THC, CBD, & CBN: Can cannabis protect the brain from Alzheimer’s?

Salk Institute Neurobiologist Zhibin Liang discusses the neuroprotective effects of a cannabis compound known as cannabinol, and the road ahead to validate and build on the research of his team’s recent findings.

Scientists have been exploring the therapeutic effects of medical cannabis for a host of health conditions, including neurodegenerative diseases like Alzheimer’s. Among the many compounds of cannabis, the best known are cannabidiol (CBD) and tetrahydrocannabinol (THC), which have received the bulk of the research community’s attention. However, lesser known compounds, such as cannabinol (CBN), are also making their way into research. Early study results suggest that CBN, for example, may be able to help protect brain cells in aging and neurodegenerative processes. 

Zhibin Liang, Glenn Postdoctoral Fellow in Cellular Neurobiology Laboratory and The Paul F. Glenn Center for Biology of Aging Research at Salk Institute for Biological Studies, joins Being Patient’s LiveTalk series to discuss the progress that scientists have made in studying cannabis’s potential benefits when it comes to aging and Alzheimer’s. He also shares insight into his team’s research on CBN.

 Broadly, what do scientists know and don’t know about the potential protective effects of cannabis in the context of aging and neurodegenerative diseases? 

Zhibin Liang: Medical cannabis [is an] emerging research field. Phytocannabinoids from the cannabis plant [are] well known for acting on the cannabinoid receptors [CB1 and CB2] in the brain, in the central nervous system, or in the peripheral nervous systems. 

It’s well known that this kind of compounds, especially tetrahydrocannabinol (THC) – the psychoactive compound – have pharmacological effects. For example, [they] can relieve pain. Some research [shows they can] fight cancer and improve memory or behavior. There is also some research [showing that] neurological disorders can benefit [from phytocannabinoids]. 

Right now, most people study two compounds: THC and cannabidiol (CBD). Less studied are the minor cannabinoids. There are over 150 cannabinoids identified from the plant. 

In Alzheimer’s research, [there’s some research showing that] cannabis plant extracts and also THC or CBD can improve memory and can reduce amyloid plaque in mice study and some limited clinical trials … But this class of study for cannabinoids is not comprehensive. It’s a new area for medical cannabis research. 

 To be clear, there are no cannabis products that are approved by the Food and Drug Administration for Alzheimer’s. 

Zhibin Liang: No. [There are] some clinical trials, but [they are in] very early stages. 

 Why has your team focused on the less studied compound cannabinol (CBN)?

Zhibin Liang: Although many cannabinoids [have] very similar chemical structures, THC is the psychoactive compound, affecting people’s mood, brain functions and behavior. For long-term use for Alzheimer’s patients, this psychoactive compound is not ideal because we predict really strong side effects. That’s why people study CBD. [It] is the non-psychoactive compound and [has] a beneficial effect. 

Besides these two, are there any other non-psychoactive phytocannabinoids [that] will be beneficial? And what [are] the potential mechanisms for the benefit for the Alzheimer’s patients? That is what inspired our research. We want to study the lesser, a minor, phytocannabinoid. Then, we focused on CBN. 

We can clarify what’s the difference [between] CBN, THC and CBD besides the mechanism of action. They are structurally very similar. But CBN [is] a degraded product of THC. It’s mostly found in very aged cannabis plants … CBN is no longer psychoactive compared to THC, so we think this compound could be a new candidate for us to explore the beneficial effects of cannabinoids. 

 Can you sum up the most significant findings from your team’s recent study? 

Zhibin Liang: One part of aging is your brain’s energy decrease. Energy metabolism is produced from the mitochondria. Our initial idea is whether any compound will help the mitochondria function, which can help the Alzheimer’s patient and [people with] other neurodegenerative diseases. 

In the aging process, mitochondria become [dysfunctional], or are inefficient, and it’s more dramatic in neurodegenerative diseases. Besides Alzheimer’s, it also happens in Parkinson’s disease, Huntington’s disease, frontotemporal dementia, and you name it. 

Mitochondrial dysfunction [causes] many [consequences]. One is redox [imbalance], because oxidative stress [increases] in brain cells. Then, many oxidized or dysfunctional proteins accumulate in aging brain cells. That’s why we think aging-dependent changes [in] the mitochondria will need to be taken into account to better study neurodegenerative diseases, so we can understand the root causes of age-related diseases and ultimately translate the biology of aging to novel neurotherapeutics. That’s the basic rationale for us. 

We found that CBN directly targets mitochondria, so the compound definitely interacts with mitochondria [and maintains mitochondrial function]. [It] can reduce oxidative stress in brain cells and can modulate energy metabolisms, [increasing] ATP (adenosine triphosphate) production in brain cells, [without] affecting CB1, CB2 receptors, the classical cannabinoid receptor pathway. 

 How is the team moving forward with these results? 

Zhibin Liang: Our recent published paper is more focused on the cellular level. Now, we are testing CBN in the preclinical model, so [we are] using mice models of Alzheimer’s and aging to reproduce the effects and see how CBN [works] in the animal model. A couple of things we are [focusing on with the animal study]: the safety profile, the pharmacokinetic profile, and also the efficacy. 

If the results pan out, then there may be opportunities to test the safety and efficacy of CBN in clinical trials. But that’s much further down the line in the research process, right? 

Zhibin Liang: Yea. [A] drug development campaign [takes] a long, long time. [It has] to be very, very rigorous and very careful. [It’s] got to be based on science. In terms of safety, there [are] some limited animal studies showing CBN is safe. There’s some small scale of human clinical study showing the CBN’s safety profile is reasonable.