14/12/21 10:06 MDS SIC Blog: Mannitol Treatment for Parkinson's Disease
Mannitol Treatment for Parkinson's Disease
Return to Blog Listing
About the Authors
Eliezer Masliah, MD
National Institute on Aging
National Institutes of Health
Bethesda, MD, USA
David Arkadir, MD PhD
Hadassah Medical Center and the Hebrew University
Jerusalem, Israel
Brian Fiske, PhD
The Michael J. Fox Foundation for Parkinson's Research
New York, NY, USA
https://www.movementdisorders.org/MDS/Scientific-Issues-Committee-Blog/Mannitol-Treatment-for-Parkinsons-Disease.htm 1/7
14/12/21 10:06 MDS SIC Blog: Mannitol Treatment for Parkinson's Disease
About the Contributor
Blog Prepared by SIC member:
Roy Alcalay, MD, MS
Colombia University, New York, NY, USA
Date: January 2020
Prepared by SIC Member: Roy Alcalay, MD, MS
Authors: Eliezer Masliah, MD; David Arkadir, MD PhD; Brian Fiske, PhD
Blog Editor: Un Jung Kang, MD
Many vitamins and food supplements have been tested for the treatment of Parkinson’s
disease (PD), including vitamin E, coenzyme Q 10, inosine and others. The notion that a food
supplement may be helpful for PD is very attractive. Vitamins and supplements are usually
well tolerated, and if ever demonstrated to be beneficial to those with PD, they could
potentially be used in at-risk population for PD prevention. Mannitol is a sweetener
commonly used as a sugar substitute (approved for diabetics), and is made by hydrogenation
of fructose. Treatment of PD with mannitol has received traction in Israel and worldwide with
a double-blind trial expecting results in 2022. Here, three experts discuss the rational and the
best methodology of testing mannitol for the treatment of PD. Dr. Eliezer Masliah discusses
the basic science on the use of mannitol for PD. Drs. David Arkadir and Brian Fiske discuss
the different methodologies (i.e., clinical trial, “crowd research,” others) to explore the
potential role of mannitol in PD.
What is the science that may support testing mannitol for treatment of people with PD?
Eliezer Masliah, MD; National Institute on Aging, National Institutes of Health, Bethesda,
MD, USA
The neurodegenerative process in PD and related disorders such as dementia with Lewy
bodies and multiple system atrophy has been associated with progressive accumulation and
https://www.movementdisorders.org/MDS/Scientific-Issues-Committee-Blog/Mannitol-Treatment-for-Parkinsons-Disease.htm 2/7
14/12/21 10:06 MDS SIC Blog: Mannitol Treatment for Parkinson's Disease
propagation of the synaptic protein α-synuclein (α-syn), therefore there is interest in
identifying compounds capable of interfering with this process. In a small-scale screen of
small molecules (primarily polyols) capable of inhibiting the aggregation of α-syn in vitro the
sugar mannitol was identified as one of the hits1. Using a ThT fluorescence assay and
Transmission Electron Microscopy (TEM), mannitol was shown to inhibit fibrillization of α-
syn at the lower concentrations tested (0.225M and 0.45M), while the higher concentration
(0.9M) significantly decreased the formation of oligomers. Although the lower
concentrations of mannitol did not inhibit formation of α-syn oligomers, they affected their
secondary structure. Therefore, we presume that mannitol exerts effect by directing α-syn
oligomers to an alternative pathway of aggregation although this possibility remains to be
elucidated.
As an initial test in vivo1, the effects of mannitol were assessed in a transgenic Drosophila
fruit fly model that expresses a highly aggregative variant of α-syn (A53T) in their nervous
system and established as a model of PD. Mannitol markedly corrected their locomotion
defects. This was accompanied by approximately 70% reduction in α-syn aggregates in the
brains of mannitol-treated flies as compared with the non-treated group.
These results were subsequently corroborated in the mThy1-a-syn transgenic mice,1 which
were injected IP with mannitol (1 g/kg) daily for four weeks, starting at an age of 16 weeks.
Immunohistochemical analysis and western blotting revealed that mannitol treatment
reduced a-syn accumulation in the hippocampus, basal ganglia and substantia nigra, which
are the main brain regions affected in PD. Total accumulation of a-syn in the brain of the
transgenic mice was decreased in both soluble and insoluble fractions as compared with non-
treated transgenic mice. Moreover, mannitol treatment ameliorated the loss of dopaminergic
fibers as evidence by the restoration of tyrosine hydroxylase immunoreactivity in the basal
ganglia.
The mechanisms of neuroprotection mediated by mannitol are not fully understood.
Certainly blocking aggregation and formation of toxic a-syn multimers might play a role;
however other effects related such as the antioxidant properties might be important.
Moreover, mannitol has been shown to increase the molecular chaperone HSP-70, which is a
marker of cellular response to stress or injury and is part of the cell's protein folding and
quality control machinery.
Dr. Arkadir, can you describe your experience and plans with regards to testing
mannitol in people with PD?
David Arkadir, MD PhD; Hadassah Medical Center and the Hebrew University, Jerusalem,
Israel
Non-patentable substances, such as mannitol, with a potential to slow the progression of PD,
or even to revert it, are constantly suggested. Such suggestions are based on personal
experience of patients and doctors, on theoretical assumptions, on epidemiological studies,
and on in vitro or in vivo animal experiments. A 'critical mass' of evidence is required before
efforts are given to robustly test the true effect of such substances in humans. But even when
enough evidences are accumulated, in many cases, some non-patentable substances would
https://www.movementdisorders.org/MDS/Scientific-Issues-Committee-Blog/Mannitol-Treatment-for-Parkinsons-Disease.htm 3/7
14/12/21 10:06 MDS SIC Blog: Mannitol Treatment for Parkinson's Disease
never be tested. From the story of mannitol we can learn about the possible fates of non-
patentable substances.
The potential of high-dose mannitol to reduce aggregation of a-synuclein (in vivo and in vitro)
and to restore the motor activity in the fruit-fly model of Parkinson's disease was published
in 2013 (by Shaltiel-Karyo and colleagues1). Following this publication, a small number of
Parkinson's patients around the world started taking mannitol. At that point, the lack of
interest of the medical community in studying the effects of mannitol led a group of
enthusiastic friends with personal connections to Parkinson's disease to establish Clinicrowd,
a free website to collect data regarding the use of mannitol from patients. The fate of
mannitol took a different course when in 2016 a famous Israeli patient publically reported
that he suffered from PD and described a dramatic benefit he had from mannitol. Large
number of Parkinson's patients started taking mannitol following this, with variable
subjective reports regarding the relief of symptoms.
This situation where a large number of patients consuming a substance that was pre-
clinically shown to be effective in experimental models, but the lack of robust clinical trials to
test this hypothesis, required a change. Luckily, public funding (from the Israeli ministry of
science and technology) that would support such a trial was received. The first double-blind
clinical trial of mannitol in PD started in our center (Hadassah Medical Center, Jerusalem,
Israel, ClinicalTrials.gov Identifier: NCT03823638) in late 2018 and is expected to end by
early 2022.
So what did I learn from the mannitol story? That public and philanthropic support is crucial
for testing the true potential of non-patentable substances; that enthusiastic individuals can
advocate for trials; and that a bit of luck can always help, even for chemical substances.
Some websites (such as CLINICROWD and Fox Insight) provide an online platform for
people with PD to report the effect of interventions like mannitol on their symptoms.
Should we consider such alternative tools to test vitamins and supplements in PD, or
should we stick to clinical trials?
Brian Fiske, PhD; The Michael J. Fox Foundation for Parkinson’s Research, New York, NY,
USA
The gold standard for assessing clinical benefit of therapeutic interventions is the
randomized controlled trial. Traditionally, such trials are conducted in clinic, where variables
that might influence study endpoints can be more carefully controlled, ultimately increasing
confidence in trial results. However, there are challenges to this approach. Participants must
reside within reasonable geographic distance from clinical sites, which limits inclusion of
participants (including often more diverse and under-represented communities) and can be a
delay to study recruitment timelines. Participants are usually assessed in artificial
surroundings, providing a brief ‘snapshot’ of their current health status that may not
adequately reflect issues they experience in the home or real-world environment.
Additionally, costs for supporting clinical site staff and other study expenses (e.g.,
transportation, parking, etc.) can increase the overall expense for doing clinical trials. These
issues can limit how many trials are funded and performed, reducing the number of
potentially promising ideas that can be tested at any time.
https://www.movementdisorders.org/MDS/Scientific-Issues-Committee-Blog/Mannitol-Treatment-for-Parkinsons-Disease.htm 4/7
14/12/21 10:06 MDS SIC Blog: Mannitol Treatment for Parkinson's Disease
With technological advances, the ability to conduct studies remotely through online
platforms has become an area of increasing interest. These platforms offer opportunities to
engage people wherever they live, increasing the involvement and diversity of patient input
and accelerating the collection of data. Paired with other technologies (e.g., remote
monitoring devices), such approaches can increase the kinds of data and information
collected in a trial. As an example, at The Michael J. Fox Foundation for Parkinson’s Research,
we have been using our own online portal Fox Insight (https://foxinsight.michaeljfox.org/) to
survey people with Parkinson’s disease (as well as healthy controls) on a variety of issues
related to their disease. More recently, we’ve begun — in collaboration with leading clinical
experts — to ask participants about their experience with various types of interventions, such
as mindfulness and meditation, as a way to obtain more insight on the impact of these
approaches where some data exist that could be clarified with real-world information from a
larger and diverse population of people with Parkinson’s.
Importantly, it is not an either/or debate about whether in-clinic or online trial methods are
better for testing interventions such as mannitol. Online platforms can provide insight that
may not be seen in the clinic and at a scale that traditional studies could never achieve, but by
their nature they are ‘messy’: many confounds (e.g., treatment compliance, ability to use
properly blinded controls) are much harder to address in remote environments. If robust,
rigorous and well-controlled data are critical for making important decisions about future
drug development investment or medical care, a trial must still meet high standards
regardless of where and how data are obtained. Online platforms currently offer the ability
to obtain data on questions that can guide understanding of the experience and impact of a
potentially promising intervention and with inclusion of remote monitoring devices and even
ability to collect basic biosamples through mailed kits, might even allow answering more
sophisticated questions. But additional investment, design consideration and community
buy-in may be needed to create platforms that can truly replace the rigor of traditional trials.
So how do we proceed with mannitol? A Phase II trial is already underway in Israel which may
address many important questions around safety, tolerability and potential effects on disease
and symptom progression. One consideration would be to explore whether additional data
around some of the clinical outcomes currently planned for the trial could be enhanced (or at
least informed) by data collected from online platforms to further verify or understand
signals seen in the formal trial. Such a hybrid model might be a useful way to understand
more fully the value and impact of mannitol (or other drugs like it) while also providing data
on the realistic potential of online platforms for testing future promising Parkinson’s
therapies.
References
1Shaltiel-Karyo R, Frenkel-Pinter M, Rockenstein E, Patrick C, Levy-Sakin M, Schiller A, Egoz-
Matia N, Masliah E, Segal D, Gazit E. J Biol Chem. 2013 Jun 14;288(24):17579-88.
PMC3682557
Comments on this Blog Post
https://www.movementdisorders.org/MDS/Scientific-Issues-Committee-Blog/Mannitol-Treatment-for-Parkinsons-Disease.htm 5/7
14/12/21 10:06 MDS SIC Blog: Mannitol Treatment for Parkinson's Disease
By: Title: Clueless about best safe dose---need help asap
judith griffin
Date:
December-20-2020
5:28:14 AM
Comment:
Positive Parkinsons diagnosis with Dat scan 2 years ago---
because I have a long history of medicated bi-polar illness,
Neurologists advised me to wait as long as possible to start
levodopa/Carbidopa as my chances of hallucinations and
psychosis from these meds was more pronounced. If I
exercised many hours a day, ate tons of organic plant based
food, lots of fish etc, worked hard on no negativity, gratitude,
and plenty of meditation; I am almost symptom free. However
the Parkinsons I woke up to every morning was with a slow
almost barely functioning frontal lobe, never mind the exercise
etc----it took me an hour and a half to figure out how to walk
300 feet to the bathroom. Here is where the Mannitol comes
in-it dramatically helped me get on board organize my
thoughts etc....I am good to go with it----also slight.return of
smell--
Submit Your Comment
Name
Email
Comment Title
Comment: 1000 characters
Submit
https://www.movementdisorders.org/MDS/Scientific-Issues-Committee-Blog/Mannitol-Treatment-for-Parkinsons-Disease.htm 6/7
14/12/21 10:06 MDS SIC Blog: Mannitol Treatment for Parkinson's Disease
Cookie Policy
Privacy Notice ❯ Cookie Settings
https://www.movementdisorders.org/MDS/Scientific-Issues-Committee-Blog/Mannitol-Treatment-for-Parkinsons-Disease.htm 7/7
