Mannitol: two considerations which are moderately pessimistic (plus a new, more optimistic edit!)

[ElliotGreen]

NOTE: PLEASE SEE MY UPDATE AT THE BOTTOM OF THE POST!

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I admit, I was hyped to see the actual video of the Parkinsonian-vulnerable fruit flies that had been fed on mannitol. They were climbing the side of the tube so much more energetically and happily than the ones that didn't have mannitol.

I also am aware that some people have reported positive results from mannitol including regaining their sense of smell and other improvements. There is also evidence that mannitol can have a positive effect on gut bacteria and the production of butyrate. I think these are important and should be considered. But so should the following.

Here is the main article by the Israeli team that was hyping mannitol.

TITLE: A Blood-Brain Barrier (BBB) Disrupter Is Also a Potent alpha-Synuclein Aggregation Inhibitor

jbc.org/content/288/24/1757...

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ISSUE 1: in the study, they saw mannitol preventing the accumulation of alpha-synuclien. HOWEVER, it did NOT dissolve pre-existing clumps of alpha synuclien.

Here's a quote from their paper:

"Mannitol seems to have a preventive ability to inhibit alpha-syn aggregation, but not a reversive ability. Mannitol was not able to dissolve preformed alpha-syn aggregates in vitro nor to dissolve alpha-syn aggregates when dripped on brain sections taken from alpha-syn tg mice."

We can hope that maybe it will in the long term, but that's not what they saw in their study. ( A different research protocol would have to be followed to answer that question more fully.)

Maybe long-term it could at least help keep things from getting worse?

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ISSUE 2: Will mannitol get past the blood brain barrier into the human brain?

The Israeli team hype fact that mannitol is a blood brain barrier disrupter. This will supposedly get it into the brain where it can act.

However, this disruption of the BBB is achieved by INJECTING mannitol at high concentrations.

sci-hub.tw/https://www.scie...

Mannitol is not highly absorbed in the small intestine in the first place. It is highly doubtful that this global disruption of the BBB will be achieved through oral consumption of mannitol.

Here's a question that I would love to have answered. Does mannitol get through the blood brain barrier when it is at lower concentrations and not disrupting it? Some substances do, and others don't.

So far, my google-fu is not savvy enough to answer this question. Whenever I do research on mannitol and the blood brain barrier, all of the results discussed the disruption of the BBB at high concentrations. But can the mannitol get through at low concentrations when the BBB isn't disrupted?

Wait! Here is more information. Israeli team FED the fruit flies mannitol. They INJECTED the mice with mannitol into their abdomens daily at remarkably high doses (1 g per kg). Both had positive effects of reducing alpha-synuclien clumping.

Mice have blood brain barriers. The mannitol was getting through the blood brain barrier into the brain.

But wait again! The injections were at high enough dose that it could have been through high doses of mannitol DISRUPTING the BBB, rather than low doses of mannitol permeating the BBB. Such high doses may be effective in disrupting the BBB, but they can have rather serious side effects, too. It can kill epithelial cells along artery walls, and cause "acute brain swelling, seizure, and other neurologic complications" (see previous citation).

Again, this is relevant because humans consuming mannitol orally will have a lower dose of mannitol in the bloodstream. From my point of view, we still don't know whether this will be getting through the blood brain barrier or not.

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UPDATE (29 July 2019):

As I said in the above post, I was skeptical of the possibility of lower doses of mannitol to pass through the blood brain barrier. (These are the doses that we would take orally.) I still haven't heard evidence, one way or the other, as to whether it can. For this reason, I was somewhat skeptical of the possibilities of taking mannitol to control alpha synuclein clumping and improve Parkinson's symptoms. However, there is anecdotal evidence by some reports that it helps some people. Park_bear left a comment below saying he believed it helped him.

Anyway, my position is changed's significantly. A few days ago, I came across a study with relevant findings. It turns out that people with Parkinson's can have a compromised blood brain barrier in the striatum negra. This can cause problems for us, and it potentially is involved in the causality of Parkinson's. But it also potentially can be used to our advantage. If the blood brain barrier is compromised in the striatum negra, then blood-borne supplements and drugs may be more likely to reach the target there.

Here's a post where I described this paper. I also mentioned mannitol in a comments.

healthunlocked.com/parkinso...

[ElliotGreen]

Article on the blood brain barrier:

theconversation.com/explain...

"The tight gap allows only small molecules, fat-soluble molecules, and some gases to pass freely through the capillary wall and into brain tissue. Some larger molecules, such as glucose, can gain entry through transporter proteins, which act like special doors that open only for particular molecules."

Mannitol is about the same molecular weight as glucose (although it is a chain and not a ring). Thus, I don't think we can assume that it goes through the blood brain barrier in low concentrations.

[park_bear]

Kudos for this work trying to nail down what is going on.

One anecdotal observation for what it is worth: I tried quitting mannitol a while back, thinking it was not doing anything for me. My main symptom, motor impairment, got a bit worse, and then got a bit better when I got back on mannitol.

[Fed1000 in reply to park_bear]

Hi bear, how many grams of Mannitol do you use per day and which brand?

[park_bear in reply to Fed1000]

7.5 = level tablespoon. Amazon bulk.

[Fed1000 in reply to park_bear]

Sorry, maybe Manna? Is it in powder?

[park_bear in reply to Fed1000]

amazon.com/Bulksupplements-...

[Fed1000 in reply to park_bear]

Thank you so much.

[Rhyothemis]

You raise some good questions. Seems like it would be relatively easy to do a study on mice given oral mannitol (in their drinking water, radio-labelled) to see if any gets in their brains.

~

There may be another possible mechanism of action for mannitol - apparently mannitol via IV (but not in amounts thought to disrupt the BBB) can increase the bioavailabilty of magnesium to the brain:

"In another study of 20 patients undergoing craniotomy, magnesium sulfate administered intravenously at 60mg/kg over 15 minutes produced a maximal plasma magnesium concentration at 30 minutes, with subsequent decreases. However, a significant increase of magnesium in the CSF after 90 minutes, which persisted for more than 4 hours, was observed. A correlation between plasma and CSF magnesium concentrations was not observed. Of the 20 patients, 15 were also administered 0.5mL/kg of mannitol intravenously for better operating conditions.5This dose and route of mannitol should not cause BBB disruption."

ncbi.nlm.nih.gov/pmc/articl...

The authors do not explain exactly how this works, unfortunately, but they conclude that mannitol should be co-administered with magnesium to treat traumatic brain injury.

[Rhyothemis in reply to Rhyothemis]

Mannitol can also enhance intestinal absorption of magnesium:

ncbi.nlm.nih.gov/pubmed/232...

review article on intestinal absorption and bio-availability of magnesium:

ncbi.nlm.nih.gov/pmc/articl...