CB2 is primarily expressed in the immune cells and tissues of the body. Like CB1, CB2 is a G protein-coupled receptor which inhibits adenylyl cyclase and consequently lowers cAMP upon activation. This, in turn, regulates many second messenger pathways.

Chemical Name: 
Cannabinoid receptor type 2
IUPHAR entry: 
Wikipedia entry: 

CB2 is primarily found in cells of the immune system, such as monocytes, macrophages, B-cells and T-cells and in organs like the spleen, tonsils and thymus gland. CB2 is also found in macrophage-derived cells such as microglia, osteocytes, osteoclasts, dendritic cells and hepatic Kupffer cells CB2 is also found throughout the gastrointestinal tract where it is involved in immune reactions. CB2 is present in brain and the peripheral nervous system but lower abundant than CB1. Where CB1 is primarily found in neurons, CB2 is mostly found in microglia, consistent with a primary function in immune responses. CB2 is overexpressed in the brain under certain injury conditions and is overexpressed in cancer cells. However, distribution of CB2 remains controversial due to discrepancies between studies and the lack of validation of some immunochemistry techniques used for its localization.  

Literature Discussion: 


Mice genetically deficient for CB2, drink more alcohol (and eat more food), suggesting CB2 could be a target for the treatment of Addiction (Pradier et al., 2015). 


Infected cells secrete trans-activating factors (Tat), which consequently attract macrophages and macrophage-like cells. THC blocks this migration in a dose-dependent way via CB2 receptors (Raborn and Cabral, 2010).


There is controversy about CB1 expression in AD but CB2 is significantly increased in AD patients, probably due to microglial activation around senile plaques (reviewed in: Aso and Ferrer, 2014).

One therapeutic indication for CB2 is the stimulation of Amyloid β plaque removal by macrophages. Similar effects were seen for 2AG and MAGL inhibitors (Chen et al., 2012). CB1 is not involved in plaque clearance.


In mice genetically deficient for CB2, experimentally induced osteoArthritis was significantly worse than in control mice (Sophocleous et al., 2015). In addition, naturally occurring osteoArthritis was more severe in CB2 deficient mice than in controls.

This suggests that CB2 is involved in the development of (osteo-)Arthritis and that CB2 activation may protect against osteoArthritis


CB2-mediated signaling was significantly upregulated in peripheral blood mononuclear cells obtained from autistic children (Siniscalco et al., 2013).


Bladder Cancer

Until now, we know that human bladder cells express the cannabinoid receptors CB1CB2 and GPR55 (Bakali et al., 2014).

Bone Cancer

Research shows that bone cancer cells express CB2 receptor (Yang et al., 2015).

Breast Cancer

cannabinoids as THC and CBD have shown anti cancer properties in several studies through CB1 and CB2 receptors (Caffarel et al., 2008; Massi et al., 2013).

Cervical Cancer

cannabinoid receptors CB1CB2 and TRPV1 are expressed in the cervix (Ayakannu et al., 2015).


The specific cannabinoid receptors CB2 and GPR55 are overexpressed in glioblastomas compared to non-cancer glial cells. This overexpression is also related to the prognosis of the disease, with higher overexpression of CB2 in the most aggressive tumors (Calatozzolo et al., 2007; Ellert-Miklaszewska et al., 2007; Sánchez et al., 2001). Studies in THC and synthetic CB2 agonists shown downregulation of MMP-2, cell invasion and cell viability (Blázquez et al., 2008; Galanti et al., 2008; Hernán Pérez de la Ossa et al., 2013). CBD modulates Id-1 gene and targets receptors CB1, CB2, TRPV-1 and TRPV-2 (Solinas et al., 2013; Soroceanu et al., 2013).


Leukemia cells express functional CB1 and CB2 receptors (Moaddel et al., 2011). Also, other CB1/2 agonists showed Leukemia cell growth and proliferation inhibition (Gallotta et al., 2010; Yrjölä et al., 2015).


THC reduced bronchoconstriction, inflammation and coughing in guinea pigs through activation of CB1 and CB2 receptors (Makwana et al., 2015).

Functional Gastro-Intestinal Disorders

CB2 plays a role in Crohn´s disease (Schicho and Storr, 2014). Cannabis extract also reduced visceral pain at 3 mg/kg in a CB2-dependent way suggesting cannabis extract has distinct beneficial effects in gastro-intestinal disorders via CB1/2-dependent and independent pathways (Wallace et al., 2013).


Several studies found that CB2 was upregulated with Cystitis (Merriam et al., 2008; Tambaro et al., 2014) and that activation of CB2 with Anandamide or PEA attenuated pain and inflammation (Jaggar et al., 1998; Wang et al., 2013, 2014).


Anandamide and CB1CB2 and GPR55 receptors are implicated in the pathophysiology of Diabetes type 2 (Jenkin et al., 2014; Jourdan et al., 2014; Troy-Fioramonti et al., 2014).


PEA enhances AEA activity at CB1CB2 and TRPV1 receptors and protects against keratinocyte inflammation in a TRPV1-, but not CB1CB2 or PPARα-dependent way (Petrosino et al., 2010). In another mouse study, experimental dermatitis increased 2AG levels and suppressed inflammation via CB2 receptors (Oka et al., 2006). In mice CB1 and CB2 suppressed inflammation in allergic contact dermatitis (Karsak et al., 2007).


Neuronal activity induces a Cl- influx through 2AG/Anandamide and CB2 (den Boon et al., 2014).


Aso, E., and Ferrer, I. (2014). cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic. Front. Pharmacol. 5, 37.

Ayakannu, T., Taylor, A.H., Willets, J.M., and Konje, J.C. (2015). The evolving role of the endocannabinoid system in gynaecological cancer. Hum. Reprod. Update 21, 517–535.

Bakali, E., Elliott, R.A., Taylor, A.H., Lambert, D.G., Willets, J.M., and Tincello, D.G. (2014).Human urothelial cell lines as potential models for studying cannabinoid and excitatory receptor interactions in the urinary bladder. Naunyn. Schmiedebergs Arch. Pharmacol. 387, 581–589.

Blázquez, C., Salazar, M., Carracedo, A., Lorente, M., Egia, A., González-Feria, L., Haro, A., Velasco, G., and Guzmán, M. (2008). cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. cancer Res. 68, 1945–1952.

Calatozzolo, C., Salmaggi, A., Pollo, B., Sciacca, F.L., Lorenzetti, M., Franzini, A., Boiardi, A., Broggi, G., and Marras, C. (2007). Expression of cannabinoid receptors and neurotrophins in human gliomas. Neurol. Sci. Off. J. Ital. Neurol. Soc. Ital. Soc. Clin. Neurophysiol. 28, 304–310.

Caffarel, M.M., Moreno-Bueno, G., Cerutti, C., Palacios, J., Guzman, M., Mechta-Grigoriou, F., and Sanchez, C. (2008). JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene 27, 5033–5044.

Chen, R., Zhang, J., Wu, Y., Wang, D., Feng, G., Tang, Y.-P., … Chen, C. (2012). Monoacylglycerol lipase is a therapeutic target for Alzheimer’s disease. Cell Reports2(5), 1329-1339. https://doi.org/10.1016/j.celrep.2012.09.030

den Boon, F.S., Chameau, P., Houthuijs, K., Bolijn, S., Mastrangelo, N., Kruse, C.G., Maccarrone, M., Wadman, W.J., and Werkman, T.R. (2014). endocannabinoids produced upon action potential firing evoke a Cl(-) current via type-2 cannabinoid receptors in the medial prefrontal cortex. Pflüg. Arch. Eur. J. Physiol. 466, 2257–2268.

Ellert-Miklaszewska, A., Grajkowska, W., Gabrusiewicz, K., Kaminska, B., and Konarska, L. (2007). Distinctive pattern of cannabinoid receptor type II (CB2) expression in adult and pediatric brain tumors. Brain Res. 1137, 161–169.

Galanti, G., Fisher, T., Kventsel, I., Shoham, J., Gallily, R., Mechoulam, R., Lavie, G., Amariglio, N., Rechavi, G., and Toren, A. (2008). Delta 9-tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells. Acta Oncol. Stockh. Swed. 47, 1062–1070.

Gallotta, D., Nigro, P., Cotugno, R., Gazzerro, P., Bifulco, M., and Belisario, M.A. (2010). Rimonabant-induced apoptosis in Leukemia cell lines: activation of caspase-dependent and -independent pathways. Biochem. Pharmacol. 80, 370–380.

Hernán Pérez de la Ossa, D., Lorente, M., Gil-Alegre, M.E., Torres, S., García-Taboada, E., Aberturas, M.D.R., Molpeceres, J., Velasco, G., and Torres-Suárez, A.I. (2013). Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme. PloS One 8, e54795.

Jaggar, S.I., Hasnie, F.S., Sellaturay, S., and Rice, A.S. (1998). The anti-hyperalgesic actions of the cannabinoid Anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory painpain 76, 189–199.

Jenkin, K.A., McAinch, A.J., Zhang, Y., Kelly, D.J., and Hryciw, D.H. (2014). Elevated CB1 and GPR55 receptor expression in proximal tubule cells and whole kidney exposed to diabetic conditions. Clin. Exp. Pharmacol. Physiol.

Jourdan, T., Szanda, G., Rosenberg, A.Z., Tam, J., Earley, B.J., Godlewski, G., Cinar, R., Liu, Z., Liu, J., Ju, C., et al. (2014). Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy. Proc. Natl. Acad. Sci. U. S. A. 111, E5420–E5428.

Karsak, M., Gaffal, E., Date, R., Wang-Eckhardt, L., Rehnelt, J., Petrosino, S., Starowicz, K., Steuder, R., Schlicker, E., Cravatt, B., et al. (2007). Attenuation of allergic contact dermatitis through the endocannabinoid system. Science 316, 1494–1497.

Makwana, R., Venkatasamy, R., Spina, D., and Page, C. (2015). The effect of phytocannabinoids on airway hyperresponsiveness, airway inflammation and cough. J. Pharmacol. Exp. Ther.

Massi, P., Solinas, M., Cinquina, V., and Parolaro, D. (2013). Cannabidiol as potential anticancer drug. Br. J. Clin. Pharmacol. 75, 303–312.

Moaddel, R., Rosenberg, A., Spelman, K., Frazier, J., Frazier, C., Nocerino, S., Brizzi, A., Mugnaini, C., and Wainer, I.W. (2011). Development and characterization of immobilized cannabinoid receptor (CB1/CB2) open tubular column for on-line screening. Anal. Biochem. 412, 85–91.

Oka, S., Wakui, J., Ikeda, S., Yanagimoto, S., Kishimoto, S., Gokoh, M., Nasui, M., and Sugiura, T. (2006). Involvement of the cannabinoid CB2 receptor and its endogenous ligand 2-arachidonoylglycerol in oxazolone-induced contact dermatitis in mice. J. Immunol. Baltim. Md 1950 177, 8796–8805.

Petrosino, S., Cristino, L., Karsak, M., Gaffal, E., Ueda, N., Tüting, T., Bisogno, T., De Filippis, D., D’Amico, A., Saturnino, C., et al. (2010). Protective role of palmitoylethanolamide in contact allergic dermatitis. Allergy 65, 698–711.

Pradier, B., Erxlebe, E., Markert, A., and Rácz, I. (2015). Interaction of cannabinoid receptor 2 and social environment modulates chronic alcohol consumption. Behav. Brain Res. 287, 163–171.

Raborn, E.S., and Cabral, G.A. (2010). cannabinoid inhibition of macrophage migration to the trans-activating (Tat) protein of HIV-1 is linked to the CB(2) cannabinoid receptor. J. Pharmacol. Exp. Ther. 333, 319–327.

Sánchez, C., de Ceballos, M.L., Gomez del Pulgar, T., Rueda, D., Corbacho, C., Velasco, G., Galve-Roperh, I., Huffman, J.W., Ramón y Cajal, S., and Guzmán, M. (2001). Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. cancer Res. 61, 5784–5789.

Schicho, R., and Storr, M. (2014). Cannabis finds its way into treatment of Crohn’s disease. Pharmacology 93, 1–3.

Siniscalco, D., Sapone, A., Giordano, C., Cirillo, A., de Magistris, L., Rossi, F., Fasano, A., Bradstreet, J.J., Maione, S., and Antonucci, N. (2013). cannabinoid receptor type 2, but not type 1, is up-regulated in peripheral blood mononuclear cells of children affected by autistic disorders. J. Autism Dev. Disord. 43, 2686–2695.

Solinas, M., Massi, P., Cinquina, V., Valenti, M., Bolognini, D., Gariboldi, M., Monti, E., Rubino, T., and Parolaro, D. (2013). Cannabidiol, a Non-Psychoactive cannabinoid Compound, Inhibits Proliferation and Invasion in U87-MG and T98G Glioma Cells through a Multitarget Effect. PLoS ONE 8.

Sophocleous, A., Börjesson, A.E., Salter, D.M., and Ralston, S.H. (2015). The type 2 cannabinoid receptor regulates susceptibility to osteoArthritis in mice. Osteoarthr. Cartil. OARS Osteoarthr. Res. Soc.

Soroceanu, L., Murase, R., Limbad, C., Singer, E., Allison, J., Adrados, I., Kawamura, R., Pakdel, A., Fukuyo, Y., Nguyen, D., et al. (2013). Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target. cancer Res. 73, 1559–1569.

Troy-Fioramonti, S., Demizieux, L., Gresti, J., Muller, T., Vergès, B., and Degrace, P. (2014). Acute Activation of cannabinoid Receptors by Anandamide Reduces Gastro-Intestinal Motility and Improves Postprandial Glycemia in Mice. Diabetes.

Wallace, J.L., Flannigan, K.L., McKnight, W., Wang, L., Ferraz, J.G.P., and Tuitt, D. (2013). Pro-resolution, protective and anti-nociceptive effects of a cannabis extract in the rat gastrointestinal tract. J. Physiol. Pharmacol. Off. J. Pol. Physiol. Soc. 64, 167–175.

Wang, Z.-Y., Wang, P., and Bjorling, D.E. (2013). Activation of cannabinoid receptor 2 inhibits experimental Cystitis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 304, R846–R853.

Wang, Z.-Y., Wang, P., and Bjorling, D.E. (2014). Treatment with a cannabinoid receptor 2 agonist decreases severity of established Cystitis. J. Urol. 191, 1153–1158.

Yang, L., Li, F.-F., Han, Y.-C., Jia, B., and Ding, Y. (2015).cannabinoid receptor CB2 is involved in tetrahydrocannabinol-induced anti-inflammation against lipopolysaccharide in MG-63 cells. Mediators Inflamm. 2015, 362126.  

Yrjölä, S., Sarparanta, M., Airaksinen, A.J., Hytti, M., Kauppinen, A., Pasonen-Seppänen, S., Adinolfi, B., Nieri, P., Manera, C., Keinänen, O., et al. (2015). Synthesis, in vitro and in vivo evaluation of 1,3,5-triazines as cannabinoid CB2 receptor agonists. Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci. 67, 85–96.