Hexarelin

What hexarelin is

Hexarelin belongs to the GHRP family, the growth hormone-releasing peptides. These also include GHRP-2, GHRP-6 and ipamorelin. All of them dock at the same receptor, the ghrelin receptor in the pituitary gland, and give the same signal there: release growth hormone.

In terms of release, hexarelin is the most potent of them. In a study in 12 healthy young adults, it released about twice as much growth hormone as the body’s own regulating hormone GHRH alone. That is remarkable, and it is the reason for the reputation the substance has in the scene. It is, however, 12 participants, and that is typical of this field: the studies are old, small and mostly examine single doses; the longest ran for 16 weeks.

The first problem: hexarelin is not selective

Acutely, it is not only growth hormone that rises. In a study in 6 young adults, ACTH and cortisol also increased, to an extent similar to that after the body’s own regulating hormone of the stress axis, along with prolactin. Under 16 weeks of continuous administration, by contrast, the cortisol, ACTH and prolactin responses remained unchanged. The effect is clear in the short term and not detectable with continuous use.

The reason lies in the receptor itself. It is not only part of growth hormone regulation but belongs to a system closely intertwined with hunger, stress and energy balance. Newer members of this class such as ipamorelin do not raise ACTH and cortisol along with it in the animal model. There is something ironic about the same people who take ashwagandha to lower cortisol injecting a peptide that raises it in the short term.

The second problem: the effect wears off

This is the better documented part and the more important one. In 12 healthy older people, the growth hormone response under continuous use fell to around 55 % of the baseline value after 16 weeks, and most of the loss occurred in the first week. In children with short stature using a nasal spray, the response had halved after seven days.

The technical term for this is tachyphylaxis. The body downregulates the receptor because it is constantly being shouted at. That is not an opinion but a measured curve. Sensitivity returns, about 4 weeks after stopping, and that is the reason breaks are used in the scene. This does not change the basic question: a substance whose effect declines by almost half under continuous administration is a poor candidate for anything long-term. In the same study, IGF-I, fat mass, lean mass and bone density remained unchanged over 16 weeks.

The heart story

Scientifically, the most interesting aspect is a second pathway. Hexarelin binds not only to the ghrelin receptor but also to CD36, a receptor on heart muscle cells. Via this pathway it shows cardioprotective effects in animal experiments that are independent of growth hormone. That is a serious line of research.

These studies, however, are animal experiments in mice and rats. In humans there are small studies with a single dose: in 7 men with growth hormone deficiency, the ejection fraction rose even without an increase in growth hormone; in 24 men during bypass surgery, it rose from 10 to 90 minutes after administration, unlike under growth hormone, GHRH or placebo. In an enlarged heart chamber (dilated cardiomyopathy), nothing happened. Short-term measurements after a single dose are no basis for something one injects at home. This line of research belongs in the laboratory, not in the bathroom cabinet.

What the studies show

First studies in 12 and 6 healthy young adults

In 12 healthy young adults, hexarelin released about twice as much growth hormone as the body’s own regulating hormone GHRH alone (Ghigo 1994). In a second study in 6 participants, ACTH and cortisol also rose, to an extent similar to that after the body’s own regulating hormone of the stress axis, along with prolactin (Arvat 1997). The informative value is limited by small groups and single doses.

Desensitization under continuous use

In 12 healthy older people, the growth hormone response under 16 weeks of continuous administration fell to around 55 % of the baseline value; most of the loss occurred in the first week. Four weeks after stopping, the baseline value had been reached again. IGF-I, fat and lean mass and bone density remained unchanged (Rahim 1998). The cortisol, ACTH and prolactin responses did not change over the 16 weeks (Rahim 1999).

Cardiac effect via CD36 in animal experiments and a study in humans

In mice and rats, hexarelin shows cardioprotective effects via the receptor CD36 that are independent of growth hormone. In humans, the ejection fraction rose after a single dose in growth hormone deficiency (Bisi 1999) and during bypass surgery in coronary heart disease (Broglio 2002), but not in dilated cardiomyopathy (Imazio 2002).

Where the data stop

The longest study ran for 16 weeks in 12 healthy older people and found no change in IGF-I, body composition or bone density. Otherwise, the human data come from small, old studies on single doses; no study is registered in the US trial registry. There are no data beyond 16 weeks.

Status, approval and legal

Hexarelin is not approved as a medicine anywhere. Development was not pursued further, and the substance is available only on the gray market, without pharmacopoeia quality and without a manufacturer who is liable. In sports, hexarelin (examorelin) is prohibited at all times under the WADA list.

Safety

The most important known effects result from the lack of selectivity. Hexarelin acutely raises ACTH and cortisol, to an extent similar to the body’s own regulating hormone of the stress axis, and additionally prolactin; under 16 weeks of continuous administration, by contrast, these values were not changed. Nighttime administration reduced deep sleep in 7 healthy young men and increased growth hormone, prolactin, ACTH and cortisol during sleep; the body’s own ghrelin has the opposite effect on deep sleep. There are no safety data beyond 16 weeks. And as with all substances in this class: even if growth hormone rises, it is open whether any benefit results from it.

Sources

• Ghigo et al., J Clin Endocrinol Metab 1994 (hexarelin in 12 healthy young adults, comparison with GHRH)
• Arvat et al., Peptides 1997 (hexarelin in 6 healthy young adults, growth hormone, ACTH, cortisol and prolactin)
• Rahim and Shalet, Growth Horm IGF Res 1998 (desensitization of the growth hormone response under continuous hexarelin administration)
• Rahim et al., J Clin Endocrinol Metab 1998 (16 weeks of hexarelin: GH response, IGF-I, body composition)
• Rahim et al., Clin Endocrinol 1999 (16 weeks of hexarelin: cortisol, ACTH and prolactin)
• Klinger et al., Eur J Endocrinol 1996 (intranasal hexarelin in children with short stature)
• Bisi et al., Eur J Pharmacol 1999 (cardiac effect in growth hormone deficiency)
• Bodart et al., Circ Res 2002 (hexarelin and CD36, cardiac effects in the animal model)
• Broglio et al., Eur J Pharmacol 2002 (single hexarelin dose during bypass surgery in coronary heart disease)
• Imazio et al., Eur J Heart Fail 2002 (hexarelin in dilated and ischemic cardiomyopathy)
• Frieboes et al., Psychoneuroendocrinology 2004 (hexarelin and deep sleep)
• Raun et al., Eur J Endocrinol 1998 (ipamorelin without ACTH and cortisol increase in the animal model)