Literature Discussion


CB1 is the most abundant G-protein coupled receptor in the parts of the brain that are most involved in addictive behavior, suggesting a link. At least one genetic variation/polymorphism in CB1 is linked to increased receptor binding and increased CB1-mediated neuronal activation in the prefrontal cortex (Hutchison et al., 2008).

Post-mortem research suggests that although expression is unaffected, CB1 receptors are hyperactive in the caudate nucleus and hypoactive in the cerebellum of alcoholics (Erdozain et al., 2015).

Blocking the reward signal with CB1 antagonists blocks dopaminergic signaling in the nucleus accumbens and decreases alcohol craving and consumption (Hutchison et al., 2008).


In a rat study it was found that the therapeutic effect of amphetamins actually requires CB1 activation (Kleijn et al., 2012)

A genetics study pointed out that ADHD is tightly linked to small variations/mutations (single nucleotide polymorphisms) in the CB1 gene (CNR1)(Lu et al., 2008).


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).

In cultured astrocytes, Aβ1-42 reduced cell viability and PPARγ expression and increased cellular inflammation and anti-oxidant capacity. Specific CB1 stimulation (with WIN55,212-2, a synthetic analog of THC) prevented all these effects and increased cellular viability (Aguirre-Rueda et al., 2015).

Exercise has been shown to be beneficial in neurological disorders like Alzheimer’s disease and depression. Exercise increases the production of new neurons in the hippocampus in rats. In addition, Anandamide levels (and to a lesser degree 2AG levels) and CB1 receptor availability are increased in the hippocampus (but not in the prefrontal cortex). Blocking the endocannabinoid system prevents the production of new neurons suggesting a role for cannabinoids in this process (Hill et al., 2010).


CB1 receptors are upregulated in brains of anorexia patients and in some brain regions of bulimia patients (Gérard et al., 2011).

CB1 receptors may be upregulated in an attempt to compensate for reduced endocannabinoid signaling. In line with this, mutations in CB1 (the major cannabinoid receptor) and FAAH (the major endocannabinoid degrading enzyme) were found to be associated with anorexia and bulimia (Monteleone et al., 2009)


One study in healthy humans linked CB1 polymorphisms (small variations in a gene that are not directly linked to any particular deficit) to variations in the time people spent looking at happy faces (Chakrabarti and Baron-Cohen, 2011).

Interestingly, in another genetic mouse model of mental retardation and Autism (FMR1 knockout), blockade of CB1 normalized cognitive defects (Busquets-Garcia et al., 2013), suggesting CB1 may be a therapeutic target for Autism treatment.


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 CB1 receptors (Kawamata et al., 2010)

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. Anandamide bind to those receptors and has multiple functions on them (Ayakannu et al., 2015).


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.


CB1 receptors are upregulated in brains of Anorexia patients and in some brain regions of bulimia patients (Gérard et al., 2011).

CB1 receptors may be upregulated in an attempt to compensate for reduced endocannabinoid signaling. In line with this, mutations in CB1 (the major cannabinoid receptor) and FAAH (the major endocannabinoid degrading enzyme) were found to be associated with Anorexia and bulimia (Monteleone et al., 2009). 


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

Functional Gastro-Intestinal Disorders

Polymorphisms (small, single nucleotide mutations) in the CB1 gene/receptor are linked to the susceptibility to develop Crohn’s Disease, suggesting the involvement of the endocannabinoid system in Crohn’s Disease (Storr et al., 2010). cannabinoid-mediated reduction in gastro-intestinal motility appears to be mediated by CB1 but not CB2 (Aviello et al., 2008). CB1 and TRPV1 signaling are both required for the development of stress-induced visceral hyperalgesia and TRPV4 and TRPA1 may also be involved (Lin et al., 2013).


Another rat study found that endocannabinoid PEA and CB1 were upregulated, PPARα was downregulated and CB2 was unchanged upon induction of Cystitis (Pessina et al., 2014). PEA attenuated pain and bladder voiding. This effect was blocked by CB1 and PPARα antagonists.


CBG can activate α2 receptors and block CB1 and 5-HT1A receptors (Cascio et al., 2010), suggesting CBG does have therapeutic potential in the treatment of depression. Exercise has been shown to be beneficial in neurological disorders like Alzheimer’s disease and depression. Exercise increases the production of new neurons in the hippocampus in rats. In addition, Anandamide levels (and to a lesser degree 2AG levels) and CB1 receptor availability are increased in the hippocampus (but not in the prefrontal cortex). Blocking the endocannabinoid system prevents the production of new neurons suggesting a role for cannabinoids in this process (Hill et al., 2010)


Anandamide and CB1, CB2 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 CB1, CB2 and TRPV1 receptors and protects against keratinocyte inflammation in a TRPV1-, but not CB1, CB2 or PPARα-dependent way (Petrosino et al., 2010). In mice CB1 and CB2 suppressed inflammation in allergic contact dermatitis (Karsak et al., 2007).


In rats, THC and other synthetic CB1 agonists, reduces synchronous firing of hippocampal principal neurons, suggesting a direct role for THC in seizure prevention (Goonawardena et al., 2011). Similarly, CB1 activation decreases synchrony in cortical neurons (Sales-Carbonell et al., 2013). In mice, stimulating CB1 receptors (ACEA) or blocking TRPV1 receptors (capsazepine) protected against PTZ-induced seizures (Naderi et al., 2015). In rats, the synthetic CB1 agonist WIN 55-212-2 was protective against the development of epilepsy when administered after an episode of status epilepticus (induced by pilocarpine)(Di Maio et al., 2014).


A meta-analysis of human and rodent genetics studies found consistent changes in CB1, PPARα and NAPE-PLD in patients and animal models of Huntington’s Disease (Laprairie et al., 2015), suggesting involvement of the endocannabinoid system.

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 CB1 reduces astrocytic reaction, neuronal death and dendritic loss in a stoke model in adult mice (Caltana et al., 2015). 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).


In a model of maternal separation, sleep reduction has been related to the endocannabinoid system through the expression of CB1 in the prefrontal cortex and hypothalamus while oleamide improved sleep in adult rats (Reyes Prieto et al., 2012). Activation of CB1 receptors in the endopeduncular nucleus can induce sleep while their blockade promotes Insomnia-type symptoms in rats (Méndez-Díaz et al., 2013). CB1 receptors mediated sleep effects caused by Anandamide in a rat model with in vivo microdialysis (Murillo-Rodriguez et al., 2003). In a EEG experiment with rats, administration of a synthetic CB1 antagonist showed arousal-enhancing properties, suggesting again a role of the endocannabinoid system in sleep (Santucci et al., 1996).


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). TRPV1-mediated antinociception is thought to work in synergy with CB1-mediated neuronal inhibition in pain management (Hoffmann et al., 2012).

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).


Rimonabant also induces anxiogenic effects in contrast to THCV, probably because THCV acts as a neutral CB1 receptor antagonist while Rimonabant acts as inverse agonist (O’Brien et al., 2013).


In one study in mice, CB1 antagonist CBD, but not CBDVTHCV or CBG, effectively suppressed obsessive compulsive behavior (marble burying)(Deiana et al., 2012). In line with this the endogenous CB1 agonist Anandamide stimulates marble seeking behavior (Umathe et al., 2012).


Blocking CB1 completely prevents the analgesic action of paracetamol suggesting CB1 is required for analgesia (Bertolini et al., 2006). In a rat model, THC was found to suppress muscle pain via activation of CB1 (Bagüés et al., 2014)


THC and CBD were neuroprotective via CB1 or CB2 receptors (Lastres-Becker et al., 2005)

psychosis and schizophrenia

There is controversy regarding the role of the endocannabinoid receptor CB1 density, with studies showing lower density in schizophrenia patients than in controls and vice versa. CB1 density could also be affected by antipsychotic treatment (Dean et al., 2001; Ranganathan et al., 2015). CB1 receptor agonist THC has been reported to mimic psychotic symptoms in healthy volunteers, supporting the argument of a role of the endocannabinoid system in schizophrenia (Bossong et al., 2014). CBD acts as inverse agonist in CB1 receptor and THCV acts as an antagonist of CB1 receptor. These properties would counteract the psychotic symptoms of THC (Iseger and Bossong, 2015; Pertwee, 2005)


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).


Similar to chronic stress, people with PTSD have 15-20% lower CB1 levels and more than 50% reduced Anandamide levels (Neumeister et al., 2013) which may form a mechanistic insight in the development of PTSD and/or depression.


CB1 receptors and 2AG are expressed in the auditory brainsteam and their role may involve modulation of the balance of excitation and inhibition in auditory circuits  (Zhao et al., 2009). The  development of Tinnitus in rats may be related to a reduced number of CB1 receptors in the ventral cochlear nucleus (Zheng et al., 2007).


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Distribution Summary

CB1 is the main cannabinoid receptor in the brain and shows particularly strong expression in hippocampus, neocortex, cerebellum, basal ganglia and spinal cord. In the rest of the body, CB1 is expressed in fat, muscle and liver cells and in the digestive tract.

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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