Hexarelin

Hexarelin (His-D-2-methylTrp-Ala-Trp-D-Phe-Lys-NH2) is a synthetic analogue of GHRP-6, developed in Italy in the early 1990s. It is the most potent acute growth hormone releaser among the peptide secretagogues that have been tested head to head in people [4].

Acute effect. In 12 healthy young volunteers, 1 ug/kg intravenously released about twice as much growth hormone as 1 ug/kg of GHRH, and 2 ug/kg released more still. The same study measured every route: the subcutaneous route was about 77% as effective as intravenous, intranasal 4.8%, and oral 0.3% [1]. Intranasal hexarelin works, but needs about 20 times the intravenous dose [5].

In older people. The growth hormone response to hexarelin falls with age — about 2,100 vs 4,800 ug.min/L in elderly against young men — but it can be restored: adding arginine brought the elderly response back up to young levels, while adding GHRH potentiated both groups [6]. This is the same pattern seen with GHRP-6, where the response is far better preserved with age than the response to GHRH [7].

Long-term. This is where it falls down. Sixteen weeks of 1.5 ug/kg twice daily subcutaneously cut the growth hormone response to a test dose from 19.1 to 10.5 ug/L.h. Serum IGF-1 and IGF-binding protein-3 did not change over the whole 20-week period, and neither did total body fat, lean mass or bone mineral density. Four weeks after stopping, the growth hormone response was back to baseline [3].

As a diagnostic test. Low-dose hexarelin (0.25 ug/kg) with GHRH produced a mean growth hormone peak of 83.6 ug/L in healthy adults and 2.6 ug/L in hypopituitary adults, separating the groups as well as the insulin tolerance test [2]. Sequential GHRH followed by hexarelin has also been used to probe pituitary reserve [8].

Hexarelin acts at GHS-R1a, the ghrelin receptor, not at the GHRH receptor. The cleanest evidence for where it acts comes from people with a functional pituitary stalk disconnection: their growth hormone response to GHRH is normal, but the response to GH-releasing peptide is completely blocked, and the usual synergy between the two disappears. The main action is therefore hypothalamic [9].

That also explains the synergy with GHRH and with arginine, which works by suppressing somatostatin [6]. Selectivity is poor: at the same doses that release growth hormone, hexarelin raises prolactin, ACTH and cortisol, the last to about the same degree as CRH [4]. This is the difference between hexarelin and ipamorelin, which was designed to avoid it [10].

Beyond the pituitary, hexarelin binds cardiac tissue and has protected the heart in several animal models of infarction and cardiomyopathy [11][12]. None of this has been tested in humans.

Hexarelin is a hexapeptide supplied as an acetate salt. All four routes have been measured against each other in the same volunteers: subcutaneous injection retains about 77% of intravenous activity, a nasal spray about 5%, and an oral dose about 0.3% — which is why the oral studies used 20-40 mg against 1-2 ug/kg intravenously [1].

Human safety data amount to single doses in small volunteer groups and one 16-week study, which reported no notable problems but also no benefit [3]. Acutely, the main pharmacological concern is the parallel rise in ACTH and cortisol, which is of the same size as that produced by CRH [4], and the rise in prolactin [4].

Repeated dosing produces partial, reversible desensitisation of the pituitary response rather than escalating effect [3]. There is no long-term safety data, no data on glucose, and no data in people using it for body composition.

Hexarelin synergises strongly with GHRH — the combination released far more growth hormone than the sum of each alone in healthy people, and that synergy disappears when the hypothalamus is disconnected from the pituitary [6][9]. Arginine also potentiates it, but only in older people [6]. No interactions with other compounds on this site have been documented.