Ibutamoren (MK-677)

01 · What it is

Ibutamoren is not a peptide. It is an orally active, long-acting non-peptide small molecule — a spiroindoline derivative, catalogued in the chemical literature under the indole and spiro compound classes — that binds the growth hormone secretagogue receptor GHS-R1a and stimulates release of endogenous growth hormone ^1,3,7. It is grouped with the growth hormone-releasing peptides because it acts at their receptor, not because it resembles them structurally. Everything else in this family is injected; ibutamoren is a tablet.

It is also the best-evidenced compound in Family C, and the evidence is negative.

Two randomised, placebo-controlled trials tested ibutamoren mesylate in elderly patients recovering from hip fracture — a population chosen precisely because growth hormone axis stimulation should help there, if it helps anywhere. The first found no significant difference from placebo in functional performance measures or in the overall Sickness Impact Profile score, and concluded it was uncertain whether the observed IGF-I increase was clinically significant ⁶. The second, a multicentre phase IIb in 123 patients, raised IGF-1 by 51.4 ng/mL (95% CI 34.42 to 68.44, p < 0.001) and did not improve stair climbing power (+12.5 W, 95% CI −10.95 to 35.88, p = 0.292) or several other functional measures. That trial was terminated early due to a safety signal of congestive heart failure, and its authors concluded that ibutamoren “has an unfavorable safety profile in this patient population” ⁸.

Since then the human literature has consisted largely of case reports: hepatotoxicity with transaminitis after two months of use ¹⁵, and reversible gynaecomastia with hypogonadism from a supplement containing ibutamoren alongside a selective androgen receptor modulator ¹⁴.

As of September 2026 ibutamoren holds no marketing authorisation from any regulator.

02 · Evidence at a glance

Evidence grade

Early Clinical — the grade reflects that trials were done, not that they succeeded

Molecular class

Non-peptide small molecule, spiroindoline; orally active ^1,3,7

Molecular target

Growth hormone secretagogue receptor GHS-R1a ⁷

Randomised controlled trials in a clinical indication

2, both in hip fracture recovery ^6,8

Result of both

No significant improvement in functional performance ^6,8

Largest trial

123 patients, 25 mg/day ⁸

IGF-1 response in that trial

+51.4 ng/mL, 95% CI 34.42–68.44, p < 0.001 ⁸

Stair climbing power in that trial

+12.5 W, 95% CI −10.95 to 35.88, p = 0.292 ⁸

Why that trial stopped

Terminated early for a congestive heart failure safety signal ⁸

Authors’ safety conclusion

“Unfavorable safety profile in this patient population” ⁸

Published human case reports

Hepatotoxicity ¹⁵; gynaecomastia and hypogonadism ¹⁴

FDA compounding status

Remains in active category 2, both 503A and 503B ²²

Approval status

None, any jurisdiction

03 · Mechanism of action

GHS-R1a agonism by a non-peptide

Ibutamoren binds and activates the growth hormone secretagogue receptor GHS-R1a — the same receptor targeted by ghrelin and by the peptide secretagogues in this family — and triggers pulsatile release of endogenous growth hormone from pituitary somatotrophs, with consequent hepatic IGF-1 production ^1,3,7. Its development was the culmination of a deliberate programme to replace the peptide secretagogues with an orally bioavailable non-peptide mimetic, and by the late 1990s reviewers identified it as the most interesting molecule to emerge from that effort ¹. Its developers framed it explicitly as an ageing intervention, positioning growth hormone axis restoration among the drug opportunities the field was pursuing ⁵.

The pharmacological achievement is real and should be stated as such: an injectable peptide mechanism was successfully reproduced in an oral small molecule. What did not follow was clinical benefit.

Preserved pulsatility and an intact axis

Like the GHRH analogues, secretagogues acting at GHS-R1a stimulate the pituitary rather than supplying growth hormone directly, so secretion remains pulsatile and subject to feedback ^3,7. Ibutamoren also raised nitrogen balance without raising serum cortisol in a catabolism model ², which distinguishes it from the less selective peptide secretagogues discussed elsewhere in this family.

Where the mechanism stops explaining anything

The chain of reasoning behind this compound is: receptor activation → growth hormone release → IGF-1 elevation → anabolic effect → functional improvement. The first three links are demonstrated. The fourth is assumed. The fifth was tested twice, in the population most likely to show it, and did not occur ^6,8.

That is the central mechanistic problem, and it is not unique to ibutamoren — it recurs across every growth hormone secretagogue — but ibutamoren is where it was measured most cleanly. A trial in which IGF-1 rises with p < 0.001 while stair climbing power moves with p = 0.292 is a trial that has isolated the failure precisely: the axis responds, and the patient does not ⁸.

The cardiac signal, and what is and is not known about it

Congestive heart failure emerged as a safety signal in a limited number of patients, sufficient to terminate a trial early ⁸. The mechanism is not established in the published literature. Growth hormone excess has recognised cardiac consequences, and fluid retention is a well-documented effect of growth hormone axis stimulation, but the trial report does not attribute the signal to a specific pathway and no subsequent work has characterised it.

An unexplained cardiac safety signal in an elderly population is not the same as a demonstrated mechanism of harm — and it is also not something the absence of a mechanism makes go away.

Central nervous system exposure

In dogs, oral MK-0677 did not alter IGF-1 or growth hormone concentrations in cerebrospinal fluid despite systemic administration ⁴, which bears on whether centrally mediated effects should be expected from peripheral dosing.

04 · Key research findings

Hip fracture recovery — trial one. Patients recovering from hip fracture received MK-0677 or placebo. There were no significant differences between groups in improvement in functional performance measures or in the overall Sickness Impact Profile–Nursing Home score. The authors concluded that although treatment increased serum IGF-I, it was uncertain whether clinically significant benefit followed ⁶.

The population was well chosen and the answer was no.

Hip fracture recovery — trial two, and the termination. A multicentre, randomised, placebo-controlled phase IIb study assigned 123 elderly hip fracture patients to 25 mg/day MK-0677 (n = 62) or placebo (n = 61). At 24 weeks: mean stair climbing power increased by 12.5 W (95% CI −10.95 to 35.88, p = 0.292); gait speed improved by a 0.7-score difference in means (95% CI 0.17–1.28, p = 0.011); there was no improvement on several other functional performance measures; falls were fewer but not significantly so (p = 0.096); and IGF-1 rose by 51.4 ng/mL (95% CI 34.42–68.44, p < 0.001). The trial was terminated early due to a safety signal of congestive heart failure in a limited number of patients ⁸.

One functional measure of several reached significance in a trial that was stopped for harm — that is the shape of a negative result, not a mixed one, and the authors said so.

Catabolism. In an earlier study, MK-677 improved nitrogen balance in diet-induced catabolism: area under the curve for days 8–14 was +2.69 ± 5.0 for MK-677 versus −8.97 ± 5.26 g/day for placebo (p < 0.001), with neither serum cortisol nor other measured hormones adversely affected ².

The one clearly positive human result in this compound’s file, on a metabolic rather than functional endpoint, in short-term dietary restriction — and it did not translate into the functional trials that followed.

Case reports since. An otherwise healthy man in his early thirties developed transaminitis after consuming MK-677 for two months ¹⁵. A separate report described reversible gynaecomastia and hypogonadism following use of commercial performance-enhancing supplements found on analysis to contain MK-677 together with RAD-140 and cardarine, plus undisclosed hormones ¹⁴. A case report documented body composition and biomarker changes in a 25-year-old man taking MK-677 with LGD-4033 for five weeks ¹².

Two of the three involve multi-ingredient exposure, which limits attribution — a recurring problem across this roadmap — but the hepatotoxicity report concerns MK-677 alone.

Reviews. Assessments of growth hormone secretagogue safety and efficacy ⁹ and of their role in body composition management in hypogonadal men ¹⁰ both include ibutamoren, alongside broader recent syntheses in sports medicine and endocrinology ^{17,18,19,20,21}.

The reviews are consistent in describing a compound with reliable endocrine effects and unvalidated clinical benefit.

Detection. Ibutamoren and its metabolites have been characterised for doping control in thoroughbred horses ¹¹, detected in equine hair after oral administration ¹³, and mapped in human hair down to a single 10 mg dose ¹⁶.

The compound is straightforwardly detectable, which matters for competitors and is unrelated to whether it works.

05 · Evidence overview

06 · Safety profile

The trial signal. The most important safety datum is that a randomised controlled trial in 123 elderly patients was terminated early due to a congestive heart failure signal, and that its authors characterised the safety profile in that population as unfavourable ⁸. This is not an adverse event report or a case series; it is a stopping decision made by people running a controlled trial with monitoring in place.

Case reports. Hepatotoxicity presenting as transaminitis after two months of use in an otherwise healthy man in his thirties ¹⁵. Reversible gynaecomastia and hypogonadism following supplements containing MK-677 with other agents ¹⁴.

Metabolic. Growth hormone antagonises insulin action, and this is intrinsic to any effective secretagogue. Reviews of the class treat glucose tolerance as the principal metabolic consideration ^9,10. The catabolism study reported no adverse effect on cortisol ², which addresses a different question.

What is genuinely unknown. The mechanism of the cardiac signal — unexplained in the trial report and uncharacterised since ⁸. Whether the signal is specific to elderly patients recovering from hip fracture, or a property of sustained growth hormone axis stimulation in anyone. Long-term hepatic safety, given a case report of hepatotoxicity at two months ¹⁵. Effects of use over years, which no study has examined. Reproductive and developmental data. Carcinogenicity data. And whether the absence of functional benefit in two trials in an elderly population predicts absence of benefit in younger people with intact physiology — untested in either direction.

07 · US regulatory status

Current as of 6 September 2026. Ibutamoren is not approved as a drug in the United States or any other jurisdiction, and is not a controlled substance.

Its compounding status differs from most compounds covered on this site, and the difference matters. Ibutamoren mesylate remains in the active category 2 table of FDA’s interim bulk drug substances policy — for 503B outsourcing facilities since 29 December 2022 and for 503A compounding since 29 September 2023 — on the stated basis of significant safety risks due to the potential for congestive heart failure in certain patients, citing the randomised trial that was terminated early ²². It did not move to the table of substances nominated but subsequently withdrawn, and it was not among the seven substances reviewed by the Pharmacy Compounding Advisory Committee in July 2026 ²³.

Where an agency’s characterisation and a primary source agree, it is worth saying so: FDA’s stated rationale here corresponds exactly to what the trial report says ⁸.

Under the World Anti-Doping Code, growth hormone secretagogues are prohibited at all times, and validated detection methods exist in human hair and equine matrices ^11,13,16. Competitors should consult the current Prohibited List directly rather than rely on secondary summaries, including this one.

08 · Limitations of the evidence

1. The two trials that tested clinical benefit both found none. Different investigator groups, the same population, the same result: no significant improvement in functional performance measures ^6,8. This is the rare case in this roadmap where a compound has been properly tested and the answer is known.
2. One trial was stopped for harm. Termination for a congestive heart failure safety signal, with the authors describing an unfavourable safety profile ⁸, is a materially different finding from a trial that simply missed its endpoint.
3. The population may not generalise, in both directions. Elderly patients recovering from hip fracture are frail, medically complex and at baseline cardiac risk. A cardiac signal there may not transfer to younger users — and neither may the absence of functional benefit. No trial has tested younger or healthier populations.
4. The mechanism of the cardiac signal is unknown. The trial report does not attribute it and no subsequent work characterises it ⁸. An uncharacterised signal cannot be designed around.
5. Human safety data outside trials is case reports. A hepatotoxicity report ¹⁵ and a multi-ingredient gynaecomastia report ¹⁴ are hypothesis-generating. Two of the three published case reports involve concurrent use of other agents, which prevents attribution.
6. Long-term data do not exist. The longest controlled exposure reported here is 24 weeks ⁸. Nothing addresses use over years, which is how the compound is discussed outside clinical research.
7. The positive metabolic result stands alone. Improved nitrogen balance in short-term dietary restriction ² is a real finding on a real endpoint, and it did not predict function in either trial that measured function.

09 · References

1. Ghigo E, Arvat E, Muccioli G, Camanni F. Growth hormone-releasing peptides. Eur J Endocrinol. 1997;136(5):445–460.

   PMID 9186261 ↗

2. Murphy MG, Plunkett LM, Gertz BJ, et al. MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. J Clin Endocrinol Metab. 1998;83(2):320–325.

   PMID 9467534 ↗

3. Camanni F, Ghigo E, Arvat E. Growth hormone-releasing peptides and their analogs. Front Neuroendocrinol. 1998;19(1):47–72.

   PMID 9465289 ↗

4. Prahalada S, Block G, Handt L, et al. Insulin-like growth factor-1 and growth hormone (GH) levels in canine cerebrospinal fluid are unaffected by GH or GH secretagogue (MK-0677) administration. Horm Metab Res. 1999;31(2–3):133–137.

   PMID 10226793 ↗

5. Smith RG. The aging process: where are the drug opportunities? Curr Opin Chem Biol. 2000;4(4):371–376.

   PMID 10959763 ↗

6. Bach MA, Rockwood K, Zetterberg C, et al. The effects of MK-0677, an oral growth hormone secretagogue, in patients with hip fracture. J Am Geriatr Soc. 2004;52(4):516–523.

   PMID 15066065 ↗

7. Smith RG. Development of growth hormone secretagogues. Endocr Rev. 2005;26(3):346–360.

   PMID 15814848 ↗

8. Adunsky A, Chandler J, Heyden N, 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;53(2):183–189.

   PMID 21067829 ↗

9. Sigalos JT, Pastuszak AW. The safety and efficacy of growth hormone secretagogues. Sex Med Rev. 2018;6(1):45–53.

   PMID 28400207 ↗

10. Sinha DK, Balasubramanian A, Tatem AJ, et al. Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Transl Androl Urol. 2020;9(Suppl 2):S149–S159.

    PMID 32257855 ↗

11. Philip M, Karakka Kal AK, Subhahar MB, Karatt TK, Mathew B, Koshy SA. Characterization of growth hormone secretagogue small molecule ibutamoren (MK-0677) and its possible metabolites in thoroughbred horses for doping control. Rapid Commun Mass Spectrom. 2022;36(18):e9337.

    PMID 35716382 ↗

12. Cardaci TD, Machek SB, Wilburn DT, et al. LGD-4033 and MK-677 use impacts body composition, circulating biomarkers, and skeletal muscle androgenic hormone and receptor content: a case report. Exp Physiol. 2022;107(12):1467–1476.

    PMID 36303408 ↗

13. Viljanto M, Cutler C, Taylor P, Habershon-Butcher J, Gray B. Detection of the growth hormone secretagogue MK-0677 in equine hair following oral administration. Drug Test Anal. 2023;15(3):361–367.

    PMID 36354265 ↗

14. Chong S, Woolnough CA, Koyyalamudi SR, Perera NJ. Reversible gynecomastia and hypogonadism due to usage of commercial performance-enhancing supplement use. JCEM Case Rep. 2024;2(8):luae148.

    PMID 39145153 ↗

15. Cobani E, Amin MS, Hasso M, Kumbar L. Hepatotoxicity induced by MK-677. BMJ Case Rep. 2025;18(7):e265728.

    PMID 40675653 ↗

16. Kintz P, Gheddar L. Knowing the minimal detectable dose can facilitate the interpretation of a hair test result: II. Case example with ibutamoren (MK-677), a growth hormone secretagogue. Clin Chim Acta. 2026;578:120578.

    PMID 40882886 ↗

17. Mendias CL, Awan TM. Safety and efficacy of approved and unapproved peptide therapies for musculoskeletal injuries and athletic performance. Sports Med. 2026;56(8):1921–1935.

    PMID 41966639 ↗

18. Tewari K, Liu TP, Im C, et al. Peptide supplements and their therapeutic applications in sports medicine. Am J Sports Med. 2026; online ahead of print.

    PMID 42578445 ↗

19. Coutinho LFD, de Oliveira Neves LF, Camilo RP. A new era of doping? Use of peptide and peptide-analog drugs in recreational and professional sport and bodybuilding: a critical review. J Sports Med Phys Fitness. 2026;66(7):880–885.

    PMID 41880199 ↗

20. Rahman OF, Lee SJ, Seeds WA. Therapeutic peptides in orthopaedics: applications, challenges, and future directions. J Am Acad Orthop Surg Glob Res Rev. 2026;10(1):e25.00236.

    PMID 41490200 ↗

21. Dominikowski A, Rękoś Z, Olejarz M, Szczepanek-Parulska E, Domin R, Ruchała M. The emerging landscape of performance-enhancing peptides modulating the GH-IGF1 axis: bridging the gap between clinical evidence and patient self-administration. Front Endocrinol (Lausanne). 2026;17:1822475.

    PMID 42395176 ↗

22. US Food and Drug Administration. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks. Page current as of 22 April 2026. Regulatory document; no PMID.

    Source ↗

23. US Food and Drug Administration. July 23–24, 2026: Meeting of the Pharmacy Compounding Advisory Committee. Docket FDA-2025-N-6895. Regulatory document; no PMID.

    Source ↗