The History of Ibutamoren (MK-677)
The original development of Ibutamoren was part of a broader effort by the pharmaceutical industry to find compounds capable of stimulating growth hormone (GH) secretion in a safe and effective manner. Unlike direct administration of exogenous GH, which can be costly and have side effects, growth hormone secretagogues (GHS) seek to boost the body's natural production.
Early 1990s: Research focused on non-peptide molecules that could be administered orally and act on the growth hormone secretagogue receptor (GHS-R), also known as the ghrelin receptor. Ghrelin, a peptide hormone discovered in 1999, is the natural endogenous ligand of this receptor and plays a crucial role in the regulation of appetite and GH release. However, the GHS-R receptor was already known before the discovery of ghrelin, and synthetic compounds interacting with it were being developed.
Merck & Co. and the Development of MK-677: Ibutamoren (MK-677) was developed by Merck & Co. in the mid-1990s. The first studies and patents describing the compound and its effects date from this time.
Name and Original Patent: "Ibutamoren" is the International Nonproprietary Name (INN), while "MK-677" was Merck's internal development code. The fundamental patents covering the chemical compound MK-677 were filed by Merck & Co. in this period. Given the standard patent lifespan (approximately 20 years from application), it is very likely that these original patents on the molecule itself have now expired.
Merck's main objective was to create an oral treatment for conditions associated with growth hormone deficiency, such as in children with short stature or in older adults with frailty and loss of muscle mass (sarcopenia).
Early Publications: Research published from 1995 and 1996 began to detail the pharmacology of MK-677, demonstrating its ability to stimulate GH release and consequently increase levels of IGF-1 (Insulin Growth Factor type 1), a key mediator of GH effects.
Mechanism of Action: Mimicking ghrelin.
MK-677 is a selective and potent agonist of the growth hormone secretagogue receptor (GHS-R1a). It acts as a ghrelin mimetic, binding to this receptor in the pituitary gland and hypothalamus. This binding triggers a signaling cascade that results in increased release of growth hormone pulses.
Unlike other secretagogues that can affect cortisol levels (such as some GH-releasing peptides or GHRH), MK-677 demonstrated in initial studies a remarkable selectivity, stimulating GH with minimal or no impact on other pituitary hormones such as cortisol, prolactin or thyroid hormone.
Clinical Trials: Exploring Therapeutic Potential
Once its preclinical efficacy was demonstrated, MK-677 advanced to human clinical trials for various indications:
Growth Hormone Deficiency in Children: This was investigated as an oral alternative to GH injections. Although it showed increases in GH and IGF-1, its development for this indication did not progress to final approval.
Frailty and Sarcopenia in Older Adults: This was one of the areas of greatest interest. Several studies evaluated the effect of MK-677 on body composition, muscle strength and bone mineral density in older people.
Promising Results: Increases in lean mass and improvements in some markers of physical function and bone density were observed. For example, a study published in the Journal of Clinical Endocrinology & Metabolism in 1998 (Smith et al.) showed that MK-677 reversed the diet-related decrease in GH secretion and IGF-1 levels. Another study in obese men (Murphy et al., 1998) also showed significant increases in GH and IGF-1 and changes in body composition.
Hip Fracture Study: A major multicenter study investigated MK-677 in older patients recovering from hip fracture. The objective was to see if increased GH and IGF-1 could improve functional recovery and bone density. While increases in lean mass and a trend toward improved gait were observed, the study was prematurely terminated in 2008, in part due to concerns about an increased incidence of congestive heart failure in a subgroup of patients, although direct causality was not conclusively established and remains a point of debate. This event marked a turning point in the clinical development of MK-677 for this population.
Catabolism and Muscle Wasting: Its use was explored in conditions of catabolism, such as in patients on calorie-restricted diets or in those with chronic diseases that cause loss of muscle mass.
Sleep Disorders: Since GH is primarily released during deep sleep, and MK-677 can improve sleep quality (particularly REM and slow wave sleep), its potential in this setting was investigated.
Side Effects and Concerns
Throughout the studies, several side effects associated with MK-677 were identified, many of which are consistent with elevated growth hormone levels:
Increased appetite (due to its ghrelin-like action).
Mild fluid retention (peripheral edema).
Muscle and joint pain.
Lethargy or drowsiness.
Increased blood glucose levels and decreased insulin sensitivity, especially in predisposed individuals or with higher doses and prolonged use. This is a significant concern, as it could increase the risk of type 2 diabetes.
Changing Course: From Pharmaceutical Development to the Gray Market
Despite promising results in certain areas, formal clinical development of MK-677 by Merck and other pharmaceutical companies for specific indications slowed or stopped. During its development, trade names such as"Oratrope" (possibly by Merck) and"Crescendo" were considered. However, since MK-677 never received approval from regulatory agencies such as the FDA (U.S. Food and Drug Administration) or the EMA (European Medicines Agency) for any medical indication, neither of these names was established as an active and recognized trademark for an approved pharmaceutical product legally approved pharmaceutical product.
The reasons for the disruption of formal development are multifactorial, including:
Study completion in patients with hip fracture.
Concerns about long-term effects, especially in relation to insulin sensitivity.
The high cost and complexity of bringing a new drug to market, especially for conditions such as frailty in the elderly.
As a result, MK-677 was never officially marketed as a drug. However, information about its anabolic and body composition-enhancing effects, coupled with its oral availability, made it attractive to communities outside the medical field:
Bodybuilding and Performance Enhancement: Beginning in the 2000s and more intensely in the 2010s, MK-677 began to gain popularity in the bodybuilding world and among athletes looking to increase muscle mass, improve recovery and reduce body fat. It is often marketed as a SARM (Selective Androgen Receptor Modulator), although technically it is not, as it does not act on androgen receptors.
Anti-aging: The idea that increasing GH levels could reverse some aspects of aging also attracted users in this field.
This demand led to the proliferation of companies selling MK-677 as "research chemical" or "not for human consumption," operating in a regulatory gray zone. The quality and purity of these products can vary significantly, adding additional risk to consumers.
Regulatory Status and Current Controversy (Until 2024-2025)
Not Approved for Medical Use: Ibutamoren (MK-677) is not approved as a drug in any country. The terms "Ibutamoren" and "MK-677" are today commonly used in the unregulated research and supplement market, without corresponding to an approved drug trade name.
Banned by the World Anti-Doping Agency (WADA): WADA includes MK-677 on its list of substances banned at all times for athletes, within the S2 category (Peptide Hormones, Growth Factors, Related Substances and Mimetics). This is due to its performance enhancing potential and its anabolic effects.
Sale as a "Research Chemical": Despite its ban in sport and lack of medical approval, MK-677 is still widely available for purchase online, often with disclaimers stating that it is for research purposes only.
Future Perspectives and Patents in Development
While formal pharmaceutical development of MK-677 by Merck for the original indications appears to have stalled and its original patents on the compound have likely expired, research on growth hormone secretagogues and ghrelin receptor modulators continues.
Companies such as Lumos Pharma are currently investigating ibutamoren (under its LUM-201 designation) for specific indications, such as pediatric growth hormone deficiency. These entities may hold newer patents or be in the process of obtaining them for specific therapeutic uses, particular formulations or methods of manufacturing ibutamoren. These secondary patents would protect these new applications or formulations, even if the original patent on the base compound has expired.
It is possible that future research may identify specific subpopulations that could benefit from compounds such as MK-677 under medical supervision, or that new analogs with improved safety and efficacy profiles may be developed.
Today, however, the Ibutamoren story is a clear example of how a promising compound in the laboratory can follow a complex trajectory, where its non-medical use and regulatory controversies largely overshadow its original therapeutic potential. The MK-677 narrative underscores the importance of rigorous research, regulatory oversight, and public education about the risks and benefits of substances that alter human physiology.