Mannitol Safe But Not Likely to Treat Parkinson’s Symptoms, Trial Reports

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by Steve Bryson PhD |

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Although safe and fairly well tolerated, treatment with the over-the-counter supplement mannitol did not lessen symptoms in adults with Parkinson’s disease over 36 weeks, a small Phase 2a clinical trial concluded.

Its researchers noted, however, that the study had too few patients to show a statistically significant impact on mannitol’s effectiveness.

Trial findings were in the study, “Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson’s Disease,” published in the journal Frontiers in Neurology.

Parkinson’s is caused by the loss of nerve cells in the brain that produce dopamine, a molecule made by the body to send messages between nerve cells. Current treatments primarily target symptoms by replacing lost dopamine.

Studies suggest that the death of these nerve cells, called dopaminergic neurons, is due to the clumping of the alpha-synuclein protein, which is toxic to cells.

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Leaving No Stone Unturned: Giving Mannitol a Try

Mannitol, a sweetener, was recently suggested as a potential disease-modifying agent for Parkinson’s. In cell-based experiments, mannitol interfered with alpha-synuclein clumping. In a fruit fly model of Parkinson’s, mannitol exposure led to the full recovery of impaired motor functions.

These results prompted many Parkinson’s patients to begin consuming oral mannitol, with self-reported outcomes including a better sense of smell, lower doses of Parkinson’s medication, and a better quality of life.

Members of the Parkinson’s community in Israel also launched a crowd-funded platform called CliniCrowd to share experiences of self-administered mannitol. The supplement’s use was also supported by the documentary “My Disease Our Revolution,” produced to bring more attention to mannitol in treating Parkinson’s.

Based on reports from CliniCrowd and physicians treating Parkinson’s, David Arkadir, MD, PhD, a physician and neurologist at Hadassah Medical Center in Jerusalem, secured funding from the Israeli government to conduct a small placebo-controlled Phase 2a trial (NCT03823638) into the safety, tolerability, and potential efficacy of increasing doses of mannitol in Parkinson’s.

In total, 22 adult patients completed the trial, which included five visits to the Jerusalem clinic. At the first visit, 14 were randomly assigned to 2.5 grams of mannitol twice daily, and 11 to an oral placebo twice daily. At the second and third visits, occurring at six-week intervals, mannitol doses were increased to 4 and 6 g twice daily, respectively.

On the fourth visit 12 weeks later, mannitol was increased to 9 g twice daily.

After another 12 weeks, totaling 36 weeks of treatment (about eight months), patients at the fifth visit underwent efficacy assessments, including tests for changes in Parkinson’s medications, constipation, sense of smell, cognitive abilities, and non-motor symptoms.

Motor assessments were documented but were not included in outcome measures because patients were not asked to stop their medications before visits. Blood tests were conducted to measure disease-related biomarkers.

No mannitol-related serious side effects were reported during the trial. Among its 14 mannitol-treated patients, six reported clinically significant gastrointestinal symptoms, such as diarrhea, nausea, and abdominal discomfort. Mannitol’s dose was reduced in five of these people. One placebo group patient also required a dose reduction due to abdominal discomfort.

Overall, the target dose of 18 g per day (9 g twice daily) was well tolerated by 64% of participants. Bloods tests taken during each visit before dosing showed no abnormalities in electrolytes, impaired kidney function, increased liver enzymes (a sign of liver damage), elevated glucose levels, or signs of systemic inflammation. Blood test outcomes did not change during the study, and laboratory tests reported no adverse events.

Across all efficacy measures, however, no significant differences were recorded between patients on mannitol and those given a placebo. In a subgroup analysis, no efficacy differences were seen among patients treated at the maximal target 18 g dose of mannitol. One mannitol-treated patient who was on any Parkinson’s medication before the study started dopamine replacement therapy during the trial.

“The study was not designed to demonstrate statistically significant differences in efficacy measures,” the researchers noted.

No observable or statistically significant differences were evident between the groups, or within groups over time, in alpha-synuclein levels or phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) levels, shown to increase in Parkinson’s models.

Although there were no observed improvements in the sense of smell, further analysis indicated that a sample size of at least 32 mannitol-treated patients would be required to show statistical significance in this outcome measure.

“This study established the safety of long-term use of oral mannitol in doses up to 18 grams per day,” the researchers wrote. “Following 36 weeks of exposure to mannitol we did not observe a clear reduction in Parkinson’s symptoms that were previously reported by patients taking mannitol.”

Larger trials targeting efficacy, however, “would have to take into account that only two thirds of participants tolerated this [target] dose,” they added.