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 endocannabinoid system (Watkins and Kim, 2014).
endocannabinoids such as OEA bind to GPR119 to increase cAMP (signals high energy/glucose content to a cell), stimulate insulin secretion and cause fat deposition (Overton et al., 2006). OEA reduced food intake and weight gain in rodents via PPARα and TRPV1 (Overton et al., 2006). This pathway offers potential for cannabinoids in the treatment of metabolic disorders such as Anorexia, Bulimia, Obesity and Diabetes.
DAGL inhibitors can avoid fasting-induced refeeding of mice, showing a similar pharmacokinetic profile to CB1 inverse agonists (Deng et al., 2017). There are other studies linking DAGL and 2-AG activity with eating disorders (Bisogno et al., 2013; Engeli et al., 2014). Also, DAGL inhibition reverts the effects on food intake and rapid eye movement sleep in rats caused by the stimulation protease activated receptor 1 (PPAR-1) in the lateral hypothalamus. This suggest synergistic actions between PAR1 and 2-AG (Pérez-Morales, Fajardo-Valdez, Méndez-Díaz, Ruiz-Contreras, & Prospéro-García, 2014)
THCV and CBD reduce the amount of circulating lipids and enable weight-loss (Silvestri et al., 2015).
THCV induced hypophagia and reduction in body weight at low doses (from 3mg/kg), suggesting a possible treatment for Obesity and metabolic syndrome. THC combination with THCV would delete these effects, but they are rescued by combining them with CBD (Riedel et al., 2009; Silvestri et al., 2015; Wargent et al., 2013).
In contrast to Rimonabant, THCV does not cause nausea but maintains the anti-Obesity potential (Rock, Sticht, Duncan, Stott, & Parker, 2013). Oral dose administration of 10mg of THCV reduces resting state functional connectivity in brain areas that are usually overactivated in obese individuals. Also, it activates areas which have reduced activity linked to Obesity (Rzepa, Tudge, & McCabe, 2015). The same dose was used in another study showing increased brain activity in Obesity related areas when presenting different types of food stimuli, suggesting also a possible therapeutic potential to treat Obesity (Tudge, Williams, Cowen, & McCabe, 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).
Bisogno, T., Mahadevan, A., Coccurello, R., Chang, J. W., Allarà, M., Chen, Y., … Di Marzo, V. (2013). A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects. British Journal of Pharmacology, 169(4), 784-793. https://doi.org/10.1111/bph.12013
Deng, H., Kooijman, S., van den Nieuwendijk, A. M. C. H., Ogasawara, D., van der Wel, T., van Dalen, F., … van der Stelt, M. (2017). Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding. Journal of Medicinal Chemistry, 60(1), 428-440. https://doi.org/10.1021/acs.jmedchem.6b01482
Engeli, S., Lehmann, A.-C., Kaminski, J., Haas, V., Janke, J., Zoerner, A. A., … Jordan, J. (2014). Influence of dietary fat intake on the endocannabinoid system in lean and obese subjects. obesity, 22(5), E70-E76. https://doi.org/10.1002/oby.20728
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
Overton, H.A., Babbs, A.J., Doel, S.M., Fyfe, M.C.T., Gardner, L.S., Griffin, G., Jackson, H.C., Procter, M.J., Rasamison, C.M., Tang-Christensen, M., et al. (2006). Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab. 3, 167–175.
Pérez-Morales, M., Fajardo-Valdez, A., Méndez-Díaz, M., Ruiz-Contreras, A. E., & Prospéro-García, O. (2014). 2-Arachidonoylglycerol into the lateral hypothalamus improves reduced sleep in adult rats subjected to maternal separation. Neuroreport, 25(18), 1437-1441. https://doi.org/10.1097/WNR.0000000000000287
Riedel, G., Fadda, P., McKillop-Smith, S., Pertwee, R. G., Platt, B., & Robinson, L. (2009). Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice. British Journal of Pharmacology, 156(7), 1154-1166. https://doi.org/10.1111/j.1476-5381.2008.00107.x
Rock, E. M., Sticht, M. A., Duncan, M., Stott, C., & Parker, L. A. (2013). Evaluation of the potential of the phytocannabinoids, cannabidivarin (CBDV) and Δ9-tetrahydrocannabivarin (THCV), to produce CB1 receptor inverse agonism symptoms of nausea in rats. British Journal of Pharmacology, 170(3), 671-678. https://doi.org/10.1111/bph.12322
Rzepa, E., Tudge, L., & McCabe, C. (2015). The CB1 Neutral Antagonist Tetrahydrocannabivarin Reduces Default Mode Network and Increases Executive Control Network Resting State Functional Connectivity in Healthy Volunteers. The International Journal of Neuropsychopharmacology, 19(2). https://doi.org/10.1093/ijnp/pyv092
Silvestri, C., Paris, D., Martella, A., Melck, D., Guadagnino, I., Cawthorne, M., … Di Marzo, V. (2015). Two non-psychoactive cannabinoids reduce intracellular lipid levels and inhibit hepatosteatosis. Journal of Hepatology, 62(6), 1382-1390. https://doi.org/10.1016/j.jhep.2015.01.001
Tudge, L., Williams, C., Cowen, P. J., & McCabe, C. (2015). Neural effects of cannabinoid CB1 neutral antagonist tetrahydrocannabivarin on food reward and aversion in healthy volunteers. The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 18(6). https://doi.org/10.1093/ijnp/pyu094
Wargent, E. T., Zaibi, M. S., Silvestri, C., Hislop, D. C., Stocker, C. J., Stott, C. G., … Cawthorne, M. A. (2013). The cannabinoid Δ9-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of Obesity. Nutrition & Diabetes, 3(5), e68. https://doi.org/10.1038/nutd.2013.9
Watkins, B.A., and Kim, J. (2014). The endocannabinoid system: directing eating behavior and macronutrient metabolism. Front. Psychol. 5, 1506.