GHRP-2 and GHRP-6: mechanisms and adverse effects

To understand how GHRP-2 differs from GHRP-6 in terms of safety, it is not enough to know that both "increase growth hormone". It is important what other hormonal systems they affect and how selectively. The editors take a detailed look at the pharmacology of the two peptides and what is known about their unwanted effects.

Common target: GHS-R1a receptor

Both peptides are growth hormone secretagogue receptor type 1a (GHS-R1a) agonists. It is a G-protein-coupled receptor that was cloned by the Howard group in 1996, and whose natural ligand turned out to be ghrelin, a peptide produced mainly in the stomach (Kojima et al., 1999). That is, GHRP-2 and GHRP-6 actually mimic the action of ghrelin.

Activation of GHS-R1a triggers an intracellular cascade through Gq protein and phospholipase C. The result is an increase in calcium concentration in the cell and the release of hormone stored in secretory granules. In pituitary somatotrophs, this means a rapid release of GH, the peak of which in studies was observed within about half an hour after intravenous administration.

The GHS-R1a receptor is not only located in the pituitary gland. It has been found in the hypothalamus (especially in the arcuate nucleus, which regulates eating behaviour), in the brainstem, as well as in the heart, blood vessels, pancreas and other tissues. Therefore, any agonist of this receptor inevitably has a wider spectrum of action than just affecting GH.

Differences between GHRP-2 and GHRP-6 at the target level relate primarily to affinity and activation efficiency. GHRP-2 binds to the receptor more tightly, which is consistent with its higher potency for GH release. In addition, interaction with the CD36 receptor in the cardiovascular system of animals has been described for GHRP-6 — this is a direction of preclinical research, the significance of which for humans has not been clarified.

How peptides trigger GH release

GH release under the action of GHRP occurs at two levels. In the pituitary gland, peptides directly stimulate somatotrophs. In the hypothalamus, they increase the release of GH releasing hormone (GHRH) and, according to a number of studies, functionally counteract somatostatin, the main inhibitor of GH secretion.

This explains the pronounced synergy: the simultaneous administration of GHRP and GHRH causes a GH response that is significantly greater than the sum of the individual responses. This phenomenon is described in detail in the work of Bowers and in the review by Ghigo et al. (1997). It also shows that preserved hypothalamic control is required for the full effect of GHRP.

The effect of both peptides is dose-dependent, but has a "ceiling": after a certain dose, a further increase no longer increases the release of GH, but may increase off-target effects. With repeated administration, the phenomenon of partial desensitization — a decrease in response — has been described, although the degree of this phenomenon varied in different studies.

Since the release of GH is short, the level of insulin-like growth factor-1 (IGF-1) changes little with single injections. More significant changes in IGF-1 have been described with long-term use in clinical studies, but such works for GHRP-2 and GHRP-6 are relatively few and small in size.

Off-target hormonal effects

The key pharmacological difference between peptides of the GHRP class is the degree of selectivity. Neither GHRP-2 nor GHRP-6 is strictly GH-selective: both are capable of increasing adrenocorticotropic hormone (ACTH) and, consequently, cortisol as well as prolactin. It is the lack of these effects in ipamorelin (Raun et al., 1998) that led it to be called the "first selective" secretagogue.

According to a summary of the reviews, GHRP-2 generally stimulates ACTH, cortisol, and prolactin more markedly than GHRP-6—attributing to its higher overall activity at the receptor. These elevations are short-lived and in healthy individuals remain within limits that are rarely clinically significant after a single administration. However, with frequent repetition, the effect on the stress axis is poorly studied.

Another important system is appetite and metabolism. Ghrelin signaling in the hypothalamus increases hunger, which is why GHRP-6 is known for its pronounced appetite stimulation. At the same time, increasing GH as a counterinsular hormone can worsen insulin sensitivity and increase glucose levels, especially with long-term use. For synthetic ghrelin agonists, this effect was confirmed in studies with ibutamoren.

Side effects compared

In clinical studies with single or short-term administration, GHRP-2 and GHRP-6 were generally well tolerated. Among the undesirable effects described are a feeling of heat or redness of the face, short-term drowsiness, increased hunger, local reactions at the injection site. Serious complications in controlled conditions have been described rarely.

However, the conditions of clinical studies are significantly different from independent use: the studies used a certified substance, a short period and medical supervision. With long-term repeated use, the following risks become theoretically significant:

• fluid retention, swelling, pain in the joints — as a result of chronically elevated GH;
• deterioration of glucose tolerance, especially in people with insulin resistance;
• influence on the axis "hypothalamus-pituitary-adrenal glands" due to repeated elevations of cortisol;
• increase in prolactin, which can affect libido and reproductive function;
• for GHRP-6 — uncontrolled calorie intake due to increased hunger.

For GHRP-2, the "effect/side effect" ratio is shifted towards stronger GH release, but also stronger stimulation of cortisol and prolactin. For GHRP-6, appetite dominates. Neither peptide has a proven safety advantage.

Finally, the real risks are often determined not by the pharmacology of the molecule, but by the quality of the product: impurities, errors in dosage, non-sterility. For injectable substances without registration, this is a separate and significant factor.

What we still don't know

Most studies of GHRP-2 and GHRP-6 in humans have been brief and small in sample size, often to study the physiology of GH secretion. There are no long-term randomised safety studies in healthy adults. Sigalos and Pastuszak's (2018) review of GH secretagogues in general highlights precisely this limitation of the evidence base.

It is not known whether long-term use leads to persistent changes in receptor sensitivity, how it affects the human cardiovascular system, and whether there are long-term risks associated with long-term IGF-1 elevation. Preclinical data on the cardioprotective effects of GHRP-6 in animals cannot be automatically transferred to humans.

There is also little data on the interaction of these peptides with other substances that are often used together in the sports environment. Combinations increase the number of unknowns, not decrease them.

Both peptides are equally banned by WADA (Section S2), and laboratories identify them and their metabolites in urine. So from the athlete's point of view, there is no difference between them - the risk of disqualification is the same.

Editorial conclusions

GHRP-2 and GHRP-6 have a common target — the ghrelin receptor GHS-R1a — and the same principle of action: stimulation of own GH secretion with pronounced synergy with GHRH.

The difference is potency and selectivity: GHRP-2 usually increases GH more strongly, but also affects cortisol and prolactin more prominently; GHRP-6 is distinguished by stronger appetite stimulation.

Short-term tolerability in clinical settings was acceptable, but long-term safety is lacking, and informal market products add risks.

For a deeper understanding of the topic, we recommend the materials "GHRP-2 or GHRP-6: what's the difference", "Ipamorelin vs GHRP-6: comparison of the mechanism of action and side effects" and our review of the "hypothalamus-pituitary-adrenal" axis.

List of used literature

1. Ghigo E, Arvat E, Muccioli G, Camanni F. Growth hormone-releasing peptides. Eur J Endocrinol. 1997;136(5):445–460.
2. Bowers CY. Growth hormone-releasing peptide (GHRP). Cell Mol Life Sci. 1998;54(12):1316–1329.
3. 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.
4. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–660.
5. Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998;139(5):552–561.
6. Sigalos JT, Pastuszak AW. The safety and efficacy of growth hormone secretagogues. Sex Med Rev. 2018;6(1):45–53.
7. World Anti-Doping Agency. International Standard — Prohibited List (розділ S2). Montreal: WADA; актуальна редакція.