Ipamorelin and GHRP-6: mechanisms and adverse effects

When they say "softer than GHRP-6" about ipamorelin, they mean not the strength of action, but its selectivity. What exactly is behind this concept at the level of receptors and hormones, which side effects are common to both peptides, and which are different, we analyze in this material.

Ghrelin receptor and "biased" agonism

Both ipamorelin and GHRP-6 bind to the GHS-R1a receptor, the ghrelin receptor. This receptor belongs to a large family of receptors associated with G-proteins and is characterized by high intrinsic (constitutive) activity: even without a ligand, it is partially "on". This feature makes it very sensitive to subtle differences between ligands.

Modern pharmacology knows the phenomenon of "biased agonism": different substances, binding to one receptor, may prefer different intracellular pathways. One molecule more strongly activates, say, the Gq-pathway, another - the pathway through beta-arrestin. For the ghrelin receptor, this phenomenon is under active study and may partially explain why ligands have different profiles of effects.

Another explanation for the differences is tissue distribution. GHS-R1a is found in the pituitary gland, hypothalamus, and brainstem, as well as in the adrenal glands, heart, and pancreas. Peptides with different physicochemical properties reach these targets in different ways, and therefore, the effect on them varies.

It is worth noting that the exact molecular mechanism why ipamorelin does not stimulate the stress axis, while GHRP-6 does, has not yet been fully described. The fact itself was recorded in experiments (Raun et al., 1998), but there is no definitive mechanistic explanation in the literature.

Effect on growth hormone secretion

Regarding the main effect — growth hormone (GH) release — both peptides are similar. In the pigs of Raun et al., ipamorelin stimulated GH with a potency and efficacy close to that of GHRP-6. Like other ghrelin receptor agonists, both act simultaneously on the pituitary gland and hypothalamus, increasing the release of GH-releasing hormone (GHRH) and decreasing the effect of somatostatin.

The GH response to both peptides is pulsed: after administration, the GH level rises rapidly, reaches a peak, and returns to baseline within a few hours. A pharmacokinetic study of ipamorelin in volunteers (Gobburu et al., 1999) described just such a short peak of GH after infusion, with a half-life of the peptide of about two hours.

Since the release of GH is short, the effect of a single injection on the level of IGF-1 is minimal. A significant increase in IGF-1 is possible only with regular repetition, and it is then that the effects characteristic of chronically elevated GH come to the fore.

So, from the point of view of the "target" effect, Ipamorelin is not weaker than GHRP-6. The difference lies not in how much GH is released, but in what else happens in the body at the same time.

Adrenal glands, prolactin and appetite

GHRP-6, like GHRP-2 and hexarelin, increases the level of adrenocorticotropic hormone (ACTH), and therefore cortisol. It also increases prolactin. In humans, these elevations are usually moderate and short-lived, but with frequent repetition, they mean regular stress on the hypothalamus-pituitary-adrenal axis.

In a study by Raun et al. (1998), ipamorelin in pigs did not increase ACTH and cortisol even at doses many times higher than those effective for GH. The authors emphasized that this selectivity is comparable to the selectivity of the GH releasing hormone itself. It was this result that made ipamorelin famous.

Appetite is a separate topic. Stimulating hunger through hypothalamic neurons is one of the strongest effects of GHRP-6. For ipamorelin, this effect is much weaker, although it is not completely absent: in experiments on animals, a certain increase in body weight was described, and in humans, the reaction is individual.

Metabolic and other side effects

The common "Achilles heel" of both peptides is the effect on glucose metabolism. Growth hormone reduces the sensitivity of tissues to insulin, therefore, with a regular increase in GH, the fasting glucose level may increase. For ghrelin receptor agonists, this was convincingly shown in a two-year study of ibutamoren (Nass et al., 2008). There are no direct long-term data for ipamorelin and GHRP-6, but the mechanism is the same.

In addition, the ghrelin receptor is present in pancreatic beta cells, and its activation can inhibit insulin secretion. This effect has been described for ghrelin itself; to what extent it is expressed for each of the peptides is not known for sure.

Other described or expected adverse effects of both peptides:

• feeling of warmth, redness of the face, dizziness shortly after administration;
• fluid retention, pastiness, joint pain with frequent use;
• headache, drowsiness;
• local reactions at the injection site, and with a non-sterile product — the risk of infection;
• for GHRP-6 — pronounced hunger, for ipamorelin — this effect is smaller.

In a phase II study in postoperative ileus (Beck et al., 2014), short-course ipamorelin was well tolerated and the incidence of adverse events did not differ significantly from placebo. However, these were patients in a hospital, a short period and a certified drug — circumstances not comparable to independent use.

How to assess risks realistically

The editors suggest looking at risks in three planes. The first is pharmacological: which systems are affected by the molecule. Here, ipamorelin really has an advantage in preclinical data. The second is duration: the effects of chronic elevation of GH are common to both and are poorly studied. The third is product quality, which is unpredictable in the informal market.

People with diabetes or pre-diabetes, with a history of cancer, with hormonal disorders, pregnant women and teenagers belong to the groups for whom any stimulation of the GH/IGF-1 axis without medical control is particularly undesirable.

It is also important to remember that both substances are banned by WADA (Section S2). For athletes subject to testing, the "selectivity" of ipamorelin is irrelevant: it is also a violation of anti-doping rules.

Finally, in 2023, the FDA added ipamorelin to its list of substances of concern for pharmaceutical safety. This suggests that regulators do not consider the available data sufficient for routine use.

Editorial conclusions

Ipamorelin and GHRP-6 stimulate the release of growth hormone approximately equally effectively by acting on the same ghrelin receptor.

The difference is selectivity: according to preclinical data, Ipamorelin has almost no effect on cortisol and prolactin and significantly less stimulation of appetite, while GHRP-6 affects all these systems.

At the same time, side effects associated with the increase in GH itself — worsening of glucose metabolism, fluid retention, joint pain — are characteristic of both peptides, and long-term safety data are lacking for both.

To complete the picture, we recommend our materials "Ipamorelin vs. GHRP-6: What's the Difference", "GHRP-2 vs GHRP-6: Comparison of Mechanism of Action and Side Effects" and "CJC-1295 with or without DAC: What's the Difference".

List of used literature

1. Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998;139(5):552–561.
2. Gobburu JV, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharm Res. 1999;16(9):1412–1416.
3. Beck DE, Sweeney WB, McCarter MD; Ipamorelin 201 Study Group. Prospective, randomized, controlled, proof-of-concept study of the ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. Int J Colorectal Dis. 2014;29(12):1527–1534.
4. 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.
5. Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273(5277):974–977.
6. Ghigo E, Arvat E, Muccioli G, Camanni F. Growth hormone-releasing peptides. Eur J Endocrinol. 1997;136(5):445–460.
7. World Anti-Doping Agency. International Standard — Prohibited List (розділ S2). Montreal: WADA; актуальна редакція.