Cardarine (GW-501516): Miracle Drug With A Catch
Cardarine, otherwise known as GW-501516, is a research chemical classed as a PPAR receptor agonist. Often mistakenly lumped into the SARMs category, cardarine has been considered heavily as an option for treating ailments such as high cholesterol and other metabolic-related issues like obesity and diabetes.
But despite being an apparent “miracle drug,” cardarine has since become topic of controversy due to findings of a potential link to the development and progression of cancer and liver damage, casting doubt on its therapeutic benefits.
What Is Cardarine?
To understand what cardarine is, you need to understand what it is not. While most people lump cardarine into the class of SARMs, this chemical compound is not a SARM but rather a PPARδ (delta) receptor agonist (1).
It’s important to distinguish this fact because cardarine’s primary influence on the body is in opposition to many SARMs. Cardarine’s influence is often catabolic in that it stimulates fat oxidation while many SARMs are used exclusively for anabolic purposes, such as building muscle and strength.
As we’ll discuss a bit later, this makes cardarine a good option for those looking to reduce body fat alongside improving other metabolic-related benefits.
Under its chemical label GW-501516, cardarine was first developed primarily to treat dyslipidemia; or abnormal amounts of fat and cholesterol in the blood. But once trials began, it became apparent that cardarine might have other therapeutic benefits (2).
In addition to successfully improving lipid profiles, it was realized that cardarine as a PPAR receptor agonist would be a powerful agent for treating obesity, enhancing metabolism and potentially even preventing or treating metabolic disease states like Type II Diabetes (3, 4).
But as you’ll learn shortly, this apparent miracle chemical is not without its flaws, some of which are significant.
PPAR Receptor Agonists
Peroxisome Proliferator-Activator Receptor agonists (PPAR) influence cells in a similar manner as SARMs. PPAR receptors are considered nuclear receptors because they are within cells and influence what happens within the nucleus, triggering specific changes within the cell and throughout the body as a whole.
When a PPAR receptor agonist like cardarine is used, this chemical diffuses into the cytoplasm, or interstitial fluid of different cells depending on the specific tissue the agonist targets. Upon entering the cytoplasm, cardarine docks onto PPARδ receptors. Once it does, this receptor initiates specific gene transcription within the nucleus. This gene transcription then initiates some event in the body (5).
A good way to think of the PPAR receptor is as a messenger between the PPAR agonist and the nucleus of the cell. Cardarine, the PPAR receptor agonist, attaches to the receptor, giving it a set of instructions. The receptor transports this information into the nucleus, where it carries out those instructions.
In the case of cardarine, this process results in various effects such as increased fat metabolism and an improvement in glucose tolerance. These factors make PPAR receptor agonists like cardarine an attractive option for alleviating issues related to metabolic dysfunction, obesity and insulin resistance (6, 7).
Potential Benefits Of Cardarine
Based on the current research available, it’s clear that cardarine is a chemical that provides benefit related to improving body composition. By specifically targeting and binding with the PPARδ receptor, cardarine has a significant influence on how cells utilize and metabolize energy, specifically from fat sources.
As a result of having this level of influence over metabolism, there are quite a few specific benefits that cardarine affords, worth mentioning.
Insulin Sensitivity & Glucose Tolerance
One of the more attractive features of cardarine is that it’s a potent PPAR receptor agonist, which means it positively influences how our bodies metabolize and use glucose and other energy sources like fat. But what’s most important here is the ability of this chemical to improve glucose tolerance and insulin sensitivity.
You’ve probably heard of insulin sensitivity before since it’s a popular subject. And rightfully so, since insulin sensitivity plays a role in metabolic health and also influences the development of disease such as diabetes.
In normal, insulin-sensitive individuals, insulin functions, as it should. When you eat carbohydrates (and also protein), these carbohydrates are metabolized into glucose, a simple sugar. This sugar enters the blood, and insulin helps shuttle this sugar out of the blood and into tissues and organs that can use it such as muscle and the liver, which holds onto glucose for times of low food intake (7).
But with lack of exercise and poor food choices, a chronic elevation of blood glucose can lead to insulin resistance; a metabolic state where insulin can no longer effectively shuttle glucose out of the blood. If left untreated, this leads to complications typically in line with Type II Diabetes. You can expect weight gain, and even more serious issues like kidney damage or failure, neuropathy and heart disease (8, 9, 10).
Amazingly, animal studies testing cardarine do show promise for improving insulin sensitivity.
One fascinating study tested cardarine on insulin resistant mice to observe its influence. But in addition to standard mice, the scientists also used mice genetically engineered to have PPARδ receptors removed called “knockout” mice. If these mice display positive benefit similar to the normal mice, then scientists know this benefit is not due to stimulating that receptor. It’s an easy way for scientists to infer causality when testing drugs.
By the end of the treatment cycle, the findings became clear. When mice were provided with cardarine, their clearance of glucose from the blood was significantly enhanced compared to control and knockout mice. In fact, during standard glucose tolerance tests, the scientists showed an approximate 57% improvement in glucose disposal with cardarine-treated mice, suggesting a significant improvement of insulin sensitivity (11).
Concerning the improvement of metabolic health, these findings are meaningful. It is, however, unknown if these benefits translate to humans. If so, cardarine does show promise for the treatment and prevention of metabolic-related disease.
Summary: Cardarine improves glucose disposal and insulin sensitivity, which may prove useful for preventing the development of diabetes and obesity.
Total & LDL Cholesterol
High cholesterol, while often overstated, is an issue that plagues many. In fact, the CDC reports that nearly 29 million Americans have cholesterol levels that would be considered high and at risk for development of cardiovascular-related disease (12).
In the world of cholesterol, there are two main categories to be concerned with.
LDL (low-density lipoprotein) and in particular, VLDL (very low-density lipoprotein) are traditionally considered to be “bad cholesterol,” since these molecules often accumulate in blood vessels, causing a blockage which can result in heart attack or stroke.
HDL (high-density lipoprotein), on the other hand, does the opposite. HDL particles help transport the low-density particles for recycling and removal. Together, it’s clear that maintaining a higher level of HDL cholesterol particles is optimal.
Research regarding cardarine and cholesterol treatment does show promise.
In 2006, one of the few human trials with cardarine took place to observe the chemical’s influence on the human body. Subjects were administered either placebo, 2.5 mg of cardarine or 10 mg of cardarine daily for 2 weeks. During this time, scientists measured changes in cholesterol.
Scientists revealed that there was a dose-dependent improvement in HDL cholesterol levels when using cardarine. When administered 10 mg, subjects displayed significant improvements in HDL compared to placebo. Also worth mentioning, the subjects receiving 10 mg of cardarine were the only subjects to also display a reduction of LDL cholesterol (13).
In animal studies, the findings are more of the same. When cardarine was administered to obese rhesus monkeys, their cholesterol profile improved substantially, again in a dose-dependent manner.
In fact, relative to baseline, when these monkeys were administered the highest dose of cardarine the monkeys displayed a 79% elevation of HDL particles alongside a 50% reduction of VLDL cholesterol particles (14).
Quite clearly, cardarine provides a positive influence on cholesterol by drastically improving the ratio of HDL particles to LDL particles, which could be meaningful when attempting to treat cholesterol related ailments and disease.
Summary: Cardarine drastically improves cholesterol profiles by increasing the ratio of HDL particles to LDL particles. This could prove meaningful for individuals with low HDL cholesterol as well as others displaying abnormally high LDL cholesterol.
Weight Loss & Fat Loss Potential
In addition to its potent influence on cholesterol and insulin sensitivity, cardarine may be an attractive option for stimulating weight loss, specifically from adipose tissue or at least preventing additional weight gain.
What research shows is that specifically activating the PPARδ receptor causes a shift in how the cells of our bodies use energy. In fact, this research shows that cardarine administration drastically elevated beta-oxidation or fat metabolism in muscle (3).
This elevation of fat metabolism seems to be, at least in part, due to elevations of CPT-1 expression, induced by cardarine. Carnitine Palmitoyl Transferase-1 (CPT-1) is a rate-limiting step in the process inducing beta-oxidation or fat metabolism within mitochondria; organelles that utilize fat for energy production. This means that if CPT-1 is not up-regulated, fat burning is unable to proceed.
Amazingly, research in humans indicates that cardarine can elevate expression of CPT-1 up to 5 times more than individuals not receiving cardarine. This finding could prove meaningful for weight reduction, weight gain prevention and even metabolic-related disease (4).
Additionally, these studies suggest the administration of cardarine also stimulates mitochondrial biogenesis and proliferation. This is meaningful because mitochondria are the organelles that metabolize fat. Having a higher concentration of them within muscle means more structures to metabolize fat and a greater chance of it happening (3).
These changes, at least in mouse models, are often associated with a reduction of body weight. It does, however, remain to be revealed if the same changes will result in an equivalent amount of weight loss in humans (15).
Summary: Cardarine administration increases fat oxidation while improving the structural framework required for this process, making it an attractive option for fat and total body weight reduction.
Endurance Exercise Performance
One of the more fascinating benefits of cardarine is its influence on athletic performance and it’s ability to change how your muscles function.
Amazingly, animal research on cardarine shows that with regular administration, this chemical has the ability to change the composition of existing muscle fibers and potentially even induce hyperplasia; the generation of entirely new muscle fibers.
This is meaningful because very little evidence exists pertaining to hyperplasia, especially in humans and could have serious implications for muscle wasting diseases and other muscle-related ailments (16).
What this research tells us is that activating the PPARδ receptor initiates a shift within muscle cells. Multiple studies have revealed that when cardarine is administered, fibers that traditionally display glycolytic properties begin to act similar to that of oxidative fibers (16, 17, 18).
In the simplest sense, our muscles have different sizes and functions; traditionally categorized as Type 1 or Type 2.
Type 1 fibers are considered oxidative because they preferentially metabolize fat to produce energy over a long duration of time. These fibers are called upon during activities that are low intensity, yet long duration such as endurance running.
Type 2 fibers, on the other hand, are considered glycolytic. These fibers use glucose or sugar to produce energy and force rapidly and they do so in the absence of oxygen.
As you can then imagine, the ratio of these different types of muscle fibers your body contains determines how your body functions. If you have a large amount of Type 2 fibers relative to Type 1, you can expect that your muscles are better suited for glycolytic activities. Alternatively, if your body maintains a higher ratio of Type 1 fibers, you can expect better performance during long duration and low intensity, oxidative activities.
However, it’s important to also understand that by shifting fiber type and function to be more oxidative, you’ll also need to sacrifice performance during glycolytic activities. That means that muscle size and strength will likely diminish as a result of fiber type shifting and should be considered prior to using cardarine (19).
Summary: Research indicates that cardarine administration initiates a shift in glycolytic muscle fibers to display features associated with oxidative fibers. This may be meaningful for individuals looking to improve performance during endurance-related activities.
Adverse Side Effects Of Cardarine
Despite that fact that the apparent benefits of cardarine are quite impressive, it’s not without its flaws and unfortunately, they may be reason for avoiding use of the substance altogether.
One of the more attractive features of SARMs and PPAR receptor agonists are that they are typically non-androgenic and also target specific tissues. This means that side effects are often limited and not severe, and in the case of cardarine, this is typically true. Mostly, users of cardarine don’t report any acute, adverse side effects.
However, cardarine does come with two glaring issues, that many are quick to dismiss: the potential for cancer and liver damage.
Potential For Cancer Development & Progression
Current evidence with regard to cardarine and cancer development is conflicting. On one hand, some studies show that cardarine administration may help treat cancer. For instance, one study revealed that cardarine administration reduced markers of inflammation in pancreatic cancer cells, which could prove useful for limiting tumor cell growth (20).
However, opposing research suggests quite the opposite. In fact, the manufacturer GlaxoSmithKline abandoned clinical trials because the administration of cardarine led to the development and progression of cancer and resulted in the death of a large percentage of animal subjects (21).
Additionally, other research indicates that cardarine may be useful for stimulating endothelial cell proliferation and angiogenesis, which is the generation of new blood vessels. On one hand, this may prove useful for the treatment and prevention of heart disease but on the other, this could be further evidence of cancer potential.
While angiogenesis is beneficial for blood flow and the transport of nutrients, this process is also closely related to tumor progression. Having a more expansive network of blood vessels allows cancer cells to thrive and proliferate by hoarding nutrients. By increasing the number of blood vessels dedicated to the cancer cells, they are able to grow and multiply unchecked at a higher rate (22).
While many sources will claim that the dosages used in these studies would be extremely high when translated to human doses, the potential for cancer development is still considerable (23).
In fact, it’s worth mentioning that even the manufacturer of this seemingly miracle drug decided to abandon trials as a result. This reality should be strongly considered before deciding to use cardarine.
Research on cardarine in relation to liver health is also damaging. Studies on this chemical have revealed an increase in profibrogenic (damaging) growth factors, which results in greater liver damage (24).
Amazingly, research shows that cardarine does stimulate liver repair. But the problem, as the scientists suggest, is that this repair is unchecked, leading to further damage. Liver satellite cells differentiate or migrate to liver tissue as a result of cardarine administration but a marked increase in pro-inflammatory responses accompanies this. Together, this can lead to further progression of liver damage (25).
Summary: Clinical trials testing cardarine were abandoned due to the development of cancer in animal subjects. The possibility for these findings to translate to humans is unknown. Further, other research suggests that cardarine could exacerbate liver damage due to unchecked proliferation of satellite cells and an elevation of pro-inflammatory signaling.
Summary Of Considerations For Cardarine
Could Be Useful For Avoiding Obesity and Metabolic Disease
Research on cardarine has consistently confirmed that this chemical sets the stage for optimal metabolic health. Improved insulin sensitivity, improved glucose tolerance and increased fat oxidation are typical findings of these studies alluding to the reality that cardarine may be useful for treating metabolic-related ailments.
May Help Improve Cholesterol Profiles
Studies on cardarine consistently reveal an elevation of HDL or “good” cholesterol particles while simultaneously reducing the amount of LDL or “bad” cholesterol present, making cardarine a good option for regulating cholesterol.
Lack Of Human Evidence
The majority of research on cardarine is in animal models, with few human trials. As such, understand that benefits observed with animal trials may not translate to a human population.
It’s worth mentioning that this means there is little to no long-term evidence suggesting the safety or danger of this substance in humans.
Strong Evidence Of Cancer Development
Arguably the most important piece of information here is that cardarine has been associated with cancer development and progression. So much so that further research on the drug has been abandoned. It’s strongly advised you consider this before using this chemical.
Human trials testing cardarine used dosages ranging from 2.5 mg to 10 mg. The influence of dosing concerning cancer and liver damage is currently unknown in human populations (4).
Cardarine does indeed show promise for a number of ailments, in particular, those related to metabolic health. It’s clear that cardarine preferentially stimulates a shift in the body to metabolize fat, which may prove useful in the treatment of obesity and the prevention of metabolic-related disease.
Research on cardarine does suggest other positive influences such as an improvement in total and HDL cholesterol and even improved aerobic athletic performance.
However, the potential for cancer development and progression is very serious and should be the first consideration. While cardarine does indeed provide many positive benefits, the potential for cancer development seems to overshadow any possible benefit.
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