AICAR: Endurance Enhancement In A Bottle!?

Jay Campbell

By Jay Campbell

March 24th, 2022

 

There’s nothing more people would love than reaping all the benefits of exercising… except without the “exercising” part.

Humanity’s laziness just keeps getting worse and worse — and it won’t get better any time soon.

But for those of us who train hard and smart, and want to multiply the fruits of a good sweat even more, I have something just for you.

A drug that’s rumored to have been used by the world’s top cyclists to achieve superhuman endurance on the race track.

While also doing wonders to shed pounds of fat and intensify your mental performance

The name is AICAR, and today’s article will tell you all about this stamina-boosting molecule.

What Is AICAR?

AICAR (a.k.a. Acadesine, or AICA riboside, or “5-Aminoimidazole-4-carboxamide 1-β-d-ribofuranoside” in full) is an analog of a compound known as AMP (adenosine monophosphate).

It’s important to clarify exactly which compound I’m talking about, because many people incorrectly use the name to describe a completely different compound:

“…AICAr is often abbreviated as AICAR, although the AICAR acronym should be reserved for AICA ribotide or the phosphorylated form that is a physiological, endogenous precursor in de novo purine synthesis. The nomenclature is additionally complicated because the other name used for the endogenous substance or AICAR is ZMP. Moreover, the search of the literature reveals the common use of acadesine instead of AICAr”

Just to show you the difference, this is AICAr:

AICAR ≥98% (HPLC), powder

And this is AICAR (a.k.a. AICA ribonucleotide, or 5-Aminoimidazole-4-carboxamide ribonucleotide):

5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5′-monophosphate ≥93%

For the sake of simplicity, we’re going to use “AICAR” when we describe the first molecule I just showed you.

It first rose to prominence in the late 80s and early 90s as a form of heart protection during surgery via increased blood flow.

Although it was recognized as cardioprotective, the year 2008 was when AICAR became famous… but not for its heart benefits.

An article from Scientific American titled “Could A Pill Replace Exercise?” changed its fate forever:

” Scientists have found a drug that mimics the effects of a workout by, among other things, increasing the body’s ability to burn fat.

The study shows the pill can also increase endurance; lab mice that took it ran more than 40 percent longer on a treadmill than their untreated peers.

… In addition to supercharging stamina, the drug, called AICAR, may also be useful in treating debilitating muscular disorders such as muscular dystrophy as well as metabolic diseases such as diabetes, because it also appears to help the body use and remove sugar from the blood more effectively.

Researchers say that AICAR—which is in clinical trials to treat some heart ailments—in essence works by reprogramming muscle, switching it from sugar-burning, fast twitch muscle—which is better for speed and power—into fat-burning, slow-twitch muscle that does not tire as easily.”

With an introduction like that, AICAR now became the new doping drug of interest for athletes.

AICAR’s Mechanism Of Action

The bulk of AICAR’s effects on the body are carried out through an enzyme known as “5′ adenosine monophosphate-activated protein kinase” (a.k.a. AMP-activated protein kinase, or AMPK):

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AICAR works through penetrating the membrane of a cell, undergoing a chemical reaction called “phosphorylation” where a phosphate group is attached to the molecule (ZMP), and then binding onto and activating AMPK (similar to AMP itself).

Why is this important?

AMPK is largely responsible for the regulation of cellular energy at a baseline level:

“AMPK is a phylogenetically conserved serine/threonine protein kinase which has been proposed to act as a ‘metabolic master switch’ mediating the cellular adaptation to environmental or nutritional stress factors.

…In the last few years, AMPK has come to be regarded as a point of conversion of regulatory signals monitoring systemic and cellular energy status”

The same holds for glucose oxidation as well, which is crucial for normal blood sugar levels.

But by and far, the most important part is the increase of ATP production (and .. an essential source of energy for your cells:

“AMPK switches on catabolic pathways that generate ATP [adenosine triphosphate] such as glycolysis and fatty acid β-oxidation. At the same time, it switches off ATP-consuming processes such as biosynthesis and cell growth and proliferation.

AMPK consists of 3 subunits, with the a subunit being catalytic, the β subunit containing a glycogen-sensing domain, and the γ subunit containing 2 regulatory sites that bind the activating and inhibitory nucleotides AMP and ATP, respectively.

Although it may have evolved to respond to metabolic stress at the cellular level, hormones and cytokines such as insulin, leptin, and adiponectin can interact with the system. Hence, it appears to play a key role in maintaining energy balance at the whole body level”

This is crucial when ATP production is depleted, either due to the body temporarily being out of balance or through artificial means.

Which is why it’s no shock that mitochondrial biogenesis is also another important part of AICAR’s mechanism of action, as that is the organelle responsible for ATP production in the first place.

And if the acronym “AMPK” reminds you of how Metformin works in the human body… well, you’ve been paying attention!

I implore you to read my article on Metformin for more details about the significance of AMPK.

Also, the video below is a good primer on the similarities between AICAR and Metformin, and why the former *may be* superior:

<I have not used AICAR mySELF and would never compare anything above Metformin until I’ve had the time to experiment with it>

 

Top 7 Health Benefits Of AICAR

With over 2,000 PubMed studies published since the late 1950s, AICAR has not been desperate for more scientific attention.

The health benefits of AICAR are clear in their intended effect and the evidence supporting them grows with each passing day.

Although we are lacking in human clinical data, the existing evidence strongly points towards a net positive effect.

AICAR Mimics Exercising And Increases Your Endurance

A 2008 Cell paper published by Ronald Evans and colleagues of the Howard Hughes Medical Institute was the landmark discovery that donned AICAR as a “pharmacological equivalent” to exercise… without actually exercising:

“…we treated C57B/6J mice with AICAR (500mg/kg/day) for 4 weeks…. Interestingly, 4 weeks of drug treatment decreased epididymal fat mass to body weight ratio and increased oxygen consumption without changing body weight, supporting the speculation that AICAR may positively regulate endurance.

Indeed, in a treadmill endurance test, AICAR-treated mice ran longer (∼23%) and further (∼44%) compared to vehicle-treated mice revealing that increase in endurance can be achieved without exercise. Furthermore, global gene expression analysis of quadriceps revealed that AICAR treatment alone up-regulated a set of 32 genes linked to oxidative metabolism”

And another rat study published in the same year more-or-less replicated this result:

“We compared the effect of 10 days of treadmill training (60 min/day) with 10 days of AICAR administration (0.5 mg/g body weight ip) on subsequent AMPK activation during 45 min of treadmill exercise in male Sprague-Dawley rats

…Ten days of AICAR administration also attenuated the exercise-induced increases in AMPK signaling in the soleus although not as effectively as 10 days of exercise training (nonsignificant 1.3-fold increase in p-AMPKα; significant 3-fold increase in p-ACCβ). The increase in skeletal muscle 2-deoxyglucose uptake during exercise was greater after either 10 days of exercise training or AICAR administration.

In conclusion, 10 days of AICAR administration substantially mimics the effect of 10 days training on attenuating skeletal muscle AMPK activation in response to subsequent exercise.”

Fnhanced stamina and endurance without having to get up from the couch? It’s no wonder major outlets ran with this finding and hyped it up as a groundbreaking discovery.

I found one anonymous biohacker’s testimony on using AICAR and the results were fascinating:

“50 mg injection every other day. Cost: 900 for 2 week supply. Sublingual/Oral administration does not work as well as intramuscular injection. This is the holy grail but the gains go away instantly. Stacks well with ITPP and Mots-C.

Increased reps (some strength gains) felt like a lot like blasting Test-Cyp. I only tried a half marathon for this one and shaved 17 minutes off. Sleeping on AICAR is impossible if you’re not completely exhausted and headaches… If someone can make this as cheap as Test then we’d have a safe endurance drug.”

So what else can AICAR do for us?

AICAR Could Be Beneficial For Fat Loss

Prior research shows that AMPK activation within adipose tissue could be a big key in losing body fat:

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In the image above, the processes decreased involve pathways that consume energy, whereas the processes increased will elevate the PRODUCTION of energy.

To explain this in simpler language:

“As we age, cellular AMPK activity decreases and as a result, weight gain often follows. Excess weight, particularly in the abdominal region, accelerates aging processes. Boosting AMPK activity results in a healthier metabolic status, which can lead to less fat production.

These findings were recently confirmed in a pair of human clinical trials. Researchers activated AMPK using two natural compounds. The result was a significant drop in abdominal fat.

The first study showed that abdominal fat deposits fell by 11%. In the second study, scientists observed a significant reduction in harmful inflammation, which can contribute to weight gain.”

Thanks to the improved ability to break down adipose tissue and burn fat more effectively, you get the “right” type of weight loss.

Numerous cell and animal studies line up with what’s been observed in humans:

But be careful… I managed to dig up one paper suggesting that AMPK activation in the hypothalamus of your brain can increase food intake!

AICAR May Boost Brainpower

One of the many benefits we get from regular exercise is cognitive enhancement: The ability to think and act clearly when it counts.

Two mouse studies from Kolibo et al. suggest AICAR may also provide the same brain-boosting effects provided by hitting the gym:

“Mice were injected with GW for 7 d or AICAR for 7 or 14 d. Two weeks thereafter mice were tested in the Morris water maze. AICAR (7 d) and GW improved spatial memory. Moreover, AICAR significantly, and GW modestly, elevated dentate gyrus neurogenesis. Thus, pharmacological activation of skeletal muscle may mediate cognitive effects” (Source)

“Mice were injected with AICAR (500 mg/kg) for 3–14 d. Two weeks thereafter animals were tested in the Morris water maze, rotarod, and open field. Improved water maze performance and motor function were observed, albeit at longer duration of administration, in aged (14-d AICAR) than in young (3-d AICAR) mice… In the hippocampus, genes relevant to neuronal development and plasticity were enriched.” (Source)

However, one systematic review of “exercise in a pill” compounds like AICAR suggest these results aren’t as promising as they look:

“These effects are likely to be indirect consequences of peripheral AICAR administration, given the extremely low permeability through the blood brain barrier, the lack of spatial memory improvement by AICAR in muscle specific AMPKα2 mutant mice, and the adverse effect of direct intracranial infusion on synaptic plasticity and spatial memory in rats”

And the authors of said review even had their own results to report:

“In a recent study, we made a side-by-side comparison between effects of short- and long-term AICAR administration and exercise regimens, on gastrocnemius muscle and brain in young C57Bl/6 male mice. Both interventions induced similar AMPK pathway activation in skeletal muscle after both short (3–7 days) and longer (14 days) administration.

However, in the brain only the short-term treatment was beneficial. Specifically, in the dentate gyrus of the hippocampus, brain-derived neurotrophin (BDNF) levels and neuronal proliferation were elevated by short-term treatment, while no increase was reported after longer administration”

Food for thought!

AICAR Shows Potential In Treating Diabetes

If AICAR can help us look better and feel more alert as well as exercise can, maybe it can help treat certain lifestyle illnesses like Type 2 diabetes.

One rat study goes as far as to suggest regular AICAR use can PREVENT the onset of diabetes:

“Five-week-old, pre-diabetic ZDF [Zucker diabetic fatty] rats underwent daily treadmill running or AICAR treatment over an 8-week period and were compared with an untreated group.

In contrast to the untreated, both the exercised and AICAR-treated rats did not develop hyperglycemia during the intervention period. Whole-body insulin sensitivity, as assessed by a hyperinsulinemic-euglycemic clamp at the end of the intervention period, was markedly increased in the exercised and AICAR-treated animals compared with the untreated ZDF rats (P < 0.01).

In addition, pancreatic β-cell morphology was almost normal in the exercised and AICAR-treated animals, indicating that chronic AMPK activation in vivo might preserve β-cell function”

It all comes back to AMPK, which is now a significant target of interest for treating Type 2 diabetes (T2D):

“The regulation of AMPK is of great interest in the study of T2D and metabolic syndrome due to accumulating evidence suggesting that the dysregulation of AMPK plays an important role in the development of IR and T2D, and that AMPK activation (either physiological or pharmacological) can prevent and/or ameliorate some of the pathologies of IR and T2D.

Multiple animal models with a metabolic syndrome phenotype have exhibited decreased AMPK activity in muscle, and evidence exists that AMPK activity is diminished in the skeletal muscle or adipose of humans with T2D or obesity”

If you read my ultimate guide to Metformin, you’ll know that AMPK activation plays a big part in its ability to treat diabetes.

Believe it or not, we can see AICAR’s ability to properly regulate fat and sugar metabolism in diabetic patients:

“Stable isotope methodology and blood and muscle biopsy sampling were applied to assess blood glucose and fatty acid kinetics following continuous i.v. infusion of AICAR (0.75 mg kg−1 min−1) and/or NaCl (0.9%) in ten male type 2 diabetic patients (age 64 ± 2 years; BMI 28 ± 1 kg/m2).

…The i.v. administration of AICAR reduces hepatic glucose output, thereby lowering blood glucose concentrations in vivo in type 2 diabetic patients. Furthermore, AICAR administration stimulates hepatic fatty acid oxidation and/or inhibits whole body lipolysis, thereby reducing plasma NEFA concentration”

Add in the reduction of high blood pressure (here and here), and you have a serious competitor against Metformin!

AICAR Possesses Anti-Inflammatory Properties

AICAR has been studied several times for its effects on the different pathways of inflammation in mice

To nobody’s surprise, AICAR can do a lot for people who suffer from a high-inflammatory way of life:

While you’re at it, now is the best time to get your inflammatory biomarkers checked!

AICAR Could Be A Future Cancer Treatment

I know I sound like a broken record by mentioning AMPK once more… but it’s really that important in regulating our bodily functions.

AMPK is starting to become a major key in the suppression of cancer cell growth:

“AMPK appears to serve as a metabolic tumor suppressor to keep cell metabolism and growth at appropriate levels. Thus, in response to energy stress in the microenvironment of tumors, AMPK activation may lead to the reprogramming of cellular metabolism and elicits a metabolic checkpoint on the cell cycle through its action on mTORC1, p53 and other modulators for cell growth and survival.

The checkpoint presumably allows a cell to fix the problems. Thus, when it is lost, the cell will undergo two directions of fate: apoptosis or unrestrained growth. In this regard, it is of no doubt that AMPK is a promising target for cancer prevention.”

Some of the mechanisms through which this happens include cytotoxicity (being toxic for the cancer cell), inducing cell death via apoptosis, inhibiting cancer cell growth, decreasing blood flow to the cancer cell, and reducing cancer cell migration.

We can see this through AICAR’s efficacy in preclinical studies involving triple-negative breast cancer, prostate cancer, eye cancer, bone cancer

… and the effects are far greater when AICAR is combined with rapamycin (here and here)!

AICAR Has Many Other Potential Health Benefits

There are numerous avenues for AICAR I won’t be able to dive deeply into, but here is an idea of what this wonder molecule might be able to do one day:

The sooner we stop thinking of AICAR as a PED (performance-enhancing drug) and more as a life-optimizing Golden Age agent, the faster we can start giving it to people in dire need.

The BEST Dose Of AICAR For Near-Limitless Stamina

Here’s the honest truth: There is no clear-cut AICAR dosage that’s proven to work across numerous human subjects.

If we look at the flagship 2008 paper responsible for making AICAR famous, mice were given an intraperitoneal (i.e. body cavity) injection of 250-500 mg per kg of bodyweight per day.

This would translate to roughly 1.0 – 3.2 grams daily for a 90 kg man.

(This chart, if you want to go down this road, shows 500 mg/kg/day in a mouse is roughly 40 mg/kg/day in humans)

It’s difficult to say how to translate this precisely to human dosages, but here’s what has been said across the Internet…

  • 15-20 mg injected daily for 30 days, 100 mg injected every other day if sedentary, or 50 mg injected 3-4x/week if sedentary.. either subcutaneously or intramuscularly (Source)
  • 50 mg per day injected subcutaneously for 30 days leading up to a racing event and the last shot as close to the start of the event as possible (Source), or 500 mg (Source)
  • 10-50 mg per day injected subcutaneously for an 8-week cycle (Source)
  • 10-25 mg injected subcutaneously once a day (Source)
  • 500 mg per kg of bodyweight if used solo, or 150 mg per kg of bodyweight if stacking it with 5 mg per day of another endurance-boosting drug called GW1516 (Source
  • One person claims 10 mg of AICAR stacked with 10 mg of GW1516 is optimal for fat loss (Source)

Here’s an interesting testimonial from someone who ran a 3-week cycle of GW1516 at 5 mg per day and AICR injected intramuscularly at 150 mcg per day:

“1. Increased endurance – My pre-workout cardio is crazy now. I’m on the elliptical for 15 minutes, and I can go full bore with no issues. When done, I feel that I haven’t done anything taxing aside from the sweat I work up.

2. Recovery time – I can do a heavy set, and then ready to go again within 1 minute…sometimes less. Needless to say…I am pushing my workout partner probably a little too much! :D

3. Blood Pressure – This was what I was initially interested in. With GH, I noticed my blood pressure slowly creeping up. My MD gave me a script for HZT as I was starting to hold water. The water is gone, and my blood pressure is lower than it usually is. I would run 115/80 normally…with the water retention it had got as high as 130/90. Now I am getting an average reading of 110/70-75. So I do think this helped as studies have shown.”

Biohacker beware… unless you’re a top-tier endurance athlete who self-experiments and isn’t entering a competition anytime soon (you’ll soon see why), there’s not much reason to test AICAR.

See how it affects your physical recovery and overall performance, but don’t expect any miracles!

AICAR’s Side Effects & Safety Profile

The side effects of AICAR are not very well-known.

While clinical data from 1991 to 2012 involving the use of AICAR for coronary artery problems found the compound to be well-tolerated without any adverse events, trials for blood disorders found some renal toxicities and impairment.

One paper claims excessive buildup of lactic acid as a potential AICAR side effect, noting that could only be the tip of the iceberg:

“AICAR has been proved to have only a single negative side-effect. A group of researchers under the leadership of Prof. Goodyear scrutinized the effects of AICAR treatment on glycogen metabolism in skeletal muscle, showing that it inevitably leads to substantial increase of lactic acid in muscles (49). Nevertheless, it would be incorrect to neglect the fact that only limited tests were done on humans, so there might be further, especially long-term consequences that have not been discovered yet.”

Another paper involving the use of AICAR in vitro cited “mild hypoglycemia and fatty liver” as possible outcomes of AMPK overexpression.

I did manage to pull one list provided by a peptides manufacturer, but haven’t been able to substantiate it with any scientific proof:

“Possible enlarged growth of heart, Possible defects to the heart valve, Problems with blood flow, Problems with blood and nutrient transfer to the brain, Problems with bowels”

Outside of those few mentions, it’s anyone’s guess.

AICAR Is BANNED By The World Anti-Doping Agency!

I’ll keep this brief to warn any endurance athletes, cyclists in particular, who might get the bright idea of loading up on AICAR before a race.

Ronald Evans, author of the 2008 paper that sparked mainstream media attention, notified the World Anti-Doping Agency (WADA) about AICAR’s performance-enhancing effects BEFORE the paper was published.

It didn’t take long before competitors acted carelessly and found a way to use it:

“France’s anti-doping agency has uncovered “a surprising therapeutic arsenal,” including two drugs that are not yet licensed, after scrutinising bins in the wake of the 2009 Tour de France… the agency said it suspected that some cyclists were using blood transfusions and two unlicensed substances.

Pierre Bordry, head of the agency, told the French daily Le Monde on 28 July that he was “convinced that two new products have been used during the [2009] tour, two drugs that are not yet on the market.”

…The second compound, known as Aicar, increases performance of endurance exercise and decreases adiposity.”

AICAR was banned by WADA in 2009 and it’s stayed that way ever since under the category “S4: Hormone And Metabolic Modulators”.

Their explanation for doing so is pretty straight-forward:

“Once activated by AICAR, AMPK works to make energy more available. For example, it increases the usage of fat for energy and causes cells to make more mitochondria (the cells’ powerhouses or energy creators). AMPK basically ensures that the various tissues in the body don’t run out of energy.

There are many circumstances that activate AMPK naturally, including hypoxia (low oxygen levels during exercise or at elevation), hypoglycemia (low blood sugar with exercise or fasting), the use of cellular energy during muscle contraction, and anything that disrupts energy creation within cells.

…Too much activation of AMPK, or activating it in the wrong tissue, can cause serious side effects, including neurodegeneration, or preventing cells from dividing. The accumulation of naturally-occurring AICAR in the body is also associated with metabolic disorders in humans.”

There was only one final hurdle left to overcome:

For high-flying cheaters, the substance has a feature that its ancestors, EPO and others, haven’t had for a long time: produced naturally by the human body in small quantities, it is almost undetectable.”

Although the 2013 Tour de France competitors likely got away with cheating, that won’t be the case anymore.

Numerous doping detection methods (here, here, here, here, and here) have not only established a baseline for endogenous AICAR production, but can also detect high levels of AICAR long after you’ve given your blood sample.

(And they’ve done the same for horses!)

Oddly enough, Metformin is not a WADA-banned substance despite having similar AMPK-activating properties.

Long story short: If you are a cyclist or any type of endurance athlete who competes seriously, DO NOT touch or use AICAR!

The French documentary below says it all (Click the “CC” button for English subtitles):

How To Buy Pharma-Grade AICAR Online

You’ll be extremely hard-pressed to find a high-quality source of proper AICAR at an affordable price.

Why? If you’ll pardon my French, but this shit is incredibly expensive for your average weekend warrior:

“The experiments Professor Evans ran involved a dose of 500mg per kilo body weight for four weeks. That’s the time the experiment with mice took. A gram costs between $80 and $100 so, theoretically doses for humans would costs several hundred dollars. The French paper Libération quotes figures of half a million euro for a treatment with AICAR in a lab in Vienna”

The best compromise I could find was Peptide Sciences offering AICAR at $60 per 50 mg vial (which works out to $1,200 for a gram’s worth).

So unless you happen to be an international cyclist who’s willing to break the rules for a competitive edge, save your money.

You’re better off using the peptide MOTS-C to replicate the same effects.

When you’re ready to experience what “exercise in a pill” feels like, Limitless Life Nootropics is here to give you the best MOTS-C you can get your hands on. 

Use code JAY15 to get 15% off your order! 

Additional Reading Resources For AICAR

As you can clearly see, there’s an awful lot of speculation behind AICAR’s endurance-boosting benefits and not a lot of hard data in human subjects.

Until we start conducting more clinical trials for its fat-burning and stamina-increasing properties, or find a way to produce AICAR at a low cost, we’re fresh out of luck.

(Or you could get the hookup from a professional athlete)

So I’ll close off this article with two pieces of intel for people who REALLY want to go beyond the scope of this article…

This comprehensive 2021 literature review is the closest thing we’ll have to a book on AICAR — every study and observation on this compound collected over the last 25 years.

Sigma-Aldrich has 26 pages worth of papers collected on AICAR and the deeper workings of AMPK.

As always…

Raise Your Vibration To Optimize Your Love Creation!

PS – If you want me to personally help you achieve superhuman stamina and endurance, join The Fully Optimized Health Private Membership Group.

IT IS your greatest opportunity to fully optimize your health, gain total access to me and network with high-level men and women massively leveling up their own lives.

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