Modulating the Endocannabinoid System Reduces Huntington’s Symptoms

Huntington’s is a progressive genetic disease. Everyone diagnosed with Huntington’s will eventually succumb to the illness. But what if researchers could slow the onset of this fatal ailment? A new study published in the journal Neuropharmacology shows that modulating the endocannabinoid system can improve symptoms and slow the disease in cell cultures and mice.

Huntington’s Disease

Huntington’s disease (HD) is a deadly genetic disease that progressively breaks down the nerve cells in the brain. HD is an autosomal dominant disease. This means that parents with HD have a 50/50 chance of passing it down to each of their children.


Symptoms of HD start to appear between the ages of 30 and 50 and worsen over time. Those who have witnessed its effects describe HD as ALS, Parkinson’s and Alzheimer’s combined. Symptoms include:

  • Uncontrolled movement in the arms, legs, body, and face
  • Slurred Speech
  • Declining memory and ability to think and reason
  • Changes in mood that appear as anxiety, depression, and anger
  • Difficulty swallowing and significant weight loss

Patients suffering from the disease typically pass away from complications, such as pneumonia or heart failure.

The Cause

A single mutated gene causes HD. The mutated gene creates a faulty copy of the huntingtin protein. Medical researchers still don’t know the exact function of the huntingtin protein. However, something about the mutated version of the protein is toxic to brain cells.

The Role of the Endocannabinoid System in HD

The endocannabinoid system is a biological system made up of naturally occurring cannabinoids and cannabinoid receptors. Cannabinoid receptors are present throughout our bodies, including the brain and immune system.

Naturally occurring cannabinoids bind to and activate the cannabinoid receptors. This interaction controls a wide variety of biological functions, including appetite, mood, memory, and even your immune system.

One of the signs of HD progression is changes in gene expression in different organ systems. This usually occurs first in the striatum, a part of the brain that controls the motor and reward systems. One of the earliest striatum changes in HD is lowered levels of the cannabinoid receptor CB1.

Researchers have observed reduced CB1 levels in all models for HD from cells to mice as well as human patients diagnosed with HD. Moreover, the decrease in CB1 levels corresponds with the progression of HD symptoms. Previous research suggests that increasing the amount or activity of the CB1 receptor could help reduce the symptoms of HD.

Modulating the Endocannabinoid System

Given this intriguing relationship between HD and the cannabinoid receptor CB1, researchers have started to look for potential drug therapies. If researchers could find a way to reliably increase the signaling and abundance of CB1, they could help alleviate the symptoms and even slow the progression of HD.

An obvious candidate is THC. This cannabinoid derived from the cannabis plant binds and activates the CB1 receptor. However, using lab models for HD, THC actually reduced CB1 levels and cell viability in cell culture experiments and led to more seizures in mice experiments.

Anandamide and 2-AG, naturally-occurring cannabinoids, showed more potential than THC. While neither was able to slow disease progression, 2-AG reduced seizure frequency in mice.

To help them fine-tune the endocannabinoid system, researchers turned to another class of molecules. Pharmaceutical companies have created compounds that act to positively regulate the cannabinoid receptors. These positive regulators bind to a secondary site on a cannabinoid receptor. This enhances the receptor’s activity and ability of the receptor to bind to cannabinoids.

Treating HD with CB1 Positive Modulators: A New Study

Scientists have created three positive modulators—GAT211, GAT228, and GAT229—for the cannabinoid receptor CB1. A group of researchers from Canada wanted to test whether these CB1 modulators could effectively reduce the symptoms of HD.

They used cell cultures and mice as models for HD and look at the effect of the CB1 modulators.


The three CB1 modulators all gave slightly different though overall similar results. Interestingly, it took multiple exposures to see the effects of the compounds

GAT229 was the most promising. It improved the viability of HD cell cultures. GAT229 also improved coordination, delayed symptom onset, and improved gene expression in HD mice.

GAT228 also improved the viability of HD cell cultures and health metrics in HD mice. However, it didn’t have any effect on specific HD symptoms. GAT211, on the other hand, showed an intermediate effect between GAT229 and GAT228.

GAT229 and GAT211 also increased the levels of CB1 in the brains of the HD mice, reversing one of the earliest signs of HD.


Changes to the endocannabinoid system within the brain are one of the earliest signs of HD. This was the first study to show that positive modulators of the endocannabinoid system can treat the symptoms and progression of HD.

Endocannabinoid modulators target one of the earliest steps in the disease. Therefore, if taken early, they have the potential to ward off the onset of HD. These results will hopefully guide the development of new drug therapies.

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