Welcome to Monday Musings! I don’t expect this to be a weekly thing, but I wanted a nifty little label to slap on posts where I’m basically just thinking out loud. Wouldn’t want to delude anyone into thinking I have all the answers, now would I?
Thanks for being here!
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).
Holly Oberholtzer says
This is a wonderful blog. I learned quite a bit!
Alyssa Luck says
Thank you Holly!
I felt the same
Alyssa Luck says
Interesting! Glad it’s not just me!
I’ve been experiencing a massive brain fog after taking glutamine, I’ve beeb taking 5 mg and 10 mg doses on 1 scoop and sometimes it triggers the brain fog, sometimes it doesn’t. I take it with food and others on an empty stomach with water. I think my body handles it better when taken with food. It’s a sad situation cause I’ve read the tons of benefits for gut health and just now I’m just starting to feeling them 🙁
Alyssa Luck says
Hey Angelica! Somehow missed your comment before. That totally sucks! I mean, I’m glad to hear that you’re feeling the gut benefits, but with the brain fog, it’s a pretty tough trade-off to make. Hang in there, and good luck figuring everything out!
I don’t have this problem but I am talking to a few people that do. I think it may be a bacteria in their gut that is producing glutamate from glutamine. Read how l-glutamine is commercially produced by I think it was a yeast. Anyways, I started a search for known bacteria that can convert l-glutamine into glutamate and quickly found one in sourdough… if you want to chat more let me know. Idk how people who have this problem can heal a leaky gut. The only other hint at what is going on would be to look at people who have an IV of l-glutamine vs ingesting it and knowing that ingesting it causes problems.
Alyssa Luck says
Ah, very interesting that you know others who have the same problem! I agree that it would make sense for it to be mediated by gut bacteria, since that would explain the differences in how people react. Thanks for the comment Jonathan!
Just got directly to your blog googling brain fog and glutamine. Nice writing, thanks.
I’m taking probiotics with l glutamin 2 g and I’m feeling dizzy and brain foggy.
I stopped 3 days ago and I still have some brain fog. I have taken it for a week. Not sure how fast will dissapear.
Alyssa Luck says
Well thank you! Always very interesting hearing from folks who’ve had similar experiences. I hope your brain fog goes away soon!
Thanks for this post! I also found it through an “L-glutamine and brain fog” Google search as 5g daily supplementing has caused such pronounced neurological symptoms, it feels like I’ve suffered a concussion. Inflammation, sensory overstimulation, headache, brain fog as well as mental processing and memory problems. Would be interesting to see if there’s any research correlating SIBO with adverse l-glutamine reactions. I used to take glutamine years ago as a work out supplemt and never had problems but this is absolutely intolerable. Feels like I’m getting brain damage each time I dose.
Alyssa Luck says
Hi Katy – thanks for commenting! That’s super interesting that you’ve experienced the same thing. Good thought on SIBO potentially being a factor – someday I’ll look into this issue more. It’s definitely an interesting one considering how popular L-glutamine is for gut issues!
Same! I have been working on writing a doc for the past few weeks. Yesterday, I felt as though my brain was short-circuiting. I can’t really explain it, I just know it’s even worse than brain fog (which I had when I had Covid over a year ago, also not fun). It’s as though I feel this wall, where I can’t process anything behind it, even if I wanted to. And the only thing I’ve done different is take a supplement from Pure Therapeutics called “Leaky Gut Defense” in the morning. The “fog” was so pronounced that I started googling, and also stumbled across your post. Kind of scary that there isn’t a lot of information out there regarding this. I could barely write a cohesive sentence, and felt useless all day. I initially wondered if this was perhaps part of the “detox” process but for me, it’s not worth it. Hopefully I’ll be back to normal in a few days.
Alyssa Luck says
That’s wild! Your “wall” description is good – I know exactly the feeling you’re talking about. Hope this resolves quickly for you! And thanks for sharing. We’re conducting a little bit of citizen science here in this comment section 🙂