CANNABIDIOL (CBD) FOR ALZHEIMER’S DISEASE

Jared D. Hoffman, PhD

Alzheimer’s disease (AD) is a chronic, progressive, neurodegenerative disease and the most common form of dementia. The estimated prevalence of the disease is 10-30% in people greater than 65 years of age.¹ Although most cases of AD are the seemingly random, sporadic form (>95%), there is a strong genetic component that can impact your disease risk. In fact, the greatest genetic risk factor is the APOE4 allele, found in roughly 15% of the population. Other genetic risk factors include the Familial Alzheimer’s Disease (FAD) mutations, which can lead to early-onset AD. The disease is characterized by the accumulation of amyloid-β plaques and neurofibrillary tangles (also known as hyperphosphorylated tau) as well as neuroinflammation and metabolic deficits. As the disease slowly worsens, cognitive deficits appear in short-term memory but as AD continues to progress, the skills that are involved in everyday life, such as eating and walking, also begin to deteriorate. Eventually, the person will need around the clock care. To make matters worse, pharmaceuticals have made little impact in preventing and treating the disease. However, it has been suggested that lifestyle factors including diet, exercise, and cognitive training may help decrease one’s risk of developing AD.²

Of late, cannabidiol (CBD) has gained substantial attention. One reason for this is its effects on the endocannabinoid system, which has been implicated in AD.³ In this article, we will discuss the endocannabinoid system, how CBDimpacts this system, and the current state of the literature involving CBD’s usage in AD.

CBD and the Endocannabinoid System

The endocannabinoid system is, as the name suggests, made up of endocannabinoids, which are neurotransmitters that bind to cannabinoid receptors, e.g.cannabinoid receptor-1 (CB-1) and cannabinoid receptor-2 (CB-2). CBD was initially thought to act primarily by binding to and activating the cannabinoid receptors themselves, but it now appears that CBD may activate the endocannabinoid system by increasing endogenous cannabinoids such as anandamide, which modulates CB-1 and CB-2. Interestingly, this system has even been found to be altered in the brain tissue of AD patients.⁴

Preclinical CBD Evidence

CBD has gained substantial interest as preclinical studies (studies in cell culture and animal models) have found benefits in the brain. These studies have investigated CBD alone and in combination with tetrahydrocannabinol (THC), the psychoactive constituent of the cannabis plant. When CBD and THC are used together, they appear to have poorly understood synergistic effects. Due to this, it is difficult to tell which cannabinoid is providing benefit or if the synergism is most critical to their actions.

In cell culture studies, CBD has been demonstrated to be protective against amyloid-β neurotoxicity, oxidative stress, and to decrease reactive oxygen species production.⁵ Two other studies by Esposito et al. found CBD to inhibit tau hyperphosphorylation and the transcription of pro-inflammatory genes.^6,7 Other studies have found CBD to impact amyloid-β neurotoxicity and production.^8,9

Studies in animal models have also garnered exciting results. One study used mice that were injected with the human amyloid-β 42 peptide in the hippocampus of the brain, a region responsible for memory formation and learning, followed by CBD injections (either 2.5 or 10.5 mg/kg). Interestingly, CBD was also able to reduce protein expression of inducible nitric oxide synthase and interleukin-1β, which are inflammatory markers thought to be released by amyloid‑β prompted microglia cells. Of note, microglia cells support neurons in the brain and are the primary immune cells in the central nervous system. However, dysfunctional microglia cells are a key component of the pathogenesis of AD.Lastly, the authors suggested these findings may be due to CBD acting as an inverse agonist to CB-2.¹⁰

In a study by Martin-Moreno et al, 20 mg/kg of CBD was used in mice that had been injected with 2.5 µg of amyloid-β. In this study, cognitive deficits were reversed in the mice given CBD compared to the control mice. These authors attributed these findings to CBD modulating glial cell (the non-neuronal cells of the brain) activation.¹¹

Cheng et al. have conducted a couple studies with interesting results. Mice with Familial Alzheimer’s Disease mutations, mutations that increase amyloid-β production and deposition, were given CBD (20 mg/kg) after AD pathology had already begun. CBD was able to reverse cognitive deficits when compared to controls as shown by looking at a variety of cognitive tests.¹² In the next study by Cheng et al., mice with Familial Alzheimer’s Disease mutations were given CBD orally (also 20 mg/kg) for 8 months.¹³ They found that the CBD group had a reduction in the deficits of social recognition compared to the control group and slight changes in neuroinflammation and cholesterol. However, there were no differences in anxiety or amyloid-β.

Although these studies are indeed very exciting and warrant further investigation in clinical trials, preclinical research does not always translate to humans. This has been especially the case in AD research as therapeutics have continually failed. Nonetheless, the results do warrant further investigation in clinical trials.

Human Studies Utilizing CBD

Unfortunately, there is virtually no research using CBD for AD in humans. Further, as of this writing, there are no ongoing clinical trials investigating CBD for AD either.¹⁴With the rise in popularity of CBD, we can hope thatclinical trials will gain funding and begin as soon as possible.

To conclude, AD is a debilitating neurodegenerative disease and the most common form of dementia that has seen one failed therapeutic after another. However, hope does remain as lifestyle and nutritional interventions and other therapeutics may still provide value. One such is CBD, which can act on the endocannabinoid system. This system has been implicated in AD and although research in humans is lacking, preclinical research has shown that CBD may have potential to beneficially act on it.

Of note, by getting your genetics tested, you can actually see if you have genetic risk factors that increase your risk of AD. However, before sending your genetic information, you should consider how you will respond to the results. Even if you are genetically predisposed to a disease, it does not necessarily mean you will get it. If anything, it should be seen as a call to action to do everything in your power to ensure that you do not.

As always, check with your doctor before beginning a CBD regimen.

References:

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11. Martín-Moreno AM, Reigada D, Ramírez BG, et al. Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer’s disease. Mol. Pharmacol. 2011;79:964–973.
12. Cheng D, Low JK, Logge W, et al. Chronic cannabidiol treatment improves social and object recognition in double transgenic APP_swe/PS1Δ E9 mice. Psychopharmacology (Berl). 2014;231:3009–3017.
13. Cheng D, Spiro AS, Jenner AM, et al. Long-term cannabidiol treatment prevents the development of social recognition memory deficits in Alzheimer’s disease transgenic mice. J. Alzheimer’s Dis. 2014;42:1383–1396.
14. Clinicaltrials.gov