MK-677 (Ibutamoren)

What it is

MK-677 is a non-peptide, orally active spiroindoline derivative that acts as a potent agonist at the growth hormone secretagogue receptor (GHS-R1a), also known as the ghrelin receptor. By binding to GHS-R1a in the hypothalamus and pituitary, it stimulates pulsatile release of endogenous growth hormone (GH) and subsequently increases insulin-like growth factor-1 (IGF-1). The GHS-R1a is a G protein-coupled receptor expressed predominantly in brain, pituitary, and pancreas. MK-677 functions as an orthosteric agonist at GHS-R1a — competing directly with ghrelin at the receptor binding site — and displays higher intrinsic efficacy than ghrelin in some assay systems. GH pulse amplitude increases are proposed to occur through up to four mechanisms: increasing GHRH release, amplifying GHRH signaling in somatotrophs, reducing somatostatin release, and antagonizing somatostatin receptor signaling. MK-677 is described as a ghrelin mimetic because it mimics the N-terminal segment of ghrelin at the receptor level. Receptor binding sites have been identified in human hypothalamus, pituitary, myocardium, adrenal, gonads, arteries, lung, liver, skeletal muscle, kidney, thyroid, adipose tissue, and other peripheral tissues.

Class: Growth Hormone Secretagogue (GHS); Ghrelin Receptor (GHS-R1a) Agonist; Non-peptide spiroindoline derivative

What it's studied for

• Stimulation of GH and IGF-1 secretion / reversal of somatopause in elderly subjects Human RCT
  • 2-year RCT in 65 healthy adults aged 60–81 years. MK-677 25 mg/day orally significantly increased GH and IGF-1 to young-adult levels. Fat-free mass increased in MK-677 group vs. decrease in placebo (change +1.1 kg vs. −0.5 kg, P<0.001). Body weight increased 2.7 kg vs. 0.8 kg. No significant change in abdominal viscera PMID 18981485 Nass R et al. Ann Intern Med. 2008;149(9):601-611.
  • Double-blind crossover RCT in 8 healthy volunteers (ages 24–39). MK-677 25 mg orally once daily for 7 days reversed diet-induced protein catabolism; mean daily nitrogen balance was +0.31 g/day in MK-677 group vs. −1.48 g/day in placebo (P<0.01). IGF-1 increased significantly. Well tolerated. PMID 9467534 Murphy MG et al. J Clin Endocrinol Metab. 1998;83(2):320-325.
  • Review reporting that oral MK-0677 in elderly subjects restored amplitude of episodic GH release to that of young adults, with functional benefits including increased lean mass and bone density and modest improvements in strength. PMID 18056963 Smith RG et al. Ann NY Acad Sci. 2007;1119:97–111.
• Body composition improvement (fat-free mass, lean mass) in obese or older adults Human RCT
  • 2-month RCT in 24 healthy obese males (BMI >30). MK-677 25 mg/day significantly increased IGF-1 (~40%), GH, fat-free mass (DXA: P<0.01), and basal metabolic rate at 2 weeks. Oral glucose tolerance test showed impairment. Total and visceral fat not significantly changed. PMID 9467542 Svensson J et al. J Clin Endocrinol Metab. 1998;83(2):362-369.
  • MK-677 25 mg/day over 2 years increased fat-free mass and body cell mass in healthy older adults; limb fat also increased more than placebo. PMID 18981485 Nass R et al. Ann Intern Med. 2008;149(9):601-611.
• Functional recovery from hip fracture in elderly patients Human RCT
  • Multicenter RCT in 161 hip-fracture patients aged ≥65. MK-677 increased serum IGF-1 by 84% vs. 17% for placebo. No statistically significant differences in functional performance measures or overall SIP-NH score, although MK-677 patients showed greater improvement in 3 of 4 lower extremity measures. PMID 15066065 Bach MA et al. J Am Geriatr Soc. 2004;52(4):516-523.
  • Phase IIb RCT in 123 elderly hip-fracture patients; MK-677 25 mg/day vs. placebo. IGF-1 increased 51.4 ng/mL more than placebo (P<0.001). Gait speed improved (P=0.011). Most other functional measures did not significantly improve. Trial terminated early due to safety signal of congestive heart failure. Overall unfavora PMID 21067829 Adunsky A et al. Arch Gerontol Geriatr. 2011;53(2):183-192.
• Alzheimer's disease — slowing progression Human RCT
  • Double-blind multicenter RCT; 563 mild-to-moderate AD patients randomized to MK-677 25 mg or placebo for 12 months. MK-677 increased serum IGF-1 by 60.1% at 6 weeks and 72.9% at 12 months, but no significant differences on CIBIC-plus, ADAS-Cog, ADCS-ADL, or CDR-sob. Concluded ineffective at slowing AD progression. PMID 19015485 Sevigny JJ et al. Neurology. 2008;71(21):1699-1705.
  • In transgenic 5xFAD mice at asymptomatic stage, MK0677 fostered hippocampal neurogenesis but did not prevent Aβ deposition, synaptic loss, microglial activation, or cognitive impairment. MK0677 at 3 mg/kg significantly increased 5xFAD mouse mortality. PMID 31594237 Tian J et al. J Alzheimers Dis. 2019;71(3):1013-1025.
• Bone turnover / osteoporosis Human RCT
  • Pooled data from 3 RCTs in 187 elderly adults ≥65 years. MK-677 at 10 mg and 25 mg increased urinary NTx (bone resorption). 25 mg for 9 weeks increased osteocalcin 29.4% and BSAP 10.4% (P<0.001). Dose-response observed. IGF-1 increased 55–94%. PMID 10404019 Murphy MG et al. J Bone Miner Res. 1999;14(7):1182-1188.
  • 18-month multicenter RCT in 292 postmenopausal osteoporotic women (MK-677 25 mg ± alendronate 10 mg). MK-677 ± alendronate increased femoral neck BMD 4.2% vs. 2.5% for alendronate alone (P<0.05). MK-677 increased osteocalcin, urinary NTx, and IGF-1. GH-mediated side effects noted. PMID 11238495 Murphy MG et al. J Clin Endocrinol Metab. 2001;86(3):1116-1125.
  • 8-week RCT in 24 healthy obese males. MK-677 25 mg/day increased markers of both bone formation and resorption. IGFBP-5 increased 43–44%. PMID 9661080 Svensson J et al. J Bone Miner Res. 1998;13(7):1167-1175.
• Protein-energy wasting in end-stage renal disease / hemodialysis Human RCT
  • Randomized crossover double-blind study; 26 hemodialysis patients (22 completed). MK-0677 increased geometric mean IGF-1 1.76-fold (95% CI 1.48–2.10; P<0.001) vs. 1.07-fold for placebo. No serious adverse effects attributable to MK-0677. PMID 28400207 Campbell GA et al. Nephrol Dial Transplant. 2018;33(3):523-530.
• Lipid profile effects in obese subjects Human RCT
  • 8-week RCT in 24 obese males. MK-677 25 mg/day did not significantly change Lp(a). Early transient increases in apoA-I, apoE, HDL-C, and triglycerides. LDL-C/HDL-C ratio reduced at study end. Mean LDL particle diameter transiently decreased. PMID 10372705 Svensson J et al. J Clin Endocrinol Metab. 1999;84(6):2028-2035.
• Co-administration with LGD-4033 (SARM) — body composition and biomarker effects Human observational
  • Case report: 25-year-old male ingested LGD-4033 10 mg + MK-677 15 mg daily for 5 weeks. Body mass +6.0%, total lean mass +3.1%, total fat mass +15.4%. Negative impacts: bone mineral content −3.60%, BMD −2.1%, LDL-C +40.0%, HDL-C −36.4%, ALT +205.0%, free testosterone −85.7%, total testosterone −62.3%, FSH below referen PMID 36303408 Cardaci TD et al. Exp Physiol. 2022;107(12):1461-1478.
• GH isoform profile effects Human RCT
  • 8-week RCT in 12 obese males. MK-677 25 mg/day caused moderate changes in non-22K GH isoform proportion and 20K GH proportion over time, considered of small clinical importance. PMID 12550076 Svensson J et al. Growth Horm IGF Res. 2003;13(1):34-40.
• Ghrelin receptor (GHS-R1a) pharmacology / receptor binding characterization In vitro only
  • MK-677 acted as a simple agonist with affinity of 6.5 nM and activated all signal transduction systems with potency 0.2–1.4 nM. Acted as a neutral allosteric modulator of ghrelin signaling in receptor dimer model. PMID 15905359 Holst B et al. Mol Endocrinol. 2005;19(9):2400-2411.
  • In membranes from cells coexpressing human GHS-R and Galpha(o1), MK-677 functioned as a direct orthosteric agonist with higher efficacy than ghrelin. Data best fit by simple competition model, not allosteric modulation. PMID 19625579 Bennett KA et al. Mol Pharmacol. 2009;76(4):802-811.

Community-reported dosing

Tier key: Research = PMID-cited study · [C] = scraped community source · [S] = model-synthesized from aggregate community reports (softer evidence). How we source.

Safety signals

• Congestive heart failure: trial in elderly hip-fracture patients (MK-677 25 mg/day) terminated early due to safety signal of congestive heart failure in a limited number of patients PMID 21067829
• Hepatotoxicity (transaminitis): case report of a healthy man in his early 30s who developed transaminitis after consuming MK-677 for 2 months; resolved after stopping the supplement PMID 40675653
• Decreased insulin sensitivity / impaired glucose homeostasis: consistently observed across multiple human RCTs, including increased fasting blood glucose (~0.3 mmol/L) and impaired oral glucose tolerance test results PMID 18981485
• Impaired glucose homeostasis in obese subjects: oral glucose tolerance test showed impairment at 2 and 8 weeks of MK-677 25 mg/day treatment PMID 9467542
• Gynecomastia and hypogonadotropic hypogonadism: case report of a 40-year-old male who developed bilateral gynecomastia and biochemical hypogonadotropic hypogonadism after consuming supplements containing MK-677, RAD-140, and cardarine; resolved after cessation PMID 39145153
• Elevated liver enzymes (AST +95.8%, ALT +205.0%) during co-administration of LGD-4033 and MK-677 in a single case PMID 36303408
• Suppression of testosterone (total and free) and sex hormone-binding globulin during co-administration with LGD-4033; FSH remained below clinical reference values post-cycle PMID 36303408
• Decreased bone mineral content and bone mineral density during co-administration with LGD-4033 in a single case PMID 36303408
• Increased mortality in transgenic 5xFAD mice at MK0677 dose of 3 mg/kg PMID 31594237
• Increased appetite (subsided within a few months), transient mild lower-extremity edema, and muscle pain reported as the most frequent side effects in a 2-year RCT PMID 18981485
• Transient increase in serum cortisol (47 nmol/L above placebo) observed in a 2-year RCT in older adults PMID 18981485
• Unfavorable lipid changes (LDL-C +40.0%, HDL-C −36.4%, triglycerides +39.2%) observed in a single case report of LGD-4033 + MK-677 co-administration PMID 36303408
• GH-mediated side effects (edema, possible others) noted in groups receiving MK-677 in the postmenopausal osteoporosis trial, though adverse events leading to discontinuation were relatively infrequent PMID 11238495
• Total testosterone reduced during 8-week treatment in obese males PMID 10468903

Contraindications

• Congestive heart failure or at-risk populations: trial in elderly hip-fracture patients terminated early due to congestive heart failure safety signal; MK-677 described as having 'unfavorable safety profile' in this population PMID 21067829
• Diabetes mellitus: explicitly listed as an exclusion criterion in the hip-fracture RCT; consistent finding of decreased insulin sensitivity across studies supports caution in this population PMID 15066065
• Cancer: listed as an exclusion criterion in the hip-fracture clinical trial PMID 15066065
• Uncontrolled hypertension: listed as an exclusion criterion in the hip-fracture clinical trial PMID 15066065
• Multiple fractures or severe trauma: listed as exclusion criterion in the hip-fracture trial PMID 15066065