Donepezil is one of the most widely prescribed drugs for the treatment of Alzheimer’s. 

Its basis in medicine started back in 1976 when two researchers discovered a marked reduction in the activity of enzymes involved in the metabolism of the neurotransmitter Acetylcholine in brains of deceased patients with Alzheimer’s Disease (AD). This finding led to the hypothesis that AD was caused by a “cholinergic system failure.” At the time, the best educated guess to remedy this theorized failure was to synthesize a new class of reversable Acetylcholinesterase inhibitors – one of which was Donepezil – that were trialed and eventually approved for widespread use for the treatment of AD.

What we found a bit unnerving (no pun intended) is that nerve gas is also considered an Acetylcholine inhibitor. As are most insecticides. The main difference between acetylcholine inhibiting drugs like Donepezil and insecticides like “Raid” is whether the drug is “reversible” or “irreversible” – a condition that boils down to the chemical structure of the acetylcholine inhibitor. Here’s a table that says it all. Our point in bringing this up is to clarify that Donepezil IS NOT NERVE GAS but that it is not a benign drug.  It is affecting the single most prevalent neurotransmitters in our body controlling muscle movement.

Unfortunately, years after the 1976 discovery, Acetylcholine inhibitors like Donepezil ended up not being the home run researchers expected. In fact, from the literature, it appears these drugs are barely a base hit. Studies (and there have been lots of them) show that Donepezil provides nominal improvements to cognition and with lots of potentially troublesome side-effects in the Short Term. More importantly, there are warnings after warnings indicating that this type of drug should not be used Long Term. 

Which raises the question of: were the scientists back in 1976 wrong? What if the reduction in enzyme activity is not due to a lack of cholinergic cells? What if it’s due to something else – like the blocking of signals by a self-preservation process within the brain? The real fact is: we still don’t know what is causing the synaptic loss in Alzheimer’s brains. What we do know is that cholinesterase inhibitors are proving to not be the utopic solution we initially thought they were.

Still, Donepezil has been proven to provide a very slight cognitive improvement at the start of treatment. Which begs the question of “why”? So back to the literature we went and were not surprised to find that this class of drugs has recently been found to exhibit anti-inflammatory properties!  This completely supports our hypothesis and further supports my dad’s very compelling story

And this makes sense as scientists have now come to the realization that AD is a disease of inflammation – so of course a drug that reduces inflammation – even just a little – will have a positive impact on the patient. 

Here are just a few places where we are seeing references to the anti-inflammatory properties of Donepezil:

Study 1: “Our data suggested that the anti-inflammatory effects of donepezil may be a novel mechanism on treating EAE and provided further insights to understand the donepezil’s neuroprotective activities in MS.”

Study 2: “suggesting that DZ [Donepezil] directly prevents systemic inflammation.”

Study 3: “Recently, anti-inflammatory and neuroprotective effects of the drug have been reported. “Cholinergic anti-inflammation pathway” has major implications in these effects.”

We have firsthand experience with Donepezil. My dad – Dr. Crandall – took it for quite a while, and saw no cognitive improvement at the initial 5 mg dose and just a little at the 10mg. When he finally stopped taking it, we did see a little cognitive drop, which was quickly remedied by a 5 mg increase to his prednisone. But what was most interesting is that when dad stopped the Donepezil, we saw an improvement to his gate. This made us stop and think: is it possible the Donepezil had caused his jerky gate?  How about other tell-tale signs of dementia that care-givers keep looking for: motion disturbances, balance issues/frequent falls, incontinence, tiredness/fatigue?  From what we are learning, all of these could be explained by changes to the parasympathetic system. And Doneprezil is altering a crucial neurotransmitter of the parasympathetic system. And since no one has conducted a study on how this drug affects people after long term use – how do we really know if these physiologic changes are really the disease’s progression or actually the drug designed to slow the progression of the disease?  Another thought we had, which will never be answered is: what would have happened if dad hadn’t been on steroids when he started Donepezil?  Would he have experienced a bigger “bump” in cognition like others have reported when initially starting this drug?  

ARICEPT®
(donepezil hydrochloride) Tablets, for Oral Administration

DESCRIPTION

ARICEPT (donepezil hydrochloride) is a reversible inhibitor of the enzyme acetylcholinesterase, known chemically as (±)-2, 3-dihydro-5, 6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride. Donepezil hydrochloride is commonly referred to in the pharmacological literature as E2020. It has an empirical formula of C24H29NO3HCl and a molecular weight of 415.96. Donepezil hydrochloride is a white crystalline powder and is freely soluble in chloroform, soluble in water and in glacial acetic acid, slightly soluble in ethanol and in acetonitrile, and practically insoluble in ethyl acetate and in n-hexane.

Notice the molecular weight (416 g/mol). From our experience, it’s a bit big for all of the drug to bust through the BBB – see our earlier post on antibiotics and molecular weight to see why we even mention this…

Which means this common Alzheimer’s medication, or most of it, may not be getting into the brain and instead is relegated to run freely in the patient’s body. And since it’s method of action works on neurotransmitters critical to our parasympathetic system, while we are using the drug to (hopefully) improve brain function, we will also be inadvertently affecting bodily functions of heart rate, digestion, sweating, tearing, breathing, and muscle movement.

Wow.

When dad didn’t respond much to the drug, his prescribing doc told us that sometimes it takes a while for the drug to take effect. And so we waited – a full four years – with no improvements. The first time we attempted to stop the drug, the docs said that we had been mistakenly looking for improvements in cognition, when the real improvements we should have been looking for were a slowing of the disease progression. In fact, the neurologist literally promised that if we stopped this drug, any decline that Donepezil had prevented would hit dad like an avalanche, forcing him to suddenly experience years of decline in a matter of days/weeks. With that threat, we decided to stay on the drug.  [To be noted, the only reason dad eventually stopped taking Donepezil was because his prescribing doc was on vacation for three weeks when his script ran out and after two  weeks of not taking the drug, and actually noticing that dad’s movements were less jerky and he’d virtually stopped twitching, we decided not to pursue restarting the prescription. No avalanche. And absolutely no set backs were ever experienced in discontinuing the drug].

In talking with others, it seems this is often the case. Doctors place suspected Alzheimer’s patients on this drug at the onset of noticeable cognitive decline and never revisit the drug again. Most certainly this drug is on the M.A.R. of patients dying every day of Alzheimer’s. Yet, when this drug was approved by the FDA, it was based on initial trials testing the efficacy and side-effects over 3- and 6-month time frames. Still to this day we could not find even one meaningful long-term study that supports taking this drug longer than that 6 months.  But we did manage to find many studies that spoke to the facts about the Alzheimer’s drug Donepezil and warned of longer-term usage: 

Reference 1: Cholinesterase inhibitors offer some relief from the symptoms of Alzheimer’s disease for some people for a limited period of time. 

Study 2: Despite donepezil’s effects on major symptoms of Alzheimer’s disease, its impact on patients’ quality of life has not been consistently demonstrated

Scientific Review 3: Acetylcholinesterase inhibitors, such as donepezil, work by preventing acetylcholine from being broken down. This may improve the symptoms of dementia. However, acetylcholine is also found elsewhere in the body and so drugs of this type may have unwanted effects.

Warning 4: In many cases, Donepezil loses its effectiveness after about a year of treatment. Donepezil works best in people with mild to moderate AD because once AD becomes severe, the nerves that once produced Acetylcholine can no longer function

Scientific Journal 5: Despite the lack of evidence for their use in end-stage dementia, both cholinesterase inhibitors and memantine are commonly prescribed in this population.

Scientific Review 6: In the most comprehensive review of Donepezil we were able to find, the researchers looked at 8257 participants over 30 studies. None of the studies looked at long-term effects of taking the drug. All studies were for 6 months or less. The data found that the rates of withdrawal and adverse events were higher as dosage increased and that all stages of AD saw only SMALL BENEFITS in cognition, ADLs and overall disposition while taking the drug. 

Here’s another 2018 study that states that “cholinesterase inhibitors are usually prescribed early in the course of dementia, and some patients take these drugs for years, although no studies have investigated benefit or risk beyond 1 year.

In conclusion, mounting scientific evidence is showing that acetylcholinesterase inhibitors are not the answer to AD. What little benefit these drugs offer is likely due to their ability to reduce inflammation in the CNS. Moreover, despite never having been tested for long-term use and warnings against long-term use, these drugs are being used long-term in cases of suspected AD. This is likely due to a lack of understanding in the medical community regarding this classification of drugs. And finally, many of the documented side effects of these drugs are mimicked in the symptoms of late state dementia, which makes it unclear as to what is bringing about the symptoms – the disease or the drugs used to treat the disease.

Review of terms:

Nerve Synapse: is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron. Terms such as pre-synaptic nerve cell (neuron) and post-synaptic nerve cell (neuron) are often used to describe the signal flow.

Neurotransmitter: a chemical message released by nerve cells (neurons) to send signals to other cells, such as other neurons, muscle cells, and gland cells

Choline: is a nutrient that’s mostly gained through our diet with a very small amount also being produced by your liver. Your brain & nervous system need Choline to regulate memory, mood, muscle control, and other bodily functions. For more about the chemical Choline click here.

Acetylcholine: is an organic chemical compound comprised of Choline and Acetic Acid that functions throughout our body as a neurotransmitter. In the brain specifically, this neurotransmitter has been linked to cognition, memory and attention. Elsewhere in the body, it is the primary neurotransmitter of the parasympathetic nervous system (often called the “rest and digest” or “feed and breed” system) as well as a neurotransmitter in the autonomic nervous system, a branch of the peripheral nervous system that contracts smooth muscles, dilates blood vessels, increases bodily secretions, and slows the heart rate. 

Cholinergic System: is a group of organized nerve cells that use Acetylcholine to create some form of action like muscle movements, sweating, etc. In the brain, the cholinergic System has been associated with memory, attention and emotions and is what is most effected by Alzheimer’s.

Cholinergic Cell/Neuron: is a nerve cell which mainly uses the neurotransmitter acetylcholine (ACh) to send its messages. Many neurological systems are cholinergic.

Acetylcholinesterase: this is an enzyme. It is critical to the normal function of our nervous system. This enzyme breaks up acetylcholine into two parts: 1) Choline and 2) Acetic acid at the synapse between nerve cells. 

Anticholinergics: substances / chemicals that interfere with acetylcholine activity. 

Acetylcholinesterase inhibitor / cholinesterase inhibitor: these are interchangeable terms to describe a chemical that binds to the enzyme cholinesterase with the intent to prevent the enzyme from breaking down the neurotransmitter acetylcholine. At toxic levels, an excessive amount of acetylcholine builds up causing system dysfunction like cramping, increased salivation, excessive tearing, Donepezil reduces inflammation in the brain