Ipamorelin vs GHRP-6 (and GHRP-2): Selectivity, Potency and Appetite Data Compared

Put ipamorelin and GHRP-6 on rat pituitary cells and you’d struggle to tell them apart by GH output alone. So why do labs fight over which one to order in? It’s the extras. One drags cortisol and appetite along, the other mostly doesn’t, and GHRP-2 (we’ve added it, because nobody compares just two) lands somewhere else again. Below we go through what the primary papers actually measured, and we’ve linked every one so you can argue with us.

One receptor, three keys

Every peptide here turns on GHS-R1a, the growth hormone secretagogue receptor. Funny thing: nobody had cloned it until 1996, a dozen years after GHRP-6 was published (Howard et al., 1996). Ghrelin, the body’s own key for that lock, turned up in stomach extracts in 1999 (Kojima et al., 1999).

So for about fifteen years, people were publishing on GHRP-6 with no idea what it bound. Keep that in mind when you dig through the old stuff.

You find the receptor on somatotrophs in the pituitary and on neurons up in the hypothalamus. Flip it on and you get GH. You may also get hunger, and a nudge to the stress axis. How much of that baggage comes with each peptide? That’s really what this article is about.

Five residues versus six

Start with GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2), which has a weird backstory. Momany, Bowers and colleagues started from met-enkephalin analogs, opioid-type peptides with no obvious GH link, and found that some modified versions released GH weakly in vitro (Momany et al., 1981). Refining that lead gave them the hexapeptide. By 1984 they had a hexapeptide that let GH out in the dish and in animals, left LH, FSH, TSH and prolactin alone, and worked in rats, monkeys, lambs and calves alike (Bowers et al., 1984).

GHRP-2 has six residues too (D-Ala-D-βNal-Ala-Trp-D-Phe-Lys-NH2), with a bulky naphthylalanine sitting where GHRP-6 keeps its D-Trp. Arvat’s group described GHRP-2 and hexarelin as “super-analogs of GHRP-6” with potent GH-releasing activity (Arvat et al., 1997).

Ipamorelin is shorter. It’s a pentapeptide, Aib-His-D-2-Nal-D-Phe-Lys-NH2, that came out of a Novo Nordisk chemistry program working on compounds lacking the central Ala-Trp dipeptide of GHRP-1 (Raun et al., 1998). The Aib residue at position 1 and the D-2-naphthylalanine at position 3 are the unusual building blocks here.

Each one carries D-amino acids, and proteases tend to choke on those. We’re stating a general design rule there, not a measured comparison.

Potency: closer than you’d guess

Forum lore says GHRP-2 hits hardest and ipamorelin is the gentle one. Raun’s group ran all three side by side, which almost nobody else has done, and their numbers are messier than that:

• Cells in a dish: ipamorelin 1.3 nmol/L at about 85% of GHRP-6’s ceiling, GHRP-6 at 2.2.
• Anesthetized rats: 80 nmol/kg for ipamorelin (topping out at 1,545 ng/mL) and 115 for GHRP-6 (1,167 ng/mL).
• Awake pigs: GHRP-2 needed just 0.6 nmol/kg, ipamorelin 2.3, GHRP-6 3.9.

GHRP-2 wins on potency, then. Yet its ceiling in pigs was 56 ng/mL, under ipamorelin (65) and GHRP-6 (74) (Raun et al., 1998). Potent isn’t the same as effective. Know which one you’re measuring.

You’ll see it said that GHRP-2 has the tightest receptor binding of the three. Maybe so in particular formats, but we couldn’t find a single head-to-head binding paper to cite, so we’re leaving it as an open question rather than a fact.

Selectivity: the real dividing line

ACTH and cortisol

This is where the Raun data get interesting. In swine, none of the three peptides moved FSH, LH, prolactin or TSH. GHRP-6 and GHRP-2 both raised ACTH and cortisol. Ipamorelin did not produce ACTH or cortisol levels different from those seen after GHRH, and that held even at exposure levels more than 200-fold above its ED50 for GH release. The authors themselves called it “very surprising” and titled the paper “the first selective growth hormone secretagogue” (Raun et al., 1998).

Why does an agonist at the same receptor spare the stress axis? Nobody has nailed that down. Biased signaling is a reasonable guess. It’s still a guess. What matters practically is the observation, with one caveat: it was measured in swine, and species differences in this axis are real.

Prolactin and cortisol with GHRP-2 and GHRP-6

Published human studies point the same direction. In 18 healthy men, GHRP-6 produced a GH rise that scaled with the amount given, and serum prolactin and cortisol climbed about twofold above basal, but only at the highest level tested; LH and TSH didn’t change (Bowers et al., 1990).

GHRP-2 is less tidy. In six young adult volunteers, GHRP-2 and hexarelin produced similar increases in prolactin, ACTH and cortisol. The prolactin response was smaller than after TRH, while the ACTH and cortisol responses resembled those to hCRH. The authors’ conclusion was blunt: GHRP-2 “is not fully specific” (Arvat et al., 1997).

One of the older articles we merged here claimed GHRP-2 is cleaner than GHRP-6 on cortisol and prolactin. The primary literature doesn’t support that, so it’s gone. If anything, the evidence puts GHRP-2 at or above GHRP-6 for ACTH and cortisol, with ipamorelin clearly lowest.

GHRP-6 has a second receptor

GHRP-6 also binds CD36, a scavenger receptor on an entirely different pathway. Proulx and colleagues made aza-analogs of GHRP-6 that lost at least 100-fold affinity for GHS-R1a while some kept their CD36 binding, and several of those analogs showed antiangiogenic activity in a choroid sprouting assay (Proulx et al., 2012). You can only split two activities apart if both were there to begin with.

Is that a problem? Depends on the study. If you want a one-receptor tool, it’s a confound. If CD36 biology is your question, GHRP-6 becomes the more interesting molecule. No comparable second target has been reported for ipamorelin.

Appetite: where GHRP-6 acts like ghrelin

Rats that had already eaten their fill went back to the food after Locke’s team put GHRP-6 into their brain ventricles, and the more peptide, the more of them ate (p < 0.01). Plasma GH over the following hour didn’t track that relationship at all (Locke et al., 1995). Hunger and GH, it turns out, come apart.

Lawrence and co-workers traced the wiring seven years later. Block NPY’s Y1 receptor and neither ghrelin nor GHRP-6 made rats eat more. c-Fos staining lit up the arcuate and paraventricular nuclei, a handful of other hypothalamic and brainstem spots, and orexin cells, and that happened in rats kept away from food too (Lawrence et al., 2002).

For a GH-axis study, that orexigenic drive is noise you’d rather not have. For feeding or gut-brain research, it’s the reason to pick GHRP-6. Does ipamorelin leave appetite alone? People say so. We couldn’t find a matched feeding study against GHRP-6, so honestly, that claim is running ahead of the evidence.

Half-life and time course

Ipamorelin has the cleanest kinetic data. Gobburu’s group gave healthy men five escalating infusion rates, eight men per level. Kinetics stayed linear. Half-life: roughly 2 hours. Clearance was 0.078 L/h/kg and the steady-state volume 0.22 L/kg. GH peaked at about 0.67 hours as a single episode and then declined exponentially (Gobburu et al., 1999).

For GHRP-6, the best-known time-course data are from rats. After intravenous delivery, GH rose within 2 minutes, peaked at 10 to 20 minutes and usually returned to baseline by 2 hours (Bowers et al., 1984). That’s a GH-response profile, not a plasma half-life of the peptide itself, and we’d caution against reading it as one.

For GHRP-2 we didn’t find a plasma half-life value we could verify against a primary abstract. Rather than repeat a number of unknown origin, we’ve left that cell of the table marked as not established here.

Desensitization: pattern matters more than peptide

Continuous stimulation of GHS-R1a blunts the response. Wells and Houston showed this nicely in transgenic growth-retarded rats: continuous GHRP-6 infusion gave only a transient growth response and suppressed GH and corticosterone responses to a later GHRP-6 bolus. Interestingly, arcuate GHS-R mRNA didn’t fall. Periventricular somatostatin mRNA rose instead. Pulsatile infusion every 3 hours produced sustained growth and GH responses (Wells and Houston, 2001).

So the mechanism here may be more about hypothalamic somatostatin tone than receptor loss. That’s a useful detail when you design an experiment around repeated exposure.

The flip side: in Bowers’ 1984 work, immature rats given GHRP-6 once or twice daily for up to 25 days gained more weight than controls, and their pituitaries stayed fully responsive at the end (Bowers et al., 1984). Intermittent exposure seems to keep the system honest. Claims that ipamorelin or GHRP-2 resist desensitization better than the others circulate widely, but we couldn’t trace them to a matched comparison, so we wouldn’t build a study around them.

Synergy with GHRH

This is one of the most reproducible findings in the field. In the 1990 study in healthy men, submaximal GHRP-6 combined with GHRH-(1-44) released GH synergistically, more than the sum of each alone. Bowers’ team read that as evidence the two peptides act through independent systems (Bowers et al., 1990), a view the later cloning of a separate GHS receptor confirmed (Howard et al., 1996).

The rat data agree. In the Wells and Houston study, adding GRF to pulsatile GHRP-6 further accelerated skeletal growth, though it also depleted pituitary GH stores, which the authors flagged as possibly unsustainable (Wells and Houston, 2001). And Raun’s antagonist work showed ipamorelin acts through a GHRP-like receptor, not the GHRH receptor (Raun et al., 1998), which is why pairing it with a GHRH analog is mechanistically sensible. For the GHRH side of that pairing, see our sermorelin vs ipamorelin vs tesamorelin comparison.

Side by side

Parameter	Ipamorelin	GHRP-6	GHRP-2
Structure	Pentapeptide, Aib-His-D-2-Nal-D-Phe-Lys-NH2	Hexapeptide, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2	Hexapeptide, D-Ala-D-βNal-Ala-Trp-D-Phe-Lys-NH2
Rat pituitary EC50	1.3 nmol/L	2.2 nmol/L	Not reported in Raun et al.
Swine ED50 / Emax	2.3 nmol/kg / 65 ng/mL	3.9 nmol/kg / 74 ng/mL	0.6 nmol/kg / 56 ng/mL
ACTH / cortisol	Not raised in swine, even at 200x ED50	Raised in swine; ~2x cortisol in men at top level	Raised in swine and in human volunteers
Prolactin	Not raised in swine	~2x in men at top level only	Raised in human volunteers
Feeding in rodents	No matched data found	Strong, NPY Y1 dependent	Less characterized
Second receptor	None reported	CD36	None we could verify
Half-life	~2 h terminal (human volunteers)	GH response back to baseline ~2 h (rats)	Not established here

Research-model selection guide

Research question	Usual pick	Why
Isolated GH release, cortisol must stay flat	Ipamorelin	No ACTH/cortisol rise in swine at 200x ED50
Feeding, NPY or orexin circuitry	GHRP-6	Strong central feeding effect in rats
CD36 or angiogenesis biology	GHRP-6 (with aza-analog controls)	Dual GHS-R1a/CD36 binding
Highest potency per nmol, GH plus HPA readouts	GHRP-2	Lowest swine ED50; raises ACTH, cortisol, prolactin
Replicating classic 1980s and 1990s GHRP work	GHRP-6	Reference compound of that literature
GHRH synergy experiments	Any of the three	Separate receptor from GHRH-R

Whichever peptide you pick, a GHS-R1a antagonist arm tells you how much of your signal actually runs through that receptor. It matters most for GHRP-6, given CD36. Thinking about an oral, non-peptide option instead? Our MK-677 vs ipamorelin comparison goes through it.

Material and documentation

Compound background lives in our library pages for ipamorelin, GHRP-6 and GHRP-2. Each lot is tested by a U.S.-based third-party laboratory, and the certificates of analysis are public: ipamorelin COA, GHRP-6 COA, GHRP-2 COA.

Frequently asked questions

What is the difference between ipamorelin and GHRP-6?

On GH alone, not much: their pituitary-cell potencies nearly match. Ipamorelin is a pentapeptide that didn’t raise ACTH or cortisol in swine, while GHRP-6 is a hexapeptide that raised both, drives feeding in rodents and also binds CD36 (Raun et al., 1998).

Is GHRP-2 or GHRP-6 more potent?

In conscious swine, GHRP-2 had a lower ED50 (0.6 vs 3.9 nmol/kg) but a lower maximal GH response (56 vs 74 ng/mL). More potent, less efficacious, in that model.

Does ipamorelin raise cortisol or prolactin?

Not in the swine work that defined its profile. Prolactin was unchanged for all three peptides there, and ipamorelin’s ACTH and cortisol stayed at GHRH-like levels.

Why does GHRP-6 increase appetite in animal studies?

It copies ghrelin’s action on hypothalamic receptors. In rats, its central feeding effect was blocked by an NPY Y1 antagonist and occurred independently of GH release (Lawrence et al., 2002).

References

1. Momany FA, Bowers CY, Reynolds GA, et al. Design, synthesis, and biological activity of peptides which release growth hormone in vitro. Endocrinology. 1981. PMID 6109621
2. Bowers CY, Momany FA, Reynolds GA, Hong A. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology. 1984. PMID 6714155
3. Bowers CY, Reynolds GA, Durham D, et al. Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone. J Clin Endocrinol Metab. 1990. PMID 2108187
4. Locke W, Kirgis HD, Bowers CY, Abdoh AA. Intracerebroventricular growth-hormone-releasing peptide-6 stimulates eating without affecting plasma growth hormone responses in rats. Life Sci. 1995. PMID 8614257
5. Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996. PMID 8688086
6. Arvat E, di Vito L, Maccagno B, et al. Effects of GHRP-2 and hexarelin, two synthetic GH-releasing peptides, on GH, prolactin, ACTH and cortisol levels in man. Peptides. 1997. PMID 9285939
7. Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998. PMID 9849822
8. Gobburu JV, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharm Res. 1999. PMID 10496658
9. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999. PMID 10604470
10. Wells T, Houston PA. Skeletal growth acceleration with growth hormone secretagogues in transgenic growth retarded rats: pattern-dependent effects and mechanisms of desensitization. J Neuroendocrinol. 2001. PMID 11412336
11. Lawrence CB, Snape AC, Baudoin FM, Luckman SM. Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. Endocrinology. 2002. PMID 11751604
12. Proulx C, Picard É, Boeglin D, et al. Azapeptide analogues of the growth hormone releasing peptide 6 as cluster of differentiation 36 receptor ligands with reduced affinity for the growth hormone secretagogue receptor 1a. J Med Chem. 2012. PMID 22712585

Disclaimer: This content is intended for research purposes only and is not meant to constitute medical advice.