The idea that a simple over-the-counter supplement called mannitol might alleviate the symptoms of Parkinson’s disease has been gaining traction since at least 2013.
The film follows the journey of Daniel Vesely, a 63-year-old Parkinson’s patient in Israel who, after experiencing a decrease in his symptoms while taking mannitol, set out to advocate for more research into the supplement’s effects on the disease.
Discouraged that mannitol’s low cost and ready availability meant there was little commercial interest in pursuing it as a marketable therapy, he and several associates decided in 2017 to promote its use online, via a platform that allowed users to report their experiences using the supplement. They named their venture CliniCrowd.
Mannitol also is being studied for Parkinson’s in a small randomized, controlled Phase 2a clinical trial (NCT03823638) in Israel.
But what exactly is mannitol? How does it work, and how might it help Parkinson’s patients?
What is mannitol?
Mannitol is a sweetener often used in diabetic-friendly foods, as it is poorly absorbed by the intestines and causes less of an increase in blood sugar levels than glucose. The U.S. Food and Drug Administration lists it as a food supplement and considers it safe to use, noting only that amounts greater than 20 grams may have a laxative effect.
In 2013, researcher Daniel Segal, PhD, his longtime collaborator, Ehud Gazit, PhD, and several colleagues at Tel Aviv University published preclinical research showing that mannitol could prevent the aggregation of toxic clumps of alpha-synuclein protein. In animal models of Parkinson’s, they saw that it eased certain Parkinson’s-like symptoms and stemmed the loss of the dopamine-producing (dopaminergic) neurons that are lost over the course of the disorder.
But mannitol’s precise mechanism of action — how it does what it does — remains under study. One theory to explain the results observed in cells and in animals is that it acts as a molecular chaperone — a type of molecule that recognizes misfolded proteins and either shepherds them toward cellular waste disposal pathways, or initiates a refolding response.
Segal and his colleagues included mannitol in their initial screen because of its similarities to trehalose, another sugar with neuroprotective effects, which functions to some degree as a chaperone.
Alternatively, mannitol may interact directly with alpha-synuclein through chemical bonds.
In an interview with Parkinson’s News Today, Segal said that at the time he and his collaborators experimented with mannitol in flies and mice, they lacked the technology to really answer questions regarding mannitol’s mechanism of action.
“Our studies have not allowed us to examine whether mannitol interacts directly — covalently or with other types of hydrogen bonds, for example — with alpha-synuclein. Nowadays, we do have such techniques that would allow us to try to figure out, in more detail, what is the mechanism of action of mannitol.”
What is known, he says, is that when mannitol is present, alpha-synuclein aggregation appears to be greatly reduced.
“We also observe that it has some capacity of stopping preexisting aggregates of alpha-synuclein, but the mechanism is not known,” he said.
Mannitol’s primary medical use is as an osmotic diuretic, meaning that it can be filtered through the kidneys but not reabsorbed into them, creating osmotic pressure that restores a healthy flow of blood and other solutes through the kidneys.
This osmotic quality, coupled with mannitol’s ability to cross the blood-brain barrier, have made it useful in treating swelling within the brain. (The blood-brain barrier is a semipermeable membrane that protects the brain from the outside environment.)
Mannitol’s ability to cross the blood-brain barrier matters in the context of Parkinson’s because medicines must be able to enter the brain to access the damaged dopaminergic neurons.
CliniCrowd’s patient-reported data
The CliniCrowd platform now has about 2,000 participating Parkinson’s patients from 54 different countries who have volunteered to take mannitol, according to Amir Sadeh, CEO and co-founder of CliniCrowd.
The organization published interim results of the mannitol project in 2018, writing that “more than 1,500 Parkinson’s patients from 42 countries” had tried mannitol using the CliniCrowd platform.
Among the participants at that time, 78 had consumed it for more than six months. Of those, 56% were said to have reported improvements in their Parkinson’s grade and alleviation of their symptoms. Of particular interest, 90% reported regaining their sense of smell, the loss of which is a common Parkinson’s symptom.
But for some, that numerical disparity — 78 consistent users from more than 1,500 — raises a warning flag.
One of these skeptics is Karen Raphael, PhD, a professor of oral medicine at New York University, with decades of epidemiological experience, including the design and management of clinical trials. She was diagnosed with Parkinson’s in 2009.
The idea behind CliniCrowd appealed to her as an innovative way to crowdsource preliminary data that could be used to justify clinical trials, but she questions the utility of the data that has been made available and how it is used.
“What happened to all those other people?” she asked in an interview, in regards to the dropout rate in the 2018 CliniCrowd data.
“Fifty-six percent of them improved. That’s great, but we’re talking about 40 out of 1,500 people. … Why is there such a huge dropout rate?
“If they had better follow-up, I would feel differently about it. I’d feel entirely differently. But they’d probably have to put money into it in order to get that, and once you’re doing that, then you might as well do a clinical trial.”
Sadeh, Vesely, and their colleagues are acutely aware of this. Were they better funded, they would not have to rely on unstructured anecdotes and word-of-mouth advertising and recruitment.
“We don’t have money at all,” Sadeh said. “So we are financing the project ourselves.”
He also is quick to point out that their research is not a clinical trial: “We are just trying to open doors to get safe solutions to patients.”
Sadeh and Vesely are hopeful the coverage they do achieve, such as through the documentary, will help them to gain more in terms of both participants and funding, so that they have more results to publish in future.
On that note, Sadeh said they now have follow-up data on 1,076 participants, 645 of whom have contributed three to six months’ worth of observations.
According to him, the most recent results showed that symptoms were eased for 64% of users, 7% were neutral, and the remaining reported that their symptoms continued to worsen as the disease progressed.
These numbers may provide more convincing data. As Raphael points out, the project needs input from a large number of people over a sustained length of time, and should capture the breadth of people’s experiences, be they positive, negative, or neutral.
In the clinical trial
Although CliniCrowd’s published results may not be enough to win over skeptics, the project has succeeded in sparking one clinical trial aimed at more rigorously investigating mannitol’s potential benefit in Parkinson’s.
Based on anecdotal evidence from CliniCrowd and other physicians treating Parkinson’s cases, David Arkadir, MD, PhD, a physician and neurologist at Hadassah Medical Center in Jerusalem, secured funding for a small Phase 2a trial in 2019.
In 2016, the Israeli government offered grants to physicians studying generic substances that might be medically useful, but had no clear financial benefits. Arkadir and his colleagues submitted a proposal for mannitol and won one of these grants.
His trial consists of about 30 participants, who are assigned randomly to receive either mannitol or dextrose, a similarly sweet sugar that serves as a placebo.
The patients in this trial are followed for 36 weeks, during which the safety and tolerability of mannitol is assessed. As secondary outcomes, they also are collecting data on several clinical features of Parkinson’s.
These features include changes in levodopa dosage, the ability to detect scents, and changes in constipation, as well as changes in cognitive and motor symptoms.
At present, the trial is still in its blinded phase, meaning that although some outcomes, such as gastrointestinal complaints, have been reported, the researchers conducting the trial cannot say whether the side effect is being reported in patients taking mannitol or in those taking the placebo.
Arkadir expects the trial to end in approximately two to three months and hopes to report results sometime in mid-October.
Raphael is encouraged that a clinical trial is finally taking place to address the uncertainty surrounding mannitol. She offers some words of caution, however, regarding the trial’s outcome.
“The one risk we run into with a relatively small Phase 2 trial is they often don’t replicate in Phase 3,” she said.
The issue, she says, is that the fewer participants one has in a trial, the more likely random assignment can fail to equalize participants’ symptoms prior to treatment. Participants assigned to one treatment can differ from those assigned to another treatment. With large numbers, these differences might average out, but such an averaging effect doesn’t always work well when sample sizes are small.
This is one reason why “statistically significant” findings from small Phase 2 trials fail to replicate in larger Phase 3 trials.
This isn’t to say that this will occur in Arkadir’s study, so much as it is a reason to maintain a sense of reserve when results are finally reported.
This trial “is as good as you can do right now, with a Phase 2 study,” Raphael said.
Arkadir holds no illusion regarding such challenges. Despite addressing an important unmet need in the Parkinson’s community, recruitment into a trial like his is a challenge.
“We did not recruit the number of patients we hoped for,” he said in an interview. “And this is for two reasons. First, it’s hard to recruit patients for a study which is not supported by the industry. … [Second,] it’s not easy to do a clinical trial with a substance that you can just buy on Amazon.”
If someone hears that mannitol might help with their symptoms, for instance, and can simply order it online, then why bother with the possibility of being given a placebo instead?
Arkadir also points out that the global COVID-19 pandemic effectively halted the trial’s last year of recruitment.
Because of this, he says the study lacks sufficient power to really determine mannitol’s effectiveness.
Nonetheless, he hopes the data they are collecting will provide enough information regarding mannitol’s efficacy that he can secure funding for a larger trial.
Sadeh talks of CliniCrowd “harnessing the power of the global cloud.” It is a compelling idea, the potential of which has yet to be uncovered. As for mannitol, although evidence is growing, there is still work to be done, but with the help of CliniCrowd and Arkadir, the data needed to prove its effects on Parkinson’s — one way or the other — may become a reality.
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