The Great GW501516 Cardarine Controversy

Dr. Adam Watson from Umbrella Labs is here to talk about Cardarine, otherwise known as GW501516, which was the first breakthrough PPAR delta activator that took the research community by storm, until it ultimately fell from grace.

GW501516 Cardarine Overview

Cardarine is an activator of PPAR delta receptors, which are proteins that regulate important cellular metabolic functions that contribute to maintaining energy balance. PPAR delta is also known to influence muscle metabolism, and it can reprogram muscle fibers to enhance running endurance. 

Cardarine was discovered way back in 1992, but it only really exploded onto the scene in 2007 after some exciting research was conducted at the Salk Institute in California. If you’re not familiar with the Salk Institute, it’s produced more Nobel Laureates per capita than any other independent research institution in the world, and a great place to do cutting-edge science.

What they discovered was that Cardarine dramatically increased the physical performance and endurance of mice, so researchers everywhere began to fantasize about a potential “exercise in a pill”, which is still the holy grail of metabolism research. 

Elsewhere, Cardarine was shown to increase fatty acid metabolism in skeletal muscle and protect against diet-induced obesity and type 2 diabetes in rats. In overweight monkeys, Cardarine increased good cholesterol and lowered bad cholesterol.

All of these results encouraged human trials investigating Cardarine as a potential drug candidate for metabolic diseases and cardiovascular diseases. In particular, it was hoped that Cardarine could be leveraged to combat hypertension, which costs the United States almost $50 billion per year in health care costs according to the CDC, so clearly there is an urgent need for new therapies to address that problem. 

What makes Cardarine controversial?

Well If you Google Cardarine, you’ll be immediately warned, sometimes hysterically, about a possible link to cancer, which sounds terrifying. However, any fair discussion about Cardarine needs to be nuanced, because there are over 300 published, peer-reviewed articles regarding Cardarine, and they span basic science, translational studies, clinical studies, and reviews, and virtually all of the data concerning cancer risk is conflicting.  

What I want to highlight specifically about the controversy is that regardless what you think about risk tolerance for investigational new drugs, Cardarine is undeniably the victim of an unfortunate loophole in scientific literature known as “conference abstracts”.

The entirety of the hypothesized risk linking Cardarine to cancer initiation can be traced to two conference abstracts that were never actually published in a peer-reviewed journal. That is to say, they were never subjected to the kind of rigorous analysis that good science demands of itself.

Conference abstracts are not meant to be authoritative—they should only serve as a preview for research in progress, which you present at a scientific conference to colleagues in your field. Ideally, conference abstracts form the basis for a future published study, but sometimes hypotheses are wrong, or the science was sloppy, or the preliminary data just turns out to be misleading.

It’s worth mentioning at this point that when we talk about things that promote cancer, we need to distinguish between tumor initiators, which are factors that increase the incidence of cancer, versus tumor promoters, which are factors that can promote the progression of cancer once it’s already appeared, regardless of what caused it to manifest in the first place.

Cancer initiators are much more feared, and the World Health Organization has designated things like UV radiation from the sun, processed red meat, and alcohol as factors that increase your risk of getting cancer.

With regard to Cardarine, the only evidence that it actually increases cancer initiation comes from those suspicious conference abstracts in which rats were given insanely high doses of Cardarine every day for two years. If that data is legitimate, it would certainly support that Cardarine can cause cancer. But since that data was never peer-reviewed and published in an academic journal, the rest of the scientific community can’t judge the data independently.

The really intriguing story about Cardarine is actually about the controversy, and how the controversy itself provides a truly fascinating window into how scientific disagreements play out in academic journals. Because for every study which shows that ultra-high doses of Cardarine can promote tumor growth in mice, there’s an equally reputable yet conflicting study showing that ultra-high doses of Cardarine can actually prevent tumor growth in mice. 

In fact, the longer you spend digging, the more you’ll find seemingly contradictory conclusions. Some of this can be traced to differences in dose levels, or differences in animal models, but ultimately some of this contradiction is just part of the messy reality of biology.

Take Vitamin E for example, which we all know is an essential antioxidant, and numerous epidemiological studies demonstrate that vitamin E is associated with a reduction in cancer risk, which you probably don’t find surprising. But what is surprising is that numerous studies in very prestigious journals have found that vitamin E can actually act as a tumor promoter, and one of the largest cancer prevention trials ever conducted showed that vitamin E supplementation was associated with an increased risk of prostate cancer.

It’s plausible that Cardarine falls into a similarly murky category, or perhaps it’s beneficial overall in some patient populations while still presenting a legitimate risk profile nevertheless. Unfortunately, we’ll never really know for sure.

What makes this situation even more fascinating is that just last year in 2019, a pair of esteemed scientists from the National Heart and Lung Institute at Imperial College in London published an editorial in the journal Pulmonary Circulation in order to bring attention to the unusual situation surrounding Cardarine.

What they argue is that despite the controversy, PPAR delta activators such as Cardarine remain potentially important therapeutic tools for the future treatment of hypertension, which as I mentioned earlier is an enormous public health problem that remains to be solved.

Regardless, the controversy has certainly scared investors away from the intellectual property, which is why Cardarine will forever be stuck in limbo. 

However, Cardarine is still very much in use as a tool to help us better understand the PPAR delta signaling pathway and its physiological effects in preclinical studies. In fact, recent research conducted in collaboration with the National Cancer Institute in Maryland showed that Cardarine can prevent the spread of melanoma skin cancer in preclinical models, so there’s still no consensus on the role of Cardarine in cancer biology.

Human Studies – Beyond the Preclinical Studies

There have been 4 clinical studies which have investigated Cardarine, and the results from each study were either positive or encouraging. Clinically, Cardarine was shown to reduce harmful cholesterol, decrease plasma triglycerides and fatty acids, reduce oxidative stress, and stimulate glucose uptake in skeletal muscle cells.

Crucially, no serious adverse effects were reported in any patients from all studies combined, which comprise almost 500 patients overall.

However, that does not necessarily mean that Cardarine is without risks, because the absence of evidence is not evidence of absence. 

Please remember that Cardarine is not FDA approved for any indication, nor will it ever be, and it is definitely not a dietary supplement. As such it remains a research chemical only.

Cardarine, GW501516, SARMs

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