SARMs Selective androgen receptor modulators, the clinical residue, and the grey-market fog

01 The selectivity promise

The androgen receptor (AR) is a ligand-activated transcription factor that drives anabolic programmes in skeletal muscle and bone and androgenic programmes in prostate, sebaceous skin and hair follicles. Classical androgens activate both. Selective androgen receptor modulators are small molecules designed so that tissue-specific coactivator and corepressor sets favour anabolic transcriptional outcomes over androgenic ones — at least in the animal models that justified development (Dalton et al., 2011; Narayanan et al., 2018).

Selectivity is therefore a development claim, not a property that survives every dose, every product, or every grey-market stack. Human trials infer selectivity from endpoints (lean mass, prostate-specific antigen, skin androgenicity scores) rather than proving an absolute tissue firewall.

02 Chemical families

Most clinically discussed SARMs are nonsteroidal. Early GTx compounds such as andarine (S-4 / GTx-007) and enobosarm (ostarine / GTx-024) sit in the arylpropionamide family. Later ligands include pyrrolidinyl-benzonitrile and related scaffolds (RAD140 / testolone among them). A minority of marketed “SARMs,” notably YK-11, are steroidal or steroidal-adjacent and carry additional contested mechanism claims; they are treated separately in their compound monographs and only sketched here.

03 What is not a SARM

Three confusions dominate the shelf. First, anabolic–androgenic steroids activate AR but are not SARMs in the pharmaceutical sense. Second, Cardarine (GW501516) is a peroxisome proliferator-activated receptor‑δ agonist developed as a metabolic / exercise-mimetic drug; it does not act as a classical AR SARM and is filed in this series as its own monograph precisely so the identity error is not repeated. Third, the axonal enzyme SARM1 (sterile alpha and TIR motif containing 1) is an NAD hydrolase in neurodegeneration research — an abbreviation collision, not a fitness drug.

04 Enobosarm / Ostarine programmes

Enobosarm (ostarine, MK-2866, GTx-024, later VERU-024) is the SARM with the longest human trail. GTx and subsequent sponsors studied it in older adults and in cancer-related muscle wasting, with lean-body-mass signals that were often clearer than functional wins — a pattern that has dogged the whole class (Dobs et al., 2013; Dalton et al., 2011). Breast-cancer programmes targeting AR-positive, ER-positive disease have started and, in at least one Phase 3 setting, stopped for business rather than purely scientific reasons; registry status must be re-checked at each reissue.

The newest clinical adjacency is lean-mass preservation during GLP-1 receptor agonist weight loss. Veru’s Phase 2b QUALITY trial (NCT06282458) is a randomised, parallel, triple-masked dose-finding study whose registry record (ClinicalTrials.gov API harvest, 5 August 2026) lists status COMPLETED, actual enrollment 168, start 29 April 2024, primary completion 11 April 2025, and study completion 22 August 2025. Subjects medically indicated for a GLP-1 receptor agonist for weight management were randomised 1:1:1 to enobosarm 3 mg, enobosarm 6 mg, or placebo while on the GLP-1 agent; the primary endpoint is percentage change in total lean body mass by DEXA at 112 days, with a post–GLP-1 monotherapy extension to Day 196 to examine lean-mass maintenance and fat rebound after GLP-1 discontinuation. Those design facts are registry facts. Sponsor topline communications claiming lean-mass preservation and greater fat loss remain secondary until a peer-reviewed full text is admitted. The Ostarine compound monograph carries the programme detail; the class point is simpler: the only SARM still attracting late-stage commercial R&D at this scale is enobosarm.

Across enobosarm cachexia and older-adult programmes, lean-body-mass increments were often clearer than stair-climb or other functional wins (Dobs et al., 2013; Srinath and Dobs, 2014). That pattern is not unique to one sponsor: the class repeatedly shows tissue composition signals that do not automatically translate into the clinical endpoints regulators prefer. QUALITY’s choice of lean mass as primary endpoint, with stair-climb as a key secondary, is therefore not a quirk — it is how the field has learned to design around that gap. Whether sponsor-reported function preservation in the GLP-1 setting survives peer review is a question for the next harvest, not a conclusion of this class document.

AR is expressed in a substantial fraction of ER-positive breast cancers. Enobosarm and other SARMs have been explored as tissue-selective AR agonists in that setting (Narayanan et al., 2016; Dalton et al., 2013). Programme starts and stops belong in the Ostarine monograph; the class lesson is that SARM clinical ambition has never been only about gym culture. The same molecule can sit in an oncology protocol and on a research-chemical website, and those two contexts must not be collapsed into one evidence claim.

05 Ligandrol and the short healthy-men trial

Ligandrol (LGD-4033, later VK5211 in a hip-fracture programme) has a clean peer-reviewed human island. Basaria et al. (2013) randomised 76 healthy men to placebo or 0.1, 0.3, or 1.0 mg daily for 21 days. Lean body mass rose dose-dependently; total testosterone, SHBG, HDL cholesterol and triglycerides fell; prostate-specific antigen and aminotransferases did not change significantly in that short window; hormones and lipids moved back toward baseline after stopping. That is the controlled record. Around it sits a thinner published trail for longer fracture-recovery work and a thicker case literature of consumer liver injury at exposures often far above trial doses (see Part Three).

06 Industry codes and abandoned candidates

PubMed surfaces for GSK2881078, MK-0773, LY2452473 / OPK-88004, GLPG0492 and related codes are small. Some reached early clinical studies in sarcopenia or related indications and then stalled. They matter for completeness of the catalogue, not for the grey-market conversation. This class document keeps them as a table; they do not receive compound monographs in the present commission.

07 HPG suppression and lipids in controlled settings

Even short SARM exposures in healthy men can suppress the hypothalamic–pituitary–gonadal axis and lower HDL cholesterol. Basaria et al. (2013) documented dose-dependent falls in total testosterone, SHBG, HDL and triglycerides with LGD-4033 over three weeks, with recovery after discontinuation in that study. Similar axis and lipid themes appear across the class whenever they are measured. These are controlled-trial observations, not instructions, and they already falsify the folklore that SARMs are “non-suppressive” at every dose.

08 Drug-induced liver injury

LiverTox’s SARM chapter (NIDDK; last update cited in the 5 August 2026 Camoufox harvest as 20 September 2025) states the class framing in one place: orally available synthetic nonsteroidal AR ligands designed for tissue-selective anabolic activity on muscle and bone, with fewer androgenic effects on prostate, skin, hair, liver and heart; several agents were evaluated for cancer cachexia, osteoporosis and age-related muscle and bone wasting; none were approved for human use; yet several appear in dietary supplements — advertised or as contaminants — and have been implicated in severe cholestatic jaundice resembling anabolic-steroid jaundice (NIDDK LiverTox NBK619971). Case-series and individual reports naming products labelled ligandrol, ostarine, RAD140 and related codes sit on that same shelf (Flores et al., 2023; Mohideen et al., 2022; PMID 38059982; PMID 35340496). Two facts must stay adjacent. First, several early Phase I programmes reported little or no aminotransferase signal at the doses and durations studied. Second, many case exposures involve higher labelled amounts, multi-compound stacks, and products whose contents were never analytically confirmed. The gap between trial material and grey-market bottles is itself part of the safety story.

09 FDA warnings and WADA S1

No SARM discussed here is FDA-approved for bodybuilding, physique enhancement, or aging. The FDA has issued consumer updates and warning letters on body-building products containing SARMs, citing liver injury and other serious risks. The World Anti-Doping Agency lists selective androgen receptor modulators under S1 Anabolic Agents; athletes subject to the Code are prohibited from using them in- and out-of-competition. Those regulatory facts are independent of whether a particular grey-market seller stamps “research use only” on a label.

Twenty-one days of LGD-4033 in healthy men (Basaria et al., 2013) is enough to see lean-mass direction and axis/lipid shifts; it is not enough to settle long-term hepatic risk, cardiovascular outcomes, or functional benefit in sarcopenia. Case series of drug-induced liver injury from consumer products (Mohideen et al., 2023; Nash et al., 2024) answer a different question under different exposures. Holding both records in view — quiet aminotransferases in a short trial, injured livers in uncontrolled use — is the honest class reading.

WADA’s S1 listing means that detection chemistry and adverse analytical findings form a literature stream largely separate from therapeutic development. That stream confirms widespread exposure interest; it does not validate efficacy claims. For this series, anti-doping records are regulatory and market-context evidence, never a substitute for randomised outcomes.

10 Product fraud and analytical underdosing

Forensic and analytical surveys of “research chemical” SARMs have repeatedly found under-dosing, over-dosing, mislabelling, and undeclared second agents. That literature is market-behaviour evidence, not efficacy evidence. It does mean that a consumer case report naming “RAD140” may not be a clean exposure to RAD140, and that trial pharmacokinetics cannot be casually mapped onto bottle labels. Sibling compound monographs return to this point wherever case hepatotoxicity is discussed.

11 Why Cardarine shares the shelf

Cardarine (GW501516, endurobol) activates PPAR‑δ, a nuclear receptor programme tied to fatty-acid oxidation and endurance phenotypes in preclinical models. It is chemically and mechanistically outside the AR-SARM class. Clinical development was abandoned amid rodent carcinogenicity concerns reported in the development history; the Cardarine monograph sources that narrative to primary or high-quality secondary records rather than forum lore.

Commercial catalogues nonetheless sell Cardarine in “SARM stacks,” often beside ostarine, ligandrol or RAD140. The grouping is a marketing habit and a doping-control co-occurrence, not a pharmacological equivalence. This class monograph includes Cardarine so that the error is named once, centrally, and then corrected in every cross-reference.

Commercial “cycles” that combine a SARM with Cardarine, MK-677, or injectable androgens are marketing assemblies. Unless a specific combination was studied as a pre-specified regimen in a controlled trial, this series treats stack claims as unsupported bundling. The Cardarine monograph carries the PPAR‑δ pharmacology; this class document only records that the bundling exists and that it confuses shoppers and sometimes analysts.

12 Evidence asymmetry across the catalogue

The Radix master catalogue lists roughly twenty SARM entries (P156–P176) and zero peptide-series monographs before this commission. That gap was not an oversight of popularity; it was a scope decision. SARMs are adjacent wellness / performance small molecules, not peptide therapeutics. They enter the series now as an explicitly commissioned Adjacent Compounds cluster, with Cardarine included because the market forces the adjacency, not because the chemistry does.

What can be said without overclaiming:

• AR SARMs can raise lean mass in short controlled human studies; functional and long-horizon clinical wins have been harder.
• Axis suppression and HDL reduction appear even in short trials when measured.
• Consumer hepatotoxicity case reports are a class safety theme and often involve unverified products.
• No compound here is an approved physique drug in the United States; WADA prohibits SARMs in sport.
• Cardarine is a PPAR‑δ story, not an AR-SARM story.

Sibling monographs deepen Ostarine, Ligandrol, RAD140, Cardarine, Andarine, S-23 and YK-11. Industry codes remain table rows until new clinical packages appear.

The compound monographs commissioned alongside this class document — Ostarine, Ligandrol, RAD140, Cardarine, Andarine, S-23 and YK-11 — are not redundant with these pages. The class map states the shared pharmacology, shared safety themes, and shared identity traps. Each single carries the molecule-specific trial history, the absences that belong to that name alone, and the citations that would bloat a class narrative if repeated eight times. Readers who want a shelf overview stop here; readers who need a molecule open the sibling.

How this document was assembled

Phase A research packets in projects/adjacent_compounds_research_2026/ supplied the triage and source matrix. A deep harvest on 5 August 2026 used the local research API stack (C:\\Apps\\_env\\research_stack.env): Tavily and Exa for discovery, NCBI E-utilities for PubMed counts and abstracts, ClinicalTrials.gov API v2 for NCT06282458 / NCT03088527 / NCT00158899 protocol modules, and Camoufox for LiverTox NBK619971 and USADA GW1516 advisory pages (Firecrawl returned empty markdown on several PubMed and registry URLs). Sponsor QUALITY communications remain secondary. Body sections follow HOUSE_STYLE; figures are original SVG. PubMed-indexed reference identifiers are resolved through stage 05 against NCBI records; unresolved recall citations are refused.

Evidence handling

Study type is named in the reporting sentence. Animal and in-vitro results are not phrased as human outcomes. Conflicting signals (trial aminotransferase quietude versus consumer DILI cases) are presented as conflict, with product identity and dose as the bridging variables. Recency is weighted for active programmes (QUALITY) without letting press releases overwrite the peer-reviewed backbone.

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