AXA1125: Amino Acid Formula for Long Covid
Here is the composition, and some things that we know (and don't know).
Oxford University is testing a mix of amino acids that were chosen for the possibility of reducing fatigue and muscle weakness in Long Covid. The formula they are planning on testing was originally developed by a US company and showed some value for NASH (fatty liver). 1 The formula includes 6 amino acid compounds, and if the research pans out, might provide a safe, cost-effective way, and readily available method to reduce some of the common symptoms that Long Haulers experience.
Here’s an article from the university’s website:
“Oxford to test potential treatment for fatigue in long COVID patients.” https://www.ox.ac.uk/news/2021-10-29-oxford-test-potential-treatment-fatigue-long-covid-patients.
What is in AXA1125?
Here are the six amino acid compounds and the relative amounts of each in the 6 gram packets that were used in an early study:
Leucine - 1.00 gram
Isoleucine: 0.50 gram
Valine: 0.50 gram
Arginine: 1.81 grams
Glutamine: 2.00 grams
N-Acetyl-Cysteine: 0.15 gram
The first studies on this formula involved prepackaged envelopes of the powder with an orange flavor; participants were told to mix the powder with water immediately before drinking. The N-Acetyl-Cysteine (NAC) typically has a bit of a sulfurous smell, and when sitting in water, the acetyl group can split off over time and make it even more sulfurous and noxiously sour (acidic). An alternative is to take the NAC separately in capsules and have a 5 amino-acid beverage that is less stinky and more neutral. And the remaining amino acids are more stable and can probably be dissolved in solution for a while.
For the NASH study, subjects consumed 48 grams per day of the amino acid blend… that is 4 packets (6 grams each) dissolved in a glass of water in the morning, 4 packets dissolved in water in the evening.
How much does AXA1125 Cost?
I went online and got the following prices for each amino acid… this is in the United States, for people purchasing small amounts (1-2 pounds at a time):
Leucine: 4.0 cents per gram
Isoleucine: 5.8 cents per gram
Valine: 3.2 cents per gram
Arginine: 2.6 cents per gram
Glutamine: 4.4 cents per gram
N-Acetyl-Cysteine (NAC): 16.8 cents per gram
(Note: the NAC seemed to be in short supply and is noticeably more expensive than when I bought some a year or two ago - many people are taking it for covid concerns. Even though there are many different companies that package it for sale, most of the raw product comes from a small number of bulk manufacturers and production has not expanded enough to meet demand and keep prices of NAC low.)
If we calculate the weighted average cost for the mixture, 1 gram of mix-it-yourself generic AXA1125 is around 4.1 cents. If the standard dose is 48 grams per day, that translates to just under $2 per day.
A price of $60 per month is not particularly cheap, but if a person has significant impairment and this cocktail of amino acids alleviates some of the fatigue and lets a person live a more normal life, it could be worth it. (At this time, there isn’t evidence to say whether this helps people or not.)
Although the cost of a daily dose of AXA1125 is relatively modest, it is not cheap. If you are going to blend it yourself, you are going to have to buy in bulk, and the initial layout to get a supply costs around $120 upfront. Because some amino acids make up a big part of the formula and others are used in much smaller amounts, the DIY mixologist will have to re-order different aminos at different times to keep the stock replenished if they continue taking this supplement. If a person takes the blend daily for many months, the cost will average out to $60 per month, but the required purchases will not be evenly spaced. Put in other terms: this costs $720 a year.
As I understand it, the company sponsoring the research (Axcella) might be seeking intellectual property protection on the use of this blend of amino acids for commercial purposes. This might create an issue for anyone who tries to sell the amino acids in that particular ratio, or who makes claims while selling such a blend. It does not prevent a person from taking amino acids for their own health. In a similar way, there are patents on the use of highly purified fish oils for treating cholesterol and triglyceride levels in people with heart disease, but it is also still possible to buy generic fish oil and take it for whatever purposes a person wishes.
The Rationale
The idea behind this experimental approach is related to a large body of general research on the individual amino compounds. From a top-level view, the researchers in this study think that AXA1125 might improve vascular function, help rebuild muscle, and boost the mitochondria (our cellular energy stations).
NAC is a precursor of glutathione, an important molecule involved in antioxidation and detoxification in the body. It is also a precursor for hydrogen sulfide in the body, which can reduce mast cell hyperactivity - some of the symptoms of Long Covid may be due to hyperactive mast cells.
Arginine is a precursor of nitric oxide, a gaseous molecule that has an important role in vascular health.
Glutamine has been shown to assist with muscle gain in some experiments, and is believed to support intestinal healing … it is often used by people with ‘leaky gut’ issues.
Leucine, Isoleucine, and Valine are all branched-chained amino acids that can support building muscle mass.
All of these rationales make perfect sense on paper. We do not yet know if they will help people with long covid or not. Long Covid is a complex condition, and things that make sense on paper may or may not lead to meaningful real-world results.
» Endogenous Metabolic Modulators (EMMs)
Amino acids are (like vitamins and minerals) something we consume regularly. They have been described as Endogenous Metabolic Modulators.
Ordinarily, we don’t think about how much of the amino acid lysine we eat in a day or over a week. We just eat. But studies have shown that taking extra lysine can reduce the number of cold sores for many people.2 3 At higher doses, the lysine goes beyond simply being a building block for proteins in general. At higher doses, an EMM can start to exert biological effects that are not seen with ordinary dietary doses.
Arginine and citrulline are two related amino acids that few people think about. But these aminos are converted to nitric oxide (NO) in the body, and that opens up blood vessels, it lowers blood pressure, and it can improve blood lipids (“cholesterol” and triglycerides). If foods are chosen carefully to get a high intake of arginine and citrulline, that can have beneficial effects. 4 It gets difficult and boring to eat large amounts of the same arginine-rich foods (like almonds, watermelon, and cocoa) day after day. Taking a supplement of a few grams of pure arginine or citrulline opens the possibility of obtaining the same benefits more conveniently.
» Empty or Full Stomach?
If amino acids are being administered in large doses to try to achieve a specific effect, they are commonly taken on an empty stomach. One reason for this is that different amino acids compete against each other for various purposes.
For example, if one is trying to get tryptophan into the brain to boost serotonin levels, the blood-brain barrier (BBB) must be considered. The BBB has limited transport capabilities for Large Neutral Amino Acids (LNAAs) and tryptophan is an LNAA. If there is a surge of tryptophan while levels of other LNAA amino acids are low, then a high percentage of the tryptophan will cross into the brain because the transport system becomes saturated with tryptophan. But if a person has recently eaten a high-protein meal and the blood has lots of leucine, isoleucine, valine, phenylalanine, and threonine floating around, then those amino acids compete against the tryptophan at the BBB transport system, and much less tryptophan will make it into the brain.
In the AXA1125 study on NASH, patients were instructed to take the supplement one-half hour before a meal. The total daily amount of 48 grams was split into a 24 gram morning dose, and a 24 gram evening dose.
Safety Issues
Although amino acids are essential nutrients that we eat with every food that contains protein, the possibility of side effects increases as we move away from food proteins and include highly concentrated forms of one or a few particular amino acids. This is true of all endogenous metabolic modulators - a little bit of extra of some vitamin might be beneficial in some conditions, but more is not always better.
The study of AXA1125 for fatty liver reported that the most commonly reported side effects included diarrhea (7 cases), headache (3 cases), cholecystitis (gall bladder inflammation, 2 cases), heartburn (1 case), and toe infection (1 case). It is unclear how many of these were directly caused by the amino acid supplement, and how many simply were conditions that participants experienced while they happened to be taking the amino supplement. Participants who experienced gastro-intestinal issues were instructed to take the amino acid beverage 1 hour after a meal instead of 30 minutes before meals. Overall, the observed side effects seen with the NASH study were relatively minor. But it was a short-term study, and did not consider all possible consequences with long-term intake of a large daily dose of amino acids.
» High Protein Problems
High protein diets place a heavier load on the kidneys compared to moderate protein intake and may increase the risk of certain kidney issues, or worsen existing kidney conditions. As proteins are broken down into amino acids, the same effect is expected for purified amino acids. Amino acids in the blood are sometimes broken down into ammonia (which gets converted to urea) and this increases the load on our metabolism. Amino acids also generate acid in the body - nitrogen and sulfur in aminos usually lead to more nitric and sulfuric acids, which put a greater burden on the kidneys. This can increase the amount of urine produced, and more potassium, calcium, and magnesium are required to transport the acids through the kidneys into the urine.
The recommended dietary allowance for protein (ie, amino acids) for an average sedentary person is 0.8 grams per kilogram per day. To translate that into Americanese, a person weighing 150 or 180 pounds might be advised to get 55 to 65 grams of protein. Taking an additional 48 grams of AXA1125 is boosting that considerably.
Those who have existing kidney issues would be well served to consult their doctor before increasing protein/amino acid intake.
» Effects of Branched-Chain Amino Acids (BCCAs)
Some athletes have used BCCAs for perceived value in improving muscle building or enhancing performance. Meat and eggs are natural sources rich in BCCAs, and for that reason, some believe that this type of amino acid is well suited to building muscle mass or otherwise supporting performance.
In large doses, BCCAs might cause fatigue or loss of coordination in some people, and this could be problematic when driving a car or being involved in other high-risk activities. Because BCCAs compete with tryptophan to enter the brain, high intakes of BCCAs might theoretically lower tryptophan and serotonin levels in the brain, leading to mood changes like depression and anxiety.
According to WebMD, 5 branched-chain amino acids (including leucine, isoleucine, and valine) are probably safe for time periods up to 2 years, when given at doses of up to 12 grams per day. A dose of 48 grams of AXA1125 per day has 16 grams of branched chained aminos; this might still be safe, but it goes beyond that recommendation a bit.
» Nutrient Dilemmas and the U-Shaped Curve
Some people have cynically said that taking any action to avoid one type of disease will paradoxically increase the risks of dying of some other disease. I don’t fully agree with this - there are some things that promote health overall. But there may be a grain of truth in that perspective.
Consider the Omega-3 fats. They are essential for good health. Doctors recommend eating more fish so we get more of them. But too much of that is not a good thing. When I was living in Iceland in the 1980s, it was common for people to take a spoon of cod liver oil each morning. It is a good source of Omega-3s, it has Vitamin A and Vitamin D, so what’s not to like to about cod liver oil (other than the flavor)?? Well, recent research has shown that people who take fish oil are more prone to develop atrial fibrillation, a distressing type of arrhythmia. There is a U-Shaped Curve for DHA and EPA Omega-3s. When we take a slightly increased dose of these fats, risk goes down. Take a little more, the risk still goes down - for a while. But eventually, taking more fish oil starts raising the risk again.
We see similar U-Shaped Curves for many minerals, especially metals like zinc and iron. Even sodium has a U-Shaped Curve; some sodium is necessary, and problems will arise from EITHER too little sodium or too much sodium. It’s a situation that needs to be “Goldilocksed” — not too much, not too little, just right. And we really don’t know what the long-term Goldilock zone is for all the amino acids.
The Bottom Line
AXA1125 is an interesting idea. At this point, there is not enough evidence to support or dismiss the idea. The cost and risks seem to be somewhere in the middle compared to other approaches for dealing with Long Covid - it’s not as cheap or safe as a moderate dose Vitamin D supplement, but it seems like it is less risky and costly than many antiviral medicines that might be prescribed to Long Haulers. I hope that the studies which are in the pipeline will soon provide more information, and my fingers are crossed that it proves effective.
I have personally taken moderate doses of some amino acids for other conditions in the past. I think that this approach can be useful for some conditions, but cannot say how useful this particular approach to Long Covid will be.
Other References
“Safety, Tolerability, and Biologic Activity of AXA1125 and AXA1957 in Subjects With Nonalcoholic Fatty Liver Disease.” American Journal of Gastroenterology, 1 Dec 2021, PMID 34382947.
“Lysine prophylaxis in recurrent herpes simplex labialis: a double-blind, controlled crossover study.” Acta Dermato-venereologica, 1980, PMID 6153847.
“Subjective response to lysine in the therapy of herpes simplex.” Journal of Antimicrobial Chemotherapy, Nov 1983, PMID 6423612.
“Watermelon and l-arginine consumption improve serum lipid profile and reduce inflammation and oxidative stress by altering gene expression in rats fed an atherogenic diet.” Nutrition Research, Oct 2018, PMID 30340814.
“BRANCHED-CHAIN AMINO ACIDS (BCAA): Overview, Uses, Side Effects, Precautions, Interactions, Dosing and Reviews.” https://www.webmd.com/vitamins/ai/ingredientmono-1005/branched-chain-amino-acids.
