Deep Dive: Therapeutic Cannabinoids for Alzheimer's Disease

This Deep Dive serves as a research review that summarizes a 2022 study about cannabis for Alzheimer's disease. This article is a living document that is updated regularly based on the release of new research on this topic.

A September 2022 study conducted in Australia entitled "Therapeutic Properties of Multi-cannabinoid Treatment Strategies for Alzheimer's Disease" that was published in the journal Frontiers in Neuroscience explored the potential efficacy of cannabis cannabinoids for the neurological disease Alzheimer's.

The study's authors explained that Alzheimer's is a "disabling neurodegenerative disease and the most common form of dementia." They noted that the condition is characterized by "cognitive decline (e.g., language, memory, and executive function) and functional impairment in activities of daily living."

The Mayo Clinic in Rochester, Minnesota defines Alzheimer's as "a progressive neurologic disorder that causes the brain to shrink (atrophy) and brain cells to die." It defined dementia as a continuous decline "in thinking, behavioral, and social skills that affects a person's ability to function independently."

The Mayo Clinic noted that 5.8 million people in the United States who are age 65 or older have Alzheimer's disease. Of that nearly six million patients, 80 percent are 75 or older.

The Clinic noted that 5.8 million people in the United States who are age 65 or older have Alzheimer's disease. Of that nearly six million patients, 80 percent are 75 or older. The Clinic estimated that "out of the approximately 50 million people worldwide with dementia, 60-70 percent are estimated to have Alzheimer's disease."

One major early sign of Alzheimer's is memory problems, including "forgetting recent events or conversations." Because it is a progressive condition, significant decline in cognitive functionality and the ability to socially interact occurs in most cases of the disease. "A person with Alzheimer's disease will develop severe memory impairment and lose the ability to carry out everyday tasks," noted the Clinic.

Conventional pharmaceutical medications "may temporarily improve or slow progression of symptoms," reported the Clinic. Currently, no cure exists for Alzheimer's. "There is no treatment that cures Alzheimer's disease or alters the disease process in the brain," reported the Clinic, adding that severe cases of the disease feature "complications from severe loss of brain function," including dehydration, malnutrition, and infection that often "result in death."

The 2022 study defined the cause of Alzheimer's as "progressive neuronal dysfunction and cell death, which causes cerebral atrophy, and is pathologically hallmarked by the extracellular accumulation of plaques in the brain." It is these plaques that lead to the formation of neurofibrillary tangles (NFTs) and inflammation in the brain (neuroinflammation) that are responsible for memory and emotional problems and other forms of cognitive decline.

The study explained that current conventional therapies for Alzheimer's produce only "modest" results, "cause numerous side effects, and do not modify disease progression."

Echoing but adding detail to the Mayo Clinic citation above, the study explained that current therapies for Alzheimer's produce only "modest" results, "cause numerous side effects, and do not modify disease progression." These poor outcomes derived from conventional treatments and pharmaceutical drugs motivated the study's authors to declare that novel therapies for Alzheimer's disease (AD) are necessary and that cannabinoids from hemp and cannabis may play a positive role in achieving this goal.

The study's authors noted the role of the human endocannabinoid system in AD and that it is a logical target given its prominent role in a wide variety of human bodily functions, including "cognition (e.g., learning, memory), anxiety, neurogenesis, pain sensation, immune signaling, and inflammation."

The scientists found that the ECS becomes altered and "upregulated" in AD patients, mostly so it can deal with inflammation and other problems that this common disease causes in the brain.

"Phytocannabinoids, including cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), have gained attention as a potential therapeutic strategy for dementia, including AD," reported the study. It noted that both CBD and THC "modulate the ECS" and sometimes deliver "neuroprotective, anti-inflammatory, and antioxidant" benefits.

Emerging evidence also suggests that these cannabinoids may prevent the accumulation of the plaques in the brain that lead to cognitive decline in diseases involving neurodegeneration, including AD.

"Evidence suggests that cannabinoids [like CBD, and THC] may prevent the accumulation of the plaques in the brain that lead to cognitive decline in diseases like AD."

The researchers found that CBD, depending on dose, can reduce neuroinflammation and prevent learning deficits. "THC has been found to inhibit several AD-related pathologies," including improvement of cognitive performance (with low dose treatments) and better "learning and memory." The study also found that, in a rodent study, THC "reversed age-associated cognitive impairments."

A mouse study revealed that THC "restored cognitive function." However, the scientists observed that "THC-only treatments are not an ideal...strategy for improving cognition in AD" and that the addition of other cannabinoids, such as CBD, provides the best improvement of AD symptoms.

Image courtesy Leafwize Naturals

In addition, the study reported that THC, particularly potent doses (identified as 10 mg or more by the researchers), may lead to "adverse effects," including "psychoactivity, dizziness, disorientation, and anxiety."

However, the study noted that the side effects sometimes delivered by potent THC "may lessen over time due to tolerance effects" and that inclusion of other cannabinoids, notably CBD, "may help to block the negative effects of THC." "Low levels of THC in a cannabis-based AD medication may be of value, despite the side effect profile at higher doses," it reported.

The research observed that a number of minor cannabinoids provide anti-inflammatory benefits that are of value to inflammation-based diseases such as AD. These include cannabichromene (CBC), cannabidivarin (CBDV), cannabigerol (CBG), and cannabinol (CBN). In addition, the acidic precursor forms of CBD and THC (CBDA and THCA) were found to provide similar "neuroprotective properties for AD and could be used as alternatives to THC as they are largely non-intoxicating (or, in the case of CBN, less psychoactive than THC)."

"The study reported that a number of minor cannabinoids provide anti-inflammatory benefits that are of value to inflammation-based diseases such as AD."

The research reported that "CBN, CBC, CBDV, and CBDA prevented amyloid toxicity/[brain] cell death." It also found that CBC, CBDV, CBG, and CBN block the accumulation of chemicals that lead to the brain plaques that accumulate and cause cognitive decline in AD patients. CBN was found to provide antioxidant benefits. In addition, the cannabinoid CBC was found to have the ability to support the growth of new neurons (brain cells) and THCA "has demonstrated...neuroprotective properties."

The study noted that "cannabinoid treatments involving a combination of THC and CBD and other cannabinoids can produce greater therapeutic outcomes and less adverse effects than treatment with purified cannabinoid isolates." This observation supports the entourage effect theory which states that synergistic benefits are experienced from cannabinoid (and terpene) combinations that are sometimes called "broad-spectrum" or "full-spectrum" cannabis product formulations.

The study noted that cannabinoids work in a "dose-dependent and biphasic manner." This means that different doses of cannabinoids can provide dramatically different outcomes to AD patients. In addition, the biphasic response curve associated with most cannabinoids means that they deliver one effect at a low dose (also called a "microdose") and may provide a very different or even polar opposite effect at a more potent dose (to confuse things for wellness practitioners and caregivers, these dose levels vary between patients and over time, something that is called "subjective efficacy").

A good example is THC, which is known for producing relaxation and a reduction in anxiety at low doses. However, at strong doses—especially among new users who have built no tolerance to this cannabinoid—THC may result in an increase in anxiety. Sometimes this increase is so great that it produces full blown panic attacks and visits to hospital emergency rooms (this is most common among those who consume too large a dose of cannabis edibles).

The study noted that cannabinoids work in a "dose-dependent and biphasic manner." This means that different doses of cannabinoids can provide dramatically different outcomes.

According to the study, "it has been suggested that a 8.1:1 CBD:THC ratio might result in the observation of antagonism of CBD on THC-induced effects," but that an 1.8:1 ratio of CBD:THC "might result in potentiation of THC effects."

The scientists noted that "cannabis combination therapies" that involve THC can be complicated because "THC can be detrimental to cognition." They said that the appearance of detrimental effects from THC depend upon the age of the patient and the precise dose administered.

The study reported that the current data collected suggests that "multi-cannabinoid treatment strategies using combinations with low-dose THC or administration of THC-low cannabis extracts (or indeed 1:1 CBD:THC-rich cannabis extracts) might be the best option for AD therapy." However, it also stressed that further studies, including clinical trials involving human cohort groups, are necessary.

The study's authors noted that the practicality of using cannabinoids and cannabis-based products for the treatment of AD is challenging based on the extremely variable legal statuses throughout the world.

In the United States, cannabis (excluding CBD derived from hemp) is illegal at the federal level, although there are certain states that have medical cannabis programs."

"Internationally, the situation regarding the legalization and decriminalization of medicinal cannabis varies markedly," they noted, citing Canada as featuring both medicinal and recreational cannabis legalization at the federal level. The study reported that, overall, cannabis use is "tolerated" in the Netherlands, where it is legal for medicinal use. "In the United States, cannabis (excluding CBD derived from hemp) is illegal at the federal level, although there are certain states that have medical cannabis programs."

The study concluded that "multi-cannabinoid combination treatment strategies are valid candidates for novel AD therapies" but that further research, with an emphasis on clinical trials involving humans, "are required to determine optimal dose and ratio of cannabinoids for treatment of behavioral, cognitive, and pathological symptoms of AD."

"The study recommended the consideration of cannabinoids other than CBD and THC for treatment of diseases involving neurodegeneration such as AD."

The researchers recommended the consideration and scientific investigation of cannabinoids other than CBD and THC for AD therapy and said that most studies conducted to date have focused on these two major phytomolecules.

View the original study.