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).

Pancreatic cancer

In one study, THC effectively killed pancreatic cancer cells (in Panc1, Capan2, BxPc2 and MIA PaCa-2 cell lines) at 2 μM and higher concentrations (Carracedo et al., 2006). The authors found that both CB1 and CB2 were upregulated in cancer cells. Apoptosis was CB2-dependent (but see Fogli et al.) In mice, 15 mg/kg/d THC induced tumor cell-specific apoptosis and significantly reduced tumor growth (Carracedo et al., 2006). In human pancreatic cancer cells (MIA PaCa-2) various agonists and antagonists for CB1 and CB2 were found to induce apoptosis (Fogli et al., 2006). These effects appeared to be CB1 and CB2 independent and are counterintuitive but they do suggest the involvement of the endocannabinoid system in the pathogenesis of pancreatic cancer. In human patients, high CB1 expression in pancreatic cancer cells was associated with reduced survival. Similarly, low levels of endocannabinoid-degrading enzyme FAAH and MAGL were associated with reduced survival. Interestingly, Anandamide and 2AGlevels were unchanged in pancreatic cancer. Finally, contrary to CB1 expression in cancer cells, low CB1 in nervous tissue was associated with increased cancer pain, but also increased survival (Michalski et al., 2008). The mechanistic value of these correlations remains to be elucidated. In Panc1 cells, application of both CB1 and CB2 agonists induced AMP-kinase and ROS-dependent autophagy of cancer cells (Dando et al., 2013). The anti-tumoral effect of standard anti-cancer drug Gemcitabine was greatly enhanced by use of CB1 and CB2 agonists in both cell lines and tumor xenografts in mice (Donadelli et al., 2011), suggesting synergy between classical chemotherapy and cannabinoid-based treatment.


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).


In mice, blocking or stimulating CB2 function, respectively speeds up or slows down motor deficits, synapse loss and CNS inflammation that is associated with Huntington’s (Bouchard et al., 2012).

Hypoxic-ischemic encephalopaty

cannabinoid receptors CB1 and CB2 are upregulated and Endocannabinoids like AEA, 2-AG, OEA and PEA show increased levels after cerebral ischemia (England et al., 2015; Lara-Celador et al., 2013). Selective activation of CB2 reduces neuroinflammation, ischemic injury and cognitive deficits in different models of stroke, probably through modulation of AMPK/CREB signaling (Choi et al., 2013; Ronca et al., 2015; Zarruk et al., 2012). Activation of CB1 and CB2 through synthetic cannabinoid WIN 55,212-2 in different hypoxia-ischemic newborn animal models showed neuroprotective effects, decreased brain injury and reduced apoptotic cell death by acting on glutamatergic excitotoxicity, TNF-alpha release, and iNOS expression (Alonso-AlcoNADA et al., 2010, 2012; Fernández-López et al., 2006, 2007, 2010; Martínez-Orgado et al., 2003). CBD mechanisms would involve the modulation of excitotoxicity, oxidative stress and inflammation through CB2, 5HT1A, Adenosine A2A and PPAR-γ receptors (Castillo et al., 2010; Hind et al., 2015; Pazos et al., 2012, 2013).


In rats, THC dose dependently suppressed CSD amplitude, duration and propagation through CB1 but not CB2 activation (Kazemi et al., 2012). The pain phase of migraine is mediated by and can be blocked through both CB1 and CB2 receptors (Greco et al., 2014).

multiple sclerosis

Regarding treatment of MS with sativex, the effects of CBD were PPARγ-mediated whereas THC signaling was CB1/2 dependent (Feliú et al., 2015).


Several synthetic CB2 agonists have been patented for their analgesic properties, indicating a strong role for CB2 in painmanagement (Murineddu et al., 2012).


In a rat model of Parkinson’s Disease, THCV and CBD were neuroprotective in a CB2-independent way (García et al., 2011). In a similar study, THC and CBD were neuroprotective via CB1 or CB2 receptors (Lastres-Becker et al., 2005). In Parkinson’s patients, microglia surrounding lesions in the substantia nigra have increased CB2 levels (Gómez-Gálvez et al., 2015). Experiments in mice showed that this increase in CB2 is neuroprotective. Thus CB2 signalling may provide a therapeutic avenue to prevent neurodegeneration in Parkinson’s.


Stimulating CB1 in human keratinocytes down-regulates keratins K6 and K16 which are involved in wound healing (Ramot et al., 2013), underlining the therapeutic relevance of the cannabinoid system in the treatment of Psoriasis. The effect of cannabinoids on CB1 could lead to potential treatments for Psoriasis (Wilkinson and Williamson, 2007).


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Alonso-AlcoNADA, D., Alvarez, A., Alvarez, F.J., Martínez-Orgado, J.A., and Hilario, E. (2012). The cannabinoid WIN 55212-2 mitigates apoptosis and mitochondrial dysfunction after hypoxia ischemia. Neurochem. Res. 37, 161–170.

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.

Bouchard, J., Truong, J., Bouchard, K., Dunkelberger, D., Desrayaud, S., Moussaoui, S., … Muchowski, P. J. (2012). cannabinoid receptor 2 signaling in peripheral immune cells modulates disease onset and severity in mouse models of Huntington’s disease. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 32(50), 18259-18268. https://doi.org/10.1523/JNEUROSCI.4008-12.2012

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.

Carracedo, A., Gironella, M., Lorente, M., Garcia, S., Guzmán, M., Velasco, G., and Iovanna, J.L. (2006). cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. cancer Res. 66, 6748–6755.

Castillo, A., Tolón, M.R., Fernández-Ruiz, J., Romero, J., and Martinez-Orgado, J. (2010). The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors. Neurobiol. Dis. 37, 434–440.

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

Choi, I.-Y., Ju, C., Anthony Jalin, A.M.A., Lee, D.I., Prather, P.L., and Kim, W.-K. (2013). Activation of cannabinoid CB2 receptor-mediated AMPK/CREB pathway reduces cerebral ischemic injury. Am. J. Pathol. 182, 928–939.

Dando, I., Donadelli, M., Costanzo, C., Dalla Pozza, E., D’Alessandro, A., Zolla, L., and Palmieri, M. (2013). cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells. Cell Death Dis. 4, e664.

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.

Donadelli, M., Dando, I., Zaniboni, T., Costanzo, C., Dalla Pozza, E., Scupoli, M.T., Scarpa, A., Zappavigna, S., Marra, M., Abbruzzese, A., et al. (2011). Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism. Cell Death Dis. 2, e152.

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.

England, T.J., Hind, W.H., Rasid, N.A., and O’Sullivan, S.E. (2015). cannabinoids in experimental stroke: a systematic review and meta-analysis. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 35, 348–358.

Feliú, A., Moreno-Martet, M., Mecha, M., Carrillo-Salinas, F.J., de Lago, E., Fernández-Ruiz, J., and Guaza, C. (2015). A sativex-like combination of phytocannabinoids as a disease-modifying therapy in a viral model of multiple sclerosis.

Fernández-López, D., Martínez-Orgado, J., Nuñez, E., Romero, J., Lorenzo, P., Moro, M.A., and Lizasoain, I. (2006). Characterization of the neuroprotective effect of the cannabinoid agonist WIN-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats. Pediatr. Res. 60, 169–173.

Fernández-López, D., Pazos, M.R., Tolón, R.M., Moro, M.A., Romero, J., Lizasoain, I., and Martínez-Orgado, J. (2007). The cannabinoid agonist WIN55212 reduces brain damage in an in vivo model of Hypoxic-ischemic encephalopathy in newborn rats. Pediatr. Res. 62, 255–260.

Fernández-López, D., Pradillo, J.M., García-Yébenes, I., Martínez-Orgado, J.A., Moro, M.A., and Lizasoain, I. (2010). The cannabinoid WIN55212-2 promotes neural repair after neonatal hypoxia-ischemia. stroke J. Cereb. Circ. 41, 2956–2964.

Fogli, S., Nieri, P., Chicca, A., Adinolfi, B., Mariotti, V., Iacopetti, P., Breschi, M.C., and Pellegrini, S. (2006). cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 580, 1733–1739.

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.

García, C., Palomo-Garo, C., García-Arencibia, M., Ramos, J., Pertwee, R., and Fernández-Ruiz, J. (2011). Symptom-relieving and neuroprotective effects of the phytocannabinoid Δ9-THCV in animal models of Parkinson’s disease. Br. J. Pharmacol. 163, 1495–1506.

Gómez-Gálvez, Y., Palomo-Garo, C., Fernández-Ruiz, J., and García, C. (2015). Potential of the cannabinoid CB2 receptor as a pharmacological target against inflammation in Parkinson’s disease. Prog. Neuropsychopharmacol. Biol. Psychiatry.

Greco, R., Mangione, A.S., Sandrini, G., Nappi, G., and Tassorelli, C. (2014). Activation of CB2 receptors as a potential therapeutic target for migraine: evaluation in an animal model. J. Headache pain 15, 14.

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.

Hind, W.H., England, T.J., and O’Sullivan, S.E. (2015). Cannabidiol protects an in vitro model of the blood brain barrier (BBB) from oxygen-glucose deprivation via PPARγ and 5-HT1a. Br. J. Pharmacol.

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.

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Kazemi, H., Rahgozar, M., Speckmann, E.-J., and Gorji, A. (2012). Effect of cannabinoid receptor activation on spreading depression. Iran. J. Basic Med. Sci. 15, 926–936.

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Lastres-Becker, I., Molina-Holgado, F., Ramos, J.A., Mechoulam, R., and Fernández-Ruiz, J. (2005). cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol. Dis. 19, 96–107.

Michalski, C.W., Oti, F.E., Erkan, M., Sauliunaite, D., Bergmann, F., Pacher, P., Batkai, S., Müller, M.W., Giese, N.A., Friess, H., et al. (2008). cannabinoids in pancreatic cancer: correlation with survival and pain. Int. J. cancer 122, 742–750.

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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.

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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.

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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.

Wilkinson, J.D., and Williamson, E.M. (2007). cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of Psoriasis. J. Dermatol. Sci. 45, 87–92.

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.

Zarruk, J.G., Fernández-López, D., García-Yébenes, I., García-Gutiérrez, M.S., Vivancos, J., Nombela, F., Torres, M., Burguete, M.C., Manzanares, J., Lizasoain, I., et al. (2012). cannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophage/microglial activation concomitant to neuroprotection. stroke J. Cereb. Circ. 43, 211–219. 

Distribution Summary

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.  

Clinical Trials


Several clinical trials have tested the therapeutic potential of cannabinoids after stroke. Meta-analysis revealed that both endocannabinoids like AEA, OEA or PEA and plant cannabinoids like THC or CBD can significantly reduce neuronal degeneration after stroke (England et al., 2015). Specifically activating CB1 and/or CB2 receptors had the strongest protective effect but other receptors such as 5-TH1a and PPARα are also likely to be involved.


England, T.J., Hind, W.H., Rasid, N.A., and O’Sullivan, S.E. (2015). cannabinoids in experimental stroke: a systematic review and meta-analysis. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 35, 348–358.

Distribution from Human Protein Atlas: 
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