What is CJC-1295 ipamorelin? Two receptors, one pulse

The axis in three lines

The hypothalamus releases growth-hormone-releasing hormone (GHRH) into the blood vessels that feed the pituitary. Somatotroph cells in the pituitary answer with a burst of growth hormone (GH). GH acts on the liver and other tissues, which respond with insulin-like growth factor 1 (IGF-1), and IGF-1 feeds back to slow the whole loop. A second hypothalamic hormone, somatostatin, brakes the somatotrophs between bursts. Everything on this site happens at the somatotroph, which carries two receptors that synthetic peptides can reach from outside.

Receptor one: GHRH, and the fragment that became CJC-1295

Human GHRH is a 44-residue peptide, characterised in 1982 from a pancreatic tumour that was over-producing it; its first 29 residues carry the full activity [Rivier et al., 1982]. Those 29 residues are the parent of sermorelin, of Mod GRF 1-29 and of CJC-1295. The GHRH receptor is a G-protein-coupled receptor on the somatotroph membrane; occupying it raises cyclic AMP inside the cell, which both releases stored GH and switches on transcription of more. The native fragment is cut within minutes by dipeptidyl peptidase IV.

ConjuChem's CJC-1295 keeps the receptor-binding sequence, swaps four residues to slow the cutting, and adds a maleimide tail that bonds the peptide to serum albumin after injection, so that it circulates for days [Jetté et al., 2005]. In healthy adults the result was a half-life of 5.8 to 8.1 days and GH held 2 to 10-fold above baseline for 6 days or more from one dose [Teichman et al., 2006]. The linker's consequences, and why the blend usually omits it, are in DAC versus no DAC.

Receptor two: the one ghrelin binds, and the pentapeptide built for it

The second receptor was discovered backwards. Synthetic hexapeptides that released GH, the GHRPs, existed from the early 1980s, and they plainly did not act through the GHRH receptor; in 1996 Howard and colleagues cloned the receptor they did act through, from pituitary and hypothalamus, and called it the growth hormone secretagogue receptor [Howard et al., 1996]. Its natural ligand was found only in 1999: ghrelin, an acylated 28-residue peptide secreted by the stomach, which turned out to be a hunger signal as well as a GH secretagogue [Kojima et al., 1999].

Ipamorelin was designed in the interval. Novo Nordisk's chemists cut the GHRP scaffold down to five residues, Aib-His-D-2-Nal-D-Phe-Lys-NH2, and selected it because it released GH with the potency of GHRP-6 while, in swine, leaving ACTH and cortisol at the levels seen after GHRH even at 200 times its ED50, and leaving prolactin, TSH, FSH and LH unchanged [Raun et al., 1998]. In men, an intravenous infusion produces one GH episode that peaks at 0.67 hours; the peptide's terminal half-life is 2 hours [Gobburu et al., 1999].

Why two beat one: the 1990 experiment

The reason anyone pairs a GHRH analogue with a GHRP is one paper. In 1990 Bowers, Thorner and colleagues gave 18 normal men the hexapeptide GHRP-6 at 0.1, 0.3 and 1.0 µg/kg, GHRH(1-44) at 1.0 µg/kg, and combinations. GHRP-6 alone raised peak GH from 1.2 µg/l with placebo to 7.6, 16.5 and 68.7 µg/l. The submaximal doses of GHRP-6, 0.1 and 0.3 µg/kg, given together with 1 µg/kg of GHRH, released GH synergistically, more than the two responses added.

The authors concluded that the two peptides act independently, through separate systems, and that the GHRP system was a physiological one awaiting characterisation [Bowers et al., 1990]; the cloning of the receptor six years later and the discovery of ghrelin nine years later proved them right. The same study is the source of two safety observations: GHRP-6 raised prolactin and cortisol about 2-fold at the 1 µg/kg dose, the effect ipamorelin was later designed to lose, and GHRH caused one to three minutes of facial flushing in 16 of 18 men, the effect every GHRH analogue since has shared.

That is the entire experimental basis for the "stack". It was done with GHRH(1-44) and GHRP-6, not with CJC-1295 and ipamorelin; the principle transfers because the receptors are the same, the numbers do not. No published human study has given CJC-1295 and ipamorelin together.

Pulses, and what a week-long signal does to them

GH is not secreted steadily. It comes in bursts, several a day and the largest in the first hours of sleep, with near-zero levels between; the pattern is set by alternating GHRH and somatostatin from the hypothalamus. Physiologists have long held that the pattern matters as much as the total, which raised an obvious question about a GHRH analogue that never leaves: would a week of continuous stimulation flatten the bursts into a plateau? Ionescu and Frohman measured it.

Healthy men aged 20 to 40 were sampled every 20 minutes for 12 hours overnight, injected once with 60 or 90 µg/kg of CJC-1295, and sampled again a week later. The number of pulses and their amplitude did not change. The trough between them rose 7.5-fold, and that raised floor drove a 46 % rise in mean GH and a 45 % rise in IGF-1 [Ionescu et al., 2006].

Put the two charts together and the design of the pair becomes legible. A GHRH-type signal sets how much GH each burst can carry; a ghrelin-type signal triggers a burst. The DAC form of CJC-1295 raises the floor for a week; the linker-free form and ipamorelin each contribute to one burst and are gone.

From physiology to a vial

The research-market product called "CJC-1295 ipamorelin" translates that physiology into a single lyophilized vial: equal masses of the linker-free CJC-1295 (Mod GRF 1-29) and of ipamorelin, commonly 5 mg of each. Equal mass is not equal molarity; at 3,367.9 and 711.9 g/mol the vial holds about 4.7 molecules of ipamorelin per molecule of the GHRH analogue. Why the blend uses the linker-free form is a matter of time scale, explained in DAC versus no DAC; what a listing for such a vial must state is in CJC-1295 ipamorelin for sale.

What the mechanism does not tell you

A mechanism explains why an effect is plausible; it does not measure the effect. The GH and IGF-1 numbers above are real, and they belong to CJC-1295 with DAC given alone. For the pair as sold, there is no human measurement of GH, of IGF-1, of body composition or of sleep. For ipamorelin alone the human GH data stop at a single infusion. Pages that move from "two receptors" to "muscle, fat, recovery, sleep" have crossed from mechanism into claims that nothing in the literature supports for these molecules. The doses that were actually studied are in the dosage guide.

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