CJC-1295 and GHRP-2 Blend – Synergistic Potential on the GH-IGF-1 Axis

CJC-1295 and Growth hormone–releasing peptide–2 (GHRP-2) represent two distinct but potentially complementary strategies for increasing growth hormone (GH) output in laboratory settings. GHRP‑2 is a small, synthetic hexapeptide originally engineered from modifications of enkephalin‑like sequences. It is believed to act preferentially at the ghrelin receptor (GHSR1a). By contrast, CJC‑1295 is a tetrasubstituted analogue of the N‑terminal 29 amino acids of GH‑releasing hormone (GHRH), chemically “locked” to serum albumin via a maleimidopropionamide linker and designed to prolong receptor engagement at the classic GHRH receptor.

Although each peptide has shown promise individually in raising GH—and, secondarily, insulin-like growth factor-1 (IGF-1)—levels in preclinical and early clinical studies, there remains considerable uncertainty about whether their mechanisms might intersect or even synergize when exposed to research models in combination. On one hand, GHRP‑2 and CJC‑1295 exploit separate GPCRs with divergent downstream signaling; on the other, both ultimately converge on the somatotroph’s secretory machinery. Exploring their combined exposure to research models in laboratory settings may further reveal additive or synergistic potential on GH pulsatility in laboratory settings.

 

Research

Structural Differences of CJC-1295 and GHRP-2

Researchers such as Jette et al. suggest that CJC-1295 is “a tetrasubstituted form of hGRF1–29 with an added Nε-3-maleimidopropionamide derivative of lysine at the C terminus”.⁽¹⁾ As a reference, hGRF 1–29 refers to the 29-amino acid N-terminal fragment of growth hormone-releasing hormone (GHRH), which corresponds to the biologically active portion of the full 44-residue GHRH responsible for stimulating growth hormone release. This truncated form is commonly exposed to research models for experimental purposes due to its preserved receptor activity.

This peptide features several specific amino acid substitutions and a chemical conjugation moiety, which may confer enhanced stability and pharmacokinetic properties. Specifically, CJC-1295 possesses a D-alanine substitution at the 2-position, which possibly supports resistance to enzymatic degradation by dipeptidylpeptidase-IV (DPP-IV), a primary enzyme implicated in the rapid clearance of endogenous GHRH peptides. Additional substitutions include a glutamine residue replacing asparagine at position 8, posited to reduce asparagine-related chemical rearrangements or hydrolysis, an alanine substitution at the 15-position hypothesized to increase bioactivity, and a leucine at position 27 to mitigate methionine oxidation, potentially.

Structurally speaking, CJC-1295 also carries a Nε-3-maleimidopropionic acid (MPA) moiety attached to an extra lysine residue introduced at the C-terminus beyond the endogenous 29 amino acids of hGRF. The maleimido group is crucial to this process because it facilitates covalent binding to the free thiol group of cysteine residue 34 on albumin in extravascular fluids. This plays a critical role in extending the peptide’s plasma residence time by reducing clearance and protecting it from proteolytic degradation. Specifically, as Jette et al. comment, the half-life of observed cell cultures may be extended by up to 72 hours.

In contrast, research by Berlanga-Acosta et al. suggests that GHRP-2 is a synthetic hexapeptide derived from other GHRPs, such as GHRP-6. Notably, the class of GHRPs is inspired by modifications of enkephalins, which are regularly occurring pentapeptides that function as endogenous opioids. Initial observations suggested that certain chemical analogs of enkephalin amide may contribute to the induction of growth hormone release. They may, by extension, support the hypothesis that modifications to the enkephalin structure may produce potent synthetic peptides with novel bioactivity. Thus, GHRP-2 might be considered an engineered sequence, possibly derived from or related to enkephalins, and specifically optimized to elicit growth hormone release instead of opioid actions.

Mechanisms of Action of CJC-1295 and GHRP-2 on Pituitary Cells

The structural difference between CJC-1295 and GHRP-2 also results in significantly different receptor affinities, despite both peptides being researched for their potential to increase GH synthesis in pituitary cells. Specifically, CJC-1295 appears to engage with the GHRH receptors, which normally respond to endogenous GHRH and are considered the main type of receptors mediating GH synthesis. Research by Culhane et al. suggests this may be a two‑stage process.⁽³⁾

In the first stage, the back end of CJC‑1295 might loosely latch onto the receptor’s outer domain, a region that apadles growth‑hormone–releasing peptides. Structural studies of similar receptors suggest this “docking” may involve the peptide’s helical segment slipping into a groove on the receptor’s surface. In a second step, the front end of CJC‑1295 potentially pokes deeper into the space between the receptor’s outer loops and its membrane‑spanning helices.

By making contact in this way, CJC-1295 may subtly alter the orientation of those helices, encouraging one helix (TM6) to swing outward. This movement is commonly posited to open up the receptor’s inner face, where it may then engage G proteins and trigger the cAMP signaling cascade that leads to GH release. Altogether, these ideas suggest that CJC‑1295 might act in much the same way as endogenous GHRH. Added modifications may potentially prolong its stay on the receptor and, therefore, extend its growth–hormone–releasing potential.

On the other hand, GHRP‑2 may engage the growth‑hormone secretagogue receptor (GHSR1a, also referred to as the ghrelin receptor) in a way that mirrors, but is not identical to, the way ghrelin itself binds. Research by Yin et al. suggests that GHSR1a is a seven‑transmembrane GPCR that presents a deep binding pocket formed largely by helices II, III, V, and VI.⁽⁴⁾ It’s been posited that the C‑terminal end of GHRP‑2 first docks against key polar residues near the extracellular loops—perhaps involving contacts with Glu124 and surrounding charged side chains—much as other secretagogues do.

Once the peptide’s tail is loosely anchored, the N‑terminal segment of GHRP‑2 may then insert more fully into the crevice between the transmembrane helices, thereby permitting G‑protein coupling. This may lead to activation of phospholipase C (PLC). In this scenario, PLC would hydrolyze membrane phosphatidyl‑inositol 4,5‑bisphosphate (PIP₂) into two second messengers—inositol 1,4,5‑trisphosphate (IP₃) and diacylglycerol (DAG).

IP₃ might then diffuse through the cytosol to bind IP₃ receptors on the endoplasmic reticulum, triggering a release of stored Ca²⁺ into the cytoplasm and thereby elevating Ca²⁺ ion levels. Meanwhile, the locally generated DAG may remain in the membrane and possibly recruit and activate protein kinase C (PKC), which in turn might phosphorylate downstream targets that modulate both growth hormone exocytosis and gene transcription.

CJC-1295 and GHRP-2 Potential on the GH-IGF-1 Axis

As mentioned, both CJC-1295 and GHRP-2 are researched in the context of stimulating GH synthesis. GH acting on hepatic and other cells may also drive IGF‑1 gene transcription and secretion. IGF‑1 (insulin‑like growth factor‑1) is a peptide hormone that mediates many of GH’s growth‑promoting and metabolic potential.

Research on CJC-1295 by Teichman et al. suggests that CJC-1295 may boost “GH concentrations by 2- to 10-fold for 6 d or more”.⁽⁵⁾ This elevation appeared to occur within 2 hours after exposure to the peptide, and the cells continued to produce elevated levels of GH for about 6 days. The area under the GH curve over the first week rose from ~758 ng·h/mL (30 µg/kg) to ~1,370 ng·h/mL (250 µg/kg)—suggesting about a 2‑ to 3‑fold greater overall GH release compared with unstimulated conditions. Consequently, the levels of the anabolic mediator IGF-1 were also elevated by 1.5- to 3-fold compared to baseline.

Research on GHRP-2 by Bowers et al. also suggests that the peptide may provoke a remarkably robust amplification of GH output, on the order of 6-fold above baseline secretion.⁽⁶⁾ Specifically, the experiment involved a 24-hour continuous exposure to GHRP‑2 at a concentration of 1 µg/kg·h, which appeared to increase total daily GH secretion from roughly 20–30 µg·L⁻¹·24 h (placebo) to about 120–180 µg·L⁻¹·24 h. Furthermore, IGF‑1 rose from roughly 90–100 µg/L at baseline to about 150–160 µg/L after 24 hours of GHRP‑2 exposure and up to 180 µg/L after 30 days of exposure.

Data like this suggests that sustained GHRP-2 exposure may potentially increase IGF-1 production by 50–80%. Further research by Veldhuis et al. suggests that this increase is greater than that of GHRH analogs.⁽⁷⁾ The peak increase in GH levels during 3 hours post-exposure reached up to +23.5 μg·L⁻¹. When compared to endogenous GHRH, this GH output was roughly 1.6 times higher than with GHRH.

Potential Synergism Between CJC-1295 and GHRP-2

Currently, no research simultaneously investigates the relative implications of CJC-1295 and GHRP-2 on GH synthesis. But the aforementioned research by Bowers et al. has investigated the potential of GHRP-2 when combined with the unmodified version of GHRH.⁽⁶⁾

The researchers involved commented that combined exposure to the two peptides over 24 hours may have contributed to an increase in 24-hour GH levels of between 238 ± 28 µg·L⁻¹ and 452 ± 106 µg·L⁻¹. This represents a 16-fold increase over the baseline levels of approximately 20–30 µg·L⁻¹. This is also more than double the response to GHRP‑2 alone. This pronounced synergy suggests that engaging both the ghrelin (GHS-R) and GHRH receptors simultaneously may unlock an amplified GH secretory burst.

A second experiment by Veldhuis et al. also suggests a significant synergistic potential when GHRP-2 is combined with a GHRH analog.⁽⁸⁾ The researchers commented that GHRH alone elicited an approximately 20‑fold increase in GH secretory‑burst mass over baseline, whereas GHRP‑2 alone drove an even larger, roughly 47‑fold augmentation in pulse size. But when both peptides were evaluated together at maximally supportive concentration, the GH response rose to about a 54‑fold increase above saline, modestly exceeding the total implications of either agent on its own.

This pattern suggests that, although each secretagogue may independently trigger a pronounced GH surge, their combined exposure to research models may further support pituitary output by an additional 10–15%. This raises the possibility of an additive or mildly synergistic interaction at the level of somatotroph stimulation. Therefore, there is a clear synergistic action when GHRP-2 is evaluated simultaneously with GHRH, from which CJC-1295 is derived. Further research is needed to investigate whether the same synergism applies to a CJC-1295 and GHRP-2 combination.

You can find CJC-1295 & GHRP-2 Blend for sale with 99% purity, on our website (available for research use only).

NOTE: These products are intended for laboratory research use only. This peptide is not intended for personal use. Please review and adhere to our Terms and Conditions before ordering.

 

References:

1. Jetté L, Léger R, Thibaudeau K, Benquet C, Robitaille M, Pellerin I, Paradis V, van Wyk P, Pham K, Bridon DP. Human growth hormone-releasing factor (hGRF)1-29-albumin bioconjugates activate the GRF receptor on the anterior pituitary in rats: identification of CJC-1295 as a long-lasting GRF analog. Endocrinology. 2005 Jul;146(7):3052-8. doi: 10.1210/en.2004-1286. Epub 2005 Apr 7. PMID: 15817669.
2. Berlanga-Acosta J, Abreu-Cruz A, Herrera DGB, Mendoza-Marí Y, Rodríguez-Ulloa A, García-Ojalvo A, Falcón-Cama V, Hernández-Bernal F, Beichen Q, Guillén-Nieto G. Synthetic Growth Hormone-Releasing Peptides (GHRPs): A Historical Appraisal of the Evidence Supporting Their Cytoprotective Effects. Clin Med Insights Cardiol. 2017 Mar 2;11:1179546817694558. doi: 10.1177/1179546817694558. PMID: 28469491; PMCID: PMC5392015.
3. Culhane KJ, Liu Y, Cai Y, Yan EC. Transmembrane signal transduction by peptide hormones via family B G protein-coupled receptors. Front Pharmacol. 2015 Nov 5;6:264. doi: 10.3389/fphar.2015.00264. PMID: 26594176; PMCID: PMC4633518.
4. Yin Y, Li Y, Zhang W. The growth hormone secretagogue receptor: its intracellular signaling and regulation. Int J Mol Sci. 2014 Mar 19;15(3):4837-55. doi: 10.3390/ijms15034837. PMID: 24651458; PMCID: PMC3975427.
5. Teichman SL, Neale A, Lawrence B, Gagnon C, Castaigne JP, Frohman LA. Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults. J Clin Endocrinol Metab. 2006 Mar;91(3):799-805. doi: 10.1210/jc.2005-1536. Epub 2005 Dec 13. PMID: 16352683.
6. Bowers, C. Y., Granda, R., Mohan, S., Kuipers, J., Baylink, D., & Veldhuis, J. D. (2004). Sustained elevation of pulsatile growth hormone (GH) secretion and insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), and IGFBP-5 concentrations during 30-day continuous subcutaneous infusion of GH-releasing peptide-2 in older men and women. The Journal of clinical endocrinology and metabolism, 89(5), 2290–2300. https://doi.org/10.1210/jc.2003-031799
7. Veldhuis, J. D., Keenan, D. M., Bailey, J. N., Adeniji, A. M., Miles, J. M., & Bowers, C. Y. (2009). Novel relationships of age, visceral adiposity, insulin-like growth factor (IGF)-I and IGF binding protein concentrations to growth hormone (GH) releasing-hormone and GH releasing-peptide efficacies in men during experimental hypogonadal clamp. The Journal of clinical endocrinology and metabolism, 94(6), 2137–2143. https://doi.org/10.1210/jc.2009-0136
8. Veldhuis JD, Keenan DM. Secretagogues govern GH secretory-burst waveform and mass in healthy eugonadal and short-term hypogonadal men. Eur J Endocrinol. 2008 Nov;159(5):547-54. doi: 10.1530/EJE-08-0414. Epub 2008 Aug 14. Erratum in: Eur J Endocrinol. 2008 Dec;159(6):841. PMID: 18703567; PMCID: PMC2680123.