November/December 2021

Targeting Neuroinflammation
By Mark Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 14 No. 6 P. 18

CBD’s Promise for Individuals With Dementia

Dementia is a general term used to describe impairments of brain functions, including cognitive decline, memory loss, and changes in perception and personality. Alzheimer’s dementia (AD) is the most common type of dementia, with other common dementias including vascular dementia, dementia with Lewy bodies, and frontotemporal dementias. Persons suffering from AD experience the slow destruction of memory and thinking skills until they’re no longer able to carry out necessary daily activities. Additionally, cognitive decline and memory loss is often complicated by troubling neuropsychiatric symptoms including depression, apathy, psychosis, agitation, and problems with sleep.

There’s no known cure for AD, and current FDA-approved medications for the disease can only minimally slow progression and provide symptom management. For this reason, there’s tremendous need for new treatment options that can stop or significantly delay the progression of the disease. While more research is needed, cannabidiol (CBD) may offer hope as an alternative treatment option for persons with dementia.

CBD is a multimodal compound, and there’s evidence it can alter several important pathophysiological mechanisms believed to be involved in the development and progression of AD. CBD target mechanisms could include the accumulation of beta-amyloid plaques and subsequent formation of tau protein neurofibrillary tangles (NFTs), vascular changes, oxidative stress, inflammatory responses, and neuroexcitoxicity.

Beta-Amyloid Plaques and NFTs
AD pathogenesis is characterized by neurodegeneration (neuronal death and synaptic loss) in the presence of extracellular senile plaques consisting of beta-amyloid and intracellular tau protein NFTs. The accumulation of beta-amyloid plaques in the extracellular space between neurons causes direct damage to adjacent neurons.1 Furthermore, beta-amyloid stimulates intracellular damage by stimulating the conversion of tau protein into toxic hyperphosphorylated NFTs, which first appear in the hippocampus and then spread to other areas of the brain as the disease progresses.2 Over time—typically over the course of years—these plaques and tangles cause significant disruptions in cellular function along with neurodegenerative processes that result in the progressive loss of memory and cognitive ability observed in AD. As these plaques and tangles spread from the hippocampus to the cerebral cortex, behavior, reasoning, and language start to deteriorate as well. This degradation continues until patients can no longer perform basic bodily functions such as eating and swallowing, and, ultimately, the result is death. 

Treatment options that target beta-amyloid plaques and tau tangles could be extremely valuable in helping to prevent or slow the progression of AD.  

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors that regulate gene expression. There’s evidence that activation of PPAR-gamma improves cognition and memory in AD.3 In fact, CBD activation of PPAR-gamma results in reduced beta-amyloid plaque formation and improved brain cell survival.4 Furthermore, CBD’s interaction with CB2 receptors has been suggested to prevent beta-amyloid plaque buildup, blunt the effects of toxic tau, and protect against the development of NFTs in cases where beta-amyloid plaques underlie their pathology.5

In a study designed to investigate CBD’s effects on mechanisms that lead to neurodegenerative disorders such as AD, researchers found that CBD can effectively inhibit the expression of beta-amyloid.6 More specifically, when they pretreated mesenchymal stem cells derived from gingiva (GMSCs) with CBD, they identified that CBD interacted with vanilloid receptor 1, causing downregulation of genes linked to AD, including the coding of the genes responsible for production of amyloid plaques and tau protein tangles. CBD pretreatment also modified the genes involved in the production of beta-amyloid. In their study findings, the researchers wrote that this preliminary in vitro study demonstrates that GMSCs preconditioned with CBD have better therapeutic potential compared with control GMSCs cells, and, while additional study is needed, it may be possible that transplantation of CBD-treated stem cells in the early stage of AD may play a role in preventing or attenuating the disease onset.

Vascular Damage
Mixed dementia represents a neurological condition in which brain changes are due to two or more types of dementia. Mixed dementia is common, and, although AD is the most common type of dementia, rarely does it occur alone. Vascular mechanisms play a significant role in the development of many dementias, and one study reported that researchers who examined older adults' brains after their death found that 78% had two or more pathologies related to neurodegeneration or vascular damage.7

Vascular problems, whether a result of plaques in brain arteries, atherosclerosis, mini strokes, or other causes, can lead to reduced blood flow and oxygen to the brain. This can lead to the breakdown of the blood-brain barrier, preventing glucose from reaching the brain along with a reduced ability to clear toxic beta-amyloid plaques and tau proteins. Thus, AD may be both a cause and consequence of vascular problems in the brain that contribute to dementia. 

CBD previously has been described as an arterial vasodilator and has been shown to increase cerebral blood flow in mouse models of stroke.8 More recently, researchers found evidence that acute CBD administration causes increased regional cerebral blood flow to the hippocampus—an area of the brain associated with memory and emotion.9 For the study, researchers selected study participants with little or no history of cannabis use. Each study participant, on different occasions separated by at least a week, were given capsules identical in appearance containing either 600 mg of oral CBD or a placebo. Using magnetic resonance imaging to scan the brain, they found that CBD significantly increased blood flow in the hippocampus but not to other regions of the medial temporal lobe. CBD also caused a significant increase in blood flow in the orbitofrontal cortex, an area of the prefrontal cortex used for planning and decision making. In a summary of their findings, the researchers reported that, to their knowledge, theirs was the first study to show that CBD increases blood flow to key regions of the brain involved in memory processing, particularly the hippocampus. They also indicated that CBD has region-specific blood flow effects in the human brain, which has previously been disputed. Future replication of the study’s results could lead to further research across a range of conditions in which there are defects in the control of blood flow and how the brain processes memories, including Alzheimer’s disease, along with schizophrenia and posttraumatic stress disorder. 

Neurodegeneration 
Three primary pathogenic mechanisms known to lead to neurodegeneration in AD include neuroinflammation, oxidative stress, and neuroexcitoxicity. Each mechanism can cause damage independent of the other and also in tandem through feedback mechanisms.  For instance, cellular damage leads to a persistent neuroinflammatory response that leads to oxidative stress, which perpetuates further cellular damage and induces even more oxidative stress along with a continued neuroinflammatory response. This type of vicious and synergistic cycle of damage eventually leads to neuronal and synaptic loss.   

Neuroinflammation
Glial cells—microglia and astrocytes—play a significant role in neuroinflammation and the pathogenesis of AD. Microglia function as the macrophages of the central nervous system and are the primary immune cells in the brain.10 Astrocytes are support cells and work closely with microglia in the CNS to shape the microarchitecture of the brain, form neuronal-glial-vascular units, regulate the blood-brain barrier, control microenvironment of the central nervous system, and defend the nervous system against a multitude of insults.11 

In AD, microglia respond to deposits of beta-amyloid in the parenchyma of the brain with a robust immune response that includes the release of proinflammatory molecules including cytokines, reactive oxygen species (ROS), nitric oxide, glutamate, and other toxic chemicals. Astrocytes, along with some specialized microglia, travel to and partition off the plaque formations.10 Although these responses are intended to protect the brain, their inability to clear the plaques results in autocrine signaling, with continued release of proinflammatory molecules that self-perpetuate reactive gliosis and paracrine signaling that kills neighboring neurons, thus expanding the neuropathological damage.12 Astroglia cell atrophy occurs throughout the brain and may account for early changes in synaptic plasticity and cognitive impairment, which appear to develop before gross neurodegeneration.11

CBD has been shown to interfere with neuroinflammation through several mechanisms, including the increase of adenosine, interaction with CB2, reduced reactive astrogliosis, and the activation of PPAR-gamma receptor, among others.  

Adenosine is a modulator of excitatory and inhibitory neurotransmission in the brain and has been found to be involved in the pathogenesis of neurological diseases.13 CBD increases brain adenosine levels by reducing adenosine reuptake, with the resulting increase in adenosine associated with neuroprotection and decreased inflammation after brain trauma.13,14

CBD’s activity at microglial CB2 receptors reduces the release of proinflammatory cytokines and improves functional deficits associated with neurodegenerative disease.15 Selective stimulation of CB2 has also been found to stabilize and enhance the efficacy of the blood-brain barrier, therefore dampening the consequences of neuroinflammation injuries.16

As already discussed, CBD can reduce beta-amyloid plaques and improve brain survival through the activation of PPAR-gamma receptors. The activation of PPAR-gamma receptors has also been shown to markedly downregulate reactive gliosis by reducing proinflammatory molecules and cytokine release caused by sustained astrocyte activation.4

Oxidative Stress
Redox signaling is an intrinsic, tightly regulated component of cell metabolism, controlling cell growth, differentiation, and death.17 Neurons in the brain are at extremely high risk of excessive ROS generation and oxidative damage. When there’s dysregulation of redox signaling, oxidative stress (imbalance between oxidants and antioxidants) can occur and has been widely implicated in the initiation and the progression of many neurodegenerative diseases, including AD.  

It’s also been shown that ROS is involved in the modulation of beta-amyloid production/secretion, while beta-amyloid is reciprocally able to promote excessive ROS generation. Thus, there’s a vicious cycle, with oxidative stress leading to mitochondrial dysfunction, cell signaling impairments, and increased production of beta-amyloid. As a result, beta-amyloid overproduction augments oxidative stress, which in turn results in a response to secrete a variety of proinflammatory cytokines, chemokines, reactive nitrogen, and oxygen species.18

CBD is an antioxidant and reduces beta-amyloid–induced neuronal cell death by virtue of its ability to scavenge ROS and reduce lipid peroxidation. In addition to its anti-inflammatory properties, it’s also able to impair inducible form of nitric oxide synthase and interleukin 1 beta.19

Neuroexcitoxicity
Chronic excitotoxicity has been hypothesized to play a role in numerous neurodegenerative diseases, including AD. Potential mechanisms thought to lead to excitotoxicity include altered calcium homeostasis and increased sensitization of N-methyl D-aspartate (NMDA) receptors, which renders neurons more sensitive to excitotoxicity, which is further amplified by the increased glutamate activation. 

Beta-amyloid can cause Ca2+ dysregulation by directly increasing voltage-dependent Ca2+ channel activity, as well as by forming Ca2+-permeable pores in lipid bilayers to increase intracellular Ca2+, altering neuronal excitability. Furthermore, there’s an excessive activation of NMDA receptors, which are a subtype of glutamate receptor.19 Glutamate is a major excitatory neurotransmitter in the brain and plays an important role in memory, learning, cognition, and motor behavior. Another consequence of beta-amyloid is that it reduces glutamate uptake by astrocytes along with the excessive activation of NMDA receptors, evoking ecotoxicity.12

Through stimulation of CB2 receptors, CBD can reduce Ca2+ influx and limit excitotoxicity. CB2 activation may also stimulate neural progenitor proliferation (neurogenesis) in vitro and in vivo.20 By limiting excitotoxicity and enhancing neurogenesis, CBD may be able to slow the course of AD. 

Neuropsychiatric Symptoms
Neuropsychiatric symptoms are highly prevalent in persons with dementia. The use of high-risk medications such as antipsychotics and benzodiazepines in persons with dementia is controversial and carries significant risks. There’s some evidence that CBD may be a safer option and could be useful for managing neuropsychiatric symptoms such as agitation and anxiety, as well as helping to treat insomnia, which is common in AD. 

Pain is poorly recognized and undertreated in persons with dementia due to the difficulty patients may have in communicating their needs. The undertreatment of pain can lead to a significant reduction in quality of life, and dementia patients who express pain with agitation and anxiety can be inappropriately prescribed dangerous antipsychotics and benzodiazepines. CBD applied on the skin can help lower pain and inflammation due to arthritis, and studies have shown CBD to be able to inhibit inflammatory and neuropathic pain. 

Final Thoughts
Most of the studies and evidence supporting CBD comes from anecdotal reports or small animal studies that don’t always carry over when applied to larger clinical studies. However, the science behind CBD is encouraging, and there’s reason for hope that it may hold the key to future treatments that could help to slow or stop the progression of AD. 

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

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