Mannitol safe for Parkinson’s disease but unlikely to treat symptoms, trial finds

Although safe and fairly well tolerated, treatment with the over-the-counter mannitol supplement did not improve symptoms in adults with Parkinson’s disease for 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 the effectiveness of mannitol.

The results of the trials were in the study, “Safety and tolerability, dose escalation, double-blind trial of oral mannitol in Parkinson’s disease,» published in the magazine Frontiers in Neurology.

Parkinson’s disease 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 protein alpha-synuclein, which is toxic to the cells.

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Mannitol, a sweetener, has recently been suggested as a potential modifying agent for Parkinson’s disease. In cellular experiments, mannitol interfered with alpha-synuclein clumping. In a fruit fly model of Parkinson’s disease, exposure to mannitol resulted in complete recovery of impaired motor functions.

These findings have prompted many Parkinson’s disease patients to start taking mannitol orally, with self-reported results including better sense of smell, lower doses of Parkinson’s disease medications, and improved quality of life. .

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

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

A total of 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 oral placebo twice daily. At the second and third visits, at six-week intervals, the mannitol doses were increased to 4 and 6 g twice daily, respectively.

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

After an additional 12 weeks, totaling 36 weeks of treatment (approximately eight months), patients at the fifth visit underwent efficacy evaluations, including testing for changes in medications for Parkinson’s disease, constipation, l 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 prior to visits. Blood tests were done to measure disease-related biomarkers.

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

Overall, the target dose of 18g daily (9g twice daily) was well tolerated by 64% of participants. Blood tests taken at each visit prior to administration showed no abnormal electrolytes, impaired kidney function, increased liver enzymes (a sign of liver damage), raised blood sugar or signs of systemic inflammation. Blood test results did not change during the study and lab tests did not report any adverse events.

However, on all measures of effectiveness, no significant difference was recorded between patients on mannitol and those who received a placebo. In a subgroup analysis, no difference in efficacy was observed in patients treated with the maximum target dose of 18 g mannitol. A mannitol-treated patient who was taking any medication for Parkinson’s disease before the study started dopamine replacement therapy during the trial.

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

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

Although no improvement in smell was observed, further analysis indicated that a sample 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 at doses up to 18 grams per day,” the researchers wrote. “After 36 weeks of exposure to mannitol, we did not observe a clear reduction in symptoms of Parkinson’s disease previously reported by patients taking mannitol.”

However, larger trials targeting efficacy “should take into account that only two-thirds of participants tolerated this [target] dose,” they added.

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