GHRP-6: Complete Guide

GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) was among the first synthetic peptides found to stimulate GH release from the pituitary through a mechanism independent of GHRH. Cyril Bowers and colleagues at Tulane University developed the growth hormone releasing peptide series beginning in the early 1980s, building on their discovery that modified met-enkephalin derivatives could specifically stimulate GH release from pituitary cells. GHRP-6 emerged as one of the most potent early compounds (Bowers, Cellular and Molecular Life Sciences 1998).

The existence of GHRP-6 and its pharmacological properties raised a critical question: if synthetic peptides could activate a specific receptor to release GH, what was the body's natural ligand for that receptor? This question drove Howard et al. (1996) to clone the growth hormone secretagogue receptor (GHS-R/GHSR-1a) as an orphan receptor — one whose natural activating hormone was unknown. Kojima and colleagues at Kurume University in Japan then used GHSR-1a as bait to identify the endogenous ligand, discovering ghrelin — a 28-amino-acid peptide secreted primarily by the stomach — in 1999 (Kojima et al., Nature 1999).

GHRP-6's defining characteristic is its potent activation of hunger. Within 20 minutes of subcutaneous injection, most users experience intense hunger that lasts 30–60 minutes. This effect is mediated by the same ghrelin receptor that regulates appetite in the hypothalamic arcuate nucleus, and it distinguishes GHRP-6 from newer, more selective GH secretagogues like ipamorelin.

GHRP-6 activates GHSR-1a in multiple tissues, producing a broader range of effects than more selective GH secretagogues:

• Pituitary GH release: Direct GHSR-1a activation on somatotrophs depolarizes cell membranes via PLC/IP3/PKC-mediated calcium influx, producing dose-dependent GH pulses. The pathway is complementary to (not competitive with) GHRH signaling, enabling synergistic effects when combined
• Appetite stimulation: GHSR-1a activation in the hypothalamic arcuate nucleus stimulates NPY/AgRP neurons — the same circuit activated by endogenous ghrelin. GHRP-6 has the strongest orexigenic (appetite-stimulating) activity of any commonly used GHRP, producing intense hunger within 20 minutes that persists for 30–60 minutes
• ACTH/cortisol release: Stimulates hypothalamic CRH secretion, increasing ACTH and cortisol output. This effect is more pronounced than with ipamorelin and may partially counteract anabolic benefits during chronic use
• Prolactin elevation: Increases prolactin secretion — a side effect shared with GHRP-2 and hexarelin but absent from ipamorelin
• Gastric motility: Ghrelin-like activation of GHSR-1a in the enteric nervous system increases gastric emptying and gut motility — useful for those with delayed gastric emptying, but potentially contributing to GI discomfort in some users
• Cytoprotective effects: GHRP-6 has demonstrated GH-independent cardioprotective and hepatoprotective properties. In cardiac ischemia-reperfusion models, GHRP-6 reduces infarct size and improves cardiac function through mechanisms involving NF-κB pathway modulation and anti-inflammatory signaling (Berlanga et al., 2007)

The story of GHRP-6 is inseparable from the discovery of ghrelin — one of the most important findings in endocrinology in the past three decades. The historical sequence illustrates how pharmacological tools can reveal fundamental biology:

1. 1980s — Bowers' GHRPs: Cyril Bowers discovers that synthetic hexapeptides can specifically stimulate GH release from the pituitary through an unknown mechanism unrelated to GHRH
2. 1996 — Receptor cloning: Howard et al. clone the growth hormone secretagogue receptor (GHS-R/GHSR-1a) — an orphan G protein-coupled receptor that GHRPs activate but whose natural ligand is unknown
3. 1999 — Ghrelin discovery: Kojima et al. at Kurume University use GHSR-1a as a molecular probe to search for its endogenous ligand. They identify ghrelin — a 28-amino-acid acylated peptide produced primarily by gastric oxyntic glands — as the natural "hunger hormone" that activates the same receptor as GHRP-6
4. 2000s — Ghrelin biology explodes: Research reveals ghrelin's roles in appetite regulation, energy balance, GH secretion, gastrointestinal motility, cardiovascular protection, bone metabolism, and immune function

Without GHRP-6 and the other synthetic GH secretagogues, ghrelin might have remained undiscovered for decades. GHRP-6 is thus historically significant far beyond its pharmacological use — it opened the door to an entire field of ghrelin biology that now encompasses thousands of publications.

Beyond GH release and appetite stimulation, GHRP-6 has demonstrated tissue-protective effects that operate independently of growth hormone:

Cardioprotection

GHRP-6 reduces ischemia-reperfusion injury in cardiac models, decreasing infarct size by 50–60% in animal studies. This effect persists even when GH release is pharmacologically blocked, confirming a GH-independent mechanism. The cardioprotective pathway involves NF-κB modulation, reduced inflammatory cytokine release, and preservation of mitochondrial membrane integrity. These findings parallel the cardiac benefits observed with hexarelin, which acts primarily through CD36 receptors in cardiac tissue.

Hepatoprotection

GHRP-6 has shown hepatoprotective effects in animal models of liver injury, including ischemia-reperfusion and fibrosis models. The mechanism involves reduced oxidative stress, inflammatory cytokine suppression, and enhanced hepatocyte survival signaling. Berlanga et al. demonstrated that GHRP-6 reduces liver fibrosis progression in a CCl4-induced cirrhosis model in rats.

Neuroprotection

Emerging research suggests GHRP-6 may have neuroprotective properties through GHSR-1a activation in the central nervous system, though this area is less well-characterized than its cardiac and hepatic effects.

Must be administered fasted for optimal GH response — carbohydrates raise insulin and somatostatin, blunting GH release. The intense hunger onset (~20 min post-injection, lasting 30–60 min) can be used strategically before meals for caloric surplus goals. This makes GHRP-6 uniquely suited to a pre-meal timing protocol that other GH secretagogues do not support as effectively.

Use the peptide calculator for reconstitution. Standard reconstitution: 2 mL bacteriostatic water per 5 mg vial.

GHRP-6's side effect profile is dominated by its potent ghrelin-mimetic activity:

• Intense hunger: The defining and most disruptive side effect. Onset ~20 minutes post-injection, lasting 30–60 minutes. Described as ravenous, sometimes uncontrollable hunger. For hardgainers, this is the reason to choose GHRP-6 over other GHRPs. For those pursuing fat loss or caloric restriction, it is a significant liability
• Cortisol elevation: Significant at higher doses. Chronic ACTH/cortisol stimulation may counteract the anabolic benefits of GH by promoting protein catabolism and visceral fat deposition. More pronounced than GHRP-2 at equivalent doses
• Prolactin elevation: Can affect reproductive function, libido, and mood with chronic use. Dose-dependent and more noticeable than with ipamorelin
• Water retention: Related to GH elevation; generally mild but noticeable as facial or extremity puffiness
• Tingling/numbness: Common immediately after injection — warm sensation, pins-and-needles. Typically lasts 5–15 minutes
• Blood sugar effects: Can cause transient hypoglycemia (rebound from insulin release), which contributes to the hunger response. Monitor blood glucose if diabetic or using other glucose-lowering agents
• Dizziness/lightheadedness: Occasional, typically related to the GH pulse or transient hypoglycemia

• Bulking vs. cutting: GHRP-6 is best suited for bulking phases where caloric surplus is the goal. Its intense appetite stimulation is counterproductive during cutting or caloric restriction. For fat loss with GH support, ipamorelin is the better choice
• Hardgainer strategy: The most effective way to use GHRP-6's appetite effect is to inject 100 mcg subcutaneously 20–30 minutes before a planned large meal. The hunger peak coincides with mealtime, enabling larger caloric intake
• Combination stacks: GHRP-6 + CJC-1295 (no DAC) or sermorelin is the standard synergistic combination. Do NOT combine GHRP-6 with other GHRPs (GHRP-2, hexarelin, ipamorelin) — they compete for the same receptor without additive benefit
• Storage: Lyophilized powder stable at room temperature for weeks; refrigerated for months. Reconstituted solution: 2–8°C, use within 4–6 weeks
• Anti-doping: GHRP-6 is prohibited by WADA under S2 (peptide hormones, growth factors, related substances, and mimetics). Metabolites are detectable in urine
• Desensitization: GHRP-6 shows minimal receptor desensitization compared to hexarelin. GH response is generally maintained with chronic use, though hunger response may somewhat attenuate over weeks