Alzheimer’s disease is an irreversible, progressive brain disorder which affects memory, and eventually the ability to perform simple tasks
In the U.S alone, more than 5 million people suffer from Alzheimer’s, which is the sixth leading cause of death in the United States, (recent estimates indicate that it may rank third, just behind heart disease and cancer, as a cause of death for older people).
The prevalence of Alzheimer’s disease (AD), a devastating neurodegenerative illness, is on the rise.
However, recent evidence brings to light potential cannabinoid (active cannabis compounds) therapies that may be beneficial in the treatment of AD. The anti-inflammatory, anti-oxidant and neuroprotective properties of Cannabidiol (CBD), a non-psychoactive component of cannabis, have been well documented, prompting researchers to explore its applications in neurodegenerative diseases.
There are two hallmark features which characterize the neuropathology of AD: the neurofibrillary tangle (abnormal accumulations of abnormally shaped tau protein) and the senile Beta-amyloid plaque (Perl, 2010). Cannabinoids act on two primary receptor sites, CB1 and CB2, and the latter of which are mainly found on immune cells and have been shown to be associated in the pathogenic mechanisms of Alzheimer’s disease.
Although the exact role of the endocannabinoid system within the context of AD is not fully understood, CB2 knockout experiments demonstrate “the constitutive role of the CB2 receptor system both in reducing amyloid plaque pathology in AD,” and support the “potential of cannabinoid therapies targeting CB2 to reduce Aβ plaque” (Koppel et al., 2013). A knockout experiment involves inactivation, or “knocking out” of a specific gene to better discover its function. Furthermore, an exciting new study, featured in Frontiers in Pharmacology, demonstrates the ability of CBD to reduce reactive gliosis and the neuroinflammatory response while prompting neurogenesis. It was also shown to reverse and prevent the development of cognitive deficits in AD rodent models as demonstrated by their proficiency in object recognition memory and social recognition memory (Watt & Karl, 2017).
Considering this emerging data, this review will investigate the role of the endocannabinoid system, with particular emphasis on CBD in Alzheimer’s disease. There is currently no cure for AD, in that no available treatments stop or reverse the progression of the disease. With the endocannabinoid system demonstrably associated with the pathology of AD, cannabinoid therapy–thanks to its high therapeutic potential and low adverse risk profile–should be thoroughly investigated as a potentially novel treatment in the battle against this relentless neurodegenerative illness.
Amyloid beta peptides that eventually form the characteristic neurotoxic AD plaques come in two primary forms, with Aβ42 being more toxic due to its affinity to aggregate more easily. In experiments where scientists injected Alzheimer’s proteins into mice, intraperitoneal injections of CBD reduced reactive gliosis (a type of inflammation in the brain), and showed a dose-dependent effect (the more CBD given, the more pronounced the effect). CB2 knockout mice also showed significantly greater Aβ plaque–driven inflammation (Koppel et al., 2013). Thus, exploiting the anti-inflammatory properties of CBD with respect to treating AD may serve as an effective, new strategy in battling the progression of this illness.
Along with impairment of spatial cognition in AD patients, the cognitive impairment and decline they experience is perhaps the most traumatic for them and their loved ones. Cognitive symptoms of AD include short-term memory loss, confusion, agitation, and behavioral disturbances (Bekris et al., 2010). The need to reduce this cognitive deterioration, if not reverse it completely, is a dire one. Trials involving cannabinoid interventions, particularly those involving CBD, have been shown to have neuroprotective effects. Furthermore, CBD-THC combined formulations, seem to have an additive effect, markedly increasing their therapeutic efficacy. In their review, Watt & Karl noted that in an experiment administering intraperitoneal CBD injections over a three-week period to transgenic rats, which are rats that have been genetically manipulated to express the AD disease state, “CBD treatment was able to reverse cognitive deficits in object recognition memory and social recognition memory without influencing anxiety parameters” (Watt & Karl, 2017).
The inquisitive reader might be asking himself or herself what the significance of manipulating and observing genes in these transgenic rats is. While injecting plaques into the brains of rodents to pharmacologically induce the AD disease state is an effective way to model the disease, it does not effectively allow for long-term observation. Also, it is estimated that just under 5% of Alzheimer’s patients exhibit Early Onset Familial AD, also known as the genetic form of AD, as it results from autosomal dominant mutations in the amyloid precursor protein (APP) gene or in the presenilin 1 and 2 (PS1 and PS2) genes. Using transgenic models more accurately represents this phenomenon and allows for researchers to explore genetic components of the disease.
In another long-term, preventative study, mice were treated for 8 months with either 20 mg/kg CBD or vehicle pellets to observe long-term effects of CBD before the onset of AD. The study noted that “Long-term CBD treatment was able to prevent the development of social recognition memory deficits without affecting anxiety domains in AD transgenic mice” (Watt & Karl, 2017) Surprisingly, these benefits were not associated with reductions in Aβ42or oxidative damage. These findings not only demonstrate the value in using CBD to treat cognition in AD rodent models, but also reveal just how multimodal cannabinoid therapy can be. Unfortunately, this data can only speak accurately for rodents. However, the data is certainly encouraging and warrants further investigation in hopes of eventually achieving such beneficial results in humans.
Another study in mice, that used CBD, THC and a CBD-THC combination showed that all treatments improved memory deficits in the two-object recognition task but only the CBD-THC combination prevented the learning deficit seen in the active avoidance task” (Aso et al., 2015). The THC-CBD combined treatment also showed a reduction in soluble Aβ42 levels and changed plaque composition whereas CBD and THC individually did not (Aso et al., 2015). CBD is also able to mitigate the psychoactivity of THC, reducing the associated anxiety/euphoria symptoms associated with it. These findings would suggest the potential merit to the cognitive benefits of cannabinoid therapy in the treatment of AD in humans. Particular weight should also be given to whole plant formulations and/or THC-CBD combination therapy over the individual phytocannabinoids alone in the management of cognition in AD treatment.
The pharmacological versatility of cannabinoids in the treatment of neurodegenerative diseases is beginning to be elucidated by researchers across the globe. This review primarily focuses on the anti-inflammatory, antioxidant and neuroprotective properties of CBD in the treatment of AD.
The data presented is promising and warrants further investigation into cannabinoid interventions to slow, stop and reverse the progression of this disease. These findings also support the idea of “whole plant medicine” in that combination therapy of THC-CBD formulations provided greater therapeutic benefits, which include suppression of unwanted side effects from THC.
From improvements in memory to reduced plaque deposition, the benefits of cannabinoids on the AD disease state in rodent models is promising and warrants the need for human trials.
These studies hold promise for the ever-increasing number of patients diagnosed every day with Alzheimer’s. Unfortunately, the current Schedule I status of cannabis makes such research incredibly difficult and is a disservice by the government to its people.
While our understanding of the pathology and mechanisms by which AD forms is still incomplete, it is suggested that the endocannabinoid system plays a large role in that. As such, further exploration into the potential benefits of cannabinoid therapies for AD is crucial, and should be the next step beyond current AD treatment options.
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