Can active ingredient in cannabis protect against brain aging?

Researchers at the Salk Institute discover that cannabinol preserves mitochondrial function and prevents oxidative damage to cells.

A new study by scientists at the Salk Institute has demonstrated that cannabinol (CBN) can protect nerve cells from oxidative damage, a major pathway to cell death. The findings, published in the journal Free Radical Biology and Medicine, suggest CBN has the potential for treating age-related neurodegenerative diseases, like Alzheimer’s.

Longevity.Technology: Decades of research on medical cannabis has focused on the clinical applications of the compounds tetrahydrocannabinol (THC) and cannabidiol (CBD), just two of over one hundred cannabinoids identified in the cannabis plant.

However, less is known about the therapeutic properties of cannabinol (CBN). CBD is more popular than CBN and CBD-infused products are rising in popularity as people use the chemical to manage symptoms including anxiety, insomnia and chronic pain. But what of the lesser-known CBN? Well, there hasn’t been nearly as much research carried out on its benefits or uses, but it is slowly making its presence felt due to its potential benefits for sleep and pain management. In addition, there is mounting evidence for CBD’s benefits and effectiveness in managing seizure-causing conditions, and the first CBD drug, Epidiolex, has been approved by the FDA for the treatment of epilepsy.

As they are both derived from the cannabis plant, CBN is molecularly similar to THC, but is not psychoactive; it’s also less heavily regulated by the FDA. Previous research by the lab of the paper’s senior author, Pamela Maher, a research professor and head of Salk’s Cellular Neurobiology Laboratory, found that CBN had neuroprotective properties, but it wasn’t clear how it worked; now, this new study explains the mechanism through which CBN protects brain cells from damage and death.

“We’ve found that cannabinol protects neurons from oxidative stress and cell death, two of the major contributors to Alzheimer’s,” says Maher.
Photograph: Salk Institute

“We’ve found that cannabinol protects neurons from oxidative stress and cell death, two of the major contributors to Alzheimer’s,” says Maher. “This discovery could one day lead to the development of new therapeutics for treating this disease and other neurodegenerative disorders, like Parkinson’s disease [1].”

Maher’s team looked at the process of oxytosis, also called ferroptosis, which is thought to occur in the aging brain; there is growing evidence to suggest that oxytosis may be a cause of Alzheimer’s disease. Oxytosis can be triggered by the gradual loss of an antioxidant called glutathione, causing neural cell damage and death via lipid oxidation, so in the study, the scientists treated nerve cells with CBN, and then introduced an agent to stimulate oxidative damage.

They found that the CBN worked by protecting mitochondria, the cell’s powerhouses, within the neurons. In damaged cells, oxidation caused the mitochondria to curl up like doughnuts – a change that has also been seen in aging cells taken from the brains of people with Alzheimer’s disease. Treating cells with CBN prevented the mitochondria from curling up and also kept them functioning well [2].

To confirm the interaction between CBN and mitochondria, researchers then replicated the experiment in nerve cells that had the mitochondria removed. In these cells, CBN no longer demonstrated its protective effect [2].

“We were able to directly show that maintenance of mitochondrial function was specifically required for the protective effects of the compound,” Maher said [1].

In another key finding, researchers showed that CBN did not activate cannabinoid receptors, which are required for cannabinoids to produce a psychoactive response; this means that CBN therapeutics would work without causing the individual to become “high.”

In addition to Alzheimer’s, the findings have implications for other neurodegenerative diseases, such as Parkinson’s, which is also linked to glutathione loss.
From left: Pamela Maher and Zhibin Liang

“CBN is not a controlled substance like THC, the psychotropic compound in cannabis, and evidence has shown that CBN is safe in animals and humans,” says first author Zhibin Liang, a postdoctoral fellow in the Maher lab. “And because CBN works independently of cannabinoid receptors, CBN could also work in a wide variety of cells with ample therapeutic potential [1].”

In addition to Alzheimer’s, the findings have implications for other neurodegenerative diseases, such as Parkinson’s, which is also linked to glutathione loss. “Mitochondrial dysfunction is implicated in changes in various tissues, not just in the brain and aging, so the fact that this compound is able to maintain mitochondrial function suggests it could have more benefits beyond the context of Alzheimer’s disease,” Maher said [1].

Maher adds that the study shows the need for further research into cannabinol and other lesser-studied cannabinoids. As a next step, Maher’s team is working to see if they can reproduce their results in a preclinical mouse model.

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