Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson's Disease 03 January 2022 | doi.org/10.3389/fneur.2021....
Primary Clinical Outcome Measures (Safety and Tolerability):
Twenty-four participants initiated oral therapy (15 mannitol, 9 placebo). One participant from each of the groups terminated the study earlier than planned. Early termination of a participant receiving mannitol was due to in situ breast carcinoma discovered 3 weeks after the first visit. This severe adverse event was considered unrelated to mannitol treatment. The participant in the placebo group dropped out of the trial within a week due to nausea. This side effect was considered as related to the investigated product by the investigator.
No mannitol-related severe adverse events occurred during the study. A single severe adverse event (recurrence of prostate carcinoma), considered unrelated to the investigated product, was documented on the last visit in one patient receiving placebo. Clinically significant gastrointestinal symptoms (diarrhea, nausea, abdominal discomfort) were reported in 6/14 participants in the mannitol group who completed the study. In 5/14 participants these symptoms required dose reduction (Figure 1B). Only a single participant in the placebo group required dose reduction due to abdominal discomfort (Fisher exact P = 0.19). Overall, 64% of participants receiving mannitol tolerated well the target dose of 18 g of mannitol per day divided into two doses.
Blood tests, taken during each of the visits before dose increment, did not reveal electrolyte abnormalities, increased liver enzymes, impaired renal function, elevated non-fasting glucose level or evidence of systemic inflammation (leukocytosis or increased CRP). Blood counts and biochemistry parameters did not change during the trials and no adverse events were documented by the laboratory tests (Table 2).
Secondary Clinical Outcome Measures (Efficacy):
The study was not designed to demonstrate statistically significant differences in efficacy measures. None of the clinical measures were significantly different between the mannitol and placebo groups (Table 3). Sub-analysis, comparing the placebo group with participants who completed the trial on the maximal target dose of mannitol (18 g, n = 9), also did not reveal significant differences. Only a single participant (mannitol group), not on levodopa at screening, started levodopa therapy during the trial.
Biomarker Measures:
Blood samples taken with each increment of mannitol or placebo dose were used to measure biochemical variables that included total and pSer129 α-synuclein levels, in both lysed blood cells and in membrane pellets of lysed blood cells (6), and PI4,5P2 levels that based on recent findings are increased in PD models (8, 9). No observable or statistically significant differences were demonstrated between the groups and no intra-group longitudinal changes were observed during the trial.
Retrospective Power Calculation for Future Trials:
PD patients who buy and consume oral mannitol (not as part of controlled clinical studies) frequently report improvement of their sense of smell. In our small study no such effect was observed (in the mannitol group the median change in B-SIT score was −1, a mean change of −0.54 ± 2.22). Based on these results, a future study aiming to demonstrate an improvement of at least 1 point on the B-SIT test, with a power of 80% and a significance level of 5% in a one-sided paired t-test, would require a sample size of at least 32 subjects on mannitol.
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This is interesting, but how can we even consider a study in which only 24 people participated. After attrition, it sounds as though there were only fourteen participants left, possibly. That isn't really worth basing conclusions on because it is so small. In any case, if the only improvement tends to be the sense of smell, that can be achieved from taking high-dose thiamine anyways.
Thanks for bringing this to our attention. Credit to the investigators for using a half dozen different methods of measuring Parkinson's symptoms. Credit for also reporting a negative result - there was literally no difference between test and placebo arms, nor in scores before and after treatment.
Thank you for posting. I’ve been taking a tablespoon of mannitol that I order from Israel for about three months. I’ve experienced definite improvement in my sense of smell. It’s been a long time since I could smell things so well.
One of our regulars mentioned that he had got his sense of smell back when using a particular brand from Bulk Supplements, and when it wasn’t available, he got his supply elsewhere and his sense of smell was lost again.
There was a discussion about this and Marion gave us a pretty good explanation about the differences (I can’t remember the detail). I did try to get some from Bulk Supplements, as my husband has lost his sense of taste to a great degree, but they were out.
well done! a helpful negative result. I remember reading that Licorice works but can hurt your heart if you take too much. It would be nice if ceylon cinnimon (spelling?) could be checked for humans.
In PD the Placebo Effect is **STRONG** because thinking you feel better produces dopamine and too little dopamine (in your brain) is the reason you were prescribed Levodopa. pubmed.ncbi.nlm.nih.gov/120...
I may be reading this incorrectly, but they say the mental exam was 4 points lower in the placebo group. They don’t discuss this however, I wonder if it’s meaningful at all.
MY question is what mannitol quality did they use for the trial. The one from Israel is acquired from vegetables. Were the vegetables organic? I've begun using a Mannose taken from Mature Alovera organically grown and blended with small amounts of 17 or 18 other ingredients. I hae noticed several improvements in my health. My arms now swing when I walk, wheras prior to starting the supplememt they just hung at my sides. My gag reflex has returned. And I was having hallucinations as a side effect of the prescription medication that I am on have stopped, but i haven't cut back on the medication
I'm doing really really well, thank you for asking. I'd like to invite you to a zoom meeting tonight and another one tomorrow night, I do not know if I can be on the calls or not as I am in Florida and expect to loose power before the Hurricane has settled down. But if you are able to attend, you'll have to calculate the time. they originate at 7 'clock, Utah time. so at 9 o'clock in Florida, if i make it, to the zoom meeting, my name is Sue Rosier. The links are different each week, so i can send them to you again, if need be. I think you will be pleasantly surprised at how much you will learn. and if you have any questions, you can type them into the chat & they will answer them. or simply wait for the Q & A at the end, unmute yourself and ask your questions. Enjoy.
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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