CBN Could Protect Aging Brain Cells Without Activating Cannabinoid Receptors

Cannabinol (CBN) could help with many age-associated neurodegenerative diseases, finds a study published in Free Radical Biology and Medicine in January 2022. The study found that CBN can protect nerve cells from oxidative damage and cell death, two of the major contributors to Alzheimer’s disease.

The scientists observed the process of oxytosis, also called ferroptosis, which is thought to occur in the aging brain. The process can be triggered by the gradual loss of an antioxidant called glutathione, causing neural cell damage and death via lipid oxidation. In the study, scientists treated nerve cells with CBN and then introduced an agent to stimulate oxidative damage.

The study led by Dr. Zhibin Liang from the Cellular Neurobiology Laboratory and the Salk Institute for Biological Studies found that CBN worked by protecting mitochondria, the cell’s powerhouses, within the neurons. In damaged cells, oxidation causes the mitochondria to curl up like donuts—a change that’s 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 kept them functioning well.

Apart from protecting nerve cells from oxytosis and ferroptosis, the pathways used as a screening tool for identifying novel drug candidates for multiple age-associated neurological disorders, the scientists found that CBN protects nerve cells independently of cannabinoid receptors. This is important because cannabinoid receptors are required to produce a psychoactive response, so CBN drugs could work without causing the patient to become “high.”

What is CBN?

CBN was the first cannabinoid to be fully characterized, starting with the pioneering efforts of Professor of agriculture at the University of Cambridge Thomas Barlow Wood in 1899, who, with his colleagues, isolated it from the resin of Indian hemp and discovered its correct molecular formula. It is a metabolite of tetrahydrocannabinol (THC), with potential immunosuppressive and anti-inflammatory activities.

CBN mostly binds to the receptor CB2, which is mainly expressed in a variety of immune cells, such as T-cells, B-cells, macrophages, and dendritic cells. In these cells, stimulation of CB2 receptors by CBN is found to trigger apoptosis — programmed death of the cells damaged beyond repair, a process that plays a role in preventing cancer. As for CB1 receptors, CBN exerts minimal affinity there. However, in this new study, scientists found that CBN affects mice nerve cells separately from cannabinoid receptors.

CBN is one of the minor cannabinoids. In the European Union, it is listed in the same group as THC. In the UK, under the Misuse of Drugs Act 1971, CBN is still a class B controlled substance. Scientific evidence shows that oral administration of CBN produced no psychoactive effects at a dose of 50 mg. A study comparing single intravenous doses of delta-9-tetrahydrocannabinol (∆9-THC), CBN, and cannabidiol (CBD) found that the dose of CBN required to produce subjective psychoactive effects was over 10-fold higher than that for ∆9- THC.

What is oxytosis or ferroptosis?

First described over 30 years ago, oxytosis is a pathway for glutamate-induced cell death. Glutamate is a chemical messenger that excess in brain cells as a result of a stroke or head injury and leaves damaged neurons. A pathway with the same characteristics as oxytosis was identified in 2012 and named ferroptosis. The molecular pathways involved in the regulation of ferroptosis and oxytosis are highly similar if not identical, so the scientists have suggested that oxytosis and ferroptosis should be regarded as two names for the same cell death pathway.

The changes seen in oxytosis or ferroptosis are observed in many neurodegenerative diseases and the aging brain. This led scientists to a hypothesis that this pathway could be used as a screening tool for novel drug candidates in the treatment of multiple age-associated neurological disorders, including Alzheimer’s disease. The new study found that CBN affects this pathway and could be beneficial in the treatment of a number of such disorders.

CBN directly targets mitochondria

In the new study, the scientists demonstrated that not only does CBN protect nerve cells from oxytosis or ferroptosis, but it also does so independently of cannabinoid receptors. CBN directly targets mitochondria and preserves key mitochondrial functions including redox regulation, calcium uptake, membrane potential, bioenergetics, biogenesis, and modulation of fusion or fission dynamics that are disrupted following induction of oxytosis or ferroptosis.

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,” explained senior author Pamela Maher, a research professor and head of Salk’s Cellular Neurobiology Laboratory.

Maher adds that the study shows the need for further research into CBN 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.