L-glutamine, once a lowly amino acid vying for attention among 19 siblings, has become a darling of functional medicine for its role in gut health and intestinal permeability. L-glutamine is an important fuel source for enterocytes, which are the cells lining the intestines, and there’s pretty solid evidence that L-glutamine can help strengthen the intestinal barrier.
That all sounds fantastic, right? I sure thought so, and I supplemented accordingly, on and off, for several years. But recently, some self-experimentation has led me to suspect L-glutamine of being a contributor to some pretty intense brain fog and other mental symptoms I’ve been experiencing. L-glutamine was low on my list of suspects, because I had such positive expectations of it, so it took me a while to notice an association. But the timing was there, so I decided to investigate.
Starting with a brief Google search, there were definitely a couple anecdotal reports of people not tolerating L-glutamine well, and several associations specifically with mental symptoms. There were also a few reports of L-glutamine improving brain function, though, so obviously nothing consistent. But the vast majority of both anecdotal reports and scientific papers were about the beneficial effects of L-glutamine on the gut.
However, one potential mechanism I saw mentioned for adverse effects of glutamine is its role in ammonia metabolism. Glutamate and ammonia can be combined to form glutamine, which functions as a (supposedly benign) carrier to transport ammonia to the liver to be detoxified. This process is especially important in the brain, so there’s a connection there. Obviously too much ammonia is bad, and can have adverse effects on brain function, but could supplemental glutamine somehow contribute to that?
I found a couple papers (1, 2) discussing the role of glutamine in ammonia-related neurotoxicity associated with hepatic encephalopathy, which is basically just brain dysfunction caused by liver disease. Some of the milder symptoms of chronic HE are pretty similar to what I’ve experienced, but I don’t have liver disease, so I’m not sure if it’s relevant. I do have a history of elevated liver enzymes, though, so my liver definitely isn’t in tip-top shape.
Anyway, these papers put forth the argument that glutamine itself can be toxic to the brain if levels are too high, while also being a contributor to hyperammonemia. Another paper seems to corroborate this as a possibility, but the evidence is ultimately sparse and conflicting. And said paper also asserts that a healthy liver should be able to keep blood ammonia levels in a safe range, regardless of glutamine supplementation. (What is a “healthy liver” though? Just non-cirrhotic? I don’t have liver disease, but judging by my liver enzymes and other symptoms, my liver could definitely be healthier.)
One problem with this potential mechanism is that it’s unclear how glutamine supplementation actually affects glutamine levels in the brain, if at all. It seems likely that unless you’re taking a TON of glutamine, or getting it through parenteral nutrition (which actually, many of these studies do consider glutamine supplementation in parenteral nutrition), any rise in blood levels of glutamine would be negligible once said glutamine makes it past your gut bacteria, then your intestinal border, then your liver.
The above paper also also mentions that the kidneys produce a lot of ammonia from glutamine, which goes directly into circulation and could thus affect the brain, but likewise, how would this excess glutamine from oral supplementation get to the kidneys? Seems highly unlikely.
I did come across one case report of oral glutamine supplementation contributing to hyperammonemia, but that was in a critically ill patient with extreme catabolism, mild liver dysfunction, and other stuff going on, and she was given 30 g of glutamine per day (which is a lot!). But this case report does also confirm that rising levels of glutamine itself, not necessarily ammonia, is related to neurotoxicity.
And just to throw another wrench into the works, some papers (like this one) suggest that glutamine supplementation actually protects against hyperammonemia. Have I mentioned the body is complicated? Because it’s really complicated.
A potentially more plausible mechanism is that L-glutamine supplements somehow alter the activity of intestinal bacteria, and this affects brain function either through direct by-products of bacterial glutamine metabolism (i.e. glutamate and ammonia), or through other by-products that result from increased bacterial activity in general. This would explain why many people tolerate glutamine just fine, while others don’t, since an individual’s reaction would be mediated by their unique bacterial profile.
One paper does support the idea that extra provision of glutamine increases the activity of small intestinal bacteria in the pig, and that pathogenic bacteria in particular are eager to metabolize glutamine.
Another paper posits that ammonia produced by the bacterial metabolism of glutamine in the small intestine may play a significant role in the pathogenesis of hepatic encephalopathy. The effectiveness of Rifaximin in treating HE lends credence to this idea, because Rifaximin knocks back small intestinal bacterial growth and would decrease their by-products, ammonia being one of them. But again, it’s unclear whether this is relevant in people with non-cirrhotic livers.
A random extra thought related to this mechanism – could the high glutaminase activity of pathogenic bacteria be one mechanism by which bacterial overgrowth causes intestinal permeability? We know glutamine is important for enterocytes, so if bacteria are stealing and metabolizing all the glutamine, that kind of sucks for the intestines, right? A cursory Google Scholar search didn’t turn up any evidence along this line of reasoning, so maybe not.
Anyway, it seems that L-glutamine does cause adverse brain effects in some people (anecdotally), even if we have no idea how or why. But the good news is that the vast majority of scientific papers on the topic support L-glutamine as extremely beneficial for the intestines, so that’s awesome for the people it works for! Just be aware of your reactions and don’t be oblivious to any potential adverse reactions (like me).