWTBCFNSA-SFQUDFHCSA-N checkY
  (verify)

During plant growth, most of the CBG is converted into other cannabinoids, primarily tetrahydrocannabinol (THC) or cannabidiol (CBD), leaving about 1% CBG in the plant.[9] Some strains, however, produce larger amounts of CBG and CBGA, while having low quantities of other cannabinoids, like THC and CBD.[10]

The pharmacodynamics of CBG are complex.[1][2][3] It is a relatively weak ligand of the cannabinoid receptors, where it acts as a weak partial agonist.[1][2][3][11] Conversely, it is a much more potent agonist of the α2-adrenergic receptor, antagonist of the serotonin 5-HT1A receptor, and antagonist of the transient receptor potential channel TRPM8.[1][2][3][11] CBG also has a variety of other actions that may additionally contribute to its effects.[1][2][3][5]

Although CBG is sold as a dietary supplement, its effects and safety for human consumption are unknown.[2] Safety concerns have been raised due to the potent activation of α2-adrenergic receptors by CBG, which may produce sedation and potentially undesirable cardiovascular effects like decreased heart rate and blood pressure.[2]

Pharmacology

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Pharmacodynamics

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CBG lacks psychoactive, cannabimimetic, or psychotropic effects.[1][2][3][5] It has been reported to reduce the psychotropic effects of tetrahydrocannabinol (THC).[1] The compound has analgesic effects.[3][12][13] Preclinical research has also found that CBG reduces intraocular pressure, has antioxidant, anti-inflammatory, anti-tumoral, antibacterial, and antifungal activities, and has antidepressant-like, anxiolytic, neuromodulatory, neuroprotective, dermatological, pro-nausea, and appetite-stimulating effects, among others.[1][11][5][12]

CBG has many identified pharmacodynamic actions and its mechanism of action appears to be from interactions with multiple targets.[1][2][3]

CBG is a weak ligand of the cannabinoid CB1 and CB2 receptors with affinities (Ki) of 380–2,600 nM and 153–3,460 nM, respectively.[1][2][12][14][15] It is a weak partial agonist or antagonist of both of these receptors.[1][2][3] There is no information on the binding or activity of CBG at the GPR55 (the potential non-homologous CB3 receptor).[2][3] CBG has relatively low affinity for the cannabinoid receptors, with approximately 5-fold lower affinity for the CB1 receptor and 27-fold lower affinity for the CB2 receptor than THC.[11] The low affinity of CBG for the CB1 receptor may in part be involved in its lack of psychoactivity.[11]

CBG is a highly potent agonist of the α2-adrenergic receptor (EC50Tooltip half-maximal effective concentration = 0.2–72.8 nM) and a moderately potent antagonist of the serotonin 5-HT1A receptor (KB = 51.9 nM).[2][1][16] Activation of the α2-adrenergic receptor by CBG might produce effects including sedation, dry mouth, and decreased heart rate and blood pressure.[2] This has raised safety concerns about CBG.[2] The actions of CBG at the α2-adrenergic receptor and 5-HT1A receptor are of far greater potency than its interactions with the cannabinoid receptors and are more likely to be involved in its pharmacodynamic effects.[11] These activities may specifically contribute to the analgesic and pro-nausea effects of CBG.[12]

The compound is a weak agonist of the transient receptor potential channels TRPA1 (EC50 = 700 nM), TRPV1 (EC50 = 1,300 nM), TRPV2 (EC50 = 1,720 nM), TRPV3 (EC50 = 1,000 nM), and TRPV4 (EC50 = 5,100 nM) (efficacy 18–100% at these targets) and a more potent antagonist of the transient receptor potential channel TRPM8 (IC50Tooltip half-maximal inhibitory concentration = 160 nM).[12][2][1][14][3] It is also a weak agonist of the peroxisome proliferator-activated receptor PPAR-γ (EC50 = 1,270–15,700 nM).[2][1][14]

CBG is a voltage-gated sodium channel (VGSC) blocker (Nav1.1, Nav1.2, Nav1.5, and Nav1.7) and voltage-dependent calcium channel (VDCC) blocker.[3][1][17] Inhibition of VGSCs may be involved in the analgesic effects of CBG.[3]

It shows no inhibition of several endocannabinoid-metabolizing enzymes including fatty acid amide hydrolase (FAAH), diacylglycerol lipase (DGL), and N-acylethanolamine acid amide hydrolase (NAAA).[14] However, other research has found that CBG does inhibit FAAH and DGL, as well as monoacylglycerol lipase (MAGL), although it is less potent as an inhibitor of FAAH than cannabidiol (CBD).[11] Aside from endocannabinoid-metabolizing enzymes, CBG is a weak inhibitor of the cyclooxygenase COX-1 and COX-2 enzymes (30% inhibition of each at 25,000 nM).[1][11] In addition, it has been found to inhibit both the metabolism and reuptake of anandamide.[1]

Pharmacokinetics

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The pharmacokinetics of CBG have been studied in animals and to a lesser extent in humans.[1][11] CBG is metabolized in the liver by CYP2J2, similarly to other cannabinoids as well as endocannabinoids.[1]

Chemistry

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CBG is a highly lipophilic and hydrophobic compound.[3] Its predicted log P ranges from 7.0 to 7.5.[8][18][19]

Synthetic derivatives of CBG have been synthesized and studied.[1][11]

History

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CBG was isolated from cannabis in 1964.[5]

Society and culture

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CBG is not scheduled by the United Nations Convention on Psychotropic Substances.[citation needed] In the United States, CBG derived from marijuana is illegal under the Controlled Substances Act, while CBG derived from hemp is legal, as long as the hemp THC content is less than 0.3% of dry weight.[20][21]

In Switzerland, it is legal to produce hemp rich in CBG as a tobacco substitute, as long as its THC content remains below 1.0%.[22]

Regulation

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As of 2022, the US Food and Drug Administration has issued numerous warning letters to American companies for illegally marketing cannabis supplement products,[20] including one selling CBG products with unproven illegal claims of efficacy against the COVID-19 virus and inflammation.[23]

Biosynthesis

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Biosynthesis of CBG.

The biosynthesis of CBG begins by loading hexanoyl-CoA onto a polyketide synthase assembly protein and subsequent condensation with three molecules of malonyl-CoA.[24] This polyketide is cyclized to olivetolic acid via olivetolic acid cyclase, and then prenylated with a ten carbon isoprenoid precursor, geranyl pyrophosphate, using an aromatic prenyltransferase enzyme, geranyl-pyrophosphate—olivetolic acid geranyltransferase, to biosynthesize cannabigerolic acid, which can then be decarboxylated to yield CBG.[2][4]

Research

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CBG is under laboratory research to determine its pharmacological properties and potential effects in disease conditions, with no conclusions about therapeutic effects or safety, as of 2021.[2][15][25] A clinical trial published in July 2024 assessed the effects of CBG on anxiety, stress, and mood.[26][27]

References

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  1. ^ a b c d e f g h i j k l m n o p q r s t Calapai F, Cardia L, Esposito E, Ammendolia I, Mondello C, Lo Giudice R, Gangemi S, Calapai G, Mannucci C (2022). "Pharmacological Aspects and Biological Effects of Cannabigerol and Its Synthetic Derivatives". Evid Based Complement Alternat Med. 2022: 3336516. doi:10.1155/2022/3336516. PMC 9666035. PMID 36397993.
  2. ^ a b c d e f g h i j k l m n o p q r s t Nachnani R, Raup-Konsavage WM, Vrana KE (2021). "The pharmacological case for cannabigerol". The Journal of Pharmacology and Experimental Therapeutics. 376 (2): 204–212. doi:10.1124/jpet.120.000340. ISSN 0022-3565. PMID 33168643. S2CID 226296897.
  3. ^ a b c d e f g h i j k l m n Ghovanloo MR, Dib-Hajj SD, Goodchild SJ, Ruben PC, Waxman SG (2022). "Non-psychotropic phytocannabinoid interactions with voltage-gated sodium channels: An update on cannabidiol and cannabigerol". Front Physiol. 13: 1066455. doi:10.3389/fphys.2022.1066455. PMC 9691960. PMID 36439273.
  4. ^ a b Morales P, Reggio PH, Jagerovic N (2017). "An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol". Frontiers in Pharmacology. 8: 422. doi:10.3389/fphar.2017.00422. PMC 5487438. PMID 28701957.
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  6. ^ ElSohly MA, Radwan MM, Gul W, Chandra S, Galal A (2017). "Phytochemistry of Cannabis sativa L". Phytochemistry of Cannabis sativa L. Progress in the Chemistry of Organic Natural Products. Vol. 103. pp. 1–36. doi:10.1007/978-3-319-45541-9_1. ISBN 978-3-319-45539-6. PMID 28120229.
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  10. ^ Zagožen M, Čerenak A, Kreft S (2021-09-01). "Cannabigerol and cannabichromene in Cannabis sativa L." Acta Pharmaceutica. 71 (3): 355–364. doi:10.2478/acph-2021-0021. PMID 36654096. S2CID 231543630.
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  12. ^ a b c d e Sampson PB (January 2021). "Phytocannabinoid Pharmacology: Medicinal Properties of Cannabis sativa Constituents Aside from the "Big Two"". J Nat Prod. 84 (1): 142–160. doi:10.1021/acs.jnatprod.0c00965. PMID 33356248.
  13. ^ Evans FJ (October 1991). "Cannabinoids: the separation of central from peripheral effects on a structural basis". Planta Med. 57 (7 Suppl): S60–S67. doi:10.1055/s-2006-960231. PMID 17226225.
  14. ^ a b c d Liu, Tiqing. "BindingDB BDBM50318487 CHEMBL497318::Cannabigerol". BindingDB. Retrieved 14 August 2024.
  15. ^ a b Morales P, Hurst DP, Reggio PH (2017). "Molecular Targets of the Phytocannabinoids: A Complex Picture". Phytocannabinoids. Progress in the Chemistry of Organic Natural Products. Vol. 103. pp. 103–131. doi:10.1007/978-3-319-45541-9_4. ISBN 978-3-319-45539-6. PMC 5345356. PMID 28120232.
  16. ^ Cascio MG, Gauson LA, Stevenson LA, Ross RA, Pertwee RG (January 2010). "Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist". Br J Pharmacol. 159 (1): 129–141. doi:10.1111/j.1476-5381.2009.00515.x. PMC 2823359. PMID 20002104.
  17. ^ Ghovanloo MR, Estacion M, Higerd-Rusli GP, Zhao P, Dib-Hajj S, Waxman SG (August 2022). "Inhibition of sodium conductance by cannabigerol contributes to a reduction of dorsal root ganglion neuron excitability". Br J Pharmacol. 179 (15): 4010–4030. doi:10.1111/bph.15833. PMID 35297036.
  18. ^ "Cannabigerol: Uses, Interactions, Mechanism of Action". DrugBank Online. 1 February 2019. Retrieved 14 August 2024.
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  20. ^ a b "FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD)". US Food and Drug Administration. 21 January 2021. Retrieved 7 July 2022.
  21. ^ "USC > Title 21 > Chapter 13 > Subchapter I > Part A > § 802. Definitions: (16)" (PDF). Government Publishing Office - US Code. 2016.
  22. ^ BAG, Bundesamt für Gesundheit. "Häufig gestellte Fragen (FAQ) zu Tabakersatzprodukten mit THC-armem Hanf mit CBD". www.bag.admin.ch (in German). Retrieved 2022-07-06.
  23. ^ Ashley D (28 March 2022). "Warning Letter to Greenway Herbal Products LLC; Ref. 627042". Office of Compliance, Center for Drug Evaluation and Research, Food and Drug Administration. Retrieved 7 July 2022.
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  25. ^ Couch DG, Maudslay H, Doleman B, Lund JN, O'Sullivan SE (March 2018). "The Use of Cannabinoids in Colitis: A Systematic Review and Meta-Analysis". Inflammatory Bowel Diseases. 24 (4): 680–697. doi:10.1093/ibd/izy014. PMID 29562280.
  26. ^ Cuttler C, Stueber A, Cooper ZD, Russo E (July 2024). "Acute effects of cannabigerol on anxiety, stress, and mood: a double-blind, placebo-controlled, crossover, field trial". Sci Rep. 14 (1): 16163. Bibcode:2024NatSR..1416163C. doi:10.1038/s41598-024-66879-0. PMC 11246434. PMID 39003387.
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