High e-tone as a potential detriment to health and well-being has been associated with specific patient populations (see below), with gender (V. Satta et al., 2018;1 A. Thornton et al., 2021)2, ethnicity (V. Kantae et al., 2017),3 eating behavior, and diet.
Regarding food intake, complex crosstalk between appetite-regulating hormones (e.g., leptin, ghrelin), neurotransmitters (e.g., dopamine), and the endocannabinoid system (ECS) have been discovered to be a significant regulator of the process of eating. This is true for food-related physiological activities and the pleasurable (hedonic) aspects of eating (V. Di Marzo et al., 2001;4 B. Lau et al., 2017).5
While the use of cannabis and overactivation of the ECS has been associated with the “munchies,” overeating, and obesity, recent scientific findings are beginning to present a more complex context. Depending on the specific cells and tissues involved, neuronal, hormonal, and endocannabinoid cross-signaling may enhance or diminish appetite-related behavior.
However, based on the currently available scientific literature, overactive endocannabinoid signaling has been associated with increased food intake, fat accumulation, and unhealthy changes in sugar metabolism. As such, in patients with obesity (Giulio G. Muccioli et al., 2010),6 metabolic syndrome, and type 2 diabetes, a reduction in ECS activity may offer novel treatment approaches (V. di Marzo et al., 2009).7
Lowering e-tone may benefit patients with:
Obesity (Giulio G. Muccioli et al., 2010;8 A. Abioye et al., 2020)9
Metabolic syndrome (K. Berge et. al., 2013;10 L. Demizieux et al., 2016)11
Diabetes (type 2) (L. Geurts et al., 2011;12 A. Abioye et al., 2020)13
Practical Steps to Lower E-tone
A low ratio of omega-6 to omega-3 fatty acids in the early diet of test animals induces a marked decrease in liver endocannabinoid levels that was associated with a reduction in e-tone and improved signs and symptoms of metabolic syndrome (L. Demizieux et al., 2016).14
THCV (a CB1 antagonist) may lower CB1-associated tone (K. Jadoon et al., 2016).15
THCV ameliorates insulin sensitivity in animal models of obesity (E. Wargent et al., 2013).16
In a clinical trial, THCV significantly decreased fasting plasma glucose and improved pancreatic β-cell function (K. Jadoon et al., 2016).17
Dietary consumption of turmeric reduces CB1 expression and may lower related endocannabinoid signaling and e-tone (Z. Zhang et al., 2012).18
The use of prebiotic or CB1 antagonism decreases intestinal ECS tone (G. Muccioli et al., 2010).19
It has been established that ECS plays a significant role in glucose control and metabolism (P. Cani et al., 2014).20 Of importance is that ECS-based signaling can be tuned up or down by specific gut microbes. For example, the Mediterranean diet modulates e-tone and microbiome (increasing intestinal A. muciniphila), which may benefit patients with insulin sensitivity and chronic low-grade inflammation (S. Tagliamonte et al., 2021).21
Crosstalk between vitamin D and the ECS may contribute to downregulating intestinal CB1 receptor expressions (H. Hussein et al. 2022).22
DHA and EPA reduce peripheral endocannabinoid overactivity in obese patients and, as such, may mitigate some aspects of metabolic syndrome (K. Berge et al., 2013).23
Endnotes:
1. Satta V, Scherma M, Piscitelli F, Usai P, Castelli MP, Bisogno T, Fratta W, Fadda P. Limited Access to a High Fat Diet Alters Endocannabinoid Tone in Female Rats. Front Neurosci. 2018 Feb 2;12:40.
2. Thornton, Aoife M., Rachel M. Humphrey, Daniel M. Kerr, David P. Finn, and Michelle Roche. 2021. “Increasing Endocannabinoid Tone Alters Anxiety-Like and Stress Coping Behaviour in Female Rats Prenatally Exposed to Valproic Acid” Molecules 26, no. 12: 3720.
3. Kantae, V., Nahon, K.J., Straat, M.E. et al. Endocannabinoid tone is higher in healthy lean South Asian than white Caucasian men. Sci Rep 7, 7558 (2017).
4. Di Marzo V, Goparaju SK, Wang L, Liu J, Bátkai S, Járai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature. 2001 Apr 12;410(6830):822-5.
5. Lau BK, Cota D, Cristino L, Borgland SL. Endocannabinoid modulation of homeostatic and non-homeostatic feeding circuits. Neuropharmacology. 2017 Sep 15;124:38-51.
6. Muccioli GG, Naslain D, Bäckhed F, Reigstad CS, Lambert DM, Delzenne NM, Cani PD. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol. 2010 Jul;6:392.
7. Di Marzo V, Després JP. CB1 antagonists for obesity–what lessons have we learned from rimonabant? Nat Rev Endocrinol. 2009 Nov;5(11):633-8.
8. Muccioli GG, Naslain D, Bäckhed F, Reigstad CS, Lambert DM, Delzenne NM, Cani PD. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol. 2010 Jul;6:392.
9. Abioye, A., Ayodele, O., Marinkovic, A. et al. Δ9-Tetrahydrocannabivarin (THCV): a commentary on potential therapeutic benefit for the management of obesity and diabetes. J Cannabis Res 2, 6 (2020).
10. Berge K, Piscitelli F, Hoem N, Silvestri C, Meyer I, Banni S, Di Marzo V. Chronic treatment with krill powder reduces plasma triglyceride and anandamide levels in mildly obese men. Lipids Health Dis. 2013 May 27;12:78.
11. Demizieux L, Piscitelli F, Troy-Fioramonti S, Iannotti FA, Borrino S, Gresti J, Muller T, Bellenger J, Silvestri C, Di Marzo V, Degrace P. Early Low-Fat Diet Enriched With Linolenic Acid Reduces Liver Endocannabinoid Tone and Improves Late Glycemic Control After a High-Fat Diet Challenge in Mice. Diabetes. 2016 Jul;65(7):1824-37.
12. Geurts L, Lazarevic V, Derrien M, Everard A, Van Roye M, Knauf C, Valet P, Girard M, Muccioli GG, François P, de Vos WM, Schrenzel J, Delzenne NM, Cani PD. Altered gut microbiota and endocannabinoid system tone in obese and diabetic leptin-resistant mice: impact on apelin regulation in adipose tissue. Front Microbiol. 2011 Jul 13;2:149.
13. Abioye, A., Ayodele, O., Marinkovic, A. et al. Δ9-Tetrahydrocannabivarin (THCV): a commentary on potential therapeutic benefit for the management of obesity and diabetes. J Cannabis Res 2, 6 (2020).
14. Demizieux L, Piscitelli F, Troy-Fioramonti S, Iannotti FA, Borrino S, Gresti J, Muller T, Bellenger J, Silvestri C, Di Marzo V, Degrace P. Early Low-Fat Diet Enriched With Linolenic Acid Reduces Liver Endocannabinoid Tone and Improves Late Glycemic Control After a High-Fat Diet Challenge in Mice. Diabetes. 2016 Jul;65(7):1824-37.
15. Jadoon KA, Ratcliffe SH, Barrett DA, Thomas EL, Stott C, Bell JD, O’Sullivan SE, Tan GD. Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study. Diabetes Care. 2016 Oct;39(10):1777-86.
16. Wargent ET, Zaibi MS, Silvestri C, Hislop DC, Stocker CJ, Stott CG, Guy GW, Duncan M, Di Marzo V, Cawthorne MA. The cannabinoid Δ(9)-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of obesity. Nutr Diabetes. 2013 May 27;3(5):e68.
17. Jadoon KA, Ratcliffe SH, Barrett DA, Thomas EL, Stott C, Bell JD, O’Sullivan SE, Tan GD. Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study. Diabetes Care. 2016 Oct;39(10):1777-86.
18. Zhang Z, Guo Y, Zhang S, Zhang Y, Wang Y, Ni W, Kong D, Chen W, Zheng S. Curcumin modulates cannabinoid receptors in liver fibrosis in vivo and inhibits extracellular matrix expression in hepatic stellate cells by suppressing cannabinoid receptor type-1 in vitro. Eur J Pharmacol. 2013 Dec 5;721(1-3):133-40.
19. Muccioli GG, Naslain D, Bäckhed F, Reigstad CS, Lambert DM, Delzenne NM, Cani PD. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol. 2010 Jul;6:392.
20. Cani PD, Geurts L, Matamoros S, Plovier H, Duparc T. Glucose metabolism: focus on gut microbiota, the endocannabinoid system and beyond. Diabetes Metab. 2014 Sep;40(4):246-57.
21. Tagliamonte S, Laiola M, Ferracane R, Vitale M, Gallo MA, Meslier V, Pons N, Ercolini D, Vitaglione P. Mediterranean diet consumption affects the endocannabinoid system in overweight and obese subjects: possible links with gut microbiome, insulin resistance and inflammation. Eur J Nutr. 2021 Oct;60(7):3703-3716.
22. Hussein HM, Elyamany MF, Rashed LA, Sallam NA. Vitamin D mitigates diabetes-associated metabolic and cognitive dysfunction by modulating gut microbiota and colonic cannabinoid receptor 1. Eur J Pharm Sci. 2022 Mar 1;170:106105.
23. Berge K, Piscitelli F, Hoem N, Silvestri C, Meyer I, Banni S, Di Marzo V. Chronic treatment with krill powder reduces plasma triglyceride and anandamide levels in mildly obese men. Lipids Health Dis. 2013 May 27;12:78.
