GHRP-2

GHRP-2 (D-Ala-D-beta-Nal-Ala-Trp-D-Phe-Lys-NH2), also called pralmorelin, is a synthetic "super-analog" of GHRP-6 [1]. Like the rest of the family it acts at the ghrelin receptor, mostly at the hypothalamic level [3].

Acute potency. Compared head to head with hexarelin in six healthy young adults, 1 and 2 ug/kg intravenously produced near-identical growth hormone responses, both larger than the response to 1 ug/kg GHRH. In healthy people aged 66-73, both peptides again performed similarly [1]. In pigs, GHRP-2 was the most potent of the family tested, though with a lower maximum response than GHRP-6 or ipamorelin [4].

Synergy. GHRP-2 combines supra-additively with L-arginine in men and women, at rest and during exercise, with the rank order arginine+GHRP-2 > GHRP-2 > arginine > saline [5]. The same synergy holds with GHRH [2].

Repeated dosing. Bowers gave healthy younger and older adults GHRP-2, GHRH or both for 7-30 days. Chronic dosing with either changed the relationship between them, turning an additive combined response into a synergistic one, and whether the response desensitized depended on how much was given and how often [2].

In illness. A 21-hour infusion in patients with prolonged critical illness restored the normal temporal coupling between growth hormone, TSH and prolactin secretion, which infusions of GHRH or TRH did not [6].

What is missing is any trial of the thing people take it for. There is no controlled study of GHRP-2 on lean mass, fat mass, strength or sustained IGF-1 in healthy adults.

GHRP-2 is an agonist at GHS-R1a. That receptor was cloned from the search for what the GH-releasing peptides bind, and it shared no sequence homology with any G-protein-coupled receptor then known - which is what convinced the field a natural ligand had to exist, some years before ghrelin was found [7].

Where it acts. Pituitary and hypothalamus both, with the hypothalamic component dominant: in patients whose pituitary is functionally disconnected from the hypothalamus, GH-releasing peptide produces essentially no growth hormone while GHRH still works normally, and the usual synergy between the two vanishes [3]. What the peptides do in the hypothalamus was never settled; the field's own review leaves open an unidentified hypothalamic factor beyond GHRH and somatostatin [7].

What it resists. The signature of this class is that the influences which nearly abolish the GHRH response - neurotransmitters, glucose, free fatty acids, glucocorticoids, exogenous growth hormone, even somatostatin itself - only blunt the GHRP response. It survives in acromegaly, anorexia nervosa and hyperthyroidism, and is almost absent in stalk disconnection and Cushing's syndrome. It rises from birth to puberty and falls with age [7].

Structure. A radio-competitive assay at GHSR1a against labeled ghrelin, run across the family, identified Ala-Trp-(D-Phe)-Lys as the shared core, with positions 1, 2, 3 and 7 carrying the modifications that change activity. Running the same assay on urine collected after nasal dosing with GHRP-1, GHRP-2, GHRP-6, hexarelin and ipamorelin still detected receptor binding, so some of what is excreted is still active at the receptor [8].

The selectivity problem. In conscious swine, none of the secretagogues tested moved FSH, LH, prolactin or TSH, but GHRP-2 and GHRP-6 both raised ACTH and cortisol while Ipamorelin did not - not even at more than 200 times its ED50 for growth hormone [4]. That is the proof the two effects are separable, and that GHRP-2 sits on the wrong side of the line. In people, its ACTH and cortisol response is about as large as that to hCRH, and it raises prolactin too, though less than TRH does [1]. The route is direct rather than hypothalamic: mouse anterior pituitary cells express the receptor's mRNA, and GHRP-2 stimulated both the secretion and the synthesis of ACTH in them while raising intracellular cyclic AMP. The PKA inhibitor H89 and the PKC inhibitor bisindolylmaleimide I each blocked ACTH release, but only H89 blocked the rise in proopiomelanocortin mRNA - so release runs through both kinases and synthesis only through PKA [9].

GHRP-2 is a hexapeptide, usually supplied as the acetate. The published human route is intravenous, by bolus or infusion [1][6]; in Japan it has been used as a single-dose diagnostic injection. Urinary tests for GHRP-2 and GHRP-6 exist and are used in sport [10].

Human exposure in the published literature is almost entirely single intravenous doses in small volunteer groups, plus infusions in intensive care and up to 30 days of dosing in Bowers's studies [1][2][6]. No serious adverse effects are reported in those settings, but they are far too small and short to establish safety for ongoing use.

The predictable pharmacological problems are the cortisol and prolactin rises that come with every dose [1], and desensitization of the growth hormone response with frequent dosing [2] — the same pattern hexarelin shows clearly over 16 weeks [11]. There are no published data on glucose, on IGF-1 over months, or on any long-term outcome.