Ipamorelin vs. GHRP-6: GHRP Comparison

GHRP-6 arrived first. Developed in the 1980s by Cyril Bowers and colleagues, it was the original synthetic peptide proven to trigger dose-dependent growth hormone (GH) release both in cell cultures and in living organisms. For years, it was the default research tool for anyone studying GH secretagogue pharmacology. Then came ipamorelin. Developed by Novo Nordisk in the late 1990s, this third-generation pentapeptide matched GHRP-6's ability to release growth hormone from pituitary cells — but did so without dragging cortisol, prolactin, and appetite along for the ride.

That difference in selectivity is the central story of this comparison. Both peptides bind the same receptor. Both cause the pituitary to release GH. But the downstream consequences are not the same, and for researchers, clinicians, and anyone trying to understand which compound does what, those consequences matter more than the shared mechanism.

This article breaks down the pharmacology, the clinical data, the side-effect profiles, and the practical trade-offs between ipamorelin and GHRP-6.

---

Table of Contents

1. Quick-Reference Comparison Table
2. Shared Mechanism: The Ghrelin Receptor
3. Ipamorelin Deep Dive
4. GHRP-6 Deep Dive
5. GH Release Potency: Head-to-Head Data
6. Selectivity: The Defining Difference
7. Side-Effect Profiles
8. Appetite Effects
9. Pharmacokinetics and Half-Life
10. Desensitization and Long-Term Use
11. Stacking With GHRH Analogs
12. How They Compare to Other GHRPs
13. The Bottom Line
14. References

---

Quick-Reference Comparison Table

Parameter	Ipamorelin	GHRP-6
Structure	Pentapeptide (Aib-His-D-2-Nal-D-Phe-Lys-NH2)	Hexapeptide (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2)
Generation	Third-generation GHRP	First-generation GHRP
Primary receptor	GHS-R1a (ghrelin receptor)	GHS-R1a (ghrelin receptor)
GH release potency (in vitro EC50)	1.3 nmol/L	2.2 nmol/L
GH release potency (in vivo ED50, rats)	80 nmol/kg	115 nmol/kg
Cortisol elevation	No (even at 200x the ED50)	Yes, dose-dependent
Prolactin elevation	No	Yes
ACTH release	No	Yes
Appetite stimulation	Minimal	Strong (onset within 20-30 min)
Terminal half-life	~2 hours (IV)	~2.5 hours (IV); ~20 min functional
Oral bioavailability	Not reported	0.3%
Desensitization risk	Lower	Higher
Clinical development	Phase II (postoperative ileus)	Preclinical / investigational
Developer	Novo Nordisk	Originally Bowers lab / Merck (SKF-110679)

---

Shared Mechanism: The Ghrelin Receptor

Both ipamorelin and GHRP-6 are growth hormone secretagogues (GHS). They mimic the endogenous hormone ghrelin by binding the growth hormone secretagogue receptor type 1a (GHS-R1a), a G protein-coupled receptor concentrated in the anterior pituitary and hypothalamus.

When a GHS binds GHS-R1a on pituitary somatotroph cells, it triggers a signaling cascade through Gq/Gi proteins that activates phospholipase C, which in turn generates inositol trisphosphate (IP3) and diacylglycerol (DAG). The result: protein kinase C (PKC) activation and intracellular calcium mobilization. This pathway is cAMP-independent — a point worth noting because the body's own growth hormone-releasing hormone (GHRH) works through a different, cAMP-dependent route. That mechanistic separation is why GHS peptides and GHRH analogs produce synergistic GH release when combined.

Both peptides also suppress somatostatin, the hypothalamic brake on GH secretion. By dampening somatostatin tone while directly stimulating somatotrophs, GHS compounds amplify pulsatile GH output through two parallel pathways.

So far, identical. The divergence begins at the next level: what else each peptide activates beyond GH release.

---

Ipamorelin Deep Dive

Ipamorelin (NNC 26-0161) is a synthetic pentapeptide derived from GHRP-1. Its amino acid sequence — Aib-His-D-2-Nal-D-Phe-Lys-NH2 — was engineered to retain full GH-releasing potency while shedding the off-target hormonal effects that plagued earlier GHRPs.

The landmark study establishing ipamorelin's selectivity was published in 1998 by Raun et al. in the European Journal of Endocrinology. The researchers tested ipamorelin against GHRP-6 and GHRP-2 across three experimental models: rat pituitary cell cultures, anesthetized rats, and conscious swine.

Key findings from Raun et al. (1998)

In rat pituitary cells, ipamorelin released GH with an EC50 of 1.3 +/- 0.4 nmol/L and maximum efficacy (Emax) of 85% compared to GHRP-6. GHRP-6 itself had an EC50 of 2.2 +/- 0.3 nmol/L. In anesthetized rats receiving IV doses, ipamorelin's ED50 was 80 nmol/kg (versus 115 nmol/kg for GHRP-6), and its Emax reached 1,545 ng GH/mL plasma — actually exceeding GHRP-6's peak of 1,167 ng/mL.

The striking result was hormonal specificity. Both GHRP-6 and GHRP-2 caused measurable increases in ACTH and cortisol. Ipamorelin did not — even when administered at doses more than 200 times its ED50 for GH release. It also left FSH, LH, prolactin, and TSH unchanged.

The researchers concluded that ipamorelin was "the first GHRP-receptor agonist with a selectivity for GH release similar to that displayed by GHRH." In other words, it hit the ghrelin receptor but behaved, hormonally, like a GHRH analog.

Human Pharmacokinetics

A dose-escalation study by Gobburu et al. (1999), published in Pharmaceutical Research, gave ipamorelin intravenously to 40 healthy men at five dose levels (4.21 to 140.45 nmol/kg infused over 15 minutes). The pharmacokinetic profile was dose-proportional, with a terminal half-life of approximately 2 hours, clearance of 0.078 L/h/kg, and a volume of distribution at steady state of 0.22 L/kg.

Each dose produced a single, sharp GH pulse peaking at roughly 40 minutes post-infusion, followed by an exponential decline. The concentration required for half-maximal GH stimulation (SC50) was 214 nmol/L, and the maximal GH production rate was 694 mIU/L/h. The response was clean, predictable, and confined to GH.

Clinical Development

Novo Nordisk developed ipamorelin through early clinical work before Helsinn Therapeutics took it into Phase II trials for postoperative ileus — the gut motility shutdown that commonly follows abdominal surgery. The rationale was that ghrelin receptor agonism might restore gastric emptying. In the Phase II trial, ipamorelin at 0.03 mg/kg twice daily for up to seven days was well tolerated. However, the program was discontinued due to insufficient efficacy for its intended gastrointestinal indication.

For a full profile of ipamorelin's research history and molecular pharmacology, see our ipamorelin research guide.

---

GHRP-6 Deep Dive

GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2, development code SKF-110679) is a synthetic hexapeptide and met-enkephalin derivative. It was one of the first synthetic GH secretagogues ever tested, and its early success in animal models laid the groundwork for the entire GHRP class.

Unlike ipamorelin, GHRP-6 activates the GHS-R1a receptor with broader downstream consequences. Part of this stems from lower receptor selectivity. Part of it stems from GHRP-6's interaction with additional receptor populations — GHS-R1a is expressed not only in the pituitary but also in the heart, adrenal glands, ovaries, testes, lungs, and skeletal muscle. GHRP-6's less discriminating binding profile means it tends to elicit responses across more tissue types.

GH Release Profile

GHRP-6's GH-releasing activity was first characterized in animal models by Bowers and colleagues. In vitro, it activates somatotrophs through the PKC/calcium pathway described above. In the Raun et al. study, GHRP-6's in vitro EC50 was 2.2 nmol/L with an Emax set at 100% (as the reference compound). Its in vivo ED50 in rats was 115 nmol/kg, and its maximum GH response reached 1,167 ng/mL.

Human Pharmacokinetics

A 2012 pharmacokinetic study by Gil et al., published in the European Journal of Pharmaceutical Sciences, examined GHRP-6 in nine healthy men who received single IV boluses at 100, 200, and 400 mcg/kg. The peptide followed a bi-exponential elimination profile: a rapid distribution phase with a half-life of 7.6 minutes, followed by a terminal elimination phase of 2.5 hours. Area under the curve (AUC) increased proportionally with dose.

There is a discrepancy worth noting in the literature. Some sources cite a functional half-life of approximately 20 minutes for GHRP-6, referring to the duration of its effective GH-releasing window rather than its plasma clearance time. The terminal elimination half-life of 2.5 hours reflects how long the peptide remains detectable in blood — not necessarily how long it is pharmacologically active at the receptor.

Beyond GH: The Multi-Hormone Problem

GHRP-6 stimulates more than GH. Administration reliably increases plasma ACTH and cortisol. It elevates prolactin. And it triggers intense appetite stimulation — a direct consequence of ghrelin receptor activation in the hypothalamus's arcuate nucleus, where GHS-R1a-expressing neurons co-express neuropeptide Y (NPY), one of the most powerful orexigenic signaling molecules in the brain.

These off-target effects are not dangerous at standard research doses. At 100 mcg or less, cortisol increases tend to be mild and transient. But they do set an upper limit on dosing utility: exceeding the so-called saturation dose does not meaningfully increase GH output but does amplify cortisol, prolactin, and hunger effects.

For a comprehensive review of GHRP-6's pharmacology, see our GHRP-6 research profile.

---

GH Release Potency: Head-to-Head Data

When compared directly under controlled conditions, the two peptides produce similar GH output. The data from Raun et al. (1998) in three experimental systems:

Model	Ipamorelin	GHRP-6
In vitro (rat pituitary), EC50	1.3 +/- 0.4 nmol/L	2.2 +/- 0.3 nmol/L
In vitro, Emax	85 +/- 5%	100% (reference)
In vivo (anesthetized rats), ED50	80 +/- 42 nmol/kg	115 +/- 36 nmol/kg
In vivo, Emax	1,545 +/- 250 ng/mL	1,167 +/- 120 ng/mL
In vivo (swine), ED50	3.9 +/- 1.4 nmol/kg	Not tested alongside

Ipamorelin is slightly more potent on a per-mole basis (lower EC50 and ED50) and in rats actually achieved a higher peak GH concentration. In practical terms, however, both peptides produce GH pulses within the same order of magnitude. Neither is a weak secretagogue; neither is dramatically more powerful than the other.

For context, GHRP-2 — the second-generation GHRP — is generally considered more potent than both on a per-dose basis, with a much lower ED50 in swine (0.6 nmol/kg versus ipamorelin's 3.9 nmol/kg), though its Emax was lower (56 ng/mL versus 74 ng/mL). Hexarelin rounds out the group as the most potent GH releaser of the family, but also the one most prone to desensitization and hormonal cross-talk.

---

Selectivity: The Defining Difference

This is what separates ipamorelin from every GHRP that came before it.

In the Raun et al. study, researchers specifically measured plasma levels of ACTH, cortisol, prolactin, FSH, LH, and TSH after administering each peptide. The results:

• GHRP-6 and GHRP-2 both elevated ACTH and cortisol above baseline levels.
• Ipamorelin did not. Its ACTH and cortisol levels were statistically indistinguishable from those produced by GHRH alone. This held true at every dose tested — including doses 200 times greater than the ED50 for GH release.

None of the three peptides affected FSH, LH, or TSH.

The implication is significant. Cortisol is catabolic. It promotes fat storage, impairs protein synthesis, disrupts sleep architecture, and suppresses immune function when chronically elevated. Prolactin elevation can interfere with reproductive hormones and, in men, reduce libido. A GH secretagogue that raises both alongside GH is working against itself — building with one hand and breaking down with the other.

Ipamorelin avoids this problem. Its selectivity profile is, as the original researchers described it, analogous to GHRH itself. It acts through a GHRP receptor but produces a hormonal outcome that looks like GHRH stimulation.

---

Side-Effect Profiles

Side Effect	Ipamorelin	GHRP-6
Cortisol increase	None detected at any tested dose	Yes, dose-dependent; mild at less than or equal to 100 mcg
ACTH increase	None detected	Yes
Prolactin increase	None detected	Yes, mild to moderate
Appetite stimulation	Minimal to none	Strong; onset 20-30 min, lasts 1-3 hrs
Water retention	Possible (GH-mediated)	Possible (GH-mediated)
Injection-site reactions	Rare	Rare; occasional flushing reported
Gastric effects	Prokinetic (improves motility)	Gastric rumbling reported

Both peptides share side effects common to all GH secretagogues: potential for transient numbness or tingling in extremities, mild water retention, and the downstream effects of elevated GH/IGF-1 (which are dose- and duration-dependent). But the differentiating side effects — cortisol, prolactin, and appetite — all favor ipamorelin.

The Phase II postoperative ileus data adds an interesting wrinkle. Ipamorelin at therapeutic doses was well tolerated in surgical patients, a population that is particularly vulnerable to adverse hormonal shifts. Adverse events were rare and comparable to those seen with sermorelin, the FDA-approved GHRH analog.

---

Appetite Effects

This is where GHRP-6 is either a feature or a bug, depending on the context.

GHRP-6 produces appetite stimulation so strong that experienced researchers describe it as agonizing hunger within 20 minutes of injection. The mechanism is direct: GHS-R1a activation in the hypothalamic arcuate nucleus stimulates NPY/AgRP neurons, the brain's primary hunger-drive circuit. Some data suggest GHRP-6 can increase food intake by 100-200% during the post-injection window, with preferential consumption of palatable, calorie-dense foods.

For researchers studying cachexia — the wasting syndrome that accompanies cancer, HIV/AIDS, and chronic heart failure — this appetite effect is potentially therapeutic. GHRP-6's ability to simultaneously release GH and stimulate food intake addresses two aspects of wasting in a single molecule.

For anyone else, it is a management challenge. The hunger window typically lasts one to three hours, and if the goal is fat loss or body recomposition, intense ghrelin-driven appetite makes dietary control harder.

Ipamorelin produces minimal to no appetite stimulation in most research settings. Subjects in ipamorelin studies consumed their normal meals without reporting increased hunger. This makes it a more practical option when the goal is GH release without caloric disruption.

---

Pharmacokinetics and Half-Life

Both peptides are typically administered via subcutaneous injection. Their pharmacokinetic parameters after IV administration:

Parameter	Ipamorelin	GHRP-6
Terminal half-life	~2 hours	~2.5 hours
Distribution half-life	Not separately reported	7.6 minutes
Clearance	0.078 L/h/kg	Not reported (dose-proportional AUC)
Volume of distribution (Vss)	0.22 L/kg	Not reported
Time to peak GH	~40 minutes (IV)	~15-30 minutes (IV)
Dose proportionality	Yes	Yes

The terminal half-lives are similar. GHRP-6's faster distribution phase (7.6-minute half-life) reflects rapid initial tissue uptake before the slower elimination phase. Both peptides produce their GH pulse relatively quickly and then clear within a few hours.

Subcutaneous administration slows absorption slightly compared to IV, which extends the effective window but does not fundamentally change the pharmacokinetic profile. Neither peptide has meaningful oral bioavailability — GHRP-6's is documented at 0.3%, and ipamorelin's is presumed to be similarly negligible.

---

Desensitization and Long-Term Use

Continuous, uninterrupted stimulation of any G protein-coupled receptor can lead to tachyphylaxis — a progressive reduction in response caused by receptor internalization, uncoupling, and downregulation. Both GHS-R1a agonists carry this risk, but the practical degree differs.

GHRP-6 has a higher observed rate of desensitization. Its broader receptor activation profile — triggering cortisol, prolactin, and appetite circuits alongside GH — creates more opportunities for feedback-driven downregulation. Practitioners working with GHRP-6 commonly report diminishing GH responses after continuous daily use beyond 8-12 weeks without cycling.

Ipamorelin appears to resist desensitization more effectively. Its cleaner receptor activation — limited essentially to GH release — may produce less receptor stress and less compensatory downregulation. Longer continuous-use protocols (up to 12 weeks) have been described in research contexts without obvious attenuation of GH response, though no large-scale longitudinal studies confirm this.

Common mitigation strategies for both peptides include:

• Pulsatile dosing rather than continuous infusion, mimicking the body's natural ultradian GH rhythm
• Cycling protocols such as five days on / two days off, or 8-12 week cycles followed by a 4-week washout
• Spacing injections 6-8 hours apart to allow receptor resensitization between doses

For comparison, hexarelin — the most potent GHRP — desensitizes the most rapidly, often showing significant GH blunting within weeks. GHRP-2 falls between hexarelin and GHRP-6 in desensitization risk. Ipamorelin sits at the favorable end of the spectrum.

---

Stacking With GHRH Analogs

Both ipamorelin and GHRP-6 produce synergistic GH release when combined with GHRH analogs like CJC-1295. The reason is mechanistic: GHRPs work through the PKC/calcium pathway while GHRH works through the cAMP pathway. Activating both pathways simultaneously on the same somatotroph cell produces GH output that exceeds the sum of each alone.

This synergy principle has driven the popularity of combination protocols, particularly CJC-1295 + ipamorelin stacks. The rationale for choosing ipamorelin as the GHRP component in these stacks comes back to selectivity: if the GHRH analog is already providing maximal pathway activation on its side, the GHRP's job is to complement it — not to add cortisol and hunger to the equation.

GHRP-6 also synergizes with GHRH analogs. The GH amplification is real. But the side-effect profile scales with the GH signal, making high-dose GHRH + GHRP-6 combinations more prone to cortisol spillover and appetite surges than the equivalent ipamorelin pairing.

For a broader look at GH secretagogue combinations, including oral options, see our comparison of MK-677 vs. CJC-1295/Ipamorelin.

---

How They Compare to Other GHRPs

The GHRP family has four commonly discussed members. Where do ipamorelin and GHRP-6 sit?

Feature	GHRP-6	GHRP-2	Hexarelin	Ipamorelin
GH potency	Moderate	High	Highest	Moderate
Selectivity	Low	Low-Moderate	Low	High
Cortisol/ACTH	Yes	Yes	Yes	No
Prolactin	Yes	Yes (more than GHRP-6)	Yes	No
Appetite	Strong	Moderate	Moderate	Minimal
Desensitization	Moderate	Moderate-High	High (rapid)	Low
Best suited for	Short-term GH bursts; cachexia research	High-potency GH release (tolerating side effects)	Maximum acute GH pulse (short protocols)	Long-term, clean GH optimization

GHRP-6 is the generalist. GHRP-2 is the stronger generalist. Hexarelin is the brute-force option. Ipamorelin is the precision tool.

For a direct comparison of the two middle-ground options, see our GHRP-2 vs. GHRP-6 comparison.

---

The Bottom Line

Ipamorelin and GHRP-6 share a receptor, a mechanism, and a job description — release growth hormone from the pituitary. They do that job with roughly equivalent potency. In vitro, ipamorelin's EC50 is 1.3 nmol/L versus GHRP-6's 2.2 nmol/L. In live animals, their ED50 values are in the same range (80 vs. 115 nmol/kg). Neither is dramatically stronger than the other.

The difference is everything that happens alongside the GH release.

GHRP-6 elevates cortisol, ACTH, and prolactin. It triggers hunger that hits within 20 minutes and can double food intake. These are not theoretical side effects from high-dose abuse — they are documented pharmacological properties observed in controlled research at standard doses.

Ipamorelin avoids all three. Even at doses 200 times above its effective concentration for GH release, it does not meaningfully increase cortisol or ACTH. It does not raise prolactin. It does not drive appetite.

For most research contexts, ipamorelin is the more refined tool. It produces the GH pulse without the hormonal noise. It pairs cleanly with GHRH analogs. It resists desensitization better than its predecessors. And its Phase II clinical data, though limited, demonstrated tolerability in a vulnerable patient population.

GHRP-6 retains a role in two specific scenarios. First, in cachexia and wasting research, where the appetite stimulation is a feature rather than a side effect. Second, as a historical and pharmacological reference compound — the first in its class, well-characterized, and still useful for comparative studies.

Neither peptide is FDA-approved for therapeutic use. Both remain investigational. Anyone considering their use should do so under medical supervision, with an understanding of both the evidence supporting them and the gaps in long-term safety data.

---

References

1. Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. European Journal of Endocrinology. 1998;139(5):552-561. doi:10.1530/eje.0.1390552

2. Gobburu JV, Agersoe H, Engell HC, et al. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharmaceutical Research. 1999;16(9):1412-1416. doi:10.1023/A:1018955126402

3. Gil J, Maresova L, Martinez G, et al. Pharmacokinetic study of Growth Hormone-Releasing Peptide 6 (GHRP-6) in nine male healthy volunteers. European Journal of Pharmaceutical Sciences. 2012;48(1-2):40-46. doi:10.1016/j.ejps.2012.10.006

4. Frieboes RM, Murck H, Schier T, et al. Effects of Growth Hormone-Releasing Peptide-6 on the nocturnal secretion of GH, ACTH and cortisol and on the sleep EEG in man. Journal of Neuroendocrinology. 1999;11(6):473-478.

5. Ishida J, Saitoh M, Ebner N, et al. Growth hormone secretagogues: history, mechanism of action, and clinical development. JCSM Rapid Communications. 2020;3(1):25-37. doi:10.1002/rco2.9

6. Berlanga-Acosta J, Abreu-Cruz A, Herrera DGB, et al. Synthetic Growth Hormone-Releasing Peptides (GHRPs): A Historical Appraisal of the Evidences Supporting Their Cytoprotective Effects. Clinical Medicine Insights: Cardiology. 2017;11. doi:10.1177/1179546817694558

7. Sinha DK, Balasubramanian A, Tatem AJ, et al. Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Translational Andrology and Urology. 2020;9(Suppl 2):S149-S159. doi:10.21037/tau.2019.11.30

8. Bowers CY, Momany FA, Reynolds GA, et al. 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;114(5):1537-1545.

9. Raun K, Hansen BS, Johansen NL, et al. The GH secretagogues ipamorelin and GH-releasing peptide-6 increase bone mineral content in adult female rats. Endocrinology. 2000;141(2):567-572.

10. Greenwood-Van Meerveld B, Tyler K, Krier J. Review article: ghrelin and gastrointestinal function. Alimentary Pharmacology and Therapeutics. 2011;33(7):749-757.