MK-677, also known as Ibutamoren or L-163,191, is a potent, long-acting, orally-active, selective agonist of the ghrelin receptor and a growth hormone secretagogue.[1] Unlike growth hormone-releasing peptides (GHRPs) which typically require injection, MK-677 is a non-peptide small molecule that is stable when taken orally.
While often categorized alongside Selective Androgen Receptor Modulators (SARMs) or peptides in grey-market contexts, MK-677 acts through a distinct mechanism affecting the growth hormone (GH) and insulin-like growth factor 1 (IGF-1) axis without binding to androgen receptors.[2] It has been investigated for the treatment of growth hormone deficiency, muscle wasting, frailty in the elderly, and Alzheimer's disease, though it is not currently FDA-approved for any medical use.[3]
MK-677 mimics the action of the hunger hormone ghrelin by binding to the growth hormone secretagogue receptor (GHSR-1a) in the pituitary gland and hypothalamus.[4] This activation stimulates the release of growth hormone in a pulsatile manner, which subsequently increases systemic levels of IGF-1.
Key physiological effects include:
Research on MK-677 has focused primarily on conditions associated with low growth hormone or catabolic states.
In healthy older adults, MK-677 has been shown to significantly increase fat-free mass (FFM). A two-year randomized controlled trial (RCT) found that daily administration increased FFM by approximately 1.6 kg compared to placebo.[8] However, much of this "lean mass" increase may be attributed to intracellular water retention rather than contractile muscle tissue accretion.[9]
In a specific trial targeting elderly patients recovering from hip fracture (Adunsky et al.), MK-677 increased IGF-1 levels effectively but failed to improve functional recovery or physical performance compared to placebo.[10]
A large multicenter Phase IIb clinical trial investigated MK-677 for slowing the progression of Alzheimer's disease. Despite effectively raising IGF-1 levels, the drug failed to slow cognitive decline or improve clinical outcomes compared to placebo, leading to the discontinuation of its development for this indication.[11]
Studies have observed increases in markers of bone turnover and bone mineral density (BMD) in elderly subjects, suggesting potential benefits for osteoporosis.[12] However, the lack of fracture reduction data limits its clinical utility in this domain relative to established therapies.
While MK-677 increases IGF-1 (often considered a longevity marker in the context of sarcopenia), its safety profile presents significant challenges.
One of the most consistent adverse effects of MK-677 is an increase in fasting blood glucose and a reduction in insulin sensitivity.[13] Elevation of IGF-1 is typically associated with improved insulin sensitivity, but the direct GH-elevating effects of MK-677 can induce a diabetic or pre-diabetic state in susceptible individuals.[14]
Edema (fluid retention) is a common side effect. Of particular concern is the risk of congestive heart failure (CHF) in elderly patients. In the hip fracture study by Adunsky et al., a higher incidence of CHF was observed in the treatment group compared to placebo, which contributed to safety concerns surrounding the drug's use in frail geriatric populations.[15]
MK-677 is not approved by the FDA for any medical condition. In October 2024, the FDA issued warnings regarding the compounding and distribution of MK-677, citing potential safety risks and its status as an unapproved new drug.[16] It is frequently marketed illegally as a "dietary supplement" or "research chemical."
Elevated IGF-1 is a double-edged sword in longevity science; while it supports tissue repair and muscle mass, high levels are also associated with an increased risk of certain cancers and accelerated aging in some model organisms.[17] Long-term safety data regarding cancer risk in humans taking MK-677 is lacking.
Patchett AA, et al. Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue. Proc Natl Acad Sci U S A. 1995. https://pubmed.ncbi.nlm.nih.gov/7624358/ ↩︎
Smith RG, et al. Ghrelin receptor (GHS-R1a) agonists show potential for treating muscle wasting and frailty. Ann N Y Acad Sci. 2017. https://pubmed.ncbi.nlm.nih.gov/28806482/ ↩︎
FDA. Pharmacy Compounding Advisory: MK-677. October 2024. https://www.fda.gov/media/183016/download ↩︎
Howard AD, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996. https://pubmed.ncbi.nlm.nih.gov/8688086/ ↩︎
Nass R, et al. Effects of an oral growth hormone secretagogue (MK-677) on physical function and body composition in healthy older adults: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2008. https://pubmed.ncbi.nlm.nih.gov/18981488/ ↩︎
Murphy MG, et al. MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. J Clin Endocrinol Metab. 1998. https://pubmed.ncbi.nlm.nih.gov/9467542/ ↩︎
Chapman IM, et al. Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretagogue (MK-677) in healthy elderly subjects. J Clin Endocrinol Metab. 1996. https://pubmed.ncbi.nlm.nih.gov/8954023/ ↩︎
Nass R, et al. Effects of an oral growth hormone secretagogue (MK-677) on physical function and body composition in healthy older adults. Ann Intern Med. 2008. https://pubmed.ncbi.nlm.nih.gov/18981488/ ↩︎
Svensson J, et al. Two-month treatment of obese subjects with the oral growth hormone (GH) secretagogue MK-677 increases GH secretion, fat-free mass, and energy expenditure. J Clin Endocrinol Metab. 1998. https://pubmed.ncbi.nlm.nih.gov/9467578/ ↩︎
Adunsky A, et al. MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb study. Arch Gerontol Geriatr. 2011. https://pubmed.ncbi.nlm.nih.gov/21067829/ ↩︎
Sevigny JJ, et al. Growth hormone secretagogue MK-677: No clinical effect on AD progression in a randomized trial. Neurology. 2008. https://pubmed.ncbi.nlm.nih.gov/18565827/ ↩︎
Murphy MG, et al. Oral administration of the growth hormone secretagogue MK-677 increases markers of bone turnover in healthy and functionally impaired elderly adults. J Bone Miner Res. 1999. https://pubmed.ncbi.nlm.nih.gov/10404020/ ↩︎
Svensson J, et al. Two-month treatment of obese subjects with the oral growth hormone (GH) secretagogue MK-677 increases GH secretion, fat-free mass, and energy expenditure. J Clin Endocrinol Metab. 1998. https://pubmed.ncbi.nlm.nih.gov/9467578/ ↩︎
Nass R, et al. Effects of an oral growth hormone secretagogue (MK-677) on physical function and body composition in healthy older adults. Ann Intern Med. 2008. https://pubmed.ncbi.nlm.nih.gov/18981488/ ↩︎
Adunsky A, et al. MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb study. Arch Gerontol Geriatr. 2011. https://pubmed.ncbi.nlm.nih.gov/21067829/ ↩︎
FDA. Pharmacy Compounding Advisory: MK-677. October 2024. https://www.fda.gov/media/183016/download ↩︎
Bartke A. Growth hormone, insulin and aging: the benefits of endocrine defects. Exp Gerontol. 2011. https://pubmed.ncbi.nlm.nih.gov/20849947/ ↩︎
Chapman IM, et al. Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretagogue (MK-677) in healthy elderly subjects. J Clin Endocrinol Metab. 1996. https://pubmed.ncbi.nlm.nih.gov/8954023/ ↩︎
Copinschi G, et al. Effects of a 7-day treatment with a novel, orally active, growth hormone (GH) secretagogue, MK-677, on 24-hour GH profiles, insulin-like growth factor I, and adrenocortical function in normal young men. J Clin Endocrinol Metab. 1996. https://pubmed.ncbi.nlm.nih.gov/8855836/ ↩︎
Copinschi G, et al. Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man. Neuroendocrinology. 1997. https://pubmed.ncbi.nlm.nih.gov/9349673/ ↩︎