Peptides: Ghrelin and GHRP Class Overview
Ghrelin was identified in 1999 as the endogenous GHSR ligand (PMID 10604470). Synthetic GHRPs selectively amplify GH pulses; combined with GHRH analogues, they produce 3–4× greater GH release.
| Measure | Value | Unit | Notes |
|---|---|---|---|
| Evidence Grade | A/B | grade | Ghrelin physiology: Grade A (human RCTs, PMID 10604470; 11238505). GHRP performance protocols: Grade B (human PK studies; no RCTs for body composition) |
| Ghrelin Length | 28 | amino acids | 28-amino acid peptide; requires octanoyl (n-octanoic acid) modification at Ser3 for full GHSR activity; des-acyl ghrelin is inactive at GHSR |
| GH Synergy with GHRH | 3–4× | greater GH pulse | Combining GHRH analogue + GHRP produces approximately 3–4× greater GH pulse amplitude than either alone (PMID 16368745) |
| GHSR Saturation Dose | ~300 | mcg | Above ~300mcg per injection, GHRPs show dose-saturation for GH release; higher doses increase cortisol and prolactin proportionally more than GH |
| Orexigenic Pathway | NPY/AgRP neurons | mechanism | Ghrelin stimulates hypothalamic NPY/AgRP neurons to increase appetite; synthetic GHRPs partially replicate this — GHRP-6 most strongly, ipamorelin least |
| GHRP-6 vs GHRP-2 Hunger | GHRP-6 > GHRP-2 | comparative | GHRP-6 produces more pronounced hunger within 20–30 min post-injection due to deeper ghrelin pathway mimicry |
| Cortisol/Prolactin at High Dose | Dose-dependent increase | side effect | Both GHRP-2 and GHRP-6 increase cortisol and prolactin dose-dependently above 300mcg; ipamorelin minimal at standard doses |
Ghrelin was identified in 1999 by Kojima et al. (PMID 10604470) as the endogenous ligand for the growth hormone secretagogue receptor (GHSR-1a). The discovery explained why a class of synthetic GH-releasing peptides (GHRPs) developed in the 1980s worked — they were unknowingly mimicking a natural stomach hormone. Ghrelin is a 28-amino acid peptide requiring acylation at Ser3 for GHSR activity; the des-acyl form has negligible GH-releasing activity but retains some metabolic effects via non-GHSR pathways.
Arvat et al. 2001 (PMID 11238505) confirmed in humans that native ghrelin infusion produces robust GH pulses, elevates cortisol and prolactin, and stimulates appetite — establishing the full pharmacological profile that synthetic GHRPs partially replicate.
Dose-Response: GHRP Effects at Different Doses
| Dose | GHRP-2 GH Effect | GHRP-6 GH Effect | Hunger Side Effect | Cortisol Increase | Practical Notes |
|---|---|---|---|---|---|
| 50mcg | Modest GH pulse (~2–3× baseline) | Similar to GHRP-2 | Minimal | Minimal | Useful for testing sensitivity; below typical protocol dose |
| 100mcg | Good GH pulse (~4–5× baseline) | Similar to GHRP-2 | Mild (GHRP-6 noticeable) | Minimal | Standard starting dose; sweet spot for GH/side effect ratio |
| 200mcg | Strong GH pulse | Strong GH pulse | Moderate hunger with GHRP-6; mild with GHRP-2 | Modest increase | Common upper range for single dose |
| 300mcg | Near-maximal GH pulse; receptor approaching saturation | Near-maximal | Significant hunger with GHRP-6 | Measurable cortisol rise | Cortisol/prolactin begin to increase disproportionately |
| 500mcg+ | Minimal additional GH; receptor saturated | Similar plateau | Strong hunger, nausea possible | Marked cortisol increase | Not recommended; diminishing returns on GH, increasing adverse effects |
| Combined with CJC-1295 no-DAC (100mcg) | 3–4× greater GH pulse vs GHRP alone | 3–4× greater GH pulse | Unchanged | Unchanged | Synergy via dual receptor mechanism; this is the standard performance protocol |
GHRP Mechanism: GHSR Agonism
All synthetic GHRPs bind GHSR-1a in the pituitary and hypothalamus. This:
- Directly stimulates pituitary somatotrophs to release stored GH
- Suppresses somatostatin release from the hypothalamus (disinhibition)
- Amplifies the GHRH signal when GHRH is present simultaneously
Point 3 explains the synergy: GHRH analogues (CJC-1295, sermorelin) prime somatotroph GH synthesis, while GHRPs remove the somatostatin brake and directly trigger release — the two signals on different receptors are multiplicative, not merely additive (PMID 16368745).
Ghrelin’s Dual Role: GH Secretagogue vs. Appetite Stimulator
The orexigenic (appetite-stimulating) effect of ghrelin is mediated by separate hypothalamic pathways from its GH-releasing effects:
- GH release: GHSR-1a on pituitary somatotrophs + hypothalamic GH neurons
- Appetite: GHSR-1a on hypothalamic NPY/AgRP neurons → increased food-seeking behavior
Synthetic GHRPs differ in how much they activate the appetite pathway. GHRP-6 most closely mimics native ghrelin’s full profile (GH + appetite). GHRP-2 is somewhat more pituitary-selective. Ipamorelin is highly selective for GH release with minimal orexigenic or HPA axis effects at standard doses — making it the preferred choice for users who do not want the appetite stimulation side effect.
Related Pages
Sources
- Kojima M et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656-60. PMID 10604470
- Arvat E et al. Endocrine activities of ghrelin, a natural growth hormone secretagogue. J Clin Endocrinol Metab. 2001;86(3):1169-74. PMID 11238505
- Teichman SL et al. Prolonged stimulation of GH and IGF-I secretion by CJC-1295. J Clin Endocrinol Metab. 2006;91(3):799-805. PMID 16368745
Frequently Asked Questions
What makes ghrelin different from other GH-releasing signals?
Ghrelin acts via a completely separate receptor (GHSR-1a) from GHRH (which uses GHRH-R). This means ghrelin and GHRH signals are additive: stimulating both receptors simultaneously produces a much larger GH pulse than either signal alone. This synergy is the pharmacological basis for combining GHRH analogues (like CJC-1295) with GHRP-class peptides in performance protocols.
At what dose do GHRPs stop producing more GH and start causing more side effects?
Approximately 300mcg per injection is the saturation point for GHSR-mediated GH release. Above this dose, GH pulse amplitude plateaus or increases only marginally, while cortisol and prolactin continue to rise dose-dependently. For this reason, most protocols cap individual GHRP doses at 100–300mcg and increase frequency rather than dose size.
Why does GHRP-6 cause more hunger than GHRP-2 or ipamorelin?
GHRP-6 more closely mimics the full ghrelin molecule, including its orexigenic signaling via hypothalamic NPY/AgRP neurons. GHRP-2 is more selective for the GH-releasing aspect of GHSR activation. Ipamorelin is the most selective, with minimal orexigenic and HPA axis effects at standard 100–300mcg doses. Hunger with GHRP-6 typically peaks 20–30 minutes post-injection and resolves within 1–2 hours.