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)
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 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.
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).
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 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).
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)
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.
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).
In one study in mice, CB1 antagonist CBD, but not CBDV, THCV 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)
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).
Aguirre-Rueda, D., Guerra-Ojeda, S., Aldasoro, M., Iradi, A., Obrador, E., Mauricio, M.D., Vila, J.M., Marchio, P., and Valles, S.L. (2015). WIN 55,212-2, Agonist of cannabinoid Receptors, Prevents Amyloid β1-42 Effects on Astrocytes in Primary Culture. PloS One 10, e0122843.
Alonso-AlcoNADA, D., Alvarez, F.J., Alvarez, A., Mielgo, V.E., Goñi-de-Cerio, F., Rey-Santano, M.C., Caballero, A., Martinez-Orgado, J., and Hilario, E. (2010). The cannabinoid receptor agonist WIN 55,212-2 reduces the initial cerebral damage after hypoxic-ischemic injury in fetal lambs. Brain Res. 1362, 150–159.
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.
Aviello, G., Romano, B., and Izzo, A.A. (2008). cannabinoids and gastrointestinal motility: animal and human studies. Eur. Rev. Med. Pharmacol. Sci. 12 Suppl 1, 81–93.
Bagüés, A., Martín, M.I., and Sánchez-Robles, E.M. (2014). Involvement of central and peripheral cannabinoid receptors on antinociceptive effect of tetrahydrocannabinol in muscle pain. Eur. J. Pharmacol. 745C, 69–75.
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.
Bertolini, A., Ferrari, A., Ottani, A., Guerzoni, S., Tacchi, R., and Leone, S. (2006). Paracetamol: new vistas of an old drug. CNS Drug Rev. 12, 250–275.
Bossong, M.G., Jansma, J.M., Bhattacharyya, S., and Ramsey, N.F. (2014). Role of the endocannabinoid system in brain functions relevant for schizophrenia: an overview of human challenge studies with cannabis or 9-tetrahydrocannabinol (THC). Prog Neuropsychopharmacol Biol Psychiatry 52, 53–69
Busquets-Garcia, A., Gomis-González, M., Guegan, T., Agustín-Pavón, C., Pastor, A., Mato, S., Pérez-Samartín, A., Matute, C., de la Torre, R., Dierssen, M., et al. (2013). Targeting the endocannabinoid system in the treatment of fragile X syndrome. Nat. Med. 19, 603–607.
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.
Caltana, L., Saez, T.M., Aronne, M.P., and Brusco, A. (2015). cannabinoid receptor type 1 agonist ACEA improves motor recovery and protects neurons in ischemic stroke in mice. J. Neurochem. 135, 616–629.
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.
Cascio, M.G., Gauson, L.A., Stevenson, L.A., Ross, R.A., and Pertwee, R.G. (2010). Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. Br. J. Pharmacol. 159, 129–141.
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.
Dean, B., Sundram, S., Bradbury, R., Scarr, E., and Copolov, D. (2001). Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use. Neuroscience 103, 9–15
Deiana, S., Watanabe, A., Yamasaki, Y., Amada, N., Arthur, M., Fleming, S., Woodcock, H., Dorward, P., Pigliacampo, B., Close, S., et al. (2012). Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour. Psychopharmacology (Berl.) 219, 859–873.
Di Maio, R., Cannon, J.R., and Timothy Greenamyre, J. (2014). Post-status epilepticus treatment with the cannabinoid agonist WIN 55,212-2 prevents chronic epileptic hippocampal damage in rats. Neurobiol. Dis. 73C, 356–365.
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.
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.
Erdozain, A.M., Rubio, M., Meana, J.J., Fernández-Ruiz, J., and Callado, L.F. (2015). Altered CB1 receptor coupling to G-proteins in the post-mortem caudate nucleus and cerebellum of alcoholic subjects. J. Psychopharmacol. Oxf. Engl.
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.
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.
Goonawardena, A.V., Riedel, G., and Hampson, R.E. (2011). cannabinoids alter spontaneous firing, bursting, and cell synchrony of hippocampal principal cells. Hippocampus 21, 520–531.
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.
Hill, M.N., Titterness, A.K., Morrish, A.C., Carrier, E.J., Lee, T.T.-Y., Gil-Mohapel, J., Gorzalka, B.B., Hillard, C.J., and Christie, B.R. (2010). Endogenous cannabinoid signaling is required for voluntary exercise-induced enhancement of progenitor cell proliferation in the hippocampus. Hippocampus 20, 513–523.
Hoffmann, J., Supronsinchai, W., Andreou, A.P., Summ, O., Akerman, S., and Goadsby, P.J. (2012). Olvanil acts on transient receptor potential vanilloid channel 1 and cannabinoid receptors to modulate neuronal transmission in the trigeminovascular system. pain153, 2226–2232.
Hutchison, K.E., Haughey, H., Niculescu, M., Schacht, J., Kaiser, A., Stitzel, J., Horton, W.J., and Filbey, F. (2008). The incentive salience of alcohol: translating the effects of genetic variant in CNR1. Arch. Gen. Psychiatry 65, 841–850.
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.
Kleijn, J., Wiskerke, J., Cremers, T.I.F.H., Schoffelmeer, A.N.M., Westerink, B.H.C., and Pattij, T. (2012). Effects of amphetamine on dopamine release in the rat nucleus accumbens shell region depend on cannabinoid CB1 receptor activation. Neurochem. Int. 60, 791–798.
Laprairie, R. B., Bagher, A. M., Precious, S. V., & Denovan-Wright, E. M. (2015). Components of the endocannabinoid and dopamine systems are dysregulated in Huntington’s disease: analysis of publicly available microarray datasets. Pharmacology Research & Perspectives, 3(1). https://doi.org/10.1002/prp2.104
Lara-Celador, I., Goñi-de-Cerio, F., Alvarez, A., and Hilario, E. (2013). Using the endocannabinoid system as a neuroprotective strategy in perinatal hypoxic-ischemic brain injury. Neural Regen. Res. 8, 731–744.
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.
Lin, X.-H., Wang, Y.-Q., Wang, H.-C., Ren, X.-Q., and Li, Y.-Y. (2013). Role of endogenous cannabinoid system in the gut. Sheng Li Xue Bao 65, 451–460.
Lu, A.T., Ogdie, M.N., Järvelin, M.-R., Moilanen, I.K., Loo, S.K., McCracken, J.T., McGough, J.J., Yang, M.H., Peltonen, L., Nelson, S.F., et al. (2008). Association of the cannabinoid receptor gene (CNR1) with ADHD and post-traumatic stress disorder. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. Off. Publ. Int. Soc. Psychiatr. Genet. 147B, 1488–1494.
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.
Martínez-Orgado, J., Fernández-Frutos, B., González, R., Romero, E., Urigüen, L., Romero, J., and Viveros, M.P. (2003). Neuroprotection by the cannabinoid agonist WIN-55212 in an in vivo newborn rat model of acute severe asphyxia. Brain Res. Mol. Brain Res. 114, 132–139.
Massi, P., Solinas, M., Cinquina, V., and Parolaro, D. (2013). Cannabidiol as potential anticancer drug. Br. J. Clin. Pharmacol. 75, 303–312.
Méndez-Díaz, M., Caynas-Rojas, S., Arteaga Santacruz, V., Ruiz-Contreras, A.E., Aguilar-Roblero, R., and Prospéro-García, O. (2013). Entopeduncular nucleus endocannabinoid system modulates sleep-waking cycle and mood in rats. Pharmacol. Biochem. Behav. 107, 29–35.
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.
Monteleone, P., Bifulco, M., Di Filippo, C., Gazzerro, P., Canestrelli, B., Monteleone, F., Proto, M.C., Di Genio, M., Grimaldi, C., and Maj, M. (2009). Association of CNR1 and FAAH endocannabinoid gene polymorphisms with anorexia nervosa and bulimia nervosa: evidence for synergistic effects. Genes Brain Behav. 8, 728–732.
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.
Murillo-Rodriguez, E., Blanco-Centurion, C., Sanchez, C., Piomelli, D., and Shiromani, P.J. (2003). Anandamide enhances extracellular levels of adenosine and induces sleep: an in vivo microdialysis study. Sleep 26, 943–947
Naderi, N., Shafieirad, E., Lakpoor, D., Rahimi, A., and Mousavi, Z. (2015). Interaction between cannabinoid Compounds and Capsazepine in Protection against Acute Pentylenetetrazole-induced Seizure in Mice. Iran. J. Pharm. Res. IJPR 14, 115–120.
Neumeister, A., Normandin, M.D., Pietrzak, R.H., Piomelli, D., Zheng, M.Q., Gujarro-Anton, A., Potenza, M.N., Bailey, C.R., Lin, S.F., Najafzadeh, S., et al. (2013). Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. Mol. Psychiatry 18, 1034–1040.
O’Brien, L. D., Wills, K. L., Segsworth, B., Dashney, B., Rock, E. M., Limebeer, C. L., & Parker, L. A. (2013). Effect of chronic exposure to rimonabant and phytocannabinoids on Anxiety-like behavior and saccharin palatability. Pharmacology, Biochemistry, and Behavior, 103(3), 597-602. https://doi.org/10.1016/j.pbb.2012.10.008
Pessina, F., Capasso, R., Borrelli, F., Aveta, T., Buono, L., Valacchi, G., Fiorenzani, P., Di Marzo, V., Orlando, P., and Izzo, A.A. (2014). Protective Effect of Palmitoylethanolamide in a Rat Model of Cystitis. J. Urol.
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.
Ramot, Y., Sugawara, K., Zákány, N., Tóth, B.I., Bíró, T., and Paus, R. (2013). A novel control of human keratin expression: cannabinoid receptor 1-mediated signaling down-regulates the expression of keratins K6 and K16 in human keratinocytes in vitro and in situ. PeerJ 1, e40.
Ranganathan, M., Cortes-Briones, J., Radhakrishnan, R., Thurnauer, H., Planeta, B., Skosnik, P., Gao, H., Labaree, D., Neumeister, A., Pittman, B., et al. (2015). Reduced Brain cannabinoid Receptor Availability In schizophrenia. Biol. Psychiatry.
Reyes Prieto, N.M., Romano López, A., Pérez Morales, M., Pech, O., Méndez-Díaz, M., Ruiz Contreras, A.E., and Prospéro-García, O. (2012). Oleamide restores sleep in adult rats that were subjected to maternal separation. Pharmacol. Biochem. Behav. 103, 308–312.
Sales-Carbonell, C., Rueda-Orozco, P.E., Soria-Gómez, E., Buzsáki, G., Marsicano, G., and Robbe, D. (2013). Striatal GABAergic and cortical glutamatergic neurons mediate contrasting effects of cannabinoids on cortical network synchrony. Proc. Natl. Acad. Sci. U. S. A. 110, 719–724.
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.
Santucci, V., Storme, J., Soubrié, P., and Le Fur, G. (1996). Arousal-enhancing properties of the CB1 cannabinoid receptor antagonist SR 141716A in rats as assessed by electroencephalographic spectral and sleep-waking cycle analysis. Life Sci. 58, PL103–PL110.
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.
Storr, M., Emmerdinger, D., Diegelmann, J., Pfennig, S., Ochsenkühn, T., Göke, B., Lohse, P., and Brand, S. (2010). The cannabinoid 1 receptor (CNR1) 1359 G/A polymorphism modulates susceptibility to ulcerative colitis and the phenotype in Crohn’s disease. PloS One 5, e9453.
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.
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.
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.
Zhao, Y., Rubio, M.E., and Tzounopoulos, T. (2009). Distinct functional and anatomical architecture of the endocannabinoid system in the auditory brainstem. J. Neurophysiol. 101, 2434–2446.
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.