Ibutamoren: adverse effects and safety signals

Ibutamoren is often presented as a "soft" alternative to growth hormone, with almost no side effects. Clinical studies paint a different picture: undesirable phenomena exist, they are natural and follow directly from the mechanism of action. The editors have systematized the documented side effects and explained where they come from.

Why does ibutamoren have side effects

Ibutamoren activates the ghrelin receptor GHSR-1a. This receptor is located not only in the pituitary gland, where it triggers the secretion of growth hormone, but also in the hypothalamic appetite centers and other areas of the brain. Therefore, the effects of the substance are never limited to a "pure" increase in growth hormone.

The second source of unwanted phenomena is the growth hormone itself and IGF-1. Somatotropin excess is well studied on the example of acromegaly and recombinant hormone therapy: sodium and water retention, edema, joint pain, carpal tunnel syndrome, and impaired glucose tolerance. A secretagogue that increases growth hormone is logically capable of reproducing some of these effects.

The third source is product quality. Data from clinical studies refer to a pharmaceutical substance. Products marketed as "research chemicals" may contain different doses or impurities, and their side effect profile is unpredictable.

Finally, it is important to understand the limitations of the evidence. The longer studies discussed here covered a few dozen or hundreds of people for one or two years. Rare and delayed complications may go undetected in such settings, so absence of data does not mean absence of risk.

Appetite, weight and fluid retention

The most noticeable and frequent effect is increased appetite. This is a direct consequence of ghrelinomimetic action: ibutamoren mimics the "hunger hormone". In a two-year study by Nass et al (2008), increased appetite was one of the most common adverse events, and participants' body weight increased.

For people of normal weight or those trying to lose weight, this is a serious problem. Increased hunger makes it difficult to control caloric intake, and weight gain can include both fat and water. In a study of obese humans (Svensson et al., 1998), total fat mass did not decrease significantly despite an increase in energy expenditure.

The second typical effect is fluid retention and swelling, particularly of the legs. The mechanism is related to the effect of growth hormone on the kidneys: sodium reabsorption increases, followed by water. That is why part of the increase in "fat-free mass" in studies can be made up of water.

Fluid retention is also associated with pain and stiffness in muscles and joints, and in some people, tingling or numbness in the hands. Myalgia and arthralgia were reported in clinical trials, although mostly mild to moderate.

• Increased appetite and weight gain.
• Edema of the lower extremities.
• Pain in muscles and joints.
• Paresthesias and symptoms similar to carpal tunnel syndrome (characteristic of growth hormone excess).

Carbohydrate metabolism and insulin resistance

Growth hormone is a counterinsular hormone: it counteracts the action of insulin, enhances lipolysis and the release of glucose by the liver. Therefore, an increase in growth hormone inevitably affects carbohydrate metabolism.

In a study by Nass et al. (2008), ibutamoren increased fasting glucose and decreased insulin sensitivity. Even in early works (Chapman et al., 1996), a small increase in glucose was recorded. For a young, healthy person, these changes may not be noticeable, but for people with prediabetes, obesity, or a family history of type 2 diabetes, they are clinically significant.

Insulin resistance is also important because it can accumulate over time. Short studies do not provide an answer as to how the carbohydrate metabolism behaves after several years of continuous intake, and this is the scenario that often occurs in uncontrolled use.

Practical conclusion: People already taking ibutamoren against recommendations should at least understand that fasting glucose and glycated hemoglobin (HbA1c) are key markers of control and discuss the results with their doctor.

Heart, hormones and other systems

The strongest safety signal comes from a study in elderly patients after hip fracture (Adunsky et al., 2011). The trial was stopped early due to higher incidence of congestive heart failure in the ibutamoren group. The likely mechanism is fluid retention, which increases the workload on the heart in people with reduced cardiac reserve.

Ibutamoren, like other ghrelin receptor agonists, may increase cortisol and prolactin levels. In early studies, this increase was modest and declined over time. However, for people with pre-existing disorders of these hormones, such an effect is not neutral.

A separate issue is the theoretical risks of a long-term increase in IGF-1. Epidemiological studies have linked high IGF-1 to certain types of cancer, and IGF-1 stimulates cell proliferation. There is no direct evidence that ibutamoren increases cancer risk, but there is also no long-term data to rule it out.

Less specific effects in studies and user reports include drowsiness or lethargy, especially at the beginning of treatment, and mood changes. These effects are poorly documented in controlled settings, so the editors state them with caution.

Who is at high risk

People with diabetes, prediabetes or severe obesity should be especially careful. For them, increased glucose and insulin resistance can accelerate the progression of the disease.

People with heart disease, hypertension, or a tendency to edema are at greater risk due to fluid retention. A signal about heart failure in elderly patients should be taken seriously.

A separate group consists of people with a history of oncological diseases or with an increased oncological risk: stimulation of the growth hormone and IGF-1 axis is undesirable for them. Children and adolescents, as well as pregnant and lactating women, should not use unregistered substances that affect the hormonal system.

For athletes who pass doping control, a separate "side effect" is disqualification: Ibutamoren is prohibited by WADA at any time.

Editorial conclusions

Side effects of ibutamoren are not a coincidence, but a direct consequence of its mechanism: activation of the ghrelin receptor and increase in growth hormone.

The best documented effects are increased appetite, fluid retention, muscle pain, and impaired carbohydrate metabolism. The most serious signal is congestive heart failure in vulnerable patients.

There is no long-term safety data, and the quality of products from the market is not guaranteed, so the real risks may be higher than in clinical studies.

For a deeper understanding of the topic, the editors offer materials on the effect of ibutamoren on the lipid profile and the heart, on liver data and whether it suppresses testosterone production.

References

1. Nass R, Pezzoli SS, Oliveri MC, et al. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Ann Intern Med. 2008;149(9):601–611.
2. Chapman IM, Bach MA, Van Cauter E, et al. Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects. J Clin Endocrinol Metab. 1996;81(12):4249–4257.
3. Svensson J, Lönn L, Jansson JO, 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;83(2):362–369.
4. 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.
5. Sevigny JJ, Ryan JM, van Dyck CH, et al. Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial. Neurology. 2008;71(21):1702–1708.
6. Melmed S. Acromegaly. N Engl J Med. 2006;355(24):2558–2573.