Medical Marijuana and Alzheimer’s

Medical marijuana is accepted medicine for symptom relief in Alzheimer’s. It may also halt or reverse the progression of the disease.

Symptom relief

Over the past few years, cannabis has become widely used by patients for symptom relief in Alzheimer’s. It’s getting grudging acceptance from establishment medicine. From the British Alzheimer’s Society:

Some studies suggest cannabis could help to manage a few behavioural symptoms of dementia, such as agitation and aggression.

I guess helping with “a few” symptoms “such as agitation and aggression” is nothing to get excited about, but in fact studies have shown that marijuana helps to manage sleeplessness, anorexia, agitation, delusions, irritation, aggression, caregiver distress and cognitive decline.

All of these were small, short term studies, focusing only on symptom relief. Most of them used synthetic THC because it is legal to study. Most, though not all, showed symptom relief. A larger scale study is underway in England. But in medical marijuana states, patient and caregiver opinion is clear enough. Many memory care facilities in these states treat cannabis as a medication which, if the relatives bring it in, the facility will dispense, rather than allow patients to dose themselves.

Healing?

Symptom relief is useful, but there is also good reason to think that cannabis can slow the disease and perhaps even heal what has been damaged.

Our knowledge is limited because federal agencies have blocked clinical trials on humans, so we have to fall back on laboratory evidence and population studies. This is a general problem for medical marijuana, but it is particularly acute in the case of Alzheimer’s. It isn’t so hard to make a laboratory model when we know the cause of a condition, for example we can make a fairly accurate model of traumatic brain injury by hitting a mouse on the head. With Alzheimer’s, it’s not so easy. In fact, the lab models have failed, throwing Alzheimer’s research into crisis.

Current understanding of Alzheimer’s

Before PET scans, Alzheimer’s could only be diagnosed by autopsy. Autopsies showed that the brains of Alzheimer’s patients are filled with two incredible engines of destruction — ”amyloid-beta plaques” and “tau tangles”.

Amyloid-beta (Aβ)

Amyloid-beta is a small protein. All proteins fold themselves into a shape, and amyloid sometimes folds itself into a very toxic shape. Misfolded Aβ can stick to the cell membrane like a burr. It can penetrate the membrane, allowing calcium to leak in. Worst of all, it propagates — a molecule of misfolded Aβ can cause other Aβ molecules to misfold themselves. They stick to the cell and the group spreads as an irritating, inflammatory plaque. Like any reproducing population, it grows slowly at first and explosively at the end.

Tau

Tau pathology is also a protein folding disorder. Each nerve cell has a cytoskeleton — a scaffolding of rigid proteins that maintain its shape. Tau is one of these proteins. Tau can misfold like Aβ. Tau misfolding is triggered by Aβ, and it also propagates. Nearby tau misfolds, resulting in wadded up tangles which effectively destroy the cytoskeleton.

Inflammation

Both Aβ and misfolded tau cause oxidative stress, calcium influx, and inflammation. Mitochondria lose function, so the cell has less energy. Receptors for acetylcholine and glutamate become overactive. Meanwhile outside the cell, the plaques cause an immune response from astrocytes and microglia, which attack the nerve, resulting in loss of synapses and cell death. The blood-brain barrier is compromised and loses the ability to clear Aβ from the brain.

The consensus that failed

All of this is clearly happening in the disease, and these destructive processes are enough to explain the damage. 20 years ago this was a consensus understanding of the disease, and yet this vivid consensus did not lead to any effective medicines.

Lab models in Alzheimer’s research

One problem lies in the laboratory models we use to study the disease. The difficulty is that only 5% of Alzheimer’s cases have a known cause, so there are two kinds of Alzheimer’s. They show the same disease progression but they differ in cause.

One form of the disease is caused by mutations in genes controlling the production of Amyloid β. Mistakes in Aβ production can result in a form that is 42 amino acids instead of the more common 40. Aβ-42 is much more likely to misfold, so these mutations lead to “familial Alzheimer’s”. It strikes related members of families. This accounts for about, 5% of the cases. The other 95% are called “sporadic”, meaning they show up sporadically, meaning we don’t know the cause.

In this situation, the obvious way to produce mouse models of the disease is to model familial Alzheimer’s, by genetically engineering mice to have one of the known mutations. These models create the right progression of Aβ plaques, tau tangles, inflammation and the rest. It looks like Alzheimer’s, but based on these models over 400 drugs have reached clinical trials and none have succeeded. For example, Aβ plaques define Alzheimer’s, they are clearly damaging, but breaking them up does not stop sporadic Alzheimer’s in humans:

In recent years, the search for disease-altering drug therapy for Alzheimer’s disease has been typified by sensational Phase II trial results for treatments designed to ameliorate amyloid-b concentrations followed by a total lack of significant improvement over placebo control groups in Phase III trials.

It seems there is an unknown cause — a ghost in the machine. There are many efforts underway to identify it. Another way forward, perhaps, is to attack multiple disease mechanisms at once. A review by Berk, Paul, and Sabbagh came up with three possible ways forward.

The development of novel pharmacological interventions would be more fruitful if multitarget therapies were introduced, and unexplored mechanisms of action were expanded upon. Additionally, there is a rationale for intervening earlier in the disease, perhaps preceding or at the advent of symptoms.

So the possible strategies are — 1) use a multitarget medicine, 2) start treatment earlier, and 3) continue the search for an unknown causal mechanism, the real disease, for which Aβ plaques and tau tangles are merely symptoms.

Cannabis medicine is relevant to all three of these approaches.

1) Cannabis as multitarget therapy for Alzheimer’s

Cannabis medicine typically has multitarget effects on diseases, since it works with a body wide system whose function is to resolve inflammation and cell stress. This endocannabinoid system (ECS) is as old as nerves and skin. It is well established in the most primitive jellyfish, helping them to sense pain and temperature, and coordinate their feeding.

During the 600 million years since our bilateral ancestors diverged from the cnidarians, the endocannabinoid system has extended it’s reach and signaling capabilities. Today, for example, it is a primary communication channel between the gut and brain. It responds to almost all diseases involving humans. As a body-wide system for communicating about stress, it is a natural platform for multitarget therapy. This is particularly true for Alzheimer’s, which is something of a poster child for long term cell stress.

And in fact, cannabinoids have been shown to have beneficial effects on all of the well known pathological processes in Alzheimer’s. The evidence does not include clinical trials, because for more than 50 years the federal government has effectively outlawed clinical trials on cannabis. Congress passed a law that says marijuana has no medical use. Federal agencies have interpreted the law to mean that they should throw every possible roadblock in the way of clinical trials. For most drugs, a handful of promising preclinical results would motivate clinical trials, but for cannabis hundreds of preclinical studies are ignored.

While lab models are not able to uncover the cause of the disease, they can show which disease processes a medicine affects. One or another cannabinoid has been shown to help with all of the well known pathological processes in Alzheimer’s, including
1) Aβ production,
2) clearance of Aβ across the blood-brain barrier,
3) total Aβ load,
4) plaque aggregation,
5) oxidative damage,
6) astrocyte activation,
7) inflammatory signaling,
8) microglial clearance of plaques,
9) microglial damage to nerves,
10) induction of tau tangles,
11) downstream effects of tau pathology,
12) acetylcholine signaling,
13) NMDA signaling,
14) mitochondrial disfunction,
15) loss of myelin,
16) neurotoxicity,
17) hippocampal neurogenesis,
18) learning impairment,
19) cognitive impairment,
and of course, the behavioral symptoms described earlier.

For each of these I have linked to a single article, but there are multiple studies to support these claims. You can find review articles here, here and here.

These are all effects of Alzheimer’s that cannabinoids have been shown to remedy in preclinical studies. This list is astonishing, but in fact it understates the multitarget activity of cannabinoids, because in many cases, these beneficial effects are achieved through more than one channel. For example, cannabinoids break the link between Aβ and tau misfolding by reducing inflammatory nitrogen oxide levels, and also by restoring a stress rescue pathway. Likewise, cannabinoids promote neurogenesis by PPARγ activation, and also by restoring levels of neurotropic growth factor. If any other group of medicines had shown this many effects on the disease, it would be the main focus of worldwide study.

While producing this list, I only found one proposed Alzheimer’s process for which I cannot find a connection with cannabinoids. Dr. Beth Stevens of Boston Children’s Hospital has proposed that complement proteins in the innate immune system cause synaptic pruning early in the disease. As far as I can tell, the endocannabinoid system interacts with the innate immune system through Toll-like receptors rather than through complement signals, although there is crosstalk.

So laboratory research indicates that the right mix of cannabinoids can act against all of the known mechanisms of Alzheimer’s pathology, possibly excepting this early malfunction of the complement system.

The advantage of cannabinoids in neuroprotection is their broad-spectrum profile determined by their activity at multiple molecular sites … and the location of those potential targets for in all key cellular elements in relation to the control of neuronal survival … and also in key brain structures [e.g., blood–brain barrier (BBB)]

2) Cannabiniods as an early intervention

After multitarget therapy, the next suggestion was to begin treatment earlier. If we are to do this, we want a medicine that is safe. The safety profile of cannabis is well established. For all their years of trying and all their billions of dollars, the prohibitionists in the U.S. have yet to prove harm from marijuana. Aspirin accounts for 3,000 deaths per year in the U.S. If cannabis were as dangerous as aspirin, you would have heard about it.

3) The ghost in the machine

The last suggested way forward for Alzheimer’s treatment is to find a hitherto unknown cause of the disease. Where might we look for something like that?

Let’s begin with a thought experiment. Imagine that there is a bodily system that works with all of the participants in the disaster that is Alzheimer’s — with the nerves, astrocytes, microglia, oligodendrites and the blood-brain barrier. This system has been shown to respond to all of the accepted biomarkers for Alzheimer’s. Imagine that this system is not taught in medical schools, and established researchers are reluctant to study it. You cannot legally develop a medicine to treat this system and despite thousands of preclinical studies, papers are regularly written which say “there is no evidence” for medical marijuana, because they begin by excluding everything except double-blind placebo-controlled studies on humans. Imagine that the authors of those papers never bother to mention that the clinical trials they demand are illegal.

I’m suggesting that the mysterious ghost that we cannot find might actually be an elephant, clearly in the room, yet somehow invisible. What if we look at damage to the endocannabinoid system as a possible cause of the disease?

We can at least say that as the endocannabinoid system goes about its repair work, it is also under attack by the disease. CB1 receptor expression is markedly decreased in Alzheimer’s diseased brains. The cannabinoid AEA is depleted and the AEA depletion correlates with cognitive deficits. CB1 and CB2 receptor proteins are nitrated making them less effective.

Recently Aβ has been found to damage memory before any plaques or synaptic pruning, and it does this by attacking the ECS. Cannabinoid signals in the hippocampus are necessary in order for episodic memories to be written. Aβ can prevent these signals from doing their work. The signals get through, but the receiving cell doesn’t respond and memory is not written. This occurs well before any of the signs of physical damage.

Do we want to do something about this disease?

Let’s summarize: Marijuana is commonly used for symptom relief in AD, often in the care of nurses. There is abundant preclinical evidence that manipulating the ECS can be protective or even healing. The safety profile of medical marijuana is superior to things like the NMDA inhibitors that are already approved for memory loss. Cannabinoids interact with AD markers across the board, and the earliest effects of Aβ on memory are accomplished when it attacks the endocannabinoid system.

Unfortunately, knowing that the ECS is involved in this disease does not get us to a medicine. The ECS is complex and the numerous cannabinoids are not all the same. We need to know which cannabinoids to use, dosage and method of administration. We need to know whether the promise of cannabinoids can be realized, as medicines to heal as well as treat symptoms.