GHRP-6

1) Clinical Overview

GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-Lys-NH₂) is a synthetic hexapeptide agonist of the growth hormone secretagogue receptor (GHS-R1a; the ghrelin receptor). Activation of GHS-R1a stimulates pituitary GH release and can act additively/synergistically with GHRH (somatotroph stimulation via a distinct pathway). Early human work showed robust, dose-related GH rises and clear synergy with exogenous GHRH. 

Beyond GH, GHRP-6 (like other GHS-R agonists) can transiently raise ACTH/cortisol and sometimes prolactin, reflecting hypothalamic involvement. In controlled sleep-lab work, repeated nighttime boluses increased GH and HPA output (ACTH, cortisol) and modestly altered sleep architecture (↑ stage 2). 

The receptor target and signaling are shared with ghrelin; GHS-R1a is the canonical ghrelin receptor mediating these effects. 

2) Human Clinical Findings

Acute IV bolus (dose-response; synergy with GHRH).

18 healthy men received GHRP (GHRP-6) 0.1–1.0 µg/kg IV; GH rose in a clear dose-dependent manner. Co-administration with GHRH (1.0 µg/kg) produced more than additive GH release (synergy). Non-GH pituitary hormones were largely unaffected acutely. 

Oral activity in adults (dose-response).

In 10 healthy men, oral GHRP (30–300 µg/kg) increased peak and integrated GH; 300 µg/kg oral produced responses comparable to 1 µg/kg IV. Effects reflected increased pulse amplitude rather than frequency. 

Prolonged infusion (34 h) and pulsatility.

In 9 healthy men, a 34-hour GHRP-6 infusion increased integrated GH and pulse amplitude and raised IGF-1, while the pituitary remained responsive to test boluses—supporting sustained somatotroph drive under continuous exposure. 

Route comparisons at night (intranasal, sublingual, oral).

Overnight testing found intranasal GHRP-6 significantly increased nocturnal GH; sublingual showed a trend; oral was inactive in that protocol—illustrating route-dependent bioavailability across designs. 

Nocturnal neuroendocrine study (bolus series during sleep).

Four IV boluses (4×50 µg) during the night increased GH and HPA activity (ACTH early night; cortisol particularly in first half of the night) and increased stage-2 sleep; SWS was unchanged. 

Mechanism-of-action evidence from lesion physiology.

In patients with hypothalamo-pituitary disconnection, GHRP-6-induced GH secretion was blocked and synergy with GHRH was lost—indicating a crucial hypothalamic component to GHRP-6 action. 

Oral efficacy in pediatrics; aging/arginine modulation.

Oral GHRP-6 increased GH in short-stature children; other studies show age/sex influences and that oral L-arginine can enhance the GH response to oral GHRP-6 in older adults. 

3) Mechanism & Effects

GHRP-6 binds GHS-R1a on pituitary somatotrophs and in hypothalamic circuitry. Human data support both pituitary and hypothalamic sites of action (the latter inferred from the disconnection studies and HPA co-activation). GHRP-6 and GHRH act via distinct but complementary mechanisms, explaining their synergy. Structural and pharmacologic work around the ghrelin receptor corroborates GHRP-6 as a prototypical agonist in this class. 

Physiologic outputs observed in human studies include:

Endocrine: rapid GH elevations (often with increased pulse amplitude), rises in IGF-1 with prolonged exposure, and modest, context-dependent increases in ACTH/cortisol and occasionally prolactin. 

Sleep/chronobiology: nighttime administration increased stage-2 sleep without changing slow-wave sleep in one controlled study. 

4) Safety & Considerations

Short-term human studies generally report good tolerability, with predictable endocrine shifts (↑GH; occasional ↑ACTH/cortisol and prolactin). Route and dosing influence magnitude and co-hormone effects; long-term safety data in healthy populations remain limited. 

Regulatory/anti-doping: GHRP-6 and other GHS-R agonists are prohibited in sport (peptide hormones, growth factors, related substances; S2 class) by major anti-doping codes. 

References 

1. Bowers CY, 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;70:975-982. 
2. Hartman ML, et al. Oral administration of GH-releasing peptide stimulates GH secretion in normal men. J Clin Endocrinol Metab. 1992;74:1378-1384. 
3. Jaffe CA, et al. Effects of a prolonged GHRP-6 infusion on pulsatile GH secretion in normal men. J Clin Endocrinol Metab. 1993;77:1641-1647. 
4. Frieboes RM, et al. GHRP-6 stimulates sleep, GH, ACTH and cortisol release in normal man. Neuroendocrinology. 1995;61:584-589.
5. Popović V, et al. Blocked GHRP-6-induced GH secretion and loss of synergy with GHRH in hypothalamo-pituitary disconnection. J Clin Endocrinol Metab. 1995;80:942-947. 
6. Peñalva A, et al. Influence of sex, age and adrenergic pathways on the GH response to GHRP-6. Clin Endocrinol (Oxf). 1993;39:307-315.
7. Frieboes R, et al. Effects of GHRP-6 by different routes (p.o., s.l., i.n.) on nocturnal GH/ACTH/cortisol. J Neuroendocrinol. 1999;11:393-401.
8. Müller TD, et al. Minireview: Ghrelin. Mol Metab / Trends Endocrinol Metab (overview of ghrelin/GHS-R1a biology). 
9. VADA (aligned with WADA). Official Prohibited List 2025: peptide hormones & related substances (includes GHRPs).