The ECS as an Appetite Regulating Mechanism | cannabisMD

The Endocannabinoid System as an Appetite Regulating Mechanism

The Endocannabinoid System helps with Appetite Regulation

The growing significance of the endocannabinoid system in regulating appetite, body weight, and metabolism is of increasing interest to scientists. Although some initial success using cannabinoid receptor reverse agonists to help people lose weight was observed in a trial, the adverse effects on the central nervous system were deemed too severe to take further.

This paper outlines an experiment that used selective blockade of peripheral (not in the central nervous system) cannabinoid receptors for weight loss and metabolic control. They used AM6545, a cannabinoid signaling inhibitor that only works in the peripheral system, not the central nervous system. They report success when compared to a control.

Here is the full scientific article if you wish to download it.

Endocannabinoid Signaling Is Altered in Obesity

The effects of endocannabinoids in modulating functions like pain, drug dependence, and reward signaling are well known, but it is the “potent[ial] ability of endocannabinoids to regulate feeding behavior that has fueled attempts to harness this system for the treatment of obesity and its related complications”.

The CB1 receptor is activated by cannabinoids in the central nervous system, increasing appetite. This is mediated by at least two pathways and produces a robust response. This system is complex, involving other, non-cannabinoid signaling systems, which interact and “crosstalk”, regulating each other. It is hypothesized that these signals are dysregulated in obesity, leading to differences in appetite and metabolism that increase the likelihood of gaining weight.

CB1 antagonists reduce food intake, however, the drug previously trialed, rimonabant, produced unwanted effects in the central nervous system. This is because the endocannabinoid system is involved in regulating and mediating many more biological processes than just appetite, and blocking the interaction of CB1 receptors in the brain interferes with them.

Targeting the Endocannabinoid System and Obesity

The use of an endocannabinoid receptor antagonist that does not have the lipid solubility to make it easily past the blood-brain barrier and into the central nervous system presents an opportunity to target only the peripheral endocannabinoid system. The adverse effects of rimonabant were due to its interaction with the central nervous system, having made it through the blood-brain barrier.

AM6545 is not as lipid-soluble, so it does not have such effects. It does inhibit cannabinoid signaling effectively, and when trialed in rats, it was found to reduce food intake. The converse is true, inhibition of the catalysis of cannabinoids increases appetite in rats. This clear relationship means that it is probably possible to manipulate it in humans to reduce appetite and therefore help reduce obesity.

In this trial, subjects lost between 4 and 6 kilograms more than the controls over 6 to 12 months. Improvements in insulin resistance, hyperlipidemia, and diabetic metabolic control were also observed.

Caution Is Advised for Further Research

The use of a cannabinoid blockade that targeted the central nervous system was, in hindsight, a mistake. The side effects were severe enough that the experimenters had to call off the trial. This highlights the important role of the endocannabinoid system in many important biological functions, and focuses future research on less drastic, peripherally targeted endocannabinoid targets.

More knowledge of the complex web of interactions in the endocannabinoid system and the rest of the metabolic systems will help future researchers establish more precise targets. The endocannabinoid system is involved in mood, with other research showing clear relationships between ECS dysregulation and depression and anxiety. For these reasons, human trials of endocannabinoid blockades should proceed with caution.

The role of the endocannabinoid system in appetite is observed and partly understood, but previous blockade therapies had serious side effects. By targeting only the peripheral ECS, the researchers were able to induce weight loss over a 12 month period in subjects without severe side effects. This is only a small, pre-clinical trial, so much more research needs to be carried out before endocannabinoid blockade antagonists can be used in therapeutic conditions, if they are ever deemed safe enough by regulatory authorities.

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