A Review of Inosine Supplements on Exercise Performance

The supplement industry is cyclical. Various ingredients gain popularity, fall out of favor (most likely due to less than stellar research findings), go into the abyss for an undefined amount of time, and finally re-appear as a “hidden gem” whenever some guru claiming to do countless hours of research attempts to pull one over on consumers and includes it in their new groundbreaking pre-workout.

Inosine is one such ingredient.

At one time, inosine was believed to be a potent performance-boosting compound, but after a chain of studies showed it had no effect on performance, inosine disappeared from the scene. Now, it’s popping up in a few pre-workouts, and we’re here to give you the straight dope on whether or not you should supplement with it

Related - Top 10 Best Pre-Workout Supplements

Let’s begin by answering a simple question.

What is Inosine and What Does it Do?

Inosine is a purine nucleoside formed when hypoxanthine (another purine compound) binds to to the C1 carbon of ribose via a beta-N9 glycosidic bond. In case you didn’t know, nucleosides are basic compounds of all cells. Inosine is an intermediate in the breakdown of various purines and purine nucleosides to uric acid as well as the pathways of purine salvage. ^[14,15]

Inosine also serves as a building block for DNA and RNA. More specifically, it is occurs as an anticodon of certain transfer RNA (tRNA) molecules and can pair with any of the other three bases, including adenine (A), cytosine (C), and uracil (U). Additionally, inosine has also been associated with purine nucleoside phosphorylase deficiency and xanthinuria type I -- congenital metabolic malfunctions .

Lastly, inosine also results from the dephosphorylation of ATP -- the cellular currency of exercise.. Structurally speaking, ATP is simply an RNA nucleotide with a “tail” comprised of three phosphate groups.

During exercise in order for us to obtain energy, ATP (adenosine triphosphate) is hydrolyzed to adenosine diphosphate (ADP), meaning ATP has one of its phosphate groups cleaved. Now, the bonds between these phosphate groups are known as “high energy” bonds, and when they are broken (such as during hydrolysis), a considerable amount of energy is released, which can then be used to power your muscles during exercise.

If we perform a series of hydrolysis reactions, we then convert ADP to adenosine monophosphate (AMP). From here, adenosine monophosphate can be converted to inosine via two mechanisms:

• Remove adenosine via the adenosine deaminase enzyme to form inosine monophosphate. This is then followed by dephosphorylation (removal of a phosphate group) by a nucleotidase to form inosine.

OR

• Removing a phosphate group via nucleotidase to form adenosine followed by deamination (removal of a -NH2 amino group) to form inosine. 

As we’ve just stated, inosine is an intermediate in several purine nucleotide pathways that affect muscle function. Due to this, several fitness experts have claimed that supplementing with inosine can improve energy production and overall performance during exercise. We’ll dissect this claim in a bit.

Inosine Research and Exercise Performance

Inosine was initially considered as a means to boosting exercise performance by Eastern sports scientists in the 70s. Suffice it to say, thought that there has been a severe lack of research regarding inosine and exercise performance, despite claims made by some in the fitness community that it helps improve performance.

However, a trio of studies from the late 90s shed light on the true “powers” of this ingredient.

Inosine Exercise Study #1

The first study into the potential ergogenic effects of inosine involved nine “highly trained” endurance runners in a double-blind, placebo-controlled, crossover study. Each subject consumed with an inosine supplement (6g per day for 2 days) or placebo. They then performed three exercise tests consisting of a submaximal warm-up run, a competitive 3-mile treadmill run, and a max treadmill run. ^[1,2]

Researchers measured VO2 max, time to exhaustion, oxygen uptake (VO2), ventilation, respiratory exchange ratio, and rating of perceived exertion as well as a host of metabolic markers including:

• Glucose
• Pyruvate
• Lactate
• Phosphorus
• 2,3-diphosphoglycerate (2,3-DPG)
• Hemoglobin
• Uric acid

At the conclusion of the trial, researchers documented NO improvements in max treadmill run time 3-mile run time, VO2 Max, or any other significant metric they recorded. In fact, when the runners consumed the placebo, researchers noted that their time to exhaustion was BETTER than when they took the inosine supplement, suggesting that inosine supplementation IMPAIRS PERFORMANCE.

Based on the findings, researchers concluded:

“Based upon our data, we conclude that IN is not an effective ergogenic aid to enhance athletic performance of an aerobic nature.”

Inosine Exercise Study #2

The second study involved 10 competitive male cyclists who received either 5 grams of inosine daily or placebo for 5 days. Following, subjects completed a Wingate Bike Test consisting of a 30min self-paced cycling performance bout as well as a constant load, supramaximal cycling sprint to fatigue. ^[3]

At the end of the trial, researchers documented that there were NO significant differences between those who consumed inosine or placebo across several metrics, including:

• Peak power
• End power
• Fatigue index
• Total work completed
• Post-test lactate

Based on these findings, researchers concluded that:

“inosine supplementation does not appear to improve aerobic performance and short-term power production during cycling and may actually have an ergolytic effect under some test conditions.” ^[3]

In other words, not only did inosine not improve exercise performance, it actually REDUCED performance in some cases.

Inosine Exercise Study #3

The world of fitness is often plagued by the mindset of “more is better.” This not only applies to training, but supplementation as well. Case in point, pre-workouts. If 200mg of caffeine is effective, then 600mg should make you that much greater in your workouts.

The third study on inosine supplementation adopts this mindset and decided to have subjects consume a whopping 10 grams of the stuff prior to exercise. Seven trained men received both placebo and inosine supplements, each dosing phase separated by a 6 week washout period. Supplementation was split between an early AM dosing and late PM dosing.

Each time they reported for testing, subjects completed three exercise sessions, each comprising three tests (5 x 6-second sprints, a 30-second sprint, and 20-minute time trial). ^[3] Supplementation was carried out in a random, double-blind manner, and the exercise sessions were performed at baseline, day 6, and day 11 of supplementation.

Blood samples were collected prior to supplementation as well as on days 6 and 11 to track uric acid and 2,3-DPG.

Based on performance results, supplementing with inosine did NOT significantly improve average power, peak power, total work, or post-exercise blood lactate levels.

However, uric acid concentration was increased significantly when the men used the inosine supplement. As a result, researchers concluded that inosine demonstrates no ergogenic effects but may lead to potential health complications if taken over long periods of time. ^[4]

Speaking of health complications, let’s look briefly at the downsides to supplementing with inosine...

Inosine and Gout

Uric acid is a waste product resulting from the digestion of foods that contain purines. Purines are found in high levels in certain foods including various meats, beer, and dried beans. We also naturally produce uric acid when we break down and recycle the components of DNA and RNA.

Under normal conditions, uric acid is filtered by the kidneys and excreted through the urine. ^[5] However, when your body cannot properly dispose of uric acid, it accumulates in the blood and leads to a condition known as hyperuricemia.

Why is this bad?

It’s pretty well known that high uric acid levels are the major etiology of gout, a disorder characterized by painful, red, hot, swollen, and tender joints. ^[5] Hyperuricemia also leads to crystal formation, overly acidic urine, and eventually kidney stones.

Additionally, several cohort studies have found an association between high uric acid concentrations and hypertension (high blood pressure). ^[6,7] And to top it off, some researchers believe high uric acid levels may also play a role in certain neurological diseases. ^[5]

What does any of this have to do with inosine?

The same exercise studies demonstrating inosine does not benefit performance in any way, shape, or form also noted that inosine supplementation increases uric acid levels in the body. Therefore, supplementing with inosine could lead to eventual hyperuricemia, and with it gout, kidney stones, or hypertension. In fact, a study using multiple sclerosis patients receiving 500mg inosine per day noted that 25% of the subjects experienced kidney stones. ^[8]

It should be noted that when patients were taken of inosine and given adequate hydration the kidney stones ceased.

A Word on Creatine and Inosine

In reading up on inosine, you may have been told that supplementing with creatine depletes the body of inosine, thereby reducing exercise performance and hindering energy production.

Before you start throwing out all of your tubs of creatine monohydrate, take a breath and relax.

Sports scientists have looked into this and noted that creatine supplementation has no effect on muscle inosine monophosphate concentrations during training, even when training at 70%-80% V̇O2 Max. in fact, researchers noted (unsurprisingly) that supplementing with creatine enhances performance because it reduced the increase in muscle inosine levels. ^[9]

Confused?

Here’s how it basically works out.

During exercise, your muscle “consume” ATP to contract. As long as you are able to regenerate, your muscle keep firing and performance stays at a high level. However, when ATP demand exceeds the rate of ATP generation, fatigue sets in and performance falls off a cliff.

Additionally, levels of adenosine diphosphate (ADP) and adenosine monophosphate (AMP) increase. This leads to upregulation of myokinase and AMP deaminase activity that ultimately increases production of inosine monophosphate.

Studies independently investigating the ergogenic effects of creatine and carbohydrate supplementation have noted that both supplements attenuate the rise of inosine monophosphate in skeletal muscle compared to placebo. ^[9,10] Researchers have interpreted this to mean that decreased levels of inosine monophosphate are associated with increased levels of performance.

So, if anything, having a lower level of inosine monophosphate in your muscles (as a result of creatine supplementation) is actually a good thing.

And, as we already explained in great detail above, supplementing with inosine in no significant way helps performance. (There’s also zero evidence in humans that any sort of synergistic effects between supplementing with creatine and inosine).

That is, unless you’re a rabbit with inadequate blood supply to the brain, where research has shown that inosine preserves ATP during ischemia. ^[11]

Should You Supplement With Inosine to Enhance Performance?

NOPE.

Inosine supplementation serves no real benefit to athletes, unless you want to enhance the flavor or enjoyment of your healthy food. Studies have shown that upping the inosine monophosphate content of foods increases consumer palatability and positive emotions associated with consuming said food. ^[12,13] It also reduces negative feelings commonly associated with eating healthy foods.

In other words, adding inosine monophosphate to food makes you want to come back for more. So, if you struggle with eating certain foods, adding inosine monophosphate to it might make it more “addictive”.

In fact, inosine and inosine-5-monophosphate have been documented as appetite enhancers (gustatory feeding stimulants) for a variety of farmed fish, including turbot fry (Scophthalmus maximus) and Japanese amberjack (Seriola quinqueradiata). However, fish farmers have cooled on the prospects of using inosine due to its high cost.

Basically, if you’re a lifter that struggles to eat enough, dusting in some inosine with your food might help increase your hunger, helping you to eat more and eventually gain more muscle, but if you’re looking to boost performance, inosine is nowhere on the list of things you should be using.

The Final Word Inosine Supplements for Exercise

Suffice it to say that inosine supplements have no place in pre workouts, and not only do they not enhance your performance, they may actually make you perform worse.

The moral of the story here is, that if your pre-workout contains 40 calories of carbohydrates along with an undisclosed amount of creatine and inosine, and claims to “change the whole industry,” leave it on the shelf and find a pre-workout that contains transparently-dosed ingredients actually proven to work in humans.

References

1) Williams, M. H., Kreider, R. B., Hunter, D. W., Somma, C. T., Shall, L. M., Woodhouse, M. L., & Rokitski, L. (1990). Effect of inosine supplementation on 3-mile treadmill run performance and VO2 peak. Medicine and Science in Sports and Exercise, 22(4), 517–522.

2) Williams, M. H. (1992). Ergogenic and ergolytic substances. Medicine & Science in Sports & Exercise, 24(Supplement), 344???348. doi:10.1249/00005768-199209001-00008

3) Starling, R. D., Trappe, T. A., Short, K. R., Sheffield-Moore, M., Jozsi, A. C., Fink, W. J., & Costill, D. L. (1996). Effect of inosine supplementation on aerobic and anaerobic cycling performance. Medicine and Science in Sports and Exercise, 28(9), 1193–1198.

4) McNaughton, L., Dalton, B., & Tarr, J. (1999). Inosine Supplementation Has No Effect on Aerobic or Anaerobic Cycling Performance. International Journal of Sport Nutrition, 9(4), 333–344. doi:10.1123/ijsn.9.4.333

5) Fang P, Li X, Luo JJ, Wang H, Yang XF. A Double-edged Sword: Uric Acid and Neurological Disorders. Brain Disord Ther. 2013;2(2):109.

6) Cheng W, Wen S, Wang Y, et al. The association between serum uric acid and blood pressure in different age groups in a healthy Chinese cohort. Medicine (Baltimore). 2017;96(50):e8953.

7) Perlstein TS, Gumieniak O, Williams GH, et al. Uric acid and the development of hypertension: the normative aging study. Hypertension 2006;48:1031–6

8) Markowitz CE, Spitsin S, Zimmerman V, et al. The treatment of multiple sclerosis with inosine. J Altern Complement Med. 2009;15(6):619-25.

9) McConell, G. K., Shinewell, J., Stephens, T. J., Stathis, C. G., Canny, B. J., & Snow, R. J. (2005). Creatine Supplementation Reduces Muscle Inosine Monophosphate during Endurance Exercise in Humans. Medicine & Science in Sports & Exercise, 37(12), 2054–2061. oi:10.1249/01.mss.0000179096.03129.a4

10) McConell, G., Snow, R. J., Proietto, J., & Hargreaves, M. (1999). Muscle metabolism during prolonged exercise in humans: influence of carbohydrate availability. Journal of Applied Physiology, 87(3), 1083–1086. https://doi.org/10.1152/jappl.1999.87.3.1083

11) Devous, M. D. S., & Lewandowski, E. D. (1987). Inosine preserves ATP during ischemia and enhances recovery during reperfusion. The American Journal of Physiology, 253(5 Pt 2), H1224-33. https://doi.org/10.1152/ajpheart.1987.253.5.H1224

12) Miyaki, T., Retiveau-Krogmann, A., Byrnes, E., & Takehana, S. (2015). Umami Increases Consumer Acceptability, and Perception of Sensory and Emotional Benefits without Compromising Health Benefit Perception. Journal of Food Science, 81(2), S483–S493. doi:10.1111/1750-3841.13195

13) Yan, J., Liu, P., Xu, L., Huan, H., Zhou, W., Xu, X., & Shi, Z. (2018). Effects of exogenous inosine monophosphate on growth performance, flavor compounds, enzyme activity, and gene expression of muscle tissues in chicken. Poultry Science, 97(4), 1229–1237. https://doi.org/10.3382/ps/pex415

14) Sarvestani ST, Tate MD, Moffat JM, et al. Inosine-mediated modulation of RNA sensing by Toll-like receptor 7 (TLR7) and TLR8. J Virol. 2014;88(2):799-810.

15) Alseth, I., Dalhus, B., & Bjørås, M. (2014). Inosine in DNA and RNA. Current Opinion in Genetics & Development, 26, 116–123. https://doi.org/https://doi.org/10.1016/j.gde.2014.07.008

16) Mackie, A.M. (1987). Identification of the gustatory feeding stimulants. In: Chemoreception in Fishes. (ed. T.J. Hara). Elsevier Scientific Publishing Co., Amsterdam, pp. 275-291

17) Takeda, M. Takii, K. & Matsui, K. (1984). Identification of feeding stimulants for juvenile eel. Bull. Jap. Soc. Scient. Fish., 50: 645-651