Mannitol and Parkinson's Disease: A Review

MANNITOL SAFETY & SIDE-EFFECTS

According to the FDA in the USA, there are no known health risks of mannitol at the levels being recommended for Parkinson's Disease:

"There is no evidence in the available literature to show that mannitol constitutes a hazard to the public when used at levels that are now current, or that might reasonably be expected in future."

According to "Nutrients Review":

"Mannitol acts as an osmotic diuretic, which means it drags water from the blood into the urine and can thus quickly reduces blood pressure. As an intravenous drug is used to lower the increased pressure within the skull (intracranial pressure or ICP) and in treatment of increased pressure within the eye (glaucoma)."

"Mannitol attracts water from the intestinal wall (osmotic effect) so it can cause diarrhea if consumed in excess. Mannitol, when ingested in amounts greater than 50 mg/kg body weight (35 g by a 70 kg or 155 lbs person) may cause abdominal pain, excessive gas (flatulence), loose stools or diarrhea. According to one source, the laxation threshold for mannitol in healthy people is about 20 grams per day. There appears to be no evidence about association between mannitol and cancer."

Background research

The reference above to Mannitol's clinical use in lowering intracranial pressure is interesting in light of a recent scientific article:

Intracranial Pressure Is a Determinant of Sympathetic Activity,

which states "ICP rise compresses brain vessels and reduces cerebral blood delivery", thus potentially reducing oxygen to the brain, a known contributing factor to PD, as I covered in

PARKINSON'S AND A LACK OF OXYGEN TO THE BRAIN,

and goes on to demonstrate that Sympathetic Nervous System (fight-or-flight) and withdrawal of Vagus Nerve support (see below) correlate with ICP. So Mannitol's ability to decrease ICP is intriguing. 

In July 2013, the Parkinson's Disease Foundation reported on journal published scientific studies:

"The natural sweetener mannitol, a common component of sugar-free gums and candies, may hold potential for Parkinson’s disease (PD) according to a study, funded in part by the Parkinson's Disease Foundation, in the June 14 issue of The Journal of Biological Chemistry. In this initial study, the compound not only improved PD-like symptoms in fruit flies, but also reduced harmful levels of alpha-synuclein (the hallmark of PD) in the brains of fruit flies and mice.

Researchers took interest in mannitol because..., it has two unique properties. First, it can disrupt the blood brain barrier (meaning the drug can reach the brain). Second, it is able to stop some proteins in the body from clumping together, which is interesting in light of the fact that clumps of the protein alpha-synuclein are a well-known sign of Parkinson’s disease."

The reported results were as follows:

• "In the test tube, mannitol injections prevented alpha-synuclein protein from clumping into the Lewy bodies that form in the brains of people with PD.
• In the fruit fly model of PD, mannitol injections restored the flies’ normal movements, for example their ability to climb up test tubes.
• In the same flies, mannitol reduced alpha-synuclein clumps by 70 percent.
• In the mice model of PD, mannitol injections reduced alpha-synuclein clumps in several areas of the brain involved with classic PD and protected dopamine-producing neurons, the brain cells affected in PD."

How the brain removes toxins and pathogens

In order to understand how mannitol might work as described above we need to consider how toxins, bacteria and waste are removed from a healthy brain. The brain swims in a liquid called "cerebrospinal fluid" which fills the gap between it and the skull. This fluid is known to flush through the system daily and plays the central role of removing waste products of the cells, toxins and pathogens from the brain.

Recently, scientists demonstrated in rodent, by adding a special dye marker into their bloodstreams ,that the cerebrospinal fluid mainly exits through the lymph system, so that the brain waste eventually gets eliminated by the liver/kidneys. Prior to this discovery, it was believed that the brain didn't contain lymph vessels. Even more recently, these same lymph vessels in the brain off humans via novel MRI techniques. 

Since mannitol is not readily absorbed into body, but tends to pass through the system, if it enters the cerebrospinal fluid from the blood stream, it would take a similar path through the system as the inert dye was shown to do in the above experiments. In other words, it would flush through the brains waste removal system and then be drained into the lymph system. However, being a osmotic diuretic, as mentioned above, the mannitol would not only help to draw fluids out of the brain (one of its main medical uses), but also presumably draw toxins like alpha-synuclein and heavy metals out with it. Thus mannitol may act to enhance the normal waste removal activities of the brain, which appear to be so poor performing in people with Parkinson's Disease, due issues like sleep deprivation, dehydration and lack of motility. 

Mannitol as an Osmolyte

A 2018 scientific review on "osmolytes",

Roles of osmolytes in protein folding and aggregation in cells and their biotechnological applications,

names Mannitol as one of these bio-protective substances.

"Nature has selected osmolytes to protect intracellular macromolecules exposed to denaturing conditions and stabilize proteins. Osmolytes are small naturally occurring compounds that act as 'chemical chaperones' under changing environmental conditions and in disease states, and are present in microorganisms, animals, and plants. In the intracellular environment osmolytes naturally accumulate at high concentrations when cells/tissues are exposed to stressful conditions, which is important because protein aggregation, misfolding, and destabilization underlie the pathogenesis of several life-threatening neurodegenerative disorders. The 'chaperone' abilities of osmolytes suggests they may be therapeutically used for the treatment of several diseases associated with protein misfolding [including Parkinson's and Alzheimer's disease], and their abilities to protect proteins against stresses"

"Naturally occurring osmolyte molecules have possible therapeutic applications and do not raise concerns regarding major side effects. Under physiological conditions, it has been established intracellular osmolyte concentrations vary substantially, and the general opinion is osmolytes are accumulated to protect against cellular damage caused by stresses and that destabilize cellular structures. Folded proteins are known to be more stable in the presence of specific osmolytes, which protect them from unfolding and loss of activity. It appears that exogenous supplementation of osmolytes can be beneficial [in] clinical trials... To date, a large number of organic osmolytes have been shown to correct protein misfolding and protein propensities to aggregate during folding. Furthermore, the incorporation of stress specific osmolytes in pharmaceutical formulations might increase stress tolerance and improve drug efficacy."

Specifically, the researchers say about Mannitol:

"Mannitol protects thiol-regulated enzymes such as thioredoxin, phosphoribulokinase, ferredoxin and glutathione from inactivation by ROS; quenches hydroxyl radicals and protects the enzymes inactivation by reactive oxygen species (ROS);"

See

A NATUROPATHIC DOCTOR'S APPROACH TO THE TREATMENT OF PARKINSON'S DISEASE

for the important role of Glauthione in Parkinson's Disease, for example.

Contrast this action of Mannitol described above with a discussion about the neurotoxic chemical reactions between dopamine and iron in the Substantia Nigra area of the brain in Parkinson's Disease from

Iron and dopamine: a toxic couple:

"...involves the oxidation of dopamine by iron and oxygen, forming dopamine quinone... Quinones impart toxicity by both alkylating protein thiol and amine groups, and promoting protein oxidation in the presence of reactive oxygen species (which are also produced by an iron-mediated reaction) and glutathione disulphide. These biochemical changes to proteins result in malfunction, disruption of cell membrane integrity, and, eventually, cell death."

These indicate that Mannitol could also have a neuroprotective effect against the damage caused by iron build up in the brains of people with Parkinson's Disease.

A case study

A pdf download from Fight Parkinson's, dated May 2016, reports on the anecdotal evidence of a person with Parkinson's who took it on himself to self-experiment with Mannitol and has been taking it since January 2014:

"I am 66 years old and had all the symptoms of Parkinson’s disease i.e. tremors, drooling, tiredness, falling down, loss of balance, trouble urinating, handwriting problems, shuffling, not sleeping etc. I used myself as a research subject. I started taking mannitol orally in small doses until I found a therapeutic dose that began to restore my functioning. There were some negative side effects including diarrhea, gas and urinary retention, so I reduced the dose and added alphagalactosidase to offset the side effects.

I added vitamin D3 and vitamin K2 to feed the mitochondria that power the lysosomes that consume the defective alpha-synuclein. After 30 days I could stand and walk regularly. I had a great deal more energy, had much better balance, slept 8 to 10 hours a night, no longer had problems urinating, could walk up and down stairs without holding the rails and no longer drooled as often. I still had tremors but they were diminished.

I have given the compound to others with Parkinson’s who have had similar results. I have two patents pending on the compound. The supplement is prepared as a powder and the recommended dosage is one tablespoon daily dissolved in a cup of hot caffeinated coffee or tea.

I have been taking the supplement for over seven months as of January, 2014. I have had no new Parkinson’s symptoms during that period of time. During a one week period I stopped taking it because my left eye swelled and I was fearful it was a side effect. I saw my primary care doctor and was diagnosed with an eye infection which was treated with a topical antibiotic. However, after 7 days off the supplement, I started having an in- crease in Parkinson’s symptoms again. The symptoms diminished after 4 days back on the supplement."

~ Don McCammon

In February 2016, Don McCammon also appeared on an episode of Parkinson's Recovery Radio about mannitol and PD, where he is described as "symptom free".

Clinicrowd Outcomes

In 2016, the authors of the original scientific research launched a crowd sourcing website as a way to amass large scale pre-clinical trial data (I presume they had to resort to this "exotic" mechanism due to the failure of the scientific and health industries to fund clinical trials in humans - this is, unfortunately, the typical state of affairs when safe foodstuffs offer potential solutions for chronic conditions - as there is then no profit to be made by helping people to ease their suffering).

By December 2016, based on 800 participants at that time, the scientists reported their results on an Israeli news channel. The report includes interviews with two extremely credible sources, both people with Parkinson's themselves who have been on the trial. According to this video, Mannitol can indeed dramatically and rapidly improve the symptoms of people with Parkinson's. The therapeutic dose is reported as around just 12g. This is substantially lower than the levels for which Mannitol has been used for other medicinal purposes, and below that at which any serious side effects are known to occur.*

In March 2018, Clinicrowd published a presentation of the outcomes for people on the trial for longer than six months (to rule out a placebo effect) in which they report

• 88% regained sense of smell
• 86% improved Facial Expression
• 80% Gait Abnormality improved
• 72% reduced Drooling Severity
• 70% Muscle Cramps stopped
• 70% pain stopped
• 72% regained Arm Swing
• 69% Falls stopped

Real life experiences of people with PD

Andy Butler, who I consider to be a world authority on Parkinson's and the man behind the Parkinson's People project, writes: "People all over the world with pd take this ! I have met many pwp who have tried this and still take it. Cheap and ready available in almost every where world wide. GIVE IT A GO - IT MAY HELP YOU !"

Personal Experience

Based on the above evidence, I personally decided to add mannitol into my recovery plan. I have now been taking a tablespoon a day mixed with yoghurt for nearly a year. While it is difficult for me to pin point any specific effects,  since I am doing so many other things to help myself at the same time, I do believe that mannitol is one of the successful parts of my strategy which has allowed me to progressively reduce my symptoms over that time. I feel that, in particular, mannitol has helped with pain and rigidity reduction.

Other reasons mannitol may be effective in Parkinson's Disease

Mannitol as a Prebiotic

Mannitol is a type of "diabetic sugar" which has a low glycemic index and is barely absorbed in the body, tending to pass straight through. People with Parkinson's around the world are finding cumulative benefit with daily use of mannitol as a supplement. Andy Butler of Parkinson's People, who travels the world talking to PD groups, to seek out and share the best practices of living well with the condition, says "pain and fatigue seem to be helped by mannitol". No-one really knows why it is working so well for some PwP, but having done the research, but we do know that mannitol is a good prebiotic, as listed in:

The current trends and future perspectives of prebiotics research: a review

Due to its low GI/low absorption charaterisics, it seems to work much like the more well known prebiotic "Inulin" as it passes through the system, including that it is an "osmotic diuretic", drawing water through the gut lining, helping to create stools of good consistency and thus having beneficial impacts on the chronic constipation which many PwP suffer from. Mannitol therefore support sgood gut bacteria and healthy elimination, helping with the chronic digestive problems and the severe microbiome (gut flora) imbalances which are now strongly implicated in PD, e.g.

Link between microbiome in the gut, Parkinson's discovered

Parkinson’s disease may start in the gut and travel to the brain

Microbiology: Gut microbes augment neurodegeneration

Could Candida be Contributing to my Symptoms of Parkinson's Disease?

Helicobacter Pylori Bacteria in the Gut and Parkinson's Disease

The evidence that mannitol supplementation is indeed working as a good prebiotic in PwP is that it tends to generate a lot of gas, which is a good sign that gut bacteria are active and reproducingf!

Mannitol and Vagus Nerve Stimulation

Please see my article

the Vagus NerVe and parkinson's Disease

for a guided tour of background reading on this very important subject, created to aid understanding for anyone affected by PD. That article also includes links to the reference works for the following explanation of a further reason for how and why mannitol  mighg help some people with Parkinson's.

In brief, the Vagus Nerve and its functionality via "Vagal Tone" have pivotal roles in discharging our autonomic nervous system back to rest after an acute flight-or-fight-or-freeze stress situation: it is via the activation of the Vagus Nerve by which we come back to relaxation ("rest and digest"). Importantly, it is only under such relaxed conditions when the brain and body can attend to any inflammation and it can detoxify. Conversely, if there is a problem with the activity levels of this nerve, then this leads to problems, such as the build up of toxic metals in the brain, now known to be strongly implicated in PD onset and degeneration. The same is therefore likely to be true of problem proteins like alpha-synuclein.

It now appears that we people with Parkinson's are stuck in a "freeze" stress response - due perhaps to our nervous systems learning to inhabit such a state from some earlier physical or emotional trauma - whilst also having very weak Vagal Tone due to a damaged Vagus Nerve. Viruses and pathogens are implicated in its weakening.

All is not lost, however, because Vagus Nerve Stimulation can help activate it again, and "exercising" the nerve this way can restrengthen Vagal Tone, allowing, in time, the brain and body to begin the processes of detoxifying and reducing its chronic inflammation. There are very many ways to stimulate the Vagus Nerve effectively. It seems reasonable, therefore, that mannitol's effect is precisely because it causes digestive tract activity, through its osmotic effect in the bowel, including the laxative, and especially excessive wind, effects it creates.

Indeed, deep breathing while "bearing down" (as if one is trying to break wind!) is a very effective Vagus Nerve Stimulation excerise, and so is, as suggested in the video below discussing "coffee enemas" as a stimulation strategy, holding a bowel movement in. People who take therapeutic levels of mannitol find themselves having to practice both of these actions on a daily basis! Thus mannitol is highly likely to simply be acting as Vagal Tone improving agent, and as well as having a direct role in the brain's cleansing mechanism itself, it may also work indirectly through the activation of the digestive system, in turn creating a Vagus Nerve Stimulation effect, helping the brain to begin to naturally detoxify and remove problems molecules like alpha-synuclein.