GHRP-2 vs. GHRP-6: Detailed Comparison

GHRP-2 and GHRP-6 are the two most widely referenced growth hormone-releasing peptides in research literature. Both bind the ghrelin receptor (GHS-R1a), both trigger pulsatile growth hormone (GH) secretion, and both emerged from the same lineage of synthetic secretagogues pioneered by endocrinologist Cyril Bowers in the 1980s. Yet they are not interchangeable. The two peptides differ in GH potency, appetite stimulation, cortisol and prolactin effects, intracellular signaling, and even their non-endocrine pharmacology.

This article breaks down every meaningful difference between GHRP-2 and GHRP-6, drawing on published clinical data and preclinical findings so you can understand where each peptide stands in the current body of evidence.

Table of Contents

Quick-Reference Comparison Table
Origins and Development
Mechanism of Action
Growth Hormone Release Potency
Appetite and Food Intake
Cortisol and ACTH Effects
Prolactin Effects
Cardioprotective and Cytoprotective Research
Synergy with GHRH
How They Compare to Other GHRPs
The Bottom Line
References

Quick-Reference Comparison Table

Parameter	GHRP-2 (Pralmorelin)	GHRP-6
Generation	Second-generation GHRP	First-generation GHRP
Sequence	D-Ala-D-2-Nal-Ala-Trp-D-Phe-Lys-NH2	His-D-Trp-Ala-Trp-D-Phe-Lys-NH2
Molecular weight	~818 Da	~873 Da
GH release potency	Higher (dose for dose)	Moderate
Appetite stimulation	Mild to moderate	Strong
Cortisol elevation	Moderate at standard doses	Similar to moderate
Prolactin elevation	Slight; dose-dependent	Slight; dose-dependent
cAMP pathway	Increases intracellular cAMP	Does not increase cAMP (may decrease)
Cardioprotective data	Yes (ischemia/reperfusion, fibrosis)	Yes (MI models, doxorubicin protection)
Regulatory status	Approved in Japan as GHD diagnostic (pralmorelin)	Investigational
Oral bioavailability	Limited	Demonstrated in preclinical models

Origins and Development

The story starts with GHRP-6. In the early 1980s, Bowers discovered that certain synthetic analogs of met-enkephalin could stimulate GH release from pituitary cells in culture, a finding that was unrelated to the opioid receptor activity anyone expected. GHRP-6 became the first synthetic peptide shown to elicit dose-dependent GH release both in vitro and in vivo. It was the proof of concept that a non-GHRH pathway for GH secretion existed, years before ghrelin itself was identified in 1999.

GHRP-2, sometimes called pralmorelin, came next. It was designed as a structural refinement of GHRP-6, with the goal of achieving greater GH-releasing potency and a cleaner side-effect profile. The substitution of histidine at position 1 with D-alanine, and D-tryptophan at position 2 with D-2-naphthylalanine, gave GHRP-2 stronger binding affinity at the ghrelin receptor. Pralmorelin went on to become the first ghrelin receptor agonist used clinically, earning approval in Japan as a diagnostic tool for growth hormone deficiency.

Mechanism of Action

Both GHRP-2 and GHRP-6 act as agonists at the growth hormone secretagogue receptor type 1a (GHS-R1a), the same receptor that binds endogenous ghrelin. Activation of GHS-R1a on pituitary somatotrophs triggers GH release. But their intracellular signaling is not identical.

GHRP-2 increases intracellular cyclic AMP (cAMP) in pituitary cells, a mechanism that overlaps with the pathway used by growth hormone-releasing hormone (GHRH). This cAMP elevation may explain why GHRP-2 synergizes so effectively with GHRH: the two peptides converge on the same second-messenger system, amplifying the GH pulse beyond what either achieves alone.

GHRP-6 does not increase cAMP. In fact, some studies report that it decreases cAMP levels in pituitary cell cultures. This indicates that GHRP-6 drives GH secretion through an alternative downstream pathway, one that still requires extracellular calcium influx but diverges from the classical cAMP-PKA cascade. Both peptides' effects are suppressed by somatostatin, confirming that somatostatin remains the dominant brake on GH secretion regardless of which secretagogue is providing the stimulus.

This divergence in signaling is not just academic. It means GHRP-2 and GHRP-6 may produce different patterns of GH pulsatility and may interact differently when combined with GHRH or other secretagogues.

Growth Hormone Release Potency

In head-to-head comparisons, GHRP-2 consistently produces larger GH responses than GHRP-6 at equivalent doses. This has been demonstrated in both rat pituitary cell assays and human studies.

The dose-response curve for GHRP-2 in humans is well characterized. In a study of older men and women with decreased GH secretion, 1 mcg/kg of GHRP-2 subcutaneously produced a GH response comparable to 1 mcg/kg GHRH combined with 0.1 mcg/kg GHRP-2. Escalating to 10 mcg/kg GHRP-2 roughly doubled the GH output in both sexes. When 1 mcg/kg/hour was infused continuously for 30 days, normal pulsatile GH secretion was maintained and serum IGF-1 remained elevated throughout the entire treatment period.

GHRP-6 still produces meaningful GH elevations, but it requires comparatively higher doses to match the peak GH levels seen with GHRP-2. In clinical studies of type 1 diabetes patients, GHRP-6 and ghrelin produced comparable GH responses, with ACTH and cortisol release patterns also mirroring those of the endogenous hormone, confirming that GHRP-6 acts through the same receptor system as ghrelin.

The practical takeaway: if the primary research interest is maximizing GH output per microgram of peptide, GHRP-2 has the edge.

Appetite and Food Intake

This is where the two peptides diverge most noticeably. Both bind the ghrelin receptor, and ghrelin is the body's primary hunger hormone. But GHRP-6 activates the orexigenic (appetite-stimulating) arm of ghrelin signaling far more aggressively than GHRP-2.

Preclinical data illustrate the mechanism: intracerebroventricular injection of GHRP-6 into rats significantly stimulated food intake and activated several hypothalamic appetite centers, including the arcuate nucleus, paraventricular nucleus, dorsomedial nucleus, and lateral hypothalamus. The feeding response was blocked by a Y1 neuropeptide Y (NPY) receptor antagonist, indicating that GHRP-6's appetite effects run through the NPY/AgRP pathway, the same circuit ghrelin uses.

GHRP-2 is not appetite-neutral, however. In a controlled human trial, seven lean healthy males were subcutaneously infused with GHRP-2 at 1 mcg/kg/hour for 270 minutes, then offered a buffet-style meal. Every single subject ate more during the GHRP-2 infusion compared to saline, consuming an average of 35.9% more calories. Serum GH area under the curve during GHRP-2 infusion was 5,550 mcg/L/240 min versus 412 mcg/L/240 min with saline (p = 0.003). So GHRP-2 does increase food intake, but the effect is less intense and less immediate than what GHRP-6 produces.

For research models studying cachexia or appetite recovery, GHRP-6's robust hunger response is an asset. For body composition studies where caloric intake must be controlled, GHRP-2's milder appetite profile is generally preferred.

Cortisol and ACTH Effects

Both peptides stimulate the hypothalamic-pituitary-adrenal (HPA) axis to some degree, meaning both can raise ACTH and cortisol. This is a known property of ghrelin receptor agonists and one reason ipamorelin later attracted attention for its selectivity (it stimulates GH without meaningfully raising ACTH or cortisol).

A key clinical study by Arvat and colleagues (1997) compared GHRP-2 and hexarelin across multiple dose levels in human subjects and measured GH, prolactin, ACTH, and cortisol responses alongside those produced by GHRH, TRH, and human corticotropin-releasing hormone (hCRH). The findings:

All tested doses of GHRP-2 stimulated ACTH and cortisol to a similar extent.
The ACTH/cortisol response to GHRP-2 was comparable in magnitude to that produced by hCRH.
These elevations were dose-independent within the range tested, meaning even lower doses triggered a measurable HPA axis response.

GHRP-6 produces a similar pattern. In studies of both healthy volunteers and type 1 diabetes patients, GHRP-6 raised ACTH and cortisol in a manner paralleling the response to exogenous ghrelin. Repeated intravenous boluses of GHRP-6 during sleep increased serum cortisol levels, though notably, oral administration of GHRP-6 did not produce the same cortisol elevation, suggesting the route of administration matters.

The net difference between the two peptides' cortisol effects is small. Neither is dramatically worse than the other. However, both are distinctly less selective than ipamorelin, which has been shown to release GH without significantly raising ACTH or cortisol levels above what GHRH alone produces.

Prolactin Effects

Both GHRP-2 and GHRP-6 can raise prolactin, though the magnitude is modest compared to their GH-releasing effects.

In the Arvat study, prolactin responses to all doses of GHRP-2 (and hexarelin) were similar to each other and lower than the prolactin response produced by TRH. In practical terms, the prolactin elevation from either GHRP is rarely clinically significant at standard research doses. It becomes more relevant at high or sustained doses, where elevated prolactin can theoretically contribute to side effects such as gynecomastia, mood changes, or disrupted reproductive hormone signaling.

Again, if minimizing off-target hormonal effects is the priority, ipamorelin outperforms both GHRP-2 and GHRP-6 on this parameter. An early pharmacological profiling study demonstrated that ipamorelin did not significantly affect FSH, LH, prolactin, or TSH, nor did it raise ACTH or cortisol beyond baseline GHRH levels.

Cardioprotective and Cytoprotective Research

One of the more surprising chapters in GHRP research has nothing to do with growth hormone. Beginning in the early 2000s, mounting evidence showed that GHRP-6 and GHRP-2 possess cardioprotective and cytoprotective properties that appear to operate independently of GH release. These effects are mediated through at least two receptor systems: GHS-R1a and the scavenger receptor CD36.

GHRP-6

GHRP-6 has been the more extensively studied peptide in cardiovascular models. In a porcine model of acute myocardial infarction, GHRP-6 administration reduced infarct mass by 78% and infarct thickness by 50% compared to saline (p < 0.01). The peptide exhibited antioxidant properties that appeared to contribute to reducing ischemic myocardial damage.

More recent work (2024) examined whether GHRP-6 could prevent doxorubicin-induced cardiomyopathy, a major dose-limiting toxicity of the common chemotherapy drug. In rats, GHRP-6 co-administered with doxorubicin attenuated oxidative stress, reduced mitochondrial ultrastructural damage, and increased expression of the anti-apoptotic gene Bcl-2. This represented the first evidence that a peptidyl GH secretagogue could protect against anthracycline cardiotoxicity.

Beyond the heart, GHRP-6 reduced parenchymal necrosis and apoptosis across multiple epithelial organs and attenuated fibrotic changes in liver, kidneys, and lungs in preclinical models.

GHRP-2

GHRP-2 has shown parallel but distinct cardioprotective effects. In myocardial infarction models, it interrupted the injury cascade by reducing cardiac fibrosis, decreasing perivascular collagen deposition, and downregulating fibrosis-associated gene expression including connective tissue growth factor (CTGF) and transforming growth factor beta (TGF-beta). Its protective effects are mediated through both GHS-R1a and CD36.

GHRP-2 has also demonstrated myoprotective effects in striated muscle atrophy models, apparently through direct agonistic stimulation of GHS-R1a rather than through IGF-1 elevation. It has shown anti-inflammatory and anti-apoptotic properties in hepatic and renal ischemia/reperfusion injury models via activation of the PI3K/Akt signaling pathway.

These cytoprotective findings have opened a research trajectory that extends well beyond endocrinology. As Berlanga-Acosta and colleagues noted in a 2017 review, cardioprotection remains an "empty niche" in clinical medicine, and GHRPs are among the few compounds demonstrating robust preclinical efficacy in this space.

Synergy with GHRH

Both GHRP-2 and GHRP-6 produce their strongest GH responses when co-administered with GHRH or a GHRH analog like CJC-1295. This is because GHRPs and GHRH operate through complementary mechanisms: GHRH acts on its own receptor (GHRH-R) to initiate GH gene transcription and secretion, while GHRPs act on GHS-R1a to amplify and potentiate the signal.

The synergy is well-documented. In humans, the GH response to GHRH plus a GHRP is substantially greater than the sum of the individual responses, a hallmark of true pharmacological synergy rather than simple additivity. In fact, the GH response to GHRPs can be abolished by a GHRH antagonist or by disconnecting the hypothalamic-pituitary axis, confirming that endogenous GHRH is required for GHRPs to reach their full GH-releasing potential.

Because GHRP-2 already raises intracellular cAMP (the same pathway GHRH uses), the synergy between GHRP-2 and GHRH may have a slightly different mechanistic character than the GHRP-6/GHRH combination. Whether this translates into a clinically meaningful difference in GH output when paired with GHRH remains an open question, though both combinations dramatically outperform either peptide class used alone.

How They Compare to Other GHRPs

GHRP-2 and GHRP-6 are not the only players in this peptide family. Understanding where they sit relative to ipamorelin and hexarelin helps clarify what each brings to the table.

Ipamorelin is the most selective GHRP identified to date. It stimulates GH release with potency and efficacy similar to GHRP-6 in vitro, but it does not meaningfully raise ACTH, cortisol, prolactin, FSH, LH, or TSH. For research designs requiring clean GH stimulation without HPA axis or prolactin confounders, ipamorelin is generally preferred. For more detail, see our ipamorelin vs. GHRP-6 comparison.

Hexarelin is the most potent GHRP by raw GH output but also produces the most pronounced cortisol and prolactin elevations and is subject to rapid tachyphylaxis (desensitization with repeated dosing). For a deeper look at how it stacks up against ipamorelin, see hexarelin vs. ipamorelin.

GHRP-2 and GHRP-6 occupy the middle ground: more potent than ipamorelin (especially GHRP-2), less prone to desensitization than hexarelin, but with moderate off-target hormonal effects that fall between the two extremes.

Peptide	GH Potency	Selectivity	Appetite Effect	Desensitization Risk
Ipamorelin	Moderate	High (minimal cortisol/prolactin)	Minimal	Low
GHRP-2	High	Moderate	Mild-moderate	Low-moderate
GHRP-6	Moderate	Moderate	Strong	Low-moderate
Hexarelin	Very high	Low (notable cortisol/prolactin)	Moderate	High

The Bottom Line

GHRP-2 and GHRP-6 share a receptor, a lineage, and a core function, but they are built for different experimental questions.

GHRP-2 is the stronger GH secretagogue on a per-microgram basis. It raises cAMP in somatotrophs, synergizes with GHRH through overlapping signaling, and produces a relatively contained appetite response. It is the only GHRP approved for any clinical use (as a GHD diagnostic in Japan). Its cardioprotective and myoprotective data add a dimension that extends well beyond endocrinology.

GHRP-6 was the founding member of the family and remains the better-characterized peptide in appetite, feeding behavior, and cardiovascular protection models. Its strong activation of hypothalamic hunger circuits through the NPY/AgRP pathway makes it distinctly useful in cachexia and appetite recovery research. Its cardioprotective data, particularly in myocardial infarction and doxorubicin toxicity models, are among the most robust in the GHRP literature.

Neither peptide is "better" in absolute terms. The choice depends on the research question. For maximal GH output with controlled appetite, GHRP-2 is the more common pick. For appetite-driven models or cardiovascular protection studies, GHRP-6 has deeper supporting evidence. And for investigators who want GH stimulation with minimal hormonal side effects, neither peptide is as clean as ipamorelin.

Both remain investigational compounds in most jurisdictions. Neither is FDA-approved for therapeutic use. Any application in humans should occur only under qualified medical supervision with full regulatory compliance.

References

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Berlanga-Acosta, J. et al. (2017). "Synthetic Growth Hormone-Releasing Peptides (GHRPs): A Historical Appraisal of the Evidences Supporting Their Cytoprotective Effects." Clinical Medicine Insights: Cardiology, 11, 1179546817694558.
Berlanga-Acosta, J. et al. (2024). "Growth hormone releasing peptide-6 (GHRP-6) prevents doxorubicin-induced myocardial and extra-myocardial damages by activating prosurvival mechanisms." Frontiers in Pharmacology, 15, 1402138.
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Frieboes, R.M. et al. (1999). "Effects of growth hormone-releasing peptide-6 on the nocturnal secretion of GH, ACTH and cortisol and on the sleep EEG in man: role of routes of administration." Journal of Neuroendocrinology, 11(6), 473-478.
Garcia-del Barco, D. et al. (2006). "Growth-hormone-releasing peptide 6 (GHRP-6) prevents oxidant cytotoxicity and reduces myocardial necrosis in a model of acute myocardial infarction." Clinical Science, 111(4), 241-250.
Sinha, D.K. et al. (2020). "Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males." Translational Andrology and Urology, 9(S2), S149-S159.
Yin, Y. et al. (2014). "The Growth Hormone Secretagogue Receptor: Its Intracellular Signaling and Regulation." International Journal of Molecular Sciences, 15(3), 4837-4855.