Here is how cannabinoids like THC and CBD could slow the progression of Alzheimer’s Disease. The next step: a clinical trial.
Alzheimer’s Disease is one of the most significant challenges to the health of our society, especially with an aging population. In Part I, I covered how THC is being tested to treat certain Alzheimer’s symptoms. But a drug that goes beyond treating symptoms and actually slows or prevents Alzheimer’s would be a game changer. Here in Part II, I will review how cannabinoids could potentially slow the rate of disease progression.
Let me state up front that while studies done so far are intriguing, we do not yet have evidence in humans that cannabinoids will work. We also won’t know for a while. Because disease progression happens slowly over years, clinical trials have to follow patients for a long time to see if the drug has an effect. This makes these studies lengthy and very expensive.
Instead what we have are a lot of studies in cells and animals. These models of Alzheimer’s are imperfect and a positive result does not necessarily translate to humans. However, there is good news – one company thought that these results were strong enough to invest in a clinical trial.
The Brain of an Alzheimer’s Patient
Before we get into cannabinoids, let’s review some basics of what happens in the brain of an Alzheimer’s patient. For further reading, this website has a good explanation of Alzheimer’s pathogenesis. I will present below the minimum amount you need to know to understand how cannabinoids might work in Alzheimer’s.
There are two proteins that go awry in Alzheimer’s: amyloid beta (Aβ) and tau. Proteins normally fold into a unique 3D shape, but these proteins misfold in a way that causes them to aggregate and cause neural damage.
- Aβ is a fragment of a larger protein that forms clumps deposited outside of neurons, called senile plaques.
- Tau is an intracellular protein which can become hyperphosphorylated and also clump together, forming neurofibrillary tangles.
Cannabinoids Hit Multiple Steps in Alzheimer’s Disease
Now that we know some of the processes that lead to Alzheimer’s Disease, how can cannabinoids affect these mechanisms? Many drug candidates have targeted just a single aspect, for example an antibody against Aβ or against tau. In contrast, components of cannabis seem to inhibit almost every step of Alzheimer’s.
The studies below are not meant to be a comprehensive list, but highlight key examples of different mechanisms.
What are the different ways to reduce amyloid plaques? You can reduce levels of Aβ, either by reducing its parent protein APP or by inhibiting its processing into Aβ. You can inhibit aggregation of Aβ into plaques. You can also remove existing plaques.
Amazingly, cannabis constituents can do all three of these!
- CBD reduced Aβ production. It did this by stimulating APP ubiquitination, which targets it for degradation.
- THC reduced Aβ aggregation. In a rather incredible twist, THC did not do this through activating the CB1 recepetor, but by binding directly to Aβ.
- CB2 activation facilitated removal of Aβ plaques. This occurred by stimulating macrophages to consume the plaques.
Tau protein aggregation is driven by hyperphosphorylation. Multiple components of cannabis can inhibit tau hyperphosphorylation.
- CBD reduced tau hyperphosphorylation
- CB1 activation reduced tau hyperphosphorylation.
- CB2 activation reduced tau hyperphosphorylation.
Neuroinflammation & Oxidative Stress
There are many studies showing anti-inflammatory and anti-oxidant properties of cannabinoids. I will just mention a few here that are relevant to Alzheimer’s
- CBD reduced microglial activation.
- CB1 activation reduced neuroinflammation.
- CB2 activation reduced neuroinflammation and oxidative stress damage.
Synergistic Activity of Cannabinoids in Alzheimers?Given the mechanisms of cannabinoids in the prior section, it should be no surprise that they have positive effects in multiple animal models of Alzheimer’s Disease.
I want to highlight one study in particular because it examined whether THC and CBD could perform better together than when either one was given alone. This is yet another example of the entourage effect.
This 2015 study examined 4 different treatments using a mouse model of Alzheimer’s (the transgenic AβPP/PS1 model):
- Vehicle (no drug)
- THC alone
- CBD alone
After 5 weeks of treatment (and a washout period to eliminate any acute effects of the drugs), several things were tested: memory, Aβ levels, plaque-associated immune cells, expression of inflammatory molecules, and others.
Both THC and CBD showed improvements for many of these measures. However, there were several for which the combination of THC+CBD performed numerically better than either cannabinoid alone:
- Learning performance
- Total cortex amyloid
- Soluble Aβ42 levels (this is the most toxic form)
- Plaque-associated glial cells
- Expression of certain pro-inflammatory molecules
These results indicate that the combination of THC and CBD may be a better treatment for Alzheimer’s Disease than either cannabinoid alone.
A later 2016 study performed a similar experiment in mice lacking the CB2 receptor. They showed that the THC+CBD treatment did not depend on the CB2 receptor. However, this may indicate that THC+CBD is not optimally activating the CB2 receptor and that the addition of a potent CB2 agonist (such as the terpene β-caryophyllene) may result in additional synergistic activity.
Upcoming Clinical Trials of Cannabinoids in Alzheimer’sWe now have a large amount of evidence from lab experiments showing that cannabinoids could slow progression of Alzheimer’s Disease. However, multiple other drugs that performed well in similar experiments ended up failing in clinical trials.
The million dollar question: will anybody pay for the long and expensive clinical trials necessary to prove that a cannabinoid-based medicine actually works in humans with Alzheimer’s Disease?
Things are looking surprisingly good. A company called India Globalization Capital has become the exclusive licensee of a patent filed by the University of South Florida, entitled “THC as a Potential Therapeutic Agent for Alzheimer’s Disease.”
The company is developing a proprietary product called IGC-AD1, which contains low doses of THC. According to their CEO:
“We are putting the finishing touches on our products, which may include filing additional patents, and we very much expect to start pursuing clinical trials for our Alzheimer’s product and others this year.”
I have not yet seen any details of a clinical study posted in clinicaltrials.gov, but I am keeping my eye out and will let you know when I see something. I am interested in knowing whether their product contains only THC or if it will also contain CBD. (If you are interested in things like new clinical trial startups, you may want to join the weekly medical newsletter).
[Featured Image: Flickr/ NIH Image Gallery]
Last modified: September 15, 2017