Historical text by DatBTrue, written between 2008 and 2016 and reproduced verbatim. It records what was argued then; it is not dosing guidance and not medical advice. Read the disclaimer.

We have spent a lot of time in this thread discussing how GHRPs (such as GHRP-6, GHRP-2, Hexarelin & Ipamorelin) potentiate GHRH’s GH releasing effect. We talk of synergy, note GHRPs somatostatin inhibition at the hypothalumus & pituitary and note that GHRPs use a different method then GHRH in changing calcium concentrations within somatotrophs (GH releasing cells in the pituitary) that lead to GH secretion.

But now we learn that GHRH also enhances GHRP’s effect on GH release by binding to the GHS-receptor (obviously in addition to binding to their own GHRH receptors) and increasing the binding strength for GHRPs when they in turn bind. In other words GHRH will partially bind to a GHS-receptor and still allow GHRPs to bind as well. In fact this arrangement likely permits a double stack of two GHRP ligands thus modulating (increasing) GHRPs action.

The study uses Ghrelin but the peptides should behave identically. However the non-peptide mimetics may not.

From the CONCLUSION of Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a ,Felipe F. Casanuevaa, PNAS December 23, 2008 vol. 105 no. 51

In the present study, we provide the first evidence that GHRH specifically binds to the ghrelin receptor GHS-R1a, increasing the binding capacity of its natural ligand. This binding activates the signaling route of inositol phosphate, leading to an intracellular calcium rise, and finally leads to a GHRH-mediated ghrelin receptor endocytosis. Furthermore, GHRH augments the maximal response to ghrelin in respect to inositol phosphates turnover through Gq-associated signal transduction that increases the potency of ghrelin, at least on intracellular calcium rise. …

Thus, GHRH is able to bind to the ghrelin receptor and does not compete for binding against ghrelin. Instead, GHRH increases the affinity of ghrelin, displaying positive binding cooperativity. Furthermore, GHRH increased the maximal response to ghrelin with respect to inositol phosphates turnover through Gq-associated signal transduction. This is in accordance with the concept of GHRH being an allosteric modulator (28, 29). This enhancer function is further supported by the fact that GHRH decreased the EC50 for ghrelin, at least as measured in the calcium assay. …

Finally, and quite remarkably, GHRH activated the endocytosis of the ghrelin receptor. The GHRH/GHSR1a complex progressively disappears from the plasma membrane after 20 minutes exposure to GHRH and accumulates in the perinuclear region after 60 minutes. This observation fits in well with the kinetics of receptor endocytosis described for ghrelin in the present and previous works (27). …

With regard to molecular mechanisms, it is not possible from the present data to establish a model of GHRH action on the ghrelin receptor. A homodimeric model was recently proposed for the ghrelin receptor, in which, because of negative cooperativity, the binding of ghrelin occurs only in one subunit, preventing another ghrelin molecule from binding to the other subunit (32). On the basis of this model, we suggest that GHRH might be able to bind in a multivalent form. When GHRH is present alone, it might bind to one subunit of the dimeric receptor interacting with the orthosteric site (main ghrelin binding site) that determines the agonist properties. However, when ghrelin is also present, GHRH occupies an ‘‘allosteric site,’’ acting as co-agonist that stabilizes the ghrelin binding. This implies that GHRH allows two ghrelin molecules to bind at the same time in the two subunits, which might explain the increase in ghrelin binding capacity observed in the present study.