Endocannabinoids, Alzheimer’s disease, Neurodegenerative disease

Using the Endocannabinoid System to Address Alzheimer’s Disease

By Kellie Raydon, ND, MSOM

Whether you are a healthcare provider trying to prevent and treat Alzheimer’s disease (AD) for your patients or have a family member struggling with this disease, most of us have been faced with people we care for who are suffering with this difficult and unfortunate neurodegenerative condition. While our knowledge of the pathophysiology of AD has become more advanced in recent years, treatment still remains elusive; and finding effective prevention and treatment strategies is becoming increasingly urgent with AD on the rise.

An annual report released by the Alzheimer’s Association states that an estimated 5.8 million Americans 65 and over are living with AD in 2020, two-thirds of whom are women. Older African Americans are approximately twice as likely to suffer from the disease, and Hispanics are about one and a half times more likely than white Americans to suffer from it. AD is the fifth leading cause of death for Americans over the age of 65 and the projected annual cost for caring for people with AD in 2020 at $305 billion dollars.¹ With no existing cure in the conventional medical paradigm, (only medications that temporarily improve symptoms), it is easy to feel discouraged and hopeless with such limited and minimally effective treatments.

Perhaps the road to the cure is hidden in plain sight. Perhaps it is embodied within us already this very minute. Perhaps we need to look no further than the endocannabinoid system (ECS) that is already miraculously functioning in each of us before we are even born, maintaining homeostasis and regulating neurologic and immune functioning. As we continue to build our understanding of the neuroprotective and neurodegenerative effects innate to the endocannabinoid system and how it may be harnessed to prevent and treat neurodegenerative conditions such as AD, the fog seems to be lifting, literally and figuratively. As we continue to make headway in our understanding of cannabinoid receptors, their endogenous lipid ligands, and related enzymes, as well as phytocannabinoids, the endocannabinoid system continues to reveal its great potential as a therapeutic target for AD.

Overview of the Current Approach

The conventional treatment for mild to moderate AD is focused on the use of cholinesterase inhibitors. These medications block the breakdown of acetylcholine, which is thought to be important for memory and thinking. As AD progresses, the endogenous production of acetylcholine in our brain progressively decreases and eventually the cholinesterase inhibitors are no longer effective. For moderate to severe AD a medication called memantine is often prescribed, which is a NMDA receptor antagonist that regulates excitatory glutaminergic activity that leads to neuronal damage. These medications work to reduce symptoms for brief periods, sometimes only a few months before they are no longer effective. In addition to their limited efficacy, they are riddled with unpleasant side effects such as nausea, vomiting, headaches, fatigue, dizziness, diarrhea, and weight loss.

One of the tenants of naturopathic medicine is to identify and treat the root cause of any condition. While acetylcholine and glutamate activity certainly influence

our neuropsychiatric functioning, the fleeting efficacy of these treatments, coupled by their dreadful side effects are some of the striking indications that these drugs are missing the mark and are not addressing the root cause.

Accessing the Root Cause Through the ECS

The endocannabinoid system is one of the most important discoveries in human physiology. In particular, it holds great promise as we continue to understand its role in neuroprotection and neuro-regeneration, and its potential is only beginning to be realized.

The system consists of endocannabinoids, primarily acid ethanolamide anadamide (AEA) and 2-arachidonoylglycerol (2-AG), and their receptors CB1 (most abundant in the central nervous system) and CB2 (most abundant in peripheral nervous system and immune cells), as well as enzymes for their inactivation, such as fatty acid amide hydrolase (FAAH), and monoacylglycerol (MAGL). FAAH breaks down AEA, and MAGL breaks down 2-AG respectively, and are found throughout the body: in the brain, organs, connective tissues, glands, and immune cells. “With its complex actions in our immune system, nervous system, and virtually all of the body’s organs, the endocannabinoids are literally a bridge between body and mind. By understanding this system, we begin to see a mechanism that could connect brain activity and states of physical health and disease.”²

For decades now research has demonstrated various mechanisms through which the ECS contains regenerative and protective mechanisms. “Exogenous cannabinoids have been shown to exert neuroprotection in a variety of in vitro and in vivo models of neuronal injury via different mechanisms, such as prevention of excitotoxicity by CB1-mediated inhibition of glutamatergic transmission, reduction of calcium influx, and subsequent inhibition of deleterious cascades, TNF-alpha formation, and antioxidant activity. It has been suggested that the release of endogenous endocannabinoids during neuronal injury might be a protective response.”³

Because of its mechanism in achieving homeostasis, the ECS is perhaps the most important innate adaptogenic system. It serves to calibrate or send help where it’s needed in the body to maintain balance. Understanding the ECS is transforming the way we treat and prevent a multitude of neurological conditions, which is why it’s being embraced across a diverse group of disciplines.

By working with this innate physiological system, our bodies can create balance and healing in a highly sophisticated and multidimensional way. Our bodies produce the endogenous cannabinoids, AEA and 2-AG, as a regulatory response to excitatory or inhibitory stimuli. There are at least 120 phytocannabinoids that also engage the ECS through the CB1 and CB2 receptors and related pathways. Advances in our understanding of the ECS have brought us to the dawning of a new age in medicine. Research propelling us towards preventing and treating AD through the lens of the ECS has stimulated new hope and excitement.

The more that we investigate the ECS, the more we are seeing how any dysfunction in this system could be a possible underlying root cause of AD. The concept of an endocannabinoid deficiency syndrome (ECDS) was outlined by Ethan Russo in 2001 as a possible unifying etiology for a multitude of treatment-resistant syndromes and neurodegenerative conditions. Studies of post-mortem AD brains showing low levels of AEA and 2-AG have corroborated Russo’s theory. Also, an increase in CB2 receptors and other evidence of ECS homeostatic mechanism not performing properly has been shown in post-mortem AD brain analysis. The significant increase of CB2 levels found in AD brains mainly corresponds to receptors expressed on microglia surrounding senile plaques. Neuroinflammation, which begins with microglial activation, is a distinguishing feature in AD that leads to progressive cell damage and neuronal loss. Also, both CB1 and CB2 cannabinoid receptors in the AD brain are nitrosylated, and this could contribute to the impaired coupling of these receptors to downstream effector signaling molecules.⁴ Additionally, there are variations in the presence and activity of the enzymes related to endocannabinoid synthesis and degradation in AD brains. For example, endocannabinoid metabolizing enzyme FAAH has been shown to be upregulated in AD patients’ peripheral blood mononuclear cells as well as plaque associated glia.⁵ Another compelling study demonstrated altered 2-AG signaling during late stages of AD due to compromised MAGL recruitment as well as increased DAGL levels, which lead to synapse silencing in AD.⁶ These variations in endocannabinoid levels and receptor sites, as well as discrepancies in the presence and activity of enzymes linked to endocannabinoid synthesis and degradation, are proof that the ECS is a lens that we can look through to gain a greater understanding of preventing and treating AD.

Understanding Pathophysiology and Etiology of AD and ECS Targets

There are several genetic and acquired risk factors that are underlying AD. Miraculously the endocannabinoid system provides underlying mechanisms that offer a potential therapeutic target for each one. Apolipoprotein E (ApoE) is a protein involved in lipid metabolism encoded by ApoE gene, located on chromosome 19. Apolipoprotein E is a carrier for brain lipids and is likely the most important genetic risk factor for Alzheimer’s disease. ApoE binds the receptor sortilin, which mediates uptake of ApoE-bound contents into neurons. The significance of this uptake route for brain lipid homeostasis and AD risk is seen specifically with ApoE4.⁷ There are three ApoE alleles present in the population at different frequencies. The ApoE4 allele is the main risk factor for late-onset AD. The presence of ApoE4 in heterozygosity increases three-fold the risk of AD developing, whereas in homozygous individuals, the risk is increased 12-fold. Conversely, the presence of ApoE2 allele reduces the risk of developing AD.⁸ In the June 2020 issue of Alzheimers and Dementia, the journal of the American Alzheimer’s Association, Assaro et al. published data highlighting how “Sortilin directs the uptake and conversion of polyunsaturated fatty acids into endocannabinoids, that act through nuclear receptors to sustain neuroprotective gene expression in the brain. Sortilin function requires ApoE3 but is disrupted by binding of ApoE4, compromising neuronal endocannabinoid metabolism and action.” This is exciting new insight into the role that ECS provides in epigenetic influence of the development of AD. More specifically, how restoring endocannabinoid function, when compromised, may provide new specific preventative strategies.

Histopathogenesis of AD and ECS Targets

When we look closely at the brain of AD patients, the main pathophysiological mechanisms are deposition of beta amyloid in the brain and tau-related neurodegeneration. Nevertheless the exact mechanism by which the amyloidosis promotes neurofibrillary tangle (NFT) formation of hyperphosphorylated tau protein is not yet fully understood. Blurton-Jones and Laferla (2006)⁹ suggest four basic mechanisms: 1. The Aβ peptide promotes the activation of specific kinases (eg, GSK3β) that catalyze the hyperphosphorylation of tau protein, leading to its conformation change and formation of NFT; 2. Neuroinflammation promoted by the deposition of Aβ peptide leads to the production of proinflammatory cytokines that stimulate the phosphorylation of tau protein; 3. Reduced capacity of degradation of tau protein by the proteasome, in a process induced by Aβ peptide; 4. Defects in axonal transport promoted by Aβ peptide lead to inadequate localization of tau protein and its messenger RNA, which can lead to hyperphosphorylation and aggregation in NFT.

Once again, the endocannabinoid system provides us with therapeutic targets and new insights into each of these proposed mechanisms. It has long been known that the endocannabinoid 2-AG functions to provide neuroprotection from amyloidosis. The neuroprotective effects of 2-AG appear to be mediated via CB1 receptor-dependent suppression of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and nuclear factor-κB (NF-κB) phosphorylation and cyclooxygenase-2 (COX-2) expression.¹⁰ According to research published in Neuroscience by Chang et al, it is suggested that “elevation of endogenous 2-AG by inhibiting its hydrolysis has potential as a novel efficacious therapeutic approach for preventing, ameliorating or treating Alzheimer’s disease”

The Entourage Effect

Hope really is on the horizon now that we are investigating the neuroprotective and neuroregenerative potential in targeting the ECS to treat AD. “Several in vitro and in vivo studies have demonstrated that cannabinoids can reduce oxidative stress, neuroinflammation, and the formation of amyloid plaques and neurofibrillary tangles, the key hallmarks of late onset AD. In addition, in population-based studies, cannabinoids reduced dementia-related symptoms (e.g., behavioral disturbances).”¹¹

More human studies are needed so that we can continue to demonstrate efficacy and safety of phytocannabinoids and other medications targeting the ECS in the treatment of AD. Our scientific paradigm has long been predisposed to a reductionistic model focused on the possibility of finding the one enzyme, substrate, or substance that would be the silver bullet or golden key to target for a cure. However, those of us who use botanical medicine are constantly aware of the limitation of that model and are ever curious about the synergistic effects of compounds contained within one plant or combinations of plants, known as the entourage effect. We are seeing this play out as THC and CBD as isolates have often taken center stage in phytocannabinoid research. When looking at other various combinations of less popular and non-psychoactive cannabinoids, there appears to be a synergistic effect in targeting the ECS with various combinations for the treatment of AD patients, as research by Schubert et al show:

Eleven cannabinoids were assayed for neuroprotection in assays that recapitulate proteotoxicity, loss of trophic support, oxidative stress, energy loss, and inflammation. These compounds were also assayed for their ability to remove intraneuronal amyloid and subjected to a structure-activity relationship analysis. Pairwise combinations were assayed for their ability to synergize to produce neuroprotective effects that were greater than additive. Nine of the 11 cannabinoids have the ability to protect cells in four distinct phenotypic neurodegeneration screening assays, including those using neurons that lack CB1 and CB2 receptors. They are able to remove intraneuronal Aβ, reduce oxidative damage, and protect from the loss of energy or trophic support. Structure-activity relationship (SAR) data show that functional antioxidant groups such as aromatic hydroxyls are necessary but not sufficient for neuroprotection. Therefore, there is a need to focus upon CB1 agonists that have these functionalities if neuroprotection is the goal. Pairwise combinations of THC and CBD lead to a synergistic neuroprotective interaction. Together, these results significantly extend the published data by showing that non-psychoactive cannabinoids are potentially lead drug candidates for AD and other neurodegenerative diseases.¹²

It is exciting to see this current research embracing the complexity of the entourage effect and its benefits that will ultimately serve our patients. While it is more complicated and time consuming to study the effects with all the nuance of various combinations of phytocannabinoids, I believe it will be well worth our while to continue to advance our knowledge of this vast array of combinations and possibilities in targeting the ECS. Mounting evidence continues to confirm that investigation of the endocannibinoidome in humans and other mammals holds a multitude of exciting possibilities for biomedical research, which will continue to be utilized to develop new therapies, medications, and diagnostic biomarkers.¹³ For example this is seen in the presence of a complete and fully functional endocannabinoid system that has been revealed in human SH-5YSY cells, which serve as a widely used model for the study of neuronal cell death and damage, in addition to major human neurological disorders. Studies demonstrating the regulation of cell survival and death by endocannabinoids in stem-derived neuronal cells are moving us in a direction in their utilization as therapeutic targets. As a result, endocannabinoid-targeted drugs are being heavily researched at this time for the treatment of neurodegenerative diseases such as AD.¹⁴ A thrust towards more human studies, including the use of human SH-5YSY cells, is bringing us ever closer to effective treatments and preventative measures for AD and other neurodegenerative conditions, where we have currently been at a loss.

The Future of ECS Targeted Therapies for AD

The science, research, and treatments targeting the ECS are unfolding at breakneck speed. While it is tempting in a reductionist scientific paradigm to try to single out endo/exogenous cannabinoids, or single enzyme pathways, I believe we will continue to find that the entourage effect will bring more success and sophisticated treatment approaches. We need to continue to keep up with the ongoing breakthroughs in the research in order to bring our patients the most cutting-edge treatments.

This is no small feat due to the complexity of ECS physiology, including retrograde signaling, “which makes it difficult to fully characterize how its various components may contribute to control genesis and functional integration of adult-born neurons within the post-developmental brain. Future research on the precise role played by distinct components of the ECS in neural stem cell biology will contribute to improving our mechanistic understanding of adult neurogenesis, and could provide the basis for new therapeutic applications of ECS based drugs.”¹⁵ These advances in our understanding of how to influence and support the ECS with therapies that may control neurogenesis and integration of neurons in adult brains have created a powerful shift in what may now be possible for patients diagnosed with AD.

References

1. https://www.alz.org/about/annual-report

2. Alger. Getting High on the Endocannabinoid System. Cerebrum. 2013 Nov-Dec; 14.

3. Van der selt M Cannabinoid Receptors and their role in Neuroprotection. Mol Neurobiol. Oct-Dec 2002;26(2-3):317-46.

4. Ramírez BG, et al. Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J. Neurosci. 2005; 25: 1904–1913.

5. D’Addario C, et al. Epigenetic regulation of fatty acid amide hydrolase in Alzheimer disease. PLoS ONE. 2012; 7:e39186.

6. Mulder J, et al. Molecular reorganization of endocannabinoid signalling in Alzheimer’s disease. Brain. 2011;134:1041–1060.

7. Asaro A, et al. Apolipoprotein E4 disrupts the neuroprotective action of sortilin in neuronal lipid metabolism and endocannabinoid signaling. Alzheimers and Dementia. 2020.

8. Fernandez CG, et al. The Role of APOE4 in Disrupting the Homeostatic Functions of Astrocytes and Microglia in Aging and Alzheimer’s Disease. Front Aging Neurosci. February 11, 2019.

9. Blurton-Jones M, Laferla FM. Pathways by which Abeta facilitates tau pathology. Curr Alzheimer Res. 2006;3(5):437–48.

10. Chang et al. Endocannabinoid 2-arachidonoylglycerol Protects Neurons Against β-amyloid Insults. Neuroscience. March 31, 2011;178:159-68.

11. Ahmed A, et al. Cannabinoids in Late-Onset Alzheimer’s Disease. Clin Pharmacol Ther. June 2015;97(6):597-606.

12. Schubert D, et al. Efficacy of Cannabinoids in a Pre-Clinical Drug-Screening Platform for Alzheimer’s Disease. Molecular Neurobiology. Nov 2019;56(11):7719-7730

13. Marzo D, Wang J. The Endocannabinoidome: The World of Endocannabinoids and Related Mediators. Elsevier Inc;2015: 148-149.

14. Pasquariello N, et al. Characterization of the Endocannabinoid System in Human Neuronal Cells and Proteomic Analysis of Anandamide-induced Apoptosis. J Biol Chem. Oct 23, 2009; 284(43): 29413–29426.

15. Oddi S, Scipioni L, Maccarrone M. Endocannabinoid system and adult neurogenesis: a focused review. Current Opinion in Pharmacology. February 2020; 50: 25-32.

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Dr. Kellie Raydon earned a Bachelor of Science degree in women’s studies while completing her pre-medical education at the University of Oregon. She received a Doctorate in Naturopathic Medicine and a Master of Science in Classical Chinese Medicine from the National University of Natural Medicine in Portland, Oregon. During her residency she gained extensive clinical training in using integrative medicine in hospitals and clinics throughout Portland. Her multi-modality treatment plans include targeted nutrient therapy, herbal medicine, IV therapy, acupuncture, lifestyle counseling, as well as pharmaceutical medications when they are indicated. She is passionate about providing naturopathic and Chinese medical care to her patients to help them experience a life of optimal health and well-being. In addition to her clinical practice, Dr. Raydon is a subject matter expert on the endocannabinoid system and has been a scientific advisor for several companies in the emerging cannabis and hemp industries.