Among the arguments in favor of SARMs is often the thesis that, unlike oral anabolic steroids, they are "not toxic to the liver." But in recent years, there have been a number of reports in medical journals of liver damage in people who used SARM products. The editors have figured out what applies to S23 and what applies to the class in general, and how doctors recognize drug-induced liver damage.
Where did the thesis about "safety for the liver" come from
Classic oral anabolic steroids such as methandienone, oxandrolone or stanozolol have a methyl group at the 17-alpha position. This modification protects the molecule from destruction during the first passage through the liver, but at the same time it is associated with cholestasis, peliosis of the liver and tumors. The reputation of "pills that hit the liver" is related to this.
SARMs like S23 do not have a steroid backbone and are not 17-alpha-alkylated. Hence the assumption that they are devoid of the hepatotoxicity characteristic of tableted steroids. At the level of chemical logic, this statement is partially justified, but it does not mean that the compound is safe for the liver in general.
Any substance taken orally first passes from the intestine through the portal vein to the liver. There, it is metabolized by enzymes, particularly the cytochrome P450 system, and transformed into metabolites, some of which may be reactive. Medicinal damage to the liver is possible for drugs of the most diverse structure - from antibiotics to painkillers.
In addition, early clinical trials of SARMs involved small groups of participants for short periods. Rare idiosyncratic reactions that occur in one in several thousand patients are simply not included in such studies. Therefore, the absence of a signal in small studies is not proof of safety.
What is known about SARM hepatotoxicity
In 2020, in the journal Hepatology Communications, Flores et al described a case of drug-induced liver injury in people who consumed SARM products. A characteristic feature was a cholestatic or mixed type of lesion with pronounced jaundice and itching. Similar reports have been published for individual compounds, including LGD-4033 and RAD140.
A systematic review of the safety of SARMs in healthy adults (Vignali et al., 2023) summarized both data from clinical trials and clinical cases. The authors concluded that liver damage is among the most frequently reported serious adverse reactions in recreational SARM users.
Clinical studies of some SARMs also reported transient elevations in liver enzymes in some participants. It was usually moderate, but the fact itself indicates that the liver responds to these compounds even under controlled conditions and at relatively low doses.
The mechanism of damage has not been precisely clarified. Both direct effects of compounds or their metabolites on bile acid transporters and immune-mediated reactions are discussed. The contamination factor is also important: in some cases, the actual composition of the product was not checked, so it cannot be ruled out that another component, such as a hidden methylated steroid, was the cause.
What exactly is known about S23
There are no direct studies of the hepatotoxicity of S23 in humans, because the compound has never undergone clinical trials. The 2009 preclinical work was aimed at evaluating efficacy as a contraceptive and did not include the detailed liver toxicology analysis required by regulators.
Regarding clinical cases, S23 appears in the literature much less often than LGD-4033 or RAD140. This may be due to the compound's lower popularity rather than lower toxicity. Furthermore, in many reports, patients used multiple substances at the same time, and it is difficult to establish the role of a specific SARM.
In view of the affinity with other arylpropionamides and the oral route of administration, the editors consider a precautionary approach justified: the risk of liver damage for S23 is not proven, but not excluded. For practical conclusions, it is more important for a person to know the signs of a problem than to hope for a "safe" reputation.
Separately, it is worth emphasizing the combinations. SARM users often combine multiple compounds, add oral steroids, fat burners, or alcohol. Each of these factors increases the load on the liver, and it is impossible to predict the result of such a combination.
How liver damage is manifested
Medicinal damage to the liver in the early stages is often asymptomatic and is detected only in tests. Therefore, the absence of complaints does not guarantee that everything is fine. When symptoms appear, it usually indicates an already expressed process.
In clinical cases associated with SARMs, the following manifestations were most often described:
- jaundice — yellowing of the skin and whites of the eyes;
- severe itching of the skin associated with stasis of bile;
- darkening of urine and lightening of feces;
- weakness, nausea, loss of appetite;
- discomfort or pain in the right hypochondrium.
The appearance of any of these signs, especially jaundice, is a reason for immediate medical attention. Drug-induced liver damage in most reported cases was reversible after cessation of substance use, but recovery could take weeks or months, and some patients required hospitalization.
It is important for a doctor to know about all substances that a person has used, including supplements and "research" compounds. Correct diagnosis depends on this: without such information, doctors can spend time looking for viral, autoimmune or other causes.
Laboratory diagnostics
A standard biochemical panel is used to assess the state of the liver. The doctor evaluates not only individual indicators, but also their ratio, which helps to determine the type of damage: hepatocellular (damage of liver cells), cholestatic (disturbance of bile outflow) or mixed.
| Index | What it shows | Typical change in cholestatic lesion |
|---|---|---|
| ALT (alanine aminotransferase) | Damage to liver cells | Moderate increase |
| AST (aspartate aminotransferase) | Damage to liver and muscle cells | Moderate increase |
| Alkaline phosphatase (LF) | Outflow of bile | Pronounced increase |
| GHT (gamma-glutamyltransferase) | Outflow of bile, action of toxins | Increase |
| Bilirubin (total and direct) | Ability of the liver to excrete bile pigments | Increase, sometimes significant |
An important nuance for people who train: intense physical activity alone can increase AST and ALT due to damage to muscle fibers. Therefore, the doctor can additionally prescribe creatine kinase to distinguish the muscular origin of the enzymes from the hepatic one, and recommend taking tests after a few days of rest.
Doctors use standardized approaches to assess the probability of drug damage, and background information on the hepatotoxicity of specific substances is collected by the LiverTox database of the US National Institutes of Health. The interpretation of analyzes and the decision of further tactics should be left to a gastroenterologist or a hepatologist.
Editorial conclusion
The “liver-safe SARM” thesis is based on the absence of the 17-alpha-methyl group, but not on clinical trial data. The medical literature contains a number of cases of cholestatic liver damage in users of SARM products.
There are no direct data on the hepatotoxicity of S23, but the oral route, affinity with other SARMs, and the uncontrolled composition of the products do not give reason to consider the risk absent.
Liver damage often begins without symptoms, so a biochemical analysis and openness with the doctor about the substances used is the key to timely diagnosis.
We recommend that you also read our materials on the general side effects of S23, on the effect of this compound on the lipid profile, and on the results of laboratory tests of SARM products from the market.
References
- Flores JE, Chitturi S, Walker S. Drug-induced liver injury by selective androgenic receptor modulators. Hepatol Commun. 2020;4(3):450â452.
- Vignali JD, Pak KC, Beverley HR, et al. Systematic review of safety of selective androgen receptor modulators in healthy adults: implications for recreational users. J Xenobiot. 2023;13(2):218â236.
- Barbara M, Dhingra S, Mindikoglu AL. Ligandrol (LGD-4033)-induced liver injury. ACG Case Rep J. 2020.
- Jones A, Chen J, Hwang DJ, et al. Preclinical characterization of a (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro-4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide: a selective androgen receptor modulator for hormonal male contraception. Endocrinology. 2009;150(1):385â395.
- National Institute of Diabetes and Digestive and Kidney Diseases. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): NIDDK; 2012â.
- Van Wagoner RM, Eichner A, Bhasin S, et al. Chemical composition and labeling of substances marketed as selective androgen receptor modulators and sold via the internet. JAMA. 2017;318(20):2004â2010.
