The Metabolic Efficacy of a Cannabidiolic Acid (CBDA) Derivative in Treating Diet- and Genetic-Induced Obesity

Abstract

Obesity is a global medical problem; its common form is known as diet-induced obesity (DIO); however, there are several rare genetic disorders, such as Prader–Willi syndrome (PWS), that are also associated with obesity (genetic-induced obesity, GIO). The currently available therapeutics for treating DIO and GIO are very limited, and they result in only a partial improvement. Cannabidiolic acid (CBDA), a constituent of Cannabis sativa, gradually decarboxylates to cannabidiol (CBD). Whereas the anti-obesity properties of CBD have been reasonably identified, our knowledge of the pharmacology of CBDA is more limited due to its instability. To stabilize CBDA, a new derivative, CBDA-O-methyl ester (HU-580, EPM301), was synthesized. The therapeutic potential of EPM301 in appetite reduction, weight loss, and metabolic improvements in DIO and GIO was tested in vivo. EPM301 (40 mg/kg/d, i.p.) successfully resulted in weight loss, increased ambulation, as well as improved glycemic and lipid profiles in DIO mice. Additionally, EPM301 ameliorated DIO-induced hepatic dysfunction and steatosis. Importantly, EPM301 (20 and 40 mg/kg/d, i.p.) effectively reduced body weight and hyperphagia in a high-fat diet-fed Magel2null mouse model for PWS. In addition, when given to standard-diet-fed Magel2null mice as a preventive treatment, EPM301 completely inhibited weight gain and adiposity. Lastly, EPM301 increased the oxidation of different nutrients in each strain. All together, EPM301 ameliorated obesity and its metabolic abnormalities in both DIO and GIO. These results support the idea to further promote this synthetic CBDA derivative toward clinical evaluation in humans.

Cannabinoid Receptor 2 Blockade Prevents Anti-Depressive-like Effect of Cannabidiol Acid Methyl Ester in Female WKY Rats

“…The dose of 5 mg/kg CBDA-ME, used by us, is completely safe. In other studies, much higher doses have been used chronically, without any sign of toxicity (see for example [ 87 ], where the doses of 20 mg/kg/day and 40 mg/kg/day have been used for 4 weeks without any toxic effect).…”

Major approaches to cannabidiol in the treatment of binge eating and obesity: a systematic review

“…[11-13]. Outside the brain, the ECS system is one of the crucial modulators of the autonomic nervous system, the immune system, the endocrine system, the gastrointestinal tract, the reproductive system, and microcirculation [12]. Endocannabinoids are one of the most important systems controlling excitatory and inhibitory neurotransmission as well as neuroplasticity.…”

“…In the context of anxiety and binge eating and the consequent increase in the incidence of obese people, the activation of CB1 receptors improves eating, modulating the activity of hypothalamic neurons and, subsequently, the release of orexigenic and anorexigenic neuropeptides [11,16]. Furthermore, CB1 receptor signaling affects reward and reinforcement circuits in the mesolimbic system, leading to a preference for highly palatable foods [12,17].…”

Antiviral Activity of Cannabidiolic Acid and Its Methyl Ester against SARS-CoV-2

“…Indeed, the limited stability of CBDA negatively affects its bioactivity profile, thus enhancing the chance of compound attrition in the early phase of the drug discovery process. 22 Interestingly, CBDA methyl ester showed a good neutralizing effect on all the tested SARS-CoV-2 variants, and its stability after the in vitro administration was confirmed using ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS) analysis, performed on cell lysates after the treatments. Finally, the capacity of both CBDA and its methyl ester to interact with the virus spike protein was assessed in silico.…”

“…To overcome the issue of the very limited stability of CBDA, which, as with other cannabinoic acids, can easily undergo a spontaneous decarboxylation leading to its neutral counterpart CBD, the semisynthesis of its methyl ester (also known as HU-580) was carried out and the activity of the derivative was assessed for the first time. Indeed, the limited stability of CBDA negatively affects its bioactivity profile, thus enhancing the chance of compound attrition in the early phase of the drug discovery process . Interestingly, CBDA methyl ester showed a good neutralizing effect on all the tested SARS-CoV-2 variants, and its stability after the in vitro administration was confirmed using ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS) analysis, performed on cell lysates after the treatments.…”