Energy homeostasis (balance)  is one of the primary functions of the endocannabinoid system. cannabinoids therefore have excellent therapeutic potential for metabolic disorders ranging from Anorexia/metabolic wasting syndrome to Bulimia and obesity. One of the most salient aspects of cannabis is its ability to induce appetite (the munchies) which is to a large degree due to activation of CB1 receptors by THC.

Many clinical trials aimed to reduce food intake by blocking CB1 with synthetic cannabinoids.

Although these synthetic cannabinoids caused very significant weight loss, these clinical trials were abandoned due to excessive adverse reactions (Depression, vertigo, heart problems etc.).

Nonetheless, the endocannabinoid sytem is intricately involved in appetite and weight regulation. Endocannabinoids are derived from Poly Unsaturated Fatty Acids (PUFAs) with Anandamide and 2AG coming from Ω-6 PUFAs and EPEA and DHEA 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. In addition to the endocannabinoid system, plant cannabinoids THCV and CBD have appetite-suppressing properties and may be useful in the treatment of obesity.

Literature Discussion: 

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).

This pathway offers potential for cannabinoids in the treatment of metabolic disorders such as Anorexia, Bulimia, obesity and Diabetes.

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).
 

Literature:

J. Hepatol. Watkins, B.A., and Kim, J. (2014). The endocannabinoid system: directing eating behavior and macronutrient metabolism. Front. Psychol. 5, 1506.

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.

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

Clinical Trials: 

Many clinical trials aimed to reduce food intake by blocking CB1 with synthetic cannabinoids.

Although these synthetic cannabinoids caused very significant weight loss, these clinical trials were abandoned due to excessive adverse reactions (Depression, vertigo, heart problems etc.)(Bergholm et al., 2013; Kipnes et al., 2010; Motaghedi et al., 2011).  

Literature:

Bergholm, R., Sevastianova, K., Santos, A., Kotronen, A., Urjansson, M., Hakkarainen, A., Lundbom, J., Tiikkainen, M., Rissanen, A., Lundbom, N., et al. (2013). CB(1) blockade-induced weight loss over 48 weeks decreases liver fat in proportion to weight loss in humans. Int. J. Obes. 2005 37, 699–703.

Kipnes, M.S., Hollander, P., Fujioka, K., Gantz, I., Seck, T., Erondu, N., Shentu, Y., Lu, K., Suryawanshi, S., Chou, M., et al. (2010). A one-year study to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with type 2 Diabetes. Diabetes Obes. Metab. 12, 517–531.

Motaghedi, R., Lipman, E.G., Hogg, J.E., Christos, P.J., Vogiatzi, M.G., and Angulo, M.A. (2011). Psychiatric adverse effects of rimonobant in adults with Prader Willi syndrome. Eur. J. Med. Genet. 54, 14–18.

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