Many scientific works have been published about hexarelin, but their nature is often distorted in advertising. Most human studies have been short physiological experiments, and the most impressive effects have been obtained in animals. The editors systematized what exactly was studied, what results were obtained and why these data cannot be directly transferred to sports practice.
Chronology of scientific interest
Research on hexarelin began shortly after its synthesis in the early 1990s. The first wave of work was purely endocrinological: scientists found out how strongly the peptide increases growth hormone, which routes of administration work and how the response depends on the age and condition of the patient.
After the discovery of the growth hormone secretagogue receptor in 1996 and ghrelin in 1999, hexarelin became a convenient tool to study this system. It was used as a "probe" to find out where receptors are located and how they respond to stimulation.
In the late 1990s and early 2000s, the focus shifted to the heart. It turned out that hexarelin binds to the CD36 receptor, and in animals it has cardioprotective effects unrelated to growth hormone. It is this line of research that is most often cited today.
It is noticeable that after the mid-2000s, the number of clinical works with hexarelin decreased sharply. Pharmaceutical interest has shifted to more selective and orally active ghrelin receptor agonists, particularly anamorelin and macimorelin.
Endocrine studies on humans
The basic work was published by Guigott's group in 1994 in the Journal of Clinical Endocrinology and Metabolism. Hexarelin was administered intravenously, subcutaneously, intranasally and orally to healthy volunteers. The peptide caused a pronounced dose-dependent release of growth hormone at all routes of administration, but at intranasal and especially oral administration, the efficiency was significantly lower.
In further work by this and other groups, it was shown that hexarelin acts synergistically with GHRH and also moderately increases prolactin, ACTH and cortisol. The growth hormone response was significantly weaker in the elderly than in the young, which is explained by age-related changes in hypothalamic regulation.
Children with short stature were also studied. In the works of Laron and co-authors, hexarelin was applied intranasally, and an acceleration of the growth rate was observed in some children. However, these studies were small and short, and the drug did not become an alternative to growth hormone therapy.
| Direction | Who participated | Main finding | Limitations |
|---|---|---|---|
| Routes of administration | Healthy adults | Pronounced GH release; oral efficacy is low | Single injection |
| Synergy with GHRH | Healthy adults | The total effect is greater than each one individually | Short physiological tests |
| Influence of age | Young and elderly people | In the elderly, the response is weaker | Small groups |
| Children with short stature | Children | Growth acceleration in some participants | Small uncontrolled studies |
| Other hormones | Healthy adults | Moderate increase in prolactin, ACTH, cortisol | Short observation period |
Important: None of these studies examined the effects of hexarelin on muscle mass, strength, or athletic performance in healthy subjects. The indicator that was recorded was the level of hormones in the blood, not body composition or physical performance.
Long-term administration and tachyphylaxis
One of the most informative studies was conducted by Rahim, O'Neill, and Challet (1998). They studied how the growth hormone response changes during long-term, regular use of hexarelin in adults over several months.
The result was revealing: over time, the release of growth hormone in response to hexarelin decreased, that is, partial tachyphylaxis developed. After stopping the administration, the response was gradually restored. The authors concluded that long-term stimulation does not provide a consistently high level of growth hormone.
This fact significantly reduces the practical appeal of hexarelin for long-term use. If the effect wears off, maintaining it requires either increasing the intensity of the stimulation or taking breaks—none of these strategies have been clinically tested for safety.
It should also be remembered that in long-term studies the hormonal response was primarily evaluated. There are no systematic data on the effect of months or years of use on glucose metabolism, the cardiovascular system, or the risk of neoplasms.
The heart: from animals to humans
The most cited block of research on hexarelin concerns the heart. Locatelli et al. (1999) administered hexarelin to hypophysis-deprived rats, and it protected the heart from ischaemia and reperfusion injury. This indicated a direct, growth hormone-independent effect of the peptide on the heart.
Tivesten et al. (2000) showed that hexarelin improved heart function in rats after experimental myocardial infarction. And Bodart et al. (2002) identified a mechanism: the CD36 receptor in heart tissue, through which releasing peptides affect coronary blood flow and myocardial function.
- Experiments on animals: cardioprotection during ischaemia, improvement of function after infarction, influence on myocardial remodeling.
- Human studies: A single administration increased left ventricular ejection fraction in healthy volunteers (Bisi et al., 1999) and in patients with severe left ventricular dysfunction (Imazio et al., 2002).
- What is missing: long-term controlled clinical trials evaluating mortality, hospitalizations, or quality of life.
Thus, the cardiac data of hexarelin are a classic example of a "promising mechanism" without clinical confirmation. An acute effect on the contractility of the heart does not mean that long-term use will bring benefits, because in cardiology there are many drugs that improved the indicators, but worsened the prognosis.
How to read this data critically
The first rule is to distinguish between animal and human studies. Rats and mice have different physiology, different metabolism, and often receive doses that cannot be correctly transferred to humans. A positive result in animals is a reason for further research, not proof of effectiveness.
The second rule is to distinguish between surrogate and clinical endpoints. Growth hormone level or ejection fraction are surrogate indicators. Clinically significant consequences are life expectancy, frequency of complications, and functional status. For hexarelin, the vast majority of data refer specifically to surrogate indicators.
The third rule is to pay attention to the size and duration of studies. Human studies of hexarelin mostly involved small groups of participants and lasted from a single injection to several months. Rare or delayed side effects cannot be detected under such conditions.
Finally, the study was performed with a pharmaceutically pure peptide under controlled conditions. The product marketed today as "research hexarelin" has nothing to do with these conditions, so even the positive data available do not apply to it.
Editorial conclusions
Human studies have convincingly shown that hexarelin is a powerful stimulator of growth hormone release, acts synergistically with GHRH and is accompanied by an increase in prolactin, ACTH and cortisol.
Long-term use was accompanied by tachyphylaxis, and there are no data on the effect on muscle mass, strength and sports performance in healthy people.
The most impressive cardioprotective effects were obtained in animal experiments; in humans, they are limited to acute changes in cardiac function without long-term clinical evidence.
We also recommend reading our materials on the side effects of hexarelin, the long-term risks of the peptide and the review of tesamorelin as the only registered analogue of RH-RH.
List of used literature
- Ghigo E, Arvat E, Gianotti L, et al. Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man. J Clin Endocrinol Metab. 1994;78(3):693â698.
- Rahim A, O'Neill PA, Shalet SM. Growth hormone status during long-term hexarelin therapy. J Clin Endocrinol Metab. 1998;83(5):1644â1649.
- Locatelli V, Rossoni G, Schweiger F, et al. Growth hormone-independent cardioprotective effects of hexarelin in the rat. Endocrinology. 1999;140(9):4024â4031.
- Tivesten A, Bollano E, Caidahl K, et al. The growth hormone secretagogue hexarelin improves cardiac function in rats after experimental myocardial infarction. Endocrinology. 2000;141(1):60â66.
- Bodart V, Febbraio M, Demers A, et al. CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart. Circ Res. 2002;90(8):844â849.
- Bisi G, Podio V, Valetto MR, et al. Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH-releasing peptide, in humans. J Endocrinol Invest. 1999;22(4):266â272.
- Ghigo E, Arvat E, Muccioli G, Camanni F. Growth hormone-releasing peptides. Eur J Endocrinol. 1997;136(5):445â460.
- Mao Y, Tokudome T, Kishimoto I. The cardiovascular action of hexarelin. J Geriatr Cardiol. 2014;11(3):253â258.
