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CB1 Agonism

An agonist that binds to a CB1 receptor is a compound or drug that attaches to the receptor and produces an expected effect (see below).

CB1 antagonism vs agonism and associated effects

CB1 Agonism vs Antagonism

CB1 agonism and CB1 antagonism tend to induce opposing effects. For instance, THC is an agonist at CB1 and can generate a dose-dependent euphoria, while THCV and antagonist at CB1 can cause a dose-dependent dysphoria.

CB1 Agonism Associated Effects

Psychoactivity, changes in cognition

Antiemetic (M. Van Sickle et al., 2001; L. Wooldridge et al., 2020)1

Analgesia (A. Milligan et al., 2020)2

Appetite stimulant (E. Tarragon et al., 2019)5

Mood modulation (cannabinoid- and dose-dependent)

Salivation (reduced, dry mouth) (K. Andreis et al., 2022)8

Tearing (reduced, dry eye)(A. Thayer et al., 2020)9

Neuroprotection (M. Soliño et al., 2022;10 S. Yang et al., 2020)11

Bronchodilation (S. Grassin-Delyle et al., 2014;12 J. Ashton et al., 2018)13

Mediation of stress response (T. deRoon-Cassini et al., 2020)14

CB1 Agonists

Pharmaceutical synthetic CB1 agonists and THC analogs such as Marinol, nabilone, Syndros, dronabinol, Cesamet, and (other brand names) are synthetic versions of THC. FDA-approved for Chemotherapy-induced nausea and vomiting, anorexia, and cachexia in patients with HIV/AIDS.

Delta-9-THC is a moderate CB1 agonist with a mean ~Ki 25nM (using human tissue data from 16 trials) (J. McPartland et al., 2007).15

CBN is a weak CB1 agonist with a mean Ki ~525±308 (using human tissue data from 3 trials) (J. McPartland et al., 2007).16

Delta-8-THC is a weak CB1 agonist with a mean Ki ~165nM human cell samples (M. Tagen et al., 2022).17

Anandamide (AEA) is a weak CB1 agonist with a mean ~239±62 (using human tissue data from 16 trials)  (J. McPartland et al., 2007).18

2-AG is a very weak agonist at CB1 with a mean Ki of ~3424±3288 (using human tissue data from 3 trials)  (J. McPartland et al., 2007).19

Endnotes: 

1. Van Sickle MD, Oland LD, Ho W, Hillard CJ, Mackie K, Davison JS, Sharkey KA. Cannabinoids inhibit emesis through CB1 receptors in the brainstem of the ferret. Gastroenterology. 2001 Oct;121(4):767-74.

                  Wooldridge LM, Ji L, Liu Y, Nikas SP, Makriyannis A, Bergman J, Kangas BD. Antiemetic Effects of Cannabinoid Agonists in Nonhuman Primates. J Pharmacol Exp Ther. 2020 Sep;374(3):462-468.

2. Milligan AL, Szabo-Pardi TA, Burton MD. Cannabinoid Receptor Type 1 and Its Role as an Analgesic: An Opioid Alternative? J Dual Diagn. 2020 Jan-Mar;16(1):106-119.

3. Hama A, Sagen J. Activation of spinal and supraspinal cannabinoid-1 receptors leads to antinociception in a rat model of neuropathic spinal cord injury pain. Brain Res. 2011 Sep 15;1412:44-54.

4. Lim G, Sung B, Ji RR, Mao J. Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of Win 55,212-2 on neuropathic pain behaviors in rats. Pain. 2003 Sep;105(1-2):275-83.

5. Tarragon E, Moreno JJ. Cannabinoids, Chemical Senses, and Regulation of Feeding Behavior. Chem Senses. 2019 Jan 29;44(2):73-89.

6. Hu XF, Zhang H, Yu LL, Ge WQ, Zhan-Mu OY, Li YZ, Chen C, Hou TF, Xiang HC, Li YH, Su YS, Jing XH, Cao J, Pan HL, He W, Li M. Electroacupuncture Reduces Anxiety Associated With Inflammatory Bowel Disease By Acting on Cannabinoid CB1 Receptors in the Ventral Hippocampus in Mice. Front Pharmacol. 2022 Jul 8;13:919553.

7. Fang G, Wang Y. Hippocampal CB1 receptor mediates antidepressant-like effect of synthetic cannabinoid-HU210 in acute despair reaction model in mice. Neurosci Lett. 2023 Jan 1;792:136953.

8. Andreis, K., Billingsley, J., Naimi Shirazi, K. et al. Cannabinoid CB1 receptors regulate salivation. Sci Rep 12, 14182 (2022).

9. Amanda Thayer, Natalia Murataeva, Vanessa Delcroix, Jim Wager-Miller, Helen P. Makarenkova, Alex Straiker; THC Regulates Tearing via Cannabinoid CB1 Receptors. Invest. Ophthalmol. Vis. Sci. 2020;61(10):48.

10. Soliño M, Larrayoz IM, López EM, Rey-Funes M, Bareiro M, Loidl CF, Girardi E, Caltana L, Brusco A, Martínez A and López-Costa JJ (2022). CB1 Cannabinoid Receptor is a Target for Neuroprotection in Light Induced  Retinal Degeneration. Adv. Drug. Alco. Res. 2:10734.

11. Yang, S., Hu, B., Wang, Z. et al. Cannabinoid CB1 receptor agonist ACEA alleviates brain ischemia/reperfusion injury via CB1–Drp1 pathway. Cell Death Discov. 6, 102 (2020).

12. Grassin-Delyle S, Naline E, Buenestado A, Faisy C, Alvarez JC, Salvator H, Abrial C, Advenier C, Zemoura L, Devillier P. Cannabinoids inhibit cholinergic contraction in human airways through prejunctional CB1 receptors. Br J Pharmacol. 2014 Jun;171(11):2767-77.

13. Ashton JC, Hancox RJ. The Case for Cannabinoid CB1 Receptors as a Target for Bronchodilator Therapy for β-agonist Resistant Asthma. Curr Drug Targets. 2018;19(11):1344-1349.

14. deRoon-Cassini TA, Stollenwerk TM, Beatka M, Hillard CJ. Meet Your Stress Management Professionals: The Endocannabinoids. Trends Mol Med. 2020 Oct;26(10):953-968.

15. McPartland JM, Glass M, Pertwee RG. Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences. Br J Pharmacol. 2007 Nov;152(5):583-93.

16. Ibid.

17. Tagen M, Klumpers LE. Review of delta-8-tetrahydrocannabinol (Δ8 -THC): Comparative pharmacology with Δ9 -THC. Br J Pharmacol. 2022 Aug;179(15):3915-3933.

18. McPartland JM, Glass M, Pertwee RG. Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences. Br J Pharmacol. 2007 Nov;152(5):583-93.

19. Ibid.