"Alzheimer's disease is the leading cause of dementia among the elderly, and the numbers are growing. The Alzheimer's Association estimates 4.5 million Americans have the disease, a figure that could reach as high as 16 million by 2050. A survey by the National Center for Health Statistics noted that half of all nursing home residents have Alzheimer's disease or a related disorder. The costs of caring for Alzheimer's patients are at least $100 billion annually, according to the National Institute on Aging."
THE INTRODUCTIONScientists are currently studying if cannabis and its extracts can be used to treat different diseases and conditions such as HIV/AIDS, multiple sclerosis, Alzheimer's disease, seizures, substance use disorders and mental disorders. Cannabis contains cannabinoids, chemicals related to delta-9-tetrahydrocannabinol (THC), also known as the mind-altering ingredient. The U.S. Food and Drug Administration (FDA) has approved two medications in pill form based on this ingredient. The approved drugs, dronabinol and nabilone, are now being used to treat nausea caused by chemotherapy and increase the appetite of patients with AIDS.
Cannabinoids are structurally similar and have varying effects on brain function and metabolism. Of these, arguably the most important are THC and CBD, which have a range of physiological effects relevant to Alzheimer’s—they can reduce inflammation, act as antioxidants and neuroprotectants, and even stimulate the growth of new neural tissue—and if taken regularly, there is evidence that they can not only slow the progression of existing Alzheimer’s cases but also slow the onset of new cases.
Scientists at The Scripps Research Institute have found that the active ingredient in marijuana, tetrahydrocannabinol or THC, inhibits the formation of amyloid plaque, the primary pathological marker for Alzheimer's disease. In fact, the study said, THC is "a considerably superior inhibitor of [amyloid plaque] aggregation" to several currently approved drugs for treating the disease.
“THC is known to be a potent antioxidant with neuroprotective properties, but this is the first report that the compound directly affects Alzheimer’s pathology by decreasing amyloid beta levels, inhibiting its aggregation, and enhancing mitochondrial function,” stated study lead author Chuanhai Cao, PhD and a neuroscientist at the Byrd Alzheimer’s Institute and the USF College of Pharmacy.
"When we investigated the power of THC to inhibit the aggregation of beta-amyloid," said Kim Janda, Ph.D. "We found that THC was a very effective inhibitor of acetylcholinesterase. In addition to propidium, we also found that THC was considerably more effective than two of the approved drugs for Alzheimer's disease treatment, donepezil (Aricept ®) and tacrine (Cognex ®), which reduced amyloid aggregation by only 22 percent and 7 percent, respectively, at twice the concentration used in our studies. Our results are conclusive enough to warrant further investigation."
The term ‘amyloid beta’ refers to peptides created by the enzymatic fragmentation of amyloid precursor protein, a substance that is thought to be fundamentally involved in the regulation of synapse formation and neural plasticity. The precise primary function of amyloid precursor protein (APP) is unknown, and our comprehension of the normal functions of amyloid beta is in its infancy. However, it is clear that in individuals suffering from Alzheimer’s, excess amyloid beta accumulates in the brain and aggregates to form amyloid plaques, which are toxic to neural tissue.
A study published in the Journal of Alzheimer's Disease in 2014 by researchers at the University of South Florida investigated the relationship between the endocannabinoid system and the process of plaque production, and demonstrated that APP cells incubated with THC at very low doses produced amyloid beta at a slower than normal rate; THC also directly interacted with beta amyloid peptide and inhibited its aggregation into plaques.
The study also demonstrated that THC at low doses also reduced levels of glycogen synthase kinase 3 beta (GSK3ß), an enzyme that is normally involved in energy metabolism and neuronal cell development but is also responsible for the development of neurofibrillary tangles in the brains of Alzheimer’s patients. These neurofibrillary tangles are comprised of tau proteins, particularly paired helical filament tau (PHF-Tau); GSK3ß is believed to be responsible for the production of PHF-Tau.
The role of the endocannabinoid system in modulating the processes of oxidative stress is not fully understood, but it has been demonstrated repeatedly that administration of cannabinoids can help to reduce its effects and can provide a neuroprotective effect on the neurons, slowing the rate of oxidative cell death. In 2004, a study demonstrated that exposing cells to amyloid beta caused a significant decline in cell survival, but that treating the cells with cannabidiol prior to amyloid beta exposure caused a notable increase in cell survival.
Previous studies have linked cannabinoids to increased amounts of brain-derived neurotrophic factor (BDNF), a substance that protects brain cells and promotes the growth of new ones. Since new cell growth slows or stops during aging, increasing BDNF could potentially slow the decline in cognitive functions.
The endocannabinoid system is emerging as a key regulator of many neuronal systems that are relevant to neurodegenerative disorders. Activation of CB1 receptors regulates many neuronal functions such as Ca2+ homeostasis and metabolic activity while the CB2 receptor is mainly involved in regulating the inflammatory response.
A 2011 study on Alzheimer’s demonstrated that cannabidiol exerted its anti-inflammatory and antioxidant effects via a mechanism that is independent of the endocannabinoid system, instead working on a receptor known as the peroxisome proliferator-activated receptor-γ (PPARγ). By working on the PPARγ, cannabidiol was not only able to reduce inflammation and production of reactive oxygen species to protect existing cells, but was also able to induce neurogenesis in the hippocampus (a region of the brain that is heavily affected by Alzheimer’s) by directly blocking the action of amyloid beta.
As well as reducing inflammation and mediating the effects of oxidative stress, cannabidiol is also thought to promote the growth of new neural tissue (a process known as neurogenesis). In Alzheimer’s, the rapid destruction of neural tissue causes devastating neurological effects, and the normal processes of neurogenesis are interrupted by the presence of amyloid beta. Developing therapies that can stimulate neurogenesis may therefore slow the progression of the disease or even reverse its symptoms to some extent.
A-beta is known to impair pyramidal-cell plasticity. But Madison’s research team showed for the first time how it does so. In the study, published June 18 in Neuron, researchers analyzed A-beta’s effects on a brain structure known as the hippocampus. In all mammals, this midbrain structure serves as a combination GPS system and memory-filing assistant, along with other duties. Small clusters consisting of just a few A-beta molecules render interneuron’s endocannabinoid receptors powerless, leaving inhibition intact even in the face of important news and thus squashing plasticity.
While small A-beta clusters have been known for a decade to be toxic to nerve cells, this toxicity requires relatively long-term exposure, said Madison. The endocannabinoid-nullifying effect the new study revealed is much more transient. A possible physiological role for A-beta in the normal, healthy brain, he said, is that of supplying that organ’s sophisticated circuits with yet another, beneficial layer of discretion in processing information. Madison thinks this normal, everyday A-beta mechanism run wild may represent an entry point to the progressive and destructive stages of Alzheimer’s disease.
But smoking or ingesting marijuana results in long-acting inhibition of interneurons by the herb’s active chemical, tetrahydrocannabinol. That is vastly different from short-acting endocannabinoid bursts precisely timed to occur only when a signal is truly worthy of attention.
“Endocannabinoids in the brain are very transient and act only when important inputs come in,” said Daniel Madison, associate professor of molecular and cellular physiology and the study’s senior author. “Exposure to marijuana over minutes or hours is different: more like enhancing everything indiscriminately, so you lose the filtering effect. It’s like listening to five radio stations at once.”
Although three clinical trials studied cannabinoids for the treatment of Parkinson's Disease, these studies “did not provide a clear answer whether cannabinoids modify the progression or the outcome of the disease,” wrote Andras Bilkei-Gorzo of the Institute of Molecular Psychiatry at the University of Bonn in Germany. He found similar results for Huntington’s Disease, which, like Parkinson’s, is a progressive, degenerative brain disorder. And for the most common form of dementia, “Despite the promising preclinical results, the detailed clinical evaluation of cannabinoids in [Alzheimer’s] patients is missing,” he said in the paper.
THE VERDICTThe social and political challenges to conducting such research mean that it may be a while before we see such scientific gaps filled. Scientists have yet to conduct, for example, a solid study in which they follow marijuana smokers to see if they are more or less likely to develop Alzheimer’s— or to compare the cognitive decline of marijuana smokers to those who do not smoke. Doing so is too controversial to attract funding.
Gary Wenk, professor of neuroscience, immunology and medical genetics at Ohio State University says, “I’ve been trying to find a drug that will reduce brain inflammation and restore cognitive function in rats for over 25 years; cannabinoids are the first and only class of drugs that have ever been effective. I think that the perception about this drug is changing and in the future people will be less fearful. The evidence in animals is clear but making the leap to humans mean that you have to find a drug company willing to handle the lawsuits and the money,” Wenk said.
The U.S. government has patented marijuana molecule CBD as a neuroprotectant, even as it maintains that cannabis is a schedule 1 drug with no medical use and high potential for abuse. The federal drug war is blocking deeper research into cannabis’ impacts on brain disease, Wenk states.