Synthetic and plant‐derived cannabinoid receptor antagonists show hypophagic properties in fasted and non‐fasted mice

Abstract

Background and purpose:Obesity is a severe health problem in the modernized world and understanding the central nervous mechanisms underlying food-seeking behaviour and reward are at the forefront of medical research. Cannabinoid receptors have proven an efficient target to suppress hunger and weight gain by their pharmacological inactivation. Experimental approach: A standard fasted protocol and a novel long-term home-cage observation system with free-feeding animals were used to assess the feeding behaviour of mice treated with the CB1 antagonist AM251. Similarly, the effects of the phytocannabinoid D 9 -tetrahydrocannabivarin (D 9 -THCV), which behaves like a CB1 antagonist, were also determined in free-feeding animals. Key results: AM251 suppressed food intake and weight gain in fasted and non-fasted animals. The suppression of food intake by AM251 (10 mg·kg -1 ) endured for a period of 6-8 h when administered acutely, and was continuous when injected for four consecutive days. Pure D 9 -THCV also induced hypophagia and weight reduction at doses as low as 3 mg·kg -1 . No rebound was observed on the following day with all drug groups returning to normal activity and feeding regimes. However, a D 9 -THCV-rich cannabis-extract failed to suppress food intake and weight gain, possibly due to residual D 9 -tetrahydrocannabinol (D 9 -THC) in the extract. This D 9 -THC effect was overcome by the co-administration of cannabidiol. Conclusions and implications:The data strongly suggest (i) the long-term home-cage observation system is a sensitive and obesity-relevant tool, and (ii) the phytocannabinoid D 9 -THCV is a novel compound with hypophagic properties and a potential treatment for obesity.

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

“…Acute intraperitoneal administration of THCV in rodents at 3, 10, and 30 mg/kg body weight caused hypophagia and weight loss, with food intake and body weight returning to normal on day 2 (26). The effect was similar to that of a CB 1 antagonist, AM251, also used in the same study.…”

“…Rimonabant, a CB 1 receptor antagonist, was the first in its class to be used as antiobesity drug, but led to significant psychiatric AEs (5). Preclinical studies with the plant-derived compound THCV have shown that it produces hypophagia and weight reduction in lean mice (26) and improves glucose tolerance and insulin sensitivity in dietinduced obese mice (27). Similar results have been seen with CBD in ob/ob mice (C.S., unpublished data), and CBD has been reported to lower the incidence of diabetes in nonobese diabetic mice (33) and arrest the onset of autoimmune diabetes in nonobese diabetic mice (34).…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…-THCV suppresses saccharin palatability and the appetite for sweet taste (736) and, at doses as low as 3 mg/kg, shares the ability of synthetic CB1 antagonists to reduce food intake and body weight gain in mice (726), with potential use in the treatment of obesity (673). However, chronic administration of ⌬ 9 -THCV in animal models of obesity does not modify food intake but produces an early and transient increase in energy expenditure, reduces glucose intolerance in ob/ob mice, and improves insulin resistance in mice with high-fat diet-induced obesity, without consistently affecting plasma lipids.…”

Kannabinoide berriak: segurtasun eta eraginkortasun terapeutikoaren bila

“…Hau da, funtzionalki Δ 9 -THCVak CB 1 hartzailearen antagonista neutro gisa jokatzen du. Horrela, CB 1 hartzailearen antagonista den AM251 farmakoak bezala, arratoietan jangura inhibi dezake [36] edota rimonabant EKAIA, 31 (2017) Erik Aostri, Joseba Pineda, Aitziber Mendiguren farmakoaren antzera, 6-hidroxidopaminak induzitutako inhibizio motorra murriztu [37]. Dena dela, Δ 9 -THCVak ez ditu CB 1 hartzaileen antagonista klasikoek eragiten duten goitika eta antsietatea sortarazten [38].…”