In one study in rats, chronic stimulation of the endocannabinoid system (Anandamide) reduced addictive behavior (cocaine seeking), suggesting a role for the endocannabinoid system in suppressing Addiction (Chauvet et al., 2014).
2AG and AEA are involved in food intake regulation (Fride, Bregman, & Kirkham, 2005).
DAGLα knockout mice showed a reduction of 80% of 2-AG, reduction of AEA and increased fear and anxiety responses (Jenniches et al., 2016).
Hippocampal Anandamide, OEA and PEA were increased after social exposure (Kerr et al., 2013) once more stipulating the involvement of the endocannabinoid system in Autism.
CB2 agonists as Anandamide or THC affect the inflammatory process of bone cancer cells by modulating interleukin, tumor necrosis factor α and nuclear factor-κB expression and cofilin-1 protein (Hsu et al., 2007; Lu et al., 2015; Yang et al., 2015).
cannabinoid receptors CB1, CB2 and TRPV1 are expressed in the cervix. Anandamide bind to those receptors and has multiple functions on them (Ayakannu et al., 2015).
One of the effects of Anandamide (and THC) is to overexpress TIMP-1 with anti invasive and apoptotic functions on cancer cells (Ramer and Hinz, 2008).
However, the specific mechanism of the endocannabinoid system is not clear. Some studies suggest that Anandamide anti cancer properties depend on TRPV1 and not on CB1 or CB2 (Contassot et al., 2004; Ramer and Hinz, 2008).
In human patients, Anandamide was found to strongly inhibit bronchospasms and coughing (caused by chemical irritants) through activation of CB1 receptors (Calignano et al., 2000).
In a rat study, Anandamide was found to induce bladder inflammation pain through TRPV1 suggesting this receptor might be a therapeutic target (Dinis et al., 2004). Interestingly, the opposite was found in another study where boosting Anandamide levels by preventing its breakdown exerted potent analgesic and anti-inflammatory effects (Wang et al., 2015). FAAH was responsible of breaking down Anandamide. 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 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).
In an experimental mouse model of Eczema endocannabinoids AEA and PEA were increased and TRPV1 and PPARα were upregulated (Petrosino 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.
Anandamide reduces burst-firing in neurons (Evans et al., 2008).
Functional Gastro-Intestinal Disorders
Patients with Crohn’s Disease have significantly reduced levels of Anandamide, but not 2AG or PEA, supporting a role for the endocannabinoid system in Crohn’s Disease (Di Sabatino et al., 2011). Intracerebrovascular application of Anandamide and 2AG appeared gastro-protective in ethanol-induced ulcers suggesting the involvement of endocannabinoids in the central nervous system (Gyires and Zádori, 2016).
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). AEA modulates the function of the glia increasing its pro-inflammatory response in the brain (Vázquez et al., 2015).
CB1 receptors mediated sleep effects caused by Anandamide in a rat model with in vivo microdialysis (Murillo-Rodriguez et al., 2003). Anandamide may interact with oleamide processes to induce sleep. CBD would act as an inhibitor of Anandamide uptake through TPRV1 receptor, suggesting a role in sleep (Bisogno et al., 2001; Mechoulam et al., 1997). Administration of a synthetic inhibitor of Anandamide uptake showed increased sleep in rats and enhanced c-Fos expression in sleep related brain areas (Murillo-Rodríguez et al., 2008).
Anandamide reduced parasitaemia and increased the survival rate of infected mice through the acceleration of eryptosis of infected erythrocytes (Bobbala et al., 2010).
Pre-administered Anandamide significantly reduced nociceptive behavior in rats, suggesting that migraine may actually be a manifestation of a dysfunctional endocannabinoid system (Greco et al., 2011), which in turn offers interesting possibilities for endo- and plant cannabinoids in the treatment of migraine.
endocannabinoids are derived from Poly Unsaturated Fatty Acids (PUFAs) with Anandamide and 2AG coming from Ω-6 PUFAs and EPA and DHA coming from Ω-3 PUFAs. The typical Western diet is low on PUFAs and has a low Ω-3/Ω-6 ratio. Shifting the balance to a higher Ω-3 content leads to weight loss, presumably through differential activation of the endocannabinoidsystem (Watkins and Kim, 2014)
In line with this the endogenous CB1 agonist Anandamide stimulates marble seeking behavior (Umathe et al., 2012).
In a mouse study, the endocannabinoid system was found to be required for the analgesic action of acetaminophen (paracetamol); FAAH breaks down acetaminophen to AM404 (first identified as synthetic cannabinoid but also displaying endocannabinoid activity), which in turn blocks re-uptake of Anandamide (Mallet et al., 2008). The analgesic effect of paracetamol thus seems to be due to increased ambient levels of Anandamide. Blocking CB1 completely prevents the analgesic action of paracetamol suggesting CB1 is required for analgesia (Bertolini et al., 2006). Similarly, ibuprofen was found to block the breakdown/hydrolysis of Anandamide (Fowler et al., 1999), which may contribute to the analgesic effect of ibuprofen (and similar substances).
In one study, Anandamide was found to reduce dopamine release via TRPV1 receptors (de Lago et al., 2004) suggesting their involvement in movement behaviour.
Similarly, the endocannabinoid Anandamide strongly suppresses keratinocyte proliferation and induces cell death via sequential activation of CB1 and TRPV1 (Tóth et al., 2011), suggesting the endocannabinoid system normally keeps keratinocyte proliferation in check.
psychosis and schizophrenia
Regarding the molecular mechanisms of the comorbidity between cannabis and schizophrenia, the endocannabinoid system has been related to schizophrenia. endocannabinoids like Anandamide and 2-AG play an important role on psychosis (Manseau and Goff, 2015). Some studies point to an Anandamide imbalance associated to psychosis (Leweke, 2012). In unmedicated patients with acute psychosis one of the body’s main endocannabinoids, Anandamide, is elevated 8-fold. This elevation is absent in patients on anti-psychotics and is inversely correlated with psychotic symptoms, suggesting Anandamide actually functions to suppress psychotic behavior (Giuffrida et al., 2004).
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.
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.
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.
Bisogno, T., Hanuš, L., De Petrocellis, L., Tchilibon, S., Ponde, D.E., Brandi, I., Moriello, A.S., Davis, J.B., Mechoulam, R., and Di Marzo, V. (2001). Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of Anandamide. Br. J. Pharmacol. 134, 845–852.
Bobbala, D., Alesutan, I., Föller, M., Huber, S.M., and Lang, F. (2010). Effect of Anandamide in Plasmodium Berghei-infected mice. Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol. 26, 355–362.
Calignano, A., Kátona, I., Désarnaud, F., Giuffrida, A., La Rana, G., Mackie, K., Freund, T.F., and Piomelli, D. (2000). Bidirectional control of airway responsiveness by endogenous cannabinoids. Nature 408, 96–101.
Chauvet, C., Nicolas, C., Thiriet, N., Lardeux, M.V., Duranti, A., and Solinas, M. (2014). Chronic Stimulation of the Tone of Endogenous Anandamide Reduces Cue- and Stress-Induced Relapse in Rats. Int. J. Neuropsychopharmacol. Off. Sci. J. Coll. Int. Neuropsychopharmacol. CINP.
Contassot, E., Tenan, M., Schnüriger, V., Pelte, M.-F., and Dietrich, P.-Y. (2004). Arachidonyl ethanolamide induces apoptosis of uterine cervix cancer cells via aberrantly expressed vanilloid receptor-1. Gynecol. Oncol. 93, 182–188.
de Lago, E., de Miguel, R., Lastres-Becker, I., Ramos, J.A., and Fernández-Ruiz, J. (2004). Involvement of vanilloid-like receptors in the effects of Anandamide on motor behavior and nigrostriatal dopaminergic activity: in vivo and in vitro evidence. Brain Res. 1007, 152–159.
Di Sabatino, A., Battista, N., Biancheri, P., Rapino, C., Rovedatti, L., Astarita, G., Vanoli, A., Dainese, E., Guerci, M., Piomelli, D., et al. (2011). The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease. Mucosal Immunol. 4, 574–583.
Dinis, P., Charrua, A., Avelino, A., Yaqoob, M., Bevan, S., Nagy, I., and Cruz, F. (2004). Anandamide-evoked activation of vanilloid receptor 1 contributes to the development of bladder hyperreflexia and nociceptive transmission to spinal dorsal horn neurons in Cystitis. J. Neurosci. Off. J. Soc. Neurosci. 24, 11253–11263.
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.
Evans, R.M., Wease, K.N., MacDonald, C.J., Khairy, H.A., Ross, R.A., and Scott, R.H. (2008). Modulation of sensory neuron potassium conductances by Anandamide indicates roles for metabolites. Br. J. Pharmacol. 154, 480–492.
Fezza, F., Bari, M., Florio, R., Talamonti, E., Feole, M., & Maccarrone, M. (2014). endocannabinoids, related compounds and their metabolic routes. Molecules (Basel, Switzerland), 19(11), 17078-17106. https://doi.org/10.3390/molecules191117078
Fowler, C.J., Janson, U., Johnson, R.M., Wahlström, G., Stenström, A., Norström, K., and Tiger, G. (1999). Inhibition of Anandamidehydrolysis by the enantiomers of ibuprofen, ketorolac, and flurbiprofen. Arch. Biochem. Biophys. 362, 191–196.
Fride, E., Bregman, T., & Kirkham, T. C. (2005). endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Experimental Biology and Medicine (Maywood, N.J.), 230(4), 225-234.
Greco, R., Mangione, A.S., Sandrini, G., Maccarrone, M., Nappi, G., and Tassorelli, C. (2011). Effects of Anandamide in migraine: data from an animal model. J. Headache pain 12, 177–183.
Giuffrida, A., Leweke, F.M., Gerth, C.W., Schreiber, D., Koethe, D., Faulhaber, J., Klosterkötter, J., and Piomelli, D. (2004). Cerebrospinal Anandamide Levels are Elevated in Acute schizophrenia and are Inversely Correlated with Psychotic Symptoms. Neuropsychopharmacology 29, 2108–2114.
Gyires, K., and Zádori, Z.S. (2016). Role of cannabinoids in Gastrointestinal Mucosal Defense and Inflammation. Curr. Neuropharmacol. 14, 935–951.
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.
Hsu, S.-S., Huang, C.-J., Cheng, H.-H., Chou, C.-T., Lee, H.-Y., Wang, J.-L., Chen, I.-S., Liu, S.-I., Lu, Y.-C., Chang, H.-T., et al. (2007).Anandamide-induced Ca2+ elevation leading to p38 MAPK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells. Toxicology 231, 21–29.
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 pain. pain 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.
Jenniches, I., Ternes, S., Albayram, O., Otte, D. M., Bach, K., Bindila, L., … Zimmer, A. (2016). anxiety, Stress, and Fear Response in Mice With Reduced endocannabinoid Levels. Biological Psychiatry, 79(10), 858-868. https://doi.org/10.1016/j.biopsych.2015.03.033
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.
Kerr, D.M., Downey, L., Conboy, M., Finn, D.P., and Roche, M. (2013). Alterations in the endocannabinoid system in the rat valproic acid model of Autism. Behav. Brain Res. 249, 124–132.
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.
Leweke, F.M. (2012). Anandamide dysfunction in prodromal and established psychosis. Curr. Pharm. Des. 18, 5188–5193.
Lu, C., Liu, Y., Sun, B., Sun, Y., Hou, B., Zhang, Y., Ma, Z., and Gu, X. (2015).Intrathecal Injection of JWH-015 Attenuates Bone cancerpain Via Time-Dependent Modification of Pro-inflammatory Cytokines Expression and Astrocytes Activity in Spinal Cord. Inflammation.
Mallet, C., Daulhac, L., Bonnefont, J., Ledent, C., Etienne, M., Chapuy, E., Libert, F., and Eschalier, A. (2008). endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. pain 139, 190–200.
Manseau, M.W., and Goff, D.C. (2015). cannabinoids and schizophrenia: Risks and Therapeutic Potential. Neurotherapeutics 1–9
Mechoulam, R., Fride, E., Hanu, L., Sheskin, T., Bisogno, T., Di Marzo, V., Bayewitch, M., and Vogel, Z. (1997). Anandamide may mediate sleep induction. Nature 389, 25–26.
Merriam, F.V., Wang, Z., Guerios, S.D., and Bjorling, D.E. (2008). cannabinoid receptor 2 is increased in acutely and chronically inflamed bladder of rats. Neurosci. Lett. 445, 130–134
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.
Murillo-Rodríguez, E., Millán-Aldaco, D., Di Marzo, V., and Drucker-Colín, R. (2008). The Anandamide membrane transporter inhibitor, VDM-11, modulates sleep and c-Fos expression in the rat brain. Neuroscience 157, 1–11.
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.
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.
Ramer, R., and Hinz, B. (2008). Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1. J. Natl. cancer Inst. 100, 59–69.
Tambaro, S., Casu, M.A., Mastinu, A., and Lazzari, P. (2014). Evaluation of selective cannabinoid CB(1) and CB(2) receptor agonists in a mouse model of lipopolysaccharide-induced interstitial Cystitis. Eur. J. Pharmacol. 729, 67–74.
Tóth, B.I., Dobrosi, N., Dajnoki, A., Czifra, G., Oláh, A., Szöllosi, A.G., Juhász, I., Sugawara, K., Paus, R., and Bíró, T. (2011). endocannabinoids modulate human epidermal keratinocyte proliferation and survival via the sequential engagement of cannabinoid receptor-1 and transient receptor potential vanilloid-1. J. Invest. Dermatol. 131, 1095–1104.
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.
Umathe, S.N., Manna, S.S.S., and Jain, N.S. (2012). endocannabinoid analogues exacerbate marble-burying behavior in mice via TRPV1 receptor. Neuropharmacology 62, 2024–2033.
Vázquez, C., Tolón, R. M., Pazos, M. R., Moreno, M., Koester, E. C., Cravatt, B. F., … Romero, J. (2015). Endocannabinoids regulate the activity of astrocytic hemichannels and the microglial response against an injury: In vivo studies. Neurobiology of Disease, 79, 41-50. https://doi.org/10.1016/j.nbd.2015.04.005
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.
Wang, Z.-Y., Wang, P., Hillard, C.J., and Bjorling, D.E. (2015). Attenuation of Cystitis and pain sensation in mice lacking Fatty Acid amide hydrolase. J. Mol. Neurosci. MN 55, 968–976.
Watkins, B.A., and Kim, J. (2014). The endocannabinoid system: directing eating behavior and macronutrient metabolism. Front. Psychol. 5, 1506.
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.