Sublingual SARMs 💦 vs SARM Capsules 💊

Today we won’t be delving into a particular research product, but rather we’re going to discuss a broader topic. Specifically, we’re going to explore the route of ingestion of SARMs, and whether that might evolve in the future.

One of the obvious benefits of SARMs from the standpoint of patient compliance is that they are orally bioavailable, meaning they can be swallowed rather than injected—which of course stands in contrast to most of the conventional anabolic agents that are prescribed today.

However, recent research findings and medical case reports have shed light on the potential benefits of taking a sublingual approach to SARM delivery, which essentially means absorption under the tongue.

The problem with oral anabolic steroids

Ok, so let’s examine why conventional anabolic agents such as steroids are generally no longer prescribed as oral drugs, yet SARMs are undergoing clinical trials as oral drug candidates. When drugs are swallowed in pill form they are absorbed in the gut and travel through the portal vein directly to the liver before systemic circulation, and this funneling effect to the liver brings about a phenomenon called first-pass metabolism, which can be problematic for two reasons:

First, the liver is the predominant site of steroid inactivation and breakdown, so oral steroids were historically prescribed at higher doses in order to compensate for this early inactivation inside the body. Yet increasing the oral dose actually worsens a different problem, which is that anabolic steroids have been implicated in four distinct forms of liver injury:

  1. transient serum enzyme elevations
  2. an acute cholestatic syndrome
  3. chronic vascular injury to the liver
  4. hepatic tumors including adenomas and hepatocellular carcinoma.

These adverse events have been most closely linked with the C-17 alkylated testosterones, although unmodified and esterified testosterone preparations can still cause liver injury.

Fortunately, SARMs undergo less extensive liver metabolism and have a better clinical safety record when it comes to hepatotoxicity, which is why all major clinical trials of SARMs have used a pill that’s swallowed rather than an injection.

However, despite their relative safety, high doses of SARMs may nonetheless elevate liver enzyme levels significantly, which indicates organ stress.

For instance, the ongoing Phase 3 trial of RAD-140 is utilizing up to 100 mg per day, which is far higher than was previously anticipated in the research community. Moreover, dozens of medical case reports have been published which show a correlation between SARM use and liver injury, so the research community needs to continue to optimize SARM delivery to further reduce the potential side effects of long-term use once SARMs become prescribed off-label.

The value of sublingual SARMs

Fortunately, there’s an easy way to mitigate the potential problems associated with swallowing SARMS, which is to utilize the sublingual tissues under the tongue for absorption. Keep in mind that not all compounds are effectively absorbed under the tongue, but most SARMs satisfy the basic biochemical requirements to do so.

Substances that are absorbed under the tongue, or in the other tissues of the mouth, or even in the upper half of the esophagus do not get funneled to the liver from the GI tract, but rather they actually get funneled to the superior vena cava, which delivers them to the heart to get pumped throughout the body before they reach the liver. As a result, substances that are absorbed sublingually actually bypass first-pass metabolism in the liver.

There are obvious benefits to bypassing first-pass metabolism, especially for any anabolic substance whose targets are the muscles and bones throughout the body. Once they do reach the liver indirectly, sublingually absorbed substances have already been taken up by the muscles and bones to a significant degree, so their circulating concentrations are much lower, thus the potential stress on the liver is also lower.

Sublingual SARMs such as the Poly-Cell Formulas are designed to innovate clinical trials by reducing the potential burden on the liver, especially in cases where high doses of SARMs are indicated, or in other cases where patients have preexisting liver conditions or co-morbidities which place them at increased risk for hepatotoxicity.

What are polymeric micelles?

The sublingual Poly-Cell formulas are named due to their utilization of polymeric micelles, which are nanomolecular structures that form molecular cages around hydrophobic compounds, such as SARMs, in order to better facilitate their transport across tissue membranes. Polymeric micelles are formed by spontaneous arrangement of copolymers in aqueous solutions, and they have a hydrophobic core plus hydrophilic shell architecture that facilitates the loading of hydrophobic compounds into the core. The major benefit they offer is to improve the solubility of and bioavailability of compounds that otherwise have poor solubility and absorption in the body.

However, polymeric micelles can also be engineered to be multifunctional, so in addition to increasing the overall bioavailability of their molecular cargo, they can also be designed to preferentially release that cargo in specific locations in the body. For instance, a number of strategies have been explored to design pH-sensitive micelles, which can release their therapeutic payloads when they encounter a change in the pH of their microenvironment.

Ok so how is that relevant to SARMs? Well, skeletal muscles that are highly engaged in resistance exercise release lactic acid, so SARM-loaded micelles could be engineered to preferentially release their SARMs in the muscle groups that are exercised the most in any given activity or sport, or in recovery from an injury to a specific limb.

Other SARM-related sublingual options

Lastly, there are related research compounds other than SARMs that can benefit from sublingual absorption as well. The most obvious examples are SR-9009 and SR-9011, which are Rev ERB activators. Unfortunately for researchers, there isn’t strong evidence that the SR compounds are resistant to liver metabolism, so swallowing them may effectively destroy them in the liver before they reach systemic circulation. Keep in mind, that hypothesis remains to be tested in humans, but regardless, sublingual absorption delivers them to skeletal muscles before they reach the liver, so it becomes a moot point.

Please remember that sublingual Poly Cell Formulas not FDA approved yet, and they are not dietary supplements. As such, they remain research compounds only.

It is essential to note that all clinical research must be done with oversight from the relevant Institutional Review Board, and all preclinical research must be done with oversight from your Institutional Animal Care and Use Committee, following the guidelines of the Animal Welfare Act.

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