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CB2 Agonism

An agonist that binds to a CB2 receptor is a compound or drug that binds to the receptor and produces an expected effect (see below).

CB2 agonism and associated effects

CB2 Agonism Associated Effects (not a complete list)

No psychoactivity (T. Malan Jr. et al., 2003).1

Pain relief in cases of:

Anti-inflammatory (Leleu-Chavain et al., 2012).6

Neuroprotective (J. Fernández-Ruiz et al., 2008; Hao Yu et al., 2021; R. Ferrisi et al., 2021).7

Anti-fibrotic

Immune disorders (calming overactive immune responses)

Osteoporosis (O. Ofek et al., 2006)16

Antipsychotic (I. Cortez et al., 2020)17

Cancer

CB2 Agonists

Cannabichromene (CBC) (M. Udoh et al., 2019).23

β-Caryophyllene, is an FDA-approved food additive, cannabis-common terpene, and CB2 agonist (H. Xiang-Hu et al., 2021)24 readily available almost anywhere.

Echinacea is a moderate agonist at CB2 with a Ki of ~60nM (S. Raduner et al., 2006).25

Turmeric is an agonist at CB2 with potential cardioprotective effects (H. Pawar et al., 2022).26

Raloxifene is an FDA-approved estrogen receptor drug used to treat osteoporosis. However, it has also been shown to effectively treat visual deficits after mild TBI and/or ocular trauma via inverse agonism at CB2 (A. Reiner 2020;27 M. Honig et al., 201928) and as such is under consideration for approval for use. 

GW405833 and AM1710 (synthetic cannabinoids) (A. Dhopeshwarkar et al., 2017).29

Endnotes:

1. Malan TP Jr, Ibrahim MM, Lai J, Vanderah TW, Makriyannis A, Porreca F. CB2 cannabinoid receptor agonists: pain relief without psychoactive effects? Curr Opin Pharmacol. 2003 Feb;3(1):62-7.

2. Malan PT Jr, Ibrahim MM, Deng H, Liu Q, Mata HP, Vanderah T, Porreca F, Makriyannis A. CB2 cannabinoid receptor-mediated peripheral antinociception. Pain. 2001 Sep;93(3):239-245.

3. Vincenzi F, Targa M, Corciulo C, Tabrizi MA, Merighi S, Gessi S, Saponaro G, Baraldi PG, Borea PA, Varani K. Antinociceptive effects of the selective CB2 agonist MT178 in inflammatory and chronic rodent pain models. Pain. 2013 Jun;154(6):864-73.

4. Malan TP Jr, Ibrahim MM, Lai J, Vanderah TW, Makriyannis A, Porreca F. CB2 cannabinoid receptor agonists: pain relief without psychoactive effects? Curr Opin Pharmacol. 2003 Feb;3(1):62-7. 

                  Beltramo M, Bernardini N, Bertorelli R, Campanella M, Nicolussi E, Fredduzzi S, Reggiani A. CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur J Neurosci. 2006 Mar;23(6):1530-8. 

5. Anand P, Whiteside G, Fowler CJ, Hohmann AG. Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain Res Rev. 2009 Apr;60(1):255-66. 

6. Leleu-Chavain, N.; Body-Malapel, M.; Spencer, J.; Chavatte, P.; Desreumaux, P. and Millet, R. Recent Advances in the Development of Selective CB2 Agonists as Promising Anti-Inflammatory Agents. Bentham Science Publishers. Current Medicinal Chemistry, Volume 19, Number 21, 2012, pp. 3457-3474(18). 

7. Fernández-Ruiz J, Pazos MR, García-Arencibia M, Sagredo O, Ramos JA. Role of CB2 receptors in neuroprotective effects of cannabinoids. Mol Cell Endocrinol. 2008 Apr 16;286(1-2 Suppl 1):S91-6.

Yu H, Liu X, Chen B, Vickstrom CR, Friedman V, Kelly TJ, Bai X, Zhao L, Hillard CJ, Liu QS. The Neuroprotective Effects of the CB2 Agonist GW842166x in the 6-OHDA Mouse Model of Parkinson’s Disease. Cells. 2021 Dec 16;10(12):3548.

                  Ferrisi R, Ceni C, Bertini S, Macchia M, Manera C, Gado F. Medicinal Chemistry approach, pharmacology and neuroprotective benefits of CB2R modulators in neurodegenerative diseases. Pharmacol Res. 2021 Aug;170:105607.

8. Yu H, Liu X, Chen B, Vickstrom CR, Friedman V, Kelly TJ, Bai X, Zhao L, Hillard CJ, Liu QS. The Neuroprotective Effects of the CB2 Agonist GW842166x in the 6-OHDA Mouse Model of Parkinson’s Disease. Cells. 2021 Dec 16;10(12):3548.

Basile MS, Mazzon E. The Role of Cannabinoid Type 2 Receptors in Parkinson’s Disease. Biomedicines. 2022 Nov 20;10(11):2986.

9. Aso E, Ferrer I. CB2 Cannabinoid Receptor As Potential Target against Alzheimer’s Disease. Front Neurosci. 2016 May 31;10:243.

                  Magham SV, Thaggikuppe Krishnamurthy P, Shaji N, Mani L, Balasubramanian S. Cannabinoid receptor 2 selective agonists and Alzheimer’s disease: An insight into the therapeutic potentials. J Neurosci Res. 2021 Nov;99(11):2888-2905.

10. Akhmetshina A, Dees C, Busch N, Beer J, Sarter K, Zwerina J, Zimmer A, Distler O, Schett G, Distler JH. The cannabinoid receptor CB2 exerts antifibrotic effects in experimental dermal fibrosis. Arthritis Rheum. 2009 Apr;60(4):1129-36.

11. Julien B, Grenard P, Teixeira-Clerc F, Van Nhieu JT, Li L, Karsak M, Zimmer A, Mallat A, Lotersztajn S. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology. 2005 Mar;128(3):742-55.

                  Muñoz-Luque J, Ros J, Fernández-Varo G, Tugues S, Morales-Ruiz M, Alvarez CE, Friedman SL, Arroyo V, Jiménez W. Regression of fibrosis after chronic stimulation of cannabinoid CB2 receptor in cirrhotic rats. J Pharmacol Exp Ther. 2008 Feb;324(2):475-83.

12. Wawryk-Gawda E, Chłapek K, Zarobkiewicz MK, Lis-Sochocka M, Chylińska-Wrzos P, Boguszewska-Czubara A, Sławiński MA, Franczak A, Jodłowska-Jędrych B, Biała G. CB2R agonist prevents nicotine induced lung fibrosis. Exp Lung Res. 2018 Sep;44(7):344-351.

                  Parlar A, Arslan SO, Yumrutas O, Elibol E, Yalcin A, Uckardes F, Aydin H, Dogan MF, Kayhan Kustepe E, Ozer MK. Effects of cannabinoid receptor 2 synthetic agonist, AM1241, on bleomycin induced pulmonary fibrosis. Biotech Histochem. 2021 Jan;96(1):48-59.

13.Yuan CY, Zhou V, Sauber G, Stollenwerk T, Komorowski R, López A, Tolón RM, Romero J, Hillard CJ, Drobyski WR. Signaling through the type 2 cannabinoid receptor regulates the severity of acute and chronic graft-versus-host disease. Blood. 2021 Mar 4;137(9):1241-1255.

14. Parastouei K, Aarabi MH, Hamidi GA, Nasehi Z, Kabiri-Arani S, Jozi F, Shahaboddin ME. A CB2 Receptor Agonist Reduces the Production of Inflammatory Mediators and Improves Locomotor Activity in Experimental Autoimmune Encephalomyelitis. Rep Biochem Mol Biol. 2022 Apr;11(1):1-9.

15. Zhu M, Yu B, Bai J, Wang X, Guo X, Liu Y, Lin J, Hu S, Zhang W, Tao Y, Hu C, Yang H, Xu Y, Geng D. Cannabinoid Receptor 2 Agonist Prevents Local and Systemic Inflammatory Bone Destruction in Rheumatoid Arthritis. J Bone Miner Res. 2019 Apr;34(4):739-751.

16. Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V, Shohami E, Mechoulam R, Zimmer A, Bab I. Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):696-701.

17. Cortez IL, Rodrigues da Silva N, Guimarães FS, Gomes FV. Are CB2 Receptors a New Target for Schizophrenia Treatment? Front Psychiatry. 2020 Oct 30;11:587154.

18. Xu S, Ma H, Bo Y, Shao M. The oncogenic role of CB2 in the progression of non-small-cell lung cancer. Biomed Pharmacother. 2019 Sep;117:109080.

19. Gado F, Ferrisi R, Di Somma S, Napolitano F, Mohamed KA, Stevenson LA, Rapposelli S, Saccomanni G, Portella G, Pertwee RG, Laprairie RB, Malfitano AM, Manera C. Synthesis and In Vitro Characterization of Selective Cannabinoid CB2 Receptor Agonists: Biological Evaluation against Neuroblastoma Cancer Cells. Molecules. 2022 May 7;27(9):3019.

20. Alenabi, A., Malekinejad, H. Cannabinoids pharmacological effects are beyond the palliative effects: CB2 cannabinoid receptor agonist induced cytotoxicity and apoptosis in human colorectal cancer cells (HT-29). Mol Cell Biochem 476, 3285–3301 (2021).

21. Irrera N, D’Ascola A, Pallio G, Bitto A, Mannino F, Arcoraci V, Rottura M, Ieni A, Minutoli L, Metro D, Vaccaro M, Altavilla D, Squadrito F. β-Caryophyllene Inhibits Cell Proliferation through a Direct Modulation of CB2 Receptors in Glioblastoma Cells. Cancers (Basel). 2020 Apr 23;12(4):1038.

22. Hosami, F., Manayi, A., Salimi, V. et al. The pro-apoptosis effects of Echinacea purpurea and Cannabis sativa extracts in human lung cancer cells through caspase-dependent pathway. BMC Complement Med Ther 21, 37 (2021).

23. Udoh M, Santiago M, Devenish S, McGregor IS, Connor M. Cannabichromene is a cannabinoid CB2 receptor agonist. Br J Pharmacol. 2019 Dec;176(23):4537-4547.

24. He XH, Galaj E, Bi GH, He Y, Hempel B, Wang YL, Gardner EL, Xi ZX. (2021) β-caryophyllene, an FDA-Approved Food Additive, Inhibits Methamphetamine-Taking and Methamphetamine-Seeking Behaviors Possibly via CB2 and Non-CB2 Receptor Mechanisms. Front Pharmacol. 12:722476.

25. Raduner S, Majewska A, Chen JZ, Xie XQ, Hamon J, Faller B, Altmann KH, Gertsch J. Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects. J Biol Chem. 2006 May 19;281(20):14192-206.

26. Pawar HD, Mahajan UB, Nakhate KT, Agrawal YO, Patil CR, Meeran MFN, Sharma C, Ojha S, Goyal SN. Curcumin Protects Diabetic Mice against Isoproterenol-Induced Myocardial Infarction by Modulating CB2 Cannabinoid Receptors. Life (Basel). 2022 Apr 22;12(5):624. 

27. A. Reiner (2020). CB2 Receptor Therapy Using the FDA-Approved Drug Raloxifene to Mitigate Visual Deficits after Mild TBI and/or Ocular Trauma. U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland. 

https://apps.dtic.mil/sti/pdfs/AD1106946.pdf

28. Honig MG, Del Mar NA, Henderson DL, Ragsdale TD, Doty JB, Driver JH, Li C, Fortugno AP, Mitchell WM, Perry AM, Moore BM, Reiner A. (2019) Amelioration of visual deficits and visual system pathology after mild TBI via the cannabinoid Type-2 receptor inverse agonism of raloxifene. Exp Neurol. 322:113063.

29. Amey Dhopeshwarkar, Natalia Murataeva, Alex Makriyannis, Alex Straiker and Ken Mackie (2017). Two Janus Cannabinoids. Journal of Pharmacology and Experimental Therapeutics, 360 (2) 300-311.