The question is all in the title.

More context:

I like phở soup. I have noticed that I get restless after eating the phở soup at some restaurants. The effects are similar to the ones resulting from caffeine intake. (Ingesting a cup of Turkish coffee or a couple of espressos results in my hands shaking badly.)

The phở soups which I think trigger the reaction appear to be the most savory ones. Given that:

  1. Monosodium glutamate (MSG) is a common ingredient in phở
  2. MSG has flavor enhancing properties
  3. Glutamate is a neurotransmitter

I thought there was possibly a connection. (Or perhaps not. Or perhaps it's the intake of MSG together with the consumption of an herb containing caffeine or another psychoactive drug. Phở contains herbs in large quantities.)

I found this paper which states the effects of caffeine result from an increase of glutamic acid (GA) in the posterior hypothalamus which in turns triggers wakefulness.

Thus I guess what I am asking is: does dietary intake of MSG increase blood serum levels of GA and does an increase of GA blood serum level result in an increase of GA in the brain (or in some parts of the brain)?

  • $\begingroup$ +1, the question of dietary glutamate consumption has been occupying my mind for a long time :) Below the result of quite some thought on the matter. $\endgroup$
    – AliceD
    Aug 28 '15 at 12:33
  • 2
    $\begingroup$ This question made me hungry. $\endgroup$ Aug 28 '15 at 16:46
  • $\begingroup$ The answer is absolutely. It definitely has the potential for restlessness, and even far worse effects. BIg Food does not want people to know this and the dangers associated with high levels of free glutamates because it is found in nearly every food in the form of "natural flavors" and many other forms including actual monosodium glutamate. The neurotoxic and neuroexcitatory effects of free glutamates is not only well-known, it is exploited by Big Food which puts it into all our food because it tricks our brains into making bland food taste better. $\endgroup$
    – biology
    Sep 30 '20 at 18:49

There is no strong evidence for MSG having any kind of neurotoxic/neuromodulatory effect.

However, A 2010 article says that, in a double blind trial, it was found that the people who consumed MSG containing soda, reported headache in significantly more numbers compared to the placebo subjects [1]. The concentration of MSG used in this study was 75-150 mg/kg. Assuming that one serving of soda would be 300ml i.e 300g, the amount of MSG consumed would be maximally 45mg, which is much less than glutamate concentration in some natural food stuffs such as tomatoes (~2000mg/kg [2,3]; a tomato that weighs 6oz/~170g contains ~340mg of glutamate). Therefore, I would doubt the findings of this article. The results could have possibly been observed because of some hidden dependent variable (such as the soda formulation).

In general, the USFDA considers MSG as GRAS (generally regarded as safe) [4].

Finally, a 2014 article concludes that dietary MSG would not lead to increase in either blood or brain levels of glutamate [5].

From the Abstract:

The sodium salt of glutamate (monosodium glutamate; MSG) imparts a savory/meaty taste to foods, and has been used as a flavoring agent for millennia. Past research on MSG/glutamate has evaluated its physiologic, metabolic and behavioral actions, and its safety. Ingested MSG has been found to be safe, and to produce no remarkable effects, except on taste. However, some recent epidemiologic and animal studies have associated MSG use with obesity and aberrations in fat metabolism. Reported effects are usually attributed to direct actions of ingested MSG in brain. As these observations conflict with past MSG research findings, a symposium was convened at the 13th International Congress on Amino Acids, Peptides and Proteins to discuss them. The principal conclusions were: (1) the proposed link between MSG intake and weight gain is likely explained by co-varying environmental factors (e.g., diet, physical activity) linked to the "nutrition transition" in developing Asian countries. (2) Controlled intervention studies adding MSG to the diet of animals and humans show no effect on body weight. (3) Hypotheses positing dietary MSG effects on body weight involve results from rodent MSG injection studies that link MSG to actions in brain not applicable to MSG ingestion studies. The fundamental reason is that glutamate is metabolically compartmentalized in the body, and generally does not passively cross biologic membranes. Hence, almost no ingested glutamate/MSG passes from gut into blood, and essentially none transits placenta from maternal to fetal circulation, or crosses the blood-brain barrier. Dietary MSG, therefore, does not gain access to brain. Overall, it appears that normal dietary MSG use is unlikely to influence energy intake, body weight or fat metabolism.

  • $\begingroup$ Totally false. MSG is proven to have a strong neurotoxic and neuroexitatory effect. One of many: Regarding the mode of cell death, glutamate-induced neuronal cell death has been judged originally as necrotic from the morphological appearance. ncbi.nlm.nih.gov/books/NBK6108 This is a well-known scientific fact. $\endgroup$
    – biology
    Sep 30 '20 at 18:44
  • $\begingroup$ @biology there is a difference between consuming glutamate as food and adding glutamate directly to neurons. Read my answer carefully before saying that it's totally false. $\endgroup$
    Nov 3 '20 at 10:45

Short answer
Glutamate cannot enter the brain due to the blood-brain-barrier.

You are totally right that glutamate represents the principal excitatory neurotransmitter in the brain (Meldrum, 2000). However, glutamate is a regular amino acid and will be metabolized quickly. More importantly, the blood-brain barrier is extremely effective in keeping polar (hydrophylic) molecules out, and therefore especially ions are not coming through as they are extremely hydrophilic. The blood-brain-barrier is formed by the endothelium lining the blood capillaries in the brain. In the brain, the endothelial cells are coupled through tight-junctions, that effectively keep almost everything out of the brain. The only molecules that can get through are either actively absorbed through specialized channels (glucose transporters for example) or are lipophilic. Glutamate under physiological pH carries two negative charges and a positive charge (Fig. 1), and will hence never make it through the blood-brain-barrier. There are glutamate transporters in the endothelial cells, but these in fact transport glutamate out of the brain, rather than in (Hawkins, 2009).

Fig. 1. Glutamate at physiological pH. Source: WikiWand.

- Hawkins, Am J Clin Nutr (2009); 90(3): 867S–4S
- Meldrum, J Nutr (2000) 130(4S Suppl): 1007S-15S

  • $\begingroup$ Thanks for adding the molecular explanation. Despite this, there is some scepticism about MSG causing "headaches". $\endgroup$
    Aug 28 '15 at 12:35
  • $\begingroup$ @WYSIWYG - that is likely not through direct entrance, but by some indirect mechanism. Increased glutamate in the brain is potentially excitotoxic and it theoretically cannot enter the brain through the blood stream via dietary intake. $\endgroup$
    – AliceD
    Aug 28 '15 at 12:38
  • $\begingroup$ Just a thought: if there are one-way channels for excess glutamate to leave the brain - is it theoretically possible that higher levels of glutamate in the blood outside the barrier could reduce the rate at which glutamate leaves the brain, due to less of a diffusion gradient? So the dietary glutamate never enters the brain, but its presence in blood reduces the rate at which glutamate already in the brain is transported out? $\endgroup$ Aug 28 '15 at 15:25
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    $\begingroup$ btw. I didn't know about wikiwand. Just installed it in my browser- it's amazing :) $\endgroup$
    Aug 28 '15 at 17:42
  • $\begingroup$ How do you think glutamate gets in the brain? Obviously it enters the brain one way or another. The body doesn't just manufacture glutamate from the air you breathe. It comes in through dietary intake some way or another, indirectly or directly. $\endgroup$
    – biology
    Sep 30 '20 at 18:46

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