S23: what preclinical research shows and what remains unknown

When sellers write that the effects of S23 are "proven by studies", it is worth asking: what exactly? The editors have compiled all the available scientific evidence on this compound and found that it consists mainly of one thorough preclinical work on rats and a few analytical studies for doping control. We tell what is shown in them and what cannot be deduced from them.

Map of evidence: what is there and what is not

In evidence-based medicine, it is customary to distinguish between levels of evidence. At the top are systematic reviews of randomized controlled trials in humans, below are individual clinical trials, observational studies, clinical cases, and at the base are animal and cell experiments. The lower the level, the more cautious the conclusions about the person should be.

For S23, the upper levels of the pyramids are empty. The editors are not aware of any published clinical studies of this compound on humans — neither the first phase (safety and pharmacokinetics) nor subsequent ones. There are also no observational studies specifically devoted to S23, although some surveys of SARM users generally mention this substance as well.

The body of knowledge is a 2009 article by Jones et al. in the journal Endocrinology. It is accompanied by works by anti-doping laboratories dedicated to the detection of arylpropionamide SARMs and their metabolites, as well as reviews of the SARM class, where S23 is mentioned as a preclinical candidate.

Therefore, any claim about "human dosage," "expected weight gain," or "safe course" is not based on published data. This is an extrapolation, and sometimes just a fiction.

A study by Jones et al. (2009): design

The work of Dalton's research group at the University of Tennessee had a clear goal: to evaluate S23 as a basis for hormonal male contraception. To do this, the authors combined several experimental blocks — from cellular tests for receptor binding to multi-week experiments on rats.

First, the affinity of S23 for the androgen receptor and its ability to activate the receptor in cells were determined. The compound was then injected into castrated rats to assess how well it replaced its own androgens in various tissues: the levator ani muscle (a classic marker of anabolic activity), the prostate and seminal vesicles (markers of androgenic activity).

The third block was performed on intact (non-castrated) males. They were given S23 alone or in combination with estradiol benzoate to enhance pituitary suppression. LH and FSH levels, sperm count, organ mass and — most importantly — the ability to fertilize in mating tests were evaluated.

Body composition was studied separately: bone mineral density, fat-free and fat mass. Finally, some of the animals were observed to regain fertility after the administration was completed to verify the reversibility of the effect, a key requirement for any contraceptive.

Results: muscle, bone, fat and fertility

S23 bound to the androgen receptor with high affinity. In castrated rats, it dose-dependently restored the mass of the levator muscle, and in this tissue it acted as a full agonist. In the prostate and seminal vesicles, the effect was weaker, which the authors interpreted as tissue selectivity.

Bone mineral density and fat-free mass increased and fat mass decreased in animals treated with S23. These data are often cited as evidence of "body recomposition," but they were obtained in rats given the compound for a limited time in the laboratory.

The main result concerned reproduction. The combination of S23 with estradiol benzoate led to a marked suppression of LH and FSH, a decrease in the number of spermatozoa and a loss of the ability to fertilize. After stopping the administration, fertility in the animals was restored, although it took a long time for this to happen.

The summarized results are given in the table. The editors deliberately do not indicate specific doses, because they are calculated for rats and have no direct meaning for humans.

Why data on rats do not transfer to humans

Rats differ from humans in the rate of metabolism, in the structure of liver enzymes, in hormonal regulation, and in life expectancy. A rat dose is not converted to a human dose simply by multiplying by body weight; special calculation methods exist for this, and even these provide only a starting point for careful clinical studies.

The pharmacokinetics of S23 in humans is unknown: it is not known how much of the substance is absorbed, how quickly it is excreted, what metabolites are formed, and whether it accumulates during long-term administration. Without these data, it is impossible to predict either the effect or the toxicity.

Short-term experiments on animals also do not record rare and delayed adverse reactions. Liver damage, cardiac arrhythmias, and idiosyncratic reactions are often detected only during clinical trials involving hundreds or thousands of people or after the drug is on the market.

Finally, the study was conducted with a pharmaceutically pure substance. Products sold as S23 do not go through quality control, so even perfect preclinical data does not describe what a person is actually getting in a capsule or vial.

What the clinical data of other SARMs suggest

Since there is no human data for S23, scientists are focusing on related compounds that have passed clinical trials. The most information is on enobosarm (ostarine) and LGD-4033 (ligandrol). These studies provide insight into class effects in general, but are not evidence for S23.

In a randomized phase II study, enobosarm increased lean body mass in older men and postmenopausal women. At the same time, a dose-dependent decrease in HDL was observed. In a study of LGD-4033 in healthy young men, even low doses for three weeks suppressed total testosterone, sex hormone-binding globulin, and HDL.

These results are important for the interpretation of S23. If compounds with a more moderate effect on gonadotropins already change hormones and lipids in clinical conditions, then S23, specially selected as a powerful suppressor of the pituitary gland, is logical to expect at least an equally pronounced effect.

Systematic reviews of the safety of SARMs in healthy adults, including the 2023 paper by Vignali et al., conclude that clinical data are limited, and the most common documented adverse effects include lipid changes, hormone suppression, and liver damage. Key findings from studies of other SARMs:

• there is an anabolic effect in humans, but it is moderate compared to consumer expectations;
• HDL lowering and testosterone suppression occur even at low doses;
• duration of most studies — weeks or months, long-term data are not available.

Editorial conclusion

The scientific basis of S23 is primarily one thorough preclinical study on rats, performed to create a male contraceptive. There are no clinical studies on humans.

In animals, S23 showed a strong anabolic effect on muscle and bone and at the same time a pronounced, albeit reversible, suppression of gonadotropins and fertility.

Data from other SARMs suggest that lipid and hormone changes can be expected in humans, but the specific risk profile of S23 remains unknown.

For a more complete picture, we advise you to read our reviews about the mechanism of action of S23, about its side effects and about the effect on the lipid profile and the heart.

References

1. 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):385–395.
2. Dalton JT, Barnette KG, Bohl CE, et al. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachexia Sarcopenia Muscle. 2011;2(3):153–161.
3. Basaria S, Collins L, Dillon EL, et al. The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men. J Gerontol A Biol Sci Med Sci. 2013;68(1):87–95.
4. 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):218–236.
5. Narayanan R, Coss CC, Dalton JT. Development of selective androgen receptor modulators (SARMs). Mol Cell Endocrinol. 2018;465:134–142.
6. Thevis M, Schänzer W. Detection of SARMs in doping control analysis. Mol Cell Endocrinol. 2018;464:34–45.