The mannitol clinical trial results

# # # # Without a shadow of doubt, one of the most popular topics that readers search for on this website is ‘mannitol’.  It is a widely used sweetner that became very popular in the Parkinson’s community after a 2013 research report presented compelling results that this molecule exhibited robust anti-aggregation properties on the Parkinson’s-associated protein alpha synuclein. Recently the results of a carefully designed clinical trial evaluating mannitol have been published. In today’s post, we will look at what mannitol is, review the previous research conducted on this agent in the context of Parkinson’s, and consider the results of the clinical trial. # # # #

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Source: History

During the forty years that the Israelites wandered the desert after leaving Egypt, they faced many hardships, most notably a scarcity of food. To resolve this particular issue, God kindly provided the Israelites with “bread from heaven”.

According to the scriptures, it was a “fine, flake-like thing, fine as frost on the ground” and “It was like coriander seed, white, and the taste of it was like wafers made with honey” (Exodus, Chapter 16).

They called “manna”.

Hence the phrase: Like manna from heaven

More recently, a substance called manna, has been the focus of a lot of attention in the Parkinson’s community.

A group of Israeli researchers have been exploring the potential of the sweetener ‘Mannitol’ (also known as Manna sugar) in the context of Parkinson’s.

What is mannitol?

Mannitol is a colourless sweet-tasting, poorly metabolized crystalline alcohol sugar.

In plain English: Mannitol is a sweetener. If you stick it on your tongue, it tastes like sugar.

The chemical structure of mannitol. Source: Wikipedia

Therapeutically, mannitol is Food and Drug Administration (FDA)-approved as an osmotic diuretic agent – a treatment that inhibits the re-absorption of water and sodium.

It is widely used in the management of cerebral oedema and raised intracranial pressure. Mannitol is also used to protect the kidneys during cardiac and vascular surgery, and during kidney transplantation procedures (Click here for a review of uses of mannitol).

Ok, but how is it associated with Parkinson’s?

Back in 2013, this study was published:

Title: A blood-brain barrier (BBB) disrupter is also a potent α-synuclein (α-syn) aggregation inhibitor: a novel dual mechanism of mannitol for the treatment of Parkinson disease (PD).
Authors: Shaltiel-Karyo R, Frenkel-Pinter M, Rockenstein E, Patrick C, Levy-Sakin M, Schiller A, Egoz-Matia N, Masliah E, Segal D, Gazit E.
Journal: J Biol Chem. 2013 Jun 14;288(24):17579-88.
PMID: 23637226                       (This report is OPEN ACCESS if you want to read it)

In this study, the Israeli researchers were interested in the ability of osmolytes to stabilise proteins, particularly their ability to help reducing neurotoxic caused by misfolded, aggregated proteins.

What are osmolytes?

Osmolytes are simply compounds that affect osmosis, which is the movement of water from a less concentrated solution to a more concentrated solution.

Osmosis. Source: Wikipedia

Mannitol is an osmolyte.

For a long time, osmolytes have been reported to stabilize proteins against stress conditions, which has resulted in them being attributed neuroprotective properties. Mannitol, for example, has been shown to be neuroprotective against cerebral ischemia (inadequate blood supply to parts of the brain – Click here and here to read more about this).

The researchers in 2013 study above, however, were interested to determine if mannitol could inhibit the clustering (or aggregation) of the Parkinson’s-associated protein alpha synuclein. We have discussed alpha synuclein a lot on this website (Click here to read more about this), and we won’t repeat ourselves here. Just understand that it is believed that that aggregation of alpha synuclein is one of the pathological hallmarks of Parkinson’s, and thus any substance that inhibits that aggregation could potentially have beneficial properties in slowing down the progression of the condition.

The researchers used different concentrations of mannitol and added it to a solution that contained alpha-synuclein protein. They left this concoction shaking for 6 days (at 37°C) and then assessed the levels of aggregation. Curiously the low levels of Mannitol had the strongest inhibitory effect, while the higher concentrations had no effect. The researchers repeated the experiments several times and found similar outcome.

Lower dose of mannitol, less alpha synuclein aggregation. Source: PMC

Given this interesting result, the investigators next turned their attention to animal models of Parkinson’s in which high levels of alpha synuclein protein were artificially induced. These studies began with a genetically engineered fly that produces a lot of alpha synuclein. The researchers found that mannitol treated flies performed significantly better on behavioural tests (such as climbing), and had significantly less alpha synuclein aggregation in their brain (when compared to untreated flies).

Flies. Source: TheConservation

The researchers repeated this experiment in genetically engineered mice (which produce high levels of alpha synuclein). The investigators found that mannitol-treatment was very effective in reducing the levels of alpha synuclein aggregation in these mice as well. In addition, the investigators found that mannitol administration in mice was followed by a significant increase in the level of the HSP-70 protein.

Significant increase in HSP-70. Source: PMC

What is HSP-70?

70 kilodalton heat shock proteins (or Hsp70) is a family of heat shock proteins. Heat shock proteins are referred to as molecular chaperones.

Molecular chaperones are proteins that assist in the folding (or unfolding) and the assembly (or disassembly) of other proteins. They are like the make-up artists and wardrobe departments back stage at the theatre, making sure the actors are correctly dressed and ready for the big stage.

Source: Biosocialmethods

A newly-formed amino acid chain can fold itself into a protein, but the assistance of molecular chaperones helps ensure that everything proceeds smoothly and quickly, regardless of whatever other events might be occurring in the cell.

Molecular chaperones are also very useful in helping to reduce the levels of misfolded and aggregating proteins (such as the toxic misfolded form of alpha synuclein). And there is a lot of interesting data indicating that HSP-70 is a very effective molecular chaperone for alpha synuclein. For example:

Title: Proteasomal inhibition by alpha-synuclein filaments and oligomers.
Authors: Lindersson E, Beedholm R, Højrup P, Moos T, Gai W, Hendil KB, Jensen PH.
Journal: J Biol Chem. 2004 Mar 26;279(13):12924-34.
PMID: 14711827                    (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers found that HSP-70 binds to the toxic form of alpha synuclein and inhibits some of the dysfunctional activities it has inside of cells. This result is supported by other research that demonstrated that increasing HSP-70 levels in flies rescued dopamine cell loss in an alpha synuclein-based model of Parkinson’s (Click here to read more about that research).

For those interested: Click here for a good review of research on HSP-70 and other heat shock protein/chaperones in Parkinson’s.

Thus, the fact that mannitol treatment in mice was raising levels of HSP-70 was very interesting to the researchers in Israel. And in combination with the previous mannitol results from their study, the scientists suggested that “mannitol administration in combination with other drugs could be a promising new approach for treating PD”.

# RECAP #1:  Mannitol is a sweetener that researchers in Israel found to exhibit anti-aggregation properties against the Parkinson’s-associated protein alpha synuclein. Experimenting across multiple models of the condition, they found that mannitol reduced levels of aggregated alpha synuclein – possibly via activation of heat shock proteins. #

Interesting, so what happened next?

Stimulated by the encouraging laboratory results and keenly aware that mannitol was readily available to patients, some members of the Israeli Parkinson’s community gathered together and set up a crowd-sourced platform for individuals to share their experience of self experimenting with the sweetener.

They called it CliniCrowd.

Foundered in June 2016, the platform was set up as a social impact company that provides a registry for people to sign up to and share personal experiences of researched nutriments (not just mannitol).

Their goal is to explore potential treatments that pharmaceutical companies have no interest to investigate or promote (for example, compounds that can not be patented).

Sounds interesting – how does it work?

The community at CliniCrowd “searches for nutriments that are safe for human consumption, recognized by FDA as GRAS (Generally Recognized as Safe), and have scientific evidence (in research papers) to be used to hopefully enhance wellbeing and possibly impact symptoms of diseases” (Source: CliniCrowd).

People with Parkinson’s are able to voluntarily sign up on the registry and start reporting back about their use and response to a particular ‘nutriment’, such as what benefits or side effect that they may be experiencing.

The sweetener Mannitol was the first nutriment proposed by the company.

After signing up on the website, “patients voluntarily register for the registry and enter their health information, purchase and administer the products themselves, and enter treatment outcome data on the website” (Source: CliniCrowd).

It should be made very clear that this project was never intended to be a replacement for clinical trials of investigational compounds, but rather a method of filtering potentially interesting treatments that may have been overlooked by the biotech industry.

What happens to my personal information when I share it with Clinicrowd?

The information you provide will be used for the analysis conducted by the company. Some of your unidentifiable information (this is information that can not lead back to you specifically, for example: the year you were born, but not the date) may be shared with third parties, but the company’s privacy policy insures that your ‘identifiable’ information is kept strictly confidential.

The concept of clinicrowd was very popular with some members of the Parkinson’s community and the platform generated a lot of data from individuals testing mannitol on themselves.

Has clinicrowd ever shared any of the results regarding mannitol?

Yes they have.

In 2018, the team at Clinicrowd put out a statement (which was shared with the Parkinson’s community via various forums – such as Healthunlocked) and it made for some very interesting reading.

Since the launch of the project in 2017, over 1000 people with Parkinson’s from 42 different countries filled in the survey to be part of the project. Despite this impressive start, only 78 of them self-administered mannitol for more than 6 months.

The individuals taking mannitol conducted a self assessment/report – a questionnaire which was basically similar to available Parkinson’s rating scales (such as the UPDRS).

Of those 78 participants that took mannitol for more than 6 months, 29 (36.7%) reported that their overall situation got worse, while 6 (7.7%) indicated no change, and 43 (55.1%) indicated that their symptoms had improved. This means that 62.8% of the participants believed that they did not see deterioration during the 6 months of self administration.

Intriguingly, 85% of the participants reported no change in the severity of their tremors.

Other interesting results – from the 78 participants in the project:

• 29 had chronic constipation – 55% said that their condition got worse, and 45% got better.
• 22 reported facial expression issues: 86% reported improvement and 14% reported deterioration.
• 15 reported Hallucinations: 80% reported improvement and 20% worsening situation.
• 78 reported fatigue severity: 31% showed improvement, 56% reported no change and 13% reported deterioration.
• 23 had reported handwriting problems of which 52% had a worst report and 48% an improved handwriting.
• 78 reported muscle cramp severity: 29% showed improvement, 60% had no change and only 11% had a worsening situation.
• 78 reported no arm-swing situation: 31% showed improvement, 54% had no change and 15% had their situation worsened.

Obviously questions can be asked regarding the self-assessment aspect of this study (how valid is the result of someone assessing themselves? No controls, no blinding). Plus there may have been a positively biased filtering system at work – the results are coming from the 78 who finished 6 months of treatment out of the original 1000 who signed up (what happened to the other 922?).

But there was one rather remarkable result in the mannitol project that I found intriguing:

• Of the 37 participants that reported they had lost the ability to smell at the start of the project (in the initial survey), almost all of them (90%) reported the return of their sense of smell after the 6 month treatment of mannitol.

Wow, that’s amazing! What do we know about the loss of smell in Parkinson’s?

Firstly, that it is one of the most common non-motor symptoms of the condition, sometime being present long before the actual diagnosis of Parkinson’s (Click here and here to read more about this).

In 2017, a very thorough analysis of the region of the brain involved with our ability (called the olfactory bulb) was conducted on postmortem brain tissue from people who passed away with Parkinson’s. The results were published:

Title: A ventral glomerular deficit in Parkinson’s disease revealed by whole olfactory bulb reconstruction.
Authors: Zapiec B, Dieriks BV, Tan S, Faull RLM, Mombaerts P, Curtis MA.
Journal: Brain. 2017 Oct 1;140(10):2722-2736.
PMID: 28969383                   (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers analysed sections of olfactory bulbs from 6 control brains and 5 cases of Parkinson’s.

The human olfactory system (in yellow). Source: Quora

The investigators found a 47% reduction in the areas of the olfactory bulb containing glomeruli in the cases of Parkinson’s, suggesting fewer and/or smaller glomeruli.

What are glomeruli?

Glomeruli is a spherical structure located in the olfactory bulb where connections are made between the branches of the nerves in your nasal passage and your brain.

The location of Glomeruli. Source: Petech

The researchers also found a very high load of alpha synuclein aggregation in the olfactory bulbs of the Parkinson’s cases – the higher the amount of alpha synuclein, the more the reduction in glomeruli. The researchers concluded “a causal relationship between α-synucleinopathy and reduction of the glomerular component of the olfactory bulb”.

There is a large body of literature describing alpha synuclein/Lewy pathology in the human olfactory bulb (Click here for a good review on this topic), and it could be possible that mannitol might have been having an effect on clearing some of the alpha synuclein that is blocking up these neurons (which may allow for better olfactory processing).

I am merely speculating here and this idea really needs to be further investigated in a carefully controlled clinical trials.

# # RECAP #2:  Clinicrowd is a crowd-sourced platform for individuals to share their experience of self experimenting with agents that the biotech industry has ignored. In 2017, the coordinators of the project released a statement outlining some of the results that had been collected over time from individuals self-administering mannitol. # #

Has there ever been a carefully controlled clinical trial of mannitol in Parkinson’s?

Yes there has.

Based the compelling results coming from the Clinicrowd project, researchers in Israel decided that a carefully designed clinical study was required to assess mannitol in a randomised, unbiased fashion.

The results of that study have just recently been published:

Title: Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson’s Disease.
Authors: Linetsky E, Abd Elhadi S, Bauer M, Gallant A, Namnah M, Weiss S, Segal D, Sharon R, Arkadir D.
Journal: Front Neurol. 2022 Jan 3;12:716126.
PMID: 35046880                (This report is OPEN ACCESS if you would like to read it)

In the study, 24 individuals with Parkinson’s were recruited to take part in a 36 week study. Of these, 15 were randomly and blindly assigned to take oral mannitol, while the remaining 9 took a placebo treatment. The treatment phase of the study included four dose escalations of oral mannitol or the control treatment (to a maximal dose of 18 gram per day). For more details about the structure of the study – click here.

The primary outcome of the study – this is the predetermined measure of outcome for the study – was safety, which was determined by the number of adverse events. No severe adverse events were reported in the results, BUT (and it is a big BUT) gastrointestinal symptoms did limit the dose escalation in 6 of the 14 participants being treated with mannitol.

What does that mean?

The gastrointestinal symptoms were reported as diarrhea, nausea, and abdominal discomfort. And in 5 of the 14 participants being treated with mannitol, these symptoms were distressing enough to require dose reductions.

Despite this, 64% of individuals in the mannitol treatment group tolerated the treatment well at the target dose of 18 grams of mannitol per day (which was divided over two doses). And it is interesting to note, however, that only one participant from each of the groups withdrew from the study during the treatment phase.

A range of blood tests were conducted during the study, but these revealed no differences in “electrolyte abnormalities, increased liver enzymes, impaired renal function, elevated non-fasting glucose level or evidence of systemic inflammation (leukocytosis or increased CRP)” between the mannitol or control groups.

Was there any difference in Parkinson’s symptoms after 36 weeks? Did mannitol slow down progression?

Unfortunately, no.

The researchers stressed that their study was not “designed to demonstrate statistically significant differences in efficacy measures”. The study involved gradually increasing the dose (4 times) over the course of the 6 months treatment phase, but they observed no significant difference in the clinical scores (including UPDRS I-III) between the mannitol and placebo groups.

In addition, despite the compelling observation made in the Clinicrowd report regarding a return of a sense of smell, in this study “no such effect was observed“.

The researchers concluded their study by writing that “long-term use of 18 g per day of oral mannitol is safe in Parkinson’s disease patients but only two third of patients tolerate this maximal dose“.

So mannitol is safe?

At low doses, yes.

It is FDA approved and it is widely used in many processed foods. Mannitol is added to a wide variety of processed products (simply check the packaging of your shopping for ‘mannitol’ or food additive number e421 – Food Standards Agency, 2014). On top of this, Mannitol is naturally occurring. Cauliflower, for example, contains 3 grams of Mannitol per every 100 grams of weight.

We are all most likely consuming it on a daily basis.

But it is fair to say that mannitol can have side effects when taken at higher doses.

Common side effects of mannitol use can include:

• Headache or dizziness
• Nausea, vomiting and diarrhea
• Thirst, dehydration, and frequent urination
• Racing heartbeat, low blood pressure
• Rash or hives
• Blurry vision
• Altered levels of sodium, potassium, and chloride in the body
• Acidity in the body

But it does not impact Parkinson’s?

As the researchers who conducted the study point out, the study was not big enough or long enough to really test efficacy. It is disappointing that no differences or trends were observed in the clinical measures, but the study was not designed to assess impact on progression.

So what does it all mean?

In 2013, researchers in Israel made an interesting preclinical discovery finding that the sweetener mannitol reduces the ability of the Parkinson’s associated protein alpha synuclein to aggregate together. The local Parkinson’s community joined forces with the researchers and they set up a platform for people affected by the condition to share their experiences from self-experimenting with this molecule. And the results of that project were encouraging enough to support the initiation of a clinical study to assess the tolerability of 6 months mannitol treatment in people with Parkinson’s.

Obviously, a fairy tale ending to that trial would have made for a better way to finish this post, but it is perhaps too early for that.

It could be that mannitol has no effect on Parkinson’s. It could be that the dose used in the study was not right. It could be reducing alpha synuclein aggregation has no impact on Parkinson’s. There are lots of questions that remain to be answered.

There were also no measures of mannitol in the cerebrospinal fluid – the liquid surrounding the brain – in the study so we do not know if mannitol was crossing the blood brain barrier and accessing the central nervous system. And – rather importantly – we do not know if the effect mannitol has on the gut may have on the absorption/efficacy of orally administered L-dopa and other Parkinson’s medications.

Thus, it is difficult to make any solid judgements based on the available data. And I know that this will be disappointing to folks in the community who have experienced benefits from taking mannitol. If you are one of those individuals, by all means keep taking mannitol if you wish (as long as your clinician is aware of what you are doing!). And if you are considering this molecule, please discuss it with your doctor/clinician before making any changes to your treatment regime.

 

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The banner for today’s post was sourced from Cure Parkinson’s.