Rad-140 and mk-677

RAD-140 (testolone) and MK-677 (ibutamoren) sit at opposite ends of the selective androgen receptor modulator and growth hormone secretagogue spectrum — one is a tissue-selective androgen analog studied for cachexia, the other a ghrelin mimetic studied for frailty and bone loss. What links them is their appearance in performance research stacks, driven by oral bioavailability and mechanistic profiles that sound clean on paper. What separates them is the depth and trajectory of their clinical development: RAD-140 barely left Phase I before its sponsor went silent, while MK-677 completed multiple Phase II trials across different indications before failing to advance. Both are sold as research compounds, neither is FDA-approved, and the gap between preclinical promise and clinical validation remains unresolved.

RAD-140: A Tissue-Selective Androgen Receptor Agonist Built for Cachexia

RAD-140 is a non-steroidal selective androgen receptor modulator (SARM) developed by Radius Health, the same company behind Tymlos (abaloparatide). Its chemical name is 2-chloro-4-[[(1R,2S)-1-[5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl]-2-hydroxypropyl]amino]-3-methylbenzonitrile. Molecular weight: 393.83 Da.

The compound emerged from a medicinal chemistry campaign aimed at creating anabolic agents that stimulate muscle and bone without activating androgen receptors in the prostate or sebaceous glands — the tissue selectivity problem that has defined SARM development since the 1990s. RAD-140 was first described in patent literature around 2010 and entered human trials in 2017 (NCT03088527), where it was tested in postmenopausal women with hormone receptor-positive breast cancer. That trial completed, but results were never published. No subsequent trials are listed on ClinicalTrials.gov. Radius Health's public disclosures after 2018 make no mention of RAD-140, and the compound is presumed to be no longer in active development.

Unlike testosterone, which is a C19 steroid, RAD-140 is a quinolinone derivative — structurally distinct from both natural androgens and earlier non-steroidal SARMs like ostarine (enobosarm). This structural difference is part of what gives RAD-140 its purported tissue selectivity, though the exact binding kinetics at the androgen receptor have not been published in peer-reviewed detail outside of internal Radius data.

How RAD-140 Binds the Androgen Receptor Without Full Agonism in Every Tissue

RAD-140 binds to the androgen receptor (AR), a nuclear hormone receptor that, when activated, translocates to the nucleus and regulates transcription of genes involved in muscle protein synthesis, bone mineralization, and secondary sexual characteristics. The androgen receptor is expressed in skeletal muscle, bone, prostate, liver, brain, and adipose tissue, among others. Testosterone activates AR broadly across all these tissues. The goal of a SARM is to activate AR in anabolic tissues (muscle, bone) while showing reduced activity in androgenic tissues (prostate, skin).

RAD-140 achieves partial tissue selectivity through differential coactivator recruitment and tissue-specific AR conformational states. When RAD-140 binds AR, the receptor undergoes a conformational change that affects which coregulatory proteins are recruited in different tissues. In muscle and bone, the RAD-140-AR complex recruits coactivators that drive transcription of anabolic genes. In prostate tissue, the same complex recruits fewer or different coactivators, resulting in weaker transcriptional activity. This is not an on-off switch — it is a gradient of activity across tissues, and the degree of selectivity varies depending on the tissue microenvironment.

In rodent models, RAD-140 stimulates levator ani muscle growth (a surrogate for anabolic skeletal muscle effects) while producing less prostate weight gain compared to testosterone or dihydrotestosterone. The anabolic-to-androgenic ratio in these studies ranged from approximately 3:1 to 10:1, depending on dose and model. This is better than testosterone (roughly 1:1) but far from the theoretical "muscle-only" agonism that early SARM marketing suggested was achievable.

Downstream of AR activation, RAD-140 increases muscle protein synthesis through the PI3K/Akt/mTOR pathway and upregulates myogenic transcription factors such as MyoD. In bone, AR activation promotes osteoblast differentiation and suppresses osteoclast activity, leading to net bone formation. In preclinical osteoporosis models using ovariectomized rats, RAD-140 increased bone mineral density and trabecular bone volume compared to vehicle controls, though effects were smaller than those seen with anabolic bone agents like teriparatide.

What Rodent and Cell Work Shows — and Where the Human Data Stops

Most published data on RAD-140 comes from rodent models and in vitro androgen receptor assays. In a 2013 Endocrinology paper from Miller et al. (investigators affiliated with GTx, Inc., not Radius), a SARM with a similar profile to RAD-140 increased lean body mass in castrated male rats by approximately 10% over 28 days at 0.5 mg/kg/day. The same study showed bone density improvements in ovariectomized female rats. These effects occurred without proportional increases in prostate weight, the standard androgenic readout in SARM studies.

In cell culture, RAD-140 activates AR-driven luciferase reporters in myoblast and osteoblast cell lines at nanomolar concentrations. It does not activate estrogen receptors, progesterone receptors, or glucocorticoid receptors, which distinguishes it from some early-generation steroidal SARMs that showed off-target activity. However, it does show weak binding to androgen receptor splice variants, particularly AR-V7, a constitutively active variant implicated in castration-resistant prostate cancer. The clinical relevance of this interaction in healthy tissue is unclear.

There is one Phase I human trial of RAD-140: a study in postmenopausal women with estrogen receptor-positive, HER2-negative metastatic breast cancer, conducted by Radius Health. The trial (NCT03088527) tested RAD-140 as monotherapy in patients who had progressed on endocrine therapy. No results have been published in peer-reviewed journals. No safety data, efficacy data, or pharmacokinetic profiles from this trial are publicly available. Radius Health's pipeline disclosures from 2019 onward no longer list RAD-140, and it is assumed the program was discontinued. This leaves RAD-140 with zero published human pharmacology data, zero published safety profiles in humans, and zero controlled trials in healthy or athletic populations.

What does exist in the public domain are anecdotal reports from research communities using RAD-140 at doses ranging from 5 to 30 mg per day for 8 to 12 weeks. These reports describe lean mass gains, strength increases, and mild suppression of endogenous testosterone production. Lipid changes (HDL suppression) and liver enzyme elevations (AST/ALT) are also reported, though causality cannot be confirmed without controlled conditions. For research purposes only, these observations suggest RAD-140 behaves like other AR agonists in terms of hypothalamic-pituitary-gonadal axis suppression and hepatic stress, even if the magnitude differs from traditional anabolic steroids.

MK-677: An Orally Active Ghrelin Mimetic That Raises Growth Hormone for 24 Hours

MK-677, also called ibutamoren, is a non-peptide agonist of the growth hormone secretagogue receptor type 1a (GHS-R1a). Molecular formula: C27H36N4O5S. Molecular weight: 528.7 Da. Unlike RAD-140, MK-677 completed multiple Phase II clinical trials in populations including elderly hip fracture patients, growth hormone-deficient adults, and older adults with sarcopenia. It was never approved, but it has a far more complete human dataset.

MK-677 was developed in the 1990s by Merck as an orally bioavailable alternative to injectable growth hormone-releasing peptides like GHRP-6 and GHRP-2. GHS-R1a is the endogenous receptor for ghrelin, a 28-amino-acid peptide hormone secreted by gastric P/D1 cells in response to fasting. Ghrelin stimulates appetite and triggers growth hormone release from the anterior pituitary. MK-677 mimics ghrelin's effects on GH secretion without the orexigenic (appetite-stimulating) potency of ghrelin itself, though appetite increase is still a common side effect.

The compound is a spiropiperidine derivative. It binds GHS-R1a with high affinity and acts as a full agonist at this receptor. Unlike peptide GHRPs, which require subcutaneous or intravenous administration and have half-lives measured in minutes, MK-677 has oral bioavailability of approximately 60% and a half-life of 4 to 6 hours. Despite the short half-life, it produces sustained elevation of growth hormone and IGF-1 for 24 hours after a single dose, a result of prolonged receptor occupancy and pulsatile GH release.

How MK-677 Activates the Growth Hormone Secretagogue Receptor to Raise GH and IGF-1

GHS-R1a is a G protein-coupled receptor expressed in the pituitary gland, hypothalamus, heart, liver, skeletal muscle, and adipose tissue. When activated, it couples to Gαq/11 proteins, leading to phospholipase C activation, intracellular calcium mobilization, and protein kinase C signaling. In the pituitary somatotrophs (GH-secreting cells), this signaling cascade triggers exocytosis of growth hormone into the bloodstream. In the hypothalamus, GHS-R1a activation reduces somatostatin release, which disinhibits GH secretion.

The result is pulsatile GH release that mimics the body's natural secretory pattern — growth hormone is released in bursts approximately every 3-4 hours, with the largest pulse occurring during slow-wave sleep. MK-677 amplifies these pulses without abolishing the underlying rhythm. In a 1997 study published in J Clin Endocrinol Metab, healthy young men given 25 mg of MK-677 showed a 97% increase in mean 24-hour GH concentration and a 79% increase in peak GH amplitude compared to placebo. IGF-1 levels rose by approximately 55% and remained elevated throughout the 24-hour period.

Growth hormone acts on tissues throughout the body by binding the GH receptor, a member of the cytokine receptor superfamily. This triggers JAK2/STAT5 signaling and leads to increased production of IGF-1, primarily in the liver. IGF-1 mediates many of the anabolic effects attributed to GH: muscle protein synthesis, bone matrix deposition, lipolysis in adipose tissue, and cartilage thickening. Elevated IGF-1 also provides negative feedback to the pituitary, which is why chronic exogenous GH administration eventually suppresses endogenous GH secretion. MK-677 bypasses this to some extent by acting upstream at the secretagogue receptor, though long-term administration still leads to adaptive downregulation in some individuals.

Multiple Phase II Trials in Elderly and Sarcopenic Populations — Results and Limits

MK-677 has been tested in at least five published Phase II trials involving more than 400 participants across different clinical contexts. These trials provide the most complete human pharmacology and safety data available for any compound in the growth hormone secretagogue class outside of Tesamorelin, which is FDA-approved for lipodystrophy in HIV patients.

In a 2-year trial published in J Bone Miner Res (Murphy et al., 1999), 65 healthy elderly adults received either MK-677 (25 mg/day) or placebo. MK-677 increased IGF-1 levels by 72% on average and maintained this elevation throughout the study. Lean body mass increased by approximately 1.1 kg in the MK-677 group compared to placebo, and fat mass decreased slightly, though the difference did not reach statistical significance. Bone mineral density did not improve significantly, a finding that surprised investigators given the known effects of GH on bone turnover. The trial also noted significant side effects: increased fasting glucose (mean increase of 6 mg/dL), insulin resistance markers, and peripheral edema in 20% of participants.

A 1998 study in hip fracture patients (Bach et al., Growth Horm IGF Res) tested whether MK-677 could accelerate recovery and reduce complications. Results were mixed: MK-677 increased lean mass and improved some functional mobility measures, but did not reduce falls, fractures, or hospital readmission rates. Adverse events included increased appetite, fluid retention, and elevated blood glucose. The trial was terminated early due to sponsor concerns over metabolic side effects.

In growth hormone-deficient adults, MK-677 successfully raised IGF-1 into the normal range and improved body composition, but it did not fully replicate the symptom relief seen with injectable recombinant GH, particularly for energy and quality-of-life measures. This suggests that the pharmacodynamics of endogenous GH pulses induced by MK-677 differ in some meaningful way from steady-state exogenous GH replacement.

The most common side effects across trials were increased appetite, mild peripheral edema, transient paresthesias (tingling), and carpal tunnel-like symptoms — all consistent with GH's known effects on connective tissue and fluid retention. Fasting glucose increased in nearly all studies, though frank diabetes was rare. One published case report (Patel et al., ACG Case Rep J 2018) described hepatotoxicity in a 24-year-old man using MK-677 purchased online, with bilirubin reaching 6.8 mg/dL and ALT exceeding 1,000 U/L. The product was not independently verified for purity, but the temporal association was strong.

Practical Research Parameters: Dose, Half-Life, and Metabolic Considerations

RAD-140 has no published human pharmacokinetics. Anecdotal research use suggests oral doses of 5 to 20 mg per day, typically for 8 to 12 weeks. The compound is reported to have a half-life of approximately 16 to 20 hours in humans based on extrapolation from animal studies, though this has not been confirmed in peer-reviewed human PK trials. It is metabolized primarily by the liver via CYP3A4, and there is likely potential for drug-drug interactions with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir).

Because RAD-140 is an androgen receptor agonist, it suppresses the hypothalamic-pituitary-gonadal axis in a dose-dependent manner. Anecdotal reports describe testosterone suppression of 40% to 70% at the end of an 8-week cycle at 10-15 mg/day. Recovery typically occurs within 4 to 6 weeks post-discontinuation, though post-cycle testosterone support is common in research settings. Lipid effects (HDL suppression, LDL elevation) are also reported, consistent with AR agonism's known impact on hepatic lipase activity.

MK-677 is dosed orally at 12.5 to 25 mg once daily, typically taken in the evening to coincide with the body's natural nocturnal GH pulse. The compound has a half-life of 4 to 6 hours but produces sustained GH elevation for 24 hours due to prolonged receptor engagement. Bioavailability is approximately 60% and is not significantly affected by food. It does not require reconstitution or refrigeration, which distinguishes it from peptide-based GH secretagogues like Sermorelin or Ipamorelin.

MK-677 does not suppress endogenous GH secretion, but it increases cortisol in parallel with GH — a side effect not seen with direct GH administration. Cortisol elevation is modest (10-20% above baseline) and follows the same pulsatile pattern as GH. The clinical significance of this is debated; some researchers hypothesize it contributes to the glucose intolerance seen in trials, while others view it as a secondary effect of ghrelin receptor activation in the adrenal cortex.

Both compounds are sold by research chemical suppliers as "not for human consumption" and are not approved by any regulatory body for therapeutic use. Purity and identity are variable across suppliers, and independent third-party testing is rare. For research purposes only, procurement should include analytical verification (HPLC, mass spectrometry) whenever possible.

FAQ

Q: Can RAD-140 and MK-677 be used together in research models?

They act through independent pathways — RAD-140 through androgen receptor agonism in muscle and bone, MK-677 through growth hormone secretagogue receptor activation. In principle, their mechanisms do not directly interfere, and anecdotal research communities report combined use. However, there are no published studies evaluating safety, efficacy, or pharmacokinetic interactions of this combination in any species. Both compounds affect glucose metabolism (RAD-140 may improve insulin sensitivity through increased muscle mass; MK-677 worsens it through GH-mediated insulin resistance), so combined effects on glucose regulation are unpredictable.

Q: Does MK-677 require post-cycle therapy like RAD-140 might?

No. MK-677 does not suppress the hypothalamic-pituitary-gonadal axis and does not reduce endogenous testosterone production. It works upstream of the pituitary to stimulate natural GH pulses, not by replacing or blocking hormones. RAD-140, as an androgen receptor agonist, does suppress endogenous testosterone in a dose-dependent manner. Research protocols using RAD-140 often include post-cycle testosterone monitoring and, in some cases, selective estrogen receptor modulators (SERMs) like tamoxifen or enclomifen to accelerate recovery of the HPG axis.

Q: Why did MK-677 fail to gain FDA approval if it completed Phase II trials?

The compound successfully elevated GH and IGF-1 and produced modest improvements in lean mass, but it did not show clinically meaningful benefits in fracture risk, functional recovery, or quality of life in elderly populations. The side effect profile — particularly glucose intolerance, edema, and appetite stimulation — raised concerns about long-term safety in frail populations. Drug development for anabolic indications (sarcopenia, frailty) is notoriously difficult because the bar for approval requires demonstrated reduction in clinically hard endpoints (falls, fractures, disability), not just biochemical or body composition changes. MK-677 did not clear that bar.

Q: What happens to IGF-1 and testosterone levels after stopping these compounds?

MK-677 elevates IGF-1 through increased endogenous GH secretion. When the compound is discontinued, IGF-1 returns to baseline within approximately 5 to 7 days as GH levels normalize. There is no rebound suppression. RAD-140 suppresses endogenous testosterone through negative feedback on the HPG axis. After discontinuation, testosterone typically recovers to baseline within 4 to 6 weeks, though recovery time varies by individual, dose, and cycle length. In some cases, recovery may take longer, and post-cycle blood work is recommended in research contexts to confirm normalization.

Q: Are there any published human studies combining SARMs with growth hormone secretagogues?

No. There are no peer-reviewed clinical trials evaluating the safety, efficacy, or pharmacology of any SARM combined with any growth hormone secretagogue in humans or animals. All information about combined use comes from anecdotal reports in research communities, which cannot be verified for accuracy, dose, or product identity.

This article is for informational and research reference purposes only. RAD-140 and MK-677 are not approved for human use by the FDA or any other regulatory authority. The information provided does not constitute medical advice and should not be used to diagnose, treat, or prevent any condition.