The cannabinoid receptor type 1, or CB1 receptor, has been known for some time to be involved in appetite and obesity. Attempts to harness this receptor for this effect have produced the first licensed anti-obesity drug in a decade, rimonabant. It works by producing a blockade effect on the CB1 receptor, blocking interactions with other cannabinoids. This drug has been shown to acutely decrease appetite by reducing the number of CB1 interactions, which can become overstimulated in obese people.
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However, the authors theorized that there are more varied effects of CB1 blockade around the body, including affecting metabolic regulation in the liver, skeletal muscle tissue, fatty (adipose) tissue, and pancreas. The combined effects are believed to be positive for obesity. The long-term effects of CB1 blockade are not known and the complex interactions of cannabinoids in the various tissues of the body are not well modelled or understood.
This study compiles what was then current knowledge of the endocannabinoid system in obesity and the effects of CB1 blockade. It highlights the limited knowledge of these systems and areas for further research. Overall, the picture is positive but there needs to be substantially more work carried out.
In this study, the effects of CB1 blockade appear promising. At the time of publication, rimonabant was available on prescription for the treatment of obesity in the EU. Since that time, it has been removed from sale due to the intolerable psychiatric effects.
By blocking the CB1 receptor, a wide variety of effects can be obtained, one of which is a decrease in appetite. Other effects include decreased insulin sensitivity, increased metabolic rate, and psychoactivity. Rimonabant, a cannabinoid antagonist that blocks CB1 receptors, has positive effects on obesity in those trialled. However, the psychoactivity it causes by interacting with the CB1 receptors in the brain is severe and intolerable, leading to its removal from license.
Alternative hormone (peptide and protein) based therapies that targeted obesity have resulted in failure. The vast and complex series of interactions that hormones mediate makes single-effect therapies next to impossible at this time.
The relative tolerability of cannabinoids and their known metabolic effects present as a viable alternative. They have shown some success in therapies but as yet their long-term safety profiles are unknown.
The problems with using cannabinoids for targeting obesity is that the ones that will have success, the CB1 ligands, are mostly blood-brain barrier permeable. When a drug can get through the blood-brain barrier, it will affect the central nervous system as well as the rest of the body.
Containing cannabinoids to the peripheries has yet to be fully explored, but if drugs like rimonabant can be made to be impermeable to the blood-brain barrier, they can exert their positive effects on metabolism and obesity without affecting the central nervous system and producing unwanted psychoactive effects.
As the authors so succinctly put it, “many questions – few answers”. Clearly, some cannabinoids can be used as anti-obesity drugs but they are largely intolerable because of the central nervous system effects like psychoactivity. Alternatives like cannabinoids that only target the peripheral nervous system are believed to be preferable. A lot more work into the endocannabinoid system is necessary.