Alzheimer’s Disease (AD) and other forms of dementia are rising within the aging population throughout the world. There are currently around 50 million people in the world with dementia, a number expected to rise to 82 million by 2030 and 152 million by 2050. Most current treatments are focused on alleviating the symptoms of dementia rather than treating the root cause of the associated neurodegeneration. Therefore, novel treatments that could potentially reduce or reverse the progression of dementia are desperately needed. Phytocannabinoids (cannabinoids derived from cannabis) or whole-plant cannabis medicines are some of the most promising future treatments, with significant preclinical and even some human evidence indicating they could work tremendously well.
The pathogenesis of AD is characterized by several phenomena, one of the biggest being the accumulation of beta-amyloid proteins in the brain. Beta-amyloid proteins are naturally occurring but increase abnormally in AD and clump together into plaques between neurons to inhibit neurotransmission. Other hallmarks of AD include neuroinflammation, impairment of mitochondria, excessive oxidation, and disruption of the blood-brain barrier. Furthermore, a protein called tau, which helps stabilize important supportive transport structures called microtubules inside neurons, has been shown to become hyperphosphorylated (addition of phosphate chemical groups at multiple binding sites on the protein) in AD, and continues to accumulate as the disease progresses. In essence, the abnormal tau proteins detach from microtubules and stick together, creating neurofibrillary tangles that impair neural communication.
The Endocannabinoid System and Alzheimer’s Disease
The endocannabinoid system (ECS) has been implicated in the pathogenesis of AD and may offer targets for its treatment. The CB1 cannabinoid receptor is especially abundant in the brain, including areas like the hippocampus and basal ganglia that are involved in memory, motor control, and emotions, which are impaired in dementia. Microglia, which are supportive immune cells of the central nervous system, express higher levels of CB2 receptors (commonly associated with the immune system in general) in AD brains than normal brains. However, the density of neurons expressing the CB1 receptor has been observed to decrease in AD patients, a reduction which may be caused by excessive activation of microglia. Activation of CB1 and CB2 receptors may potentially impair the progression of AD through different mechanisms.
Given the role of beta-amyloid accumulation in Alzheimer’s, anything that can reduce its presence is of interest. A 2009 study using a synthetic agonist of the CB2 receptor produced an interesting revelation – activation of CB2 receptors could stimulate immune cells to remove beta-amyloid protein in frozen human tissue sections. Researchers concluded, “These data corroborate the possible therapeutic interest of CB(2) cannabinoid specific chemicals in the treatment of Alzheimer’s disease.”
Preclinical Studies on CBD and Alzheimer’s Disease
Cannabidiol (CBD) is the most popular nonintoxicating phytocannabinoid in use and is easily obtainable in the United States. It holds substantial promise in obstructing the processes leading to AD and potentially other forms of dementia. For example, a 2014 study tested CBD on neurons and found that the phytocannabinoid could reduce production of beta-amyloid protein by interfering with its parent compound, known as amyloid precursor protein (APP). CBD further improved survival of neurons. All observed effects were linked to CBD’s activation of the PPARγ receptor rather than any cannabinoid receptor interactions.
Practical beneficial effects in animals have been demonstrated with CBD as well. Using a mouse model of AD, administration of 50mg/kg CBD restored deficits in social recognition memory and spatial learning observed in untreated mice. Beta-amyloid protein was also reduced in the brains of mice, although no effects on inflammation or neurodegeneration were observed. However, a different study with rats found CBD did reduce beta-amyloid-induced neuroinflammation, reduced neuronal damage, and even stimulated the production of new brain cells (neurogenesis) in the hippocampus.
An excellent summary article on CBD and Alzheimer’s disease was published in 2017, with the abstract stating, “The phytocannabinoid cannabidiol possesses neuroprotective, antioxidant and anti-inflammatory properties and reduces [beta-amyloid] production and tau hyperphosphorylation in vitro. CBD has also been shown to be effective in vivo making the phytocannabinoid an interesting candidate for novel therapeutic interventions in AD.” All these effects were reinforced in another 2017 study, which described the ability of CBD to inhibit beta-amyloid development and tau protein hyperphosphorylation potentially through increasing a biochemical pathway called Wnt/β-catenin, which is downregulated in AD. Oxidative stress, which can help destroy cells by inhibiting survival pathways, was reduced by CBD, as was excessive inflammation. The function of mitochondria, which is normally impaired in AD, was also improved. These results demonstrate comprehensive effects of CBD on the underlying pathology of AD.
Long-term potentiation (LTP) is an important process by which connections between neurons become stronger, and is likely a process that contributes to learning and memory. In a 2019 study, application of beta-amyloid protein impaired LTP in the hippocampal region of mouse brain slices, but pre-treatment of those slices with CBD at least partially reversed the impairment. As an earlier referenced study showed, CBD’s effects were dependent on activation of the PPARγ receptor.
As if all the above effects were not enough, CBD has been shown to downregulate AD-associated genes in stem cells, including those involved with promoting beta-amyloid production and tau hyperphosphorylation. CBD further inhibited an enzyme called GSK3β, which is involved with AD pathogenesis. Unlike other studies, the TRPV1 receptor was implicated in some of these effects, rather than the PPARγ receptor.
Preclinical Studies on THC and Alzheimer’s Disease
While CBD has received the bulk of attention for potentially treating AD, the primary psychoactive component of cannabis, tetrahydrocannabinol (THC), also demonstrates promise. A 2006 study tested THC’s ability to inhibit beta-amyloid development, finding that “Compared to currently approved drugs prescribed for the treatment of Alzheimer’s disease, THC is a considerably superior inhibitor of [beta-amyloid] aggregation.” A 2016 study further elucidated the mechanism of THC’s action, showing it block the harmful inflammatory response and stimulate removal of beta-amyloid protein.
Like CBD, THC has been demonstrated to reduce the harmful GSK3β enzyme, with higher amounts of THC exerting a greater effect in a cell model. THC also directly interacted with beta-amyloid to reduce aggregation, and it enhanced mitochondria function. The researchers stated, “These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer’s disease through multiple functions and pathways.”
Preclinical Studies on Whole-Plant Cannabis Preparations and Alzheimer’s Disease
Whole-plant extracts, or botanical extracts, of THC and CBD, which contain additional compounds beyond those primary phytocannabinoids, may be more effective than isolated phytocannabinoids. Although more research is needed, preliminary evidence suggests that THC and CBD extracts derived from cannabis can interfere with the progression of AD. A 2015 study found that botanical extracts of THC and CBD preserved memory and reduced learning impairment in mice with artificially-induced AD pathology when administered in the early symptomatic stage. Beta-amyloid levels and inflammatory activities were also significantly reduced. The inflammation was especially affected from the combination of THC and CBD, as either phytocannabinoid alone was less potent. Another study in 2020 using THC and CBD botanical extracts showed their potential as fighters of oxidative stress, although THC was reported to have higher antioxidant activity than CBD in this case.
Clinical Trials and Case Reports of Phytocannabinoids as Treatments for Alzheimer’s Disease and Dementia
Preclinical evidence is interesting, but what really matters is if phytocannabinoids can help real human patients. Clinical trials suggest that isolated phytocannabinoids or whole-plant extracts could be effective. One of the earliest trials conducted in 1997 with a synthetic form of THC called dronabinol pointed to the efficacy of phytocannabinoids in dementia. 11 patients with probable AD completed two study periods (six weeks each) where they were given dronabinol (2.5mg twice daily) or placebo. The dronabinol was associated with decreased disturbed behavior, an effect which continued when patients were changed to placebo from dronabinol. The dronabinol period was also associated with greater weight gain than the placebo period. While three patients had to drop out due to issues likely not associated with the dronabinol, other mild side effects like euphoria and tiredness did not cause anyone to drop out.
Patients with dementia often experience nighttime agitation, which interferes with sleep and is uncomfortable. A 2006 trial treated six patients (five with AD, one with vascular dementia) with 2.5mg dronabinol per day for two weeks. Compared to starting levels, nighttime agitation decreased with dronabinol as measured by a reduction in nocturnal motor activity. The neuropsychiatric inventory total score also improved as did aberrant motor and nighttime behavior subscores.
A 2014 study retrospectively analyzed 40 inpatients with severe dementia and the impact of dronabinol on their treatment. While precise dosing was not clear, based on other studies there is a high likelihood it was between 2.5mg to 10mg per day. Adding dronabinol was associated with improvements in all domains of the Pittsburg Agitation Scale, which include aberrant vocalization, motor agitation, aggressiveness, and resistance to caregivers. Sleep duration and percentage of meals consumed increased too.
One of the few trials to apparently use a whole-plant THC-rich oil was published in 2016 and examined effects on eleven patients with AD, ten of whom completed the trial. Overall severity of illness was observed in patients (essentially decreasing from “severely ill” to “markedly ill”), and specific symptoms of delusions, agitation/aggression, irritability, apathy, sleep, and caregiver distress improved significantly. Researchers stated, “Adding [medical cannabis oil] to AD patients’ pharmacotherapy is safe and a promising treatment option.”
On the other hand, a 2015 study testing 1.5mg THC daily for three weeks against placebo for treatment of dementia-related neuropsychiatric symptoms found no statistically significant benefit, although the treatment was well-tolerated and the authors noted the potential of exploring higher doses. Indeed, other studies with efficacy tended to use higher individual doses of dronabinol which may have been critical for observing efficacy.
Interestingly, most of the preclinical evidence has focused on CBD, whereas the clinical evidence has centered on THC, but there are some emerging observations on CBD’s benefits for dementia in humans. An article on Project CBD summarized the findings from a double-blind, placebo-controlled trial that was shared at the International Association for Cannabinoid Medicines, and revealed the real promise that CBD holds for managing symptoms. 64 dementia patients (apparently diagnosed primarily with AD) with an average age of 79 used a whole-plant CBD-rich oil or placebo for 16 weeks. Researchers found that 72% of patients in the CBD group experienced relief from dementia-induced agitation, compared to 30% in the placebo group. Other behavioral symptoms also reportedly improved.
Only one trial has apparently explored the benefits of administering THC and CBD together. A trial published in 2019 followed ten female patients with severe dementia who were cared for in a nursing home in Geneva, Switzerland. The dosing progressively increased over time, with administration of 7.6mg THC/13.2mg CBD daily after two weeks, 8.8mg THC/17.6mg CBD after a month, and 9mg THC/18mg CBD after two months. The observed benefits were quite extensive, with various symptom inventories decreasing by 40% after two months, and rigidity specifically by 50%. Half of the patients were able to decrease or discontinue psychotropic medications. Due to a need for less opioids, there was a decrease in constipation as well. The cannabis medicine never needed to be withheld because of side effects, and benefits even persisted after the two-month trial period. Ultimately, the therapy was concluded to greatly improve behavior problems, rigidity, and daily care.
Outside of trials, real experience is demonstrating the viability of cannabis medicines. Dr. Jeffrey Hergenrather, a physician in California, has reported on his experience treating dementia patients with positive results. His work was cited in a 2018 study titled “Cannabis Therapeutics and the Future of Neurology”, which described how AD patients used THC (2.5 – 30mg per dose), CBD, or THCA (the raw form of THCA) in the form of tinctures or edibles to deal with symptoms. “Marked benefit was reported on neuroleptic drug sparing, decreased agitation, increased appetite, aggression, sleep quality, objective mood, nursing care demands, self-mutilation and pain control.” Explaining directly in a 2014 interview, Dr. Hergenrather noted that many AD patients refused their previous pharmaceutical medications after experiencing the benefits of cannabis.
A patient case report shared on Weedmaps.com indicated the potential of CBD for alleviating AD symptoms. The patient’s wife, Addie Josefson, began administering CBD oil to her husband because he was experiencing substantial anxiety and distress. Oral and topical treatment was reportedly effective at making him calmer and happier, although it had no effect on memory. Josefson noted that her husband was enjoying life more and her own life was easier since utilizing CBD oil.
The Future Potential of Phytocannabinoids for Dementia
The preclinical, clinical, and case-reported evidence clearly demonstrates a role for phytocannabinoids in treating dementia, although more research is needed to clarify proper treatment protocols. The use of nonpsychoactive raw phytocannabinoids like THCA and CBDA must also be explored, as their unique antioxidant and anti-inflammatory abilities may enhance the efficacy of THC and CBD or be effective on their own. Given the aggressiveness of dementia and the growing number of cases expected, potentially groundbreaking treatments must be adequately researched.
For more information, the podcast Cannabis Helps Dementia is an excellent resource.
