What Is GHRP-2?



GHRP-2 is short for growth hormone releasing peptide-2. GHRP-2 is a synthetic peptide consisting of just seven amino acids (D-Ala-D-(β-naphthyl)-Ala-Ala-Trp-D-Phe-Lys). It is part of a series of compounds developed by Polygen (Germany) and Tulane University (United States) in an effort to create easily administered analogues of growth hormone releasing hormone1 . GHRP-2 is also known as GPA-748, pralmorelin, KP-102 D, DP-102 LN, DP-102D, and KP-102LN.


Effects of GHRP-2


GHRP-2 is a growth hormone (GH) secretagogue. It is NOT an agonist of the growth hormone releasing hormone receptor (GHRHR), but rather is an agonist of the ghrelin receptor. As a GH secretagogue, GHRP-2 causes the release of growth hormone, which in turn causes the release of insulin-like growth factor-1 (IGF-1) and a host of other hormones. The major effects of stimulating growth hormone release include hyperplasia (growth in cell numbers) and hypertrophy (growth in cell size) in bone and skeletal muscle. Additional effects include improve function of heart muscle (cardiomyocytes), increased lipid metabolism (fat loss), and decreases in blood sugar (glucose).


By stimulating ghrelin receptors, GHRP-2 also acts as an appetite stimulant. Research in lean, healthy human males, published in the Journal of Clinical Endocrinology and Metabolism, found a 35.9% increase in appetite among subjects receiving GHRP-2 injections compared to saline injections2 . Ghrelin is a known appetite stimulant and has been found to regulate growth hormone secretion as well.


Clinical Applications


GHRP-2 is currently under investigation in Japan as a treatment for short stature. It is under investigation in the United States as a potential treatment for GH deficiency. Tulane University currently holds a patent, issued in October 2002, for protection of its series of synthesized GH-releasing peptides. The patent includes GHRP-2.


A 2004 study on rats found that GHRP-2 does not have any significant side effects on nervous system, smooth muscles, respiratory system, cardiovascular system, digestive system, or urinary system (kidneys). The hope is to eventually use GHRP-2 to both diagnose GH deficiency and treat short stature that results from GH deficiency3 .




  1. Pralmorelin: GHRP 2, GPA 748, growth hormone-releasing peptide 2, KP-102 D, KP-102 LN, KP-102D, KP-102LN. Drugs RD5, 236-239 (2004).


  1. Laferrère, B., Abraham, C., Russell, C. D. & Bowers, C. Y. Growth Hormone Releasing Peptide -2 (GHRP-2), like ghrelin, increases food intake in healthy men. J. Clin. Endocrinol. Metab.90, 611-614 (2005).


  1. Furuta, S. et al. General Pharmacology of KP-102 (GHRP-2), a Potent Growth Hormone-Releasing Peptide. Arzneimittelforschung54, 868-880 (2011).

What Is Modified GRF (1-29)?

Modified GRF (1-29) is a peptide (protein) consisting of 29 amino acids. It is a modified version of growth hormone releasing factor (GRF), which is a modified version of growth-hormone releasing hormone (GHRH). Modified GRF (1-29) is also called mod GRF (1-19), tetrasubstituted GRF (1-29), and sermorelin. The latter is the standardized name of GRF (1-29), but it is also used to refer to modified GRF (1-29).

What Is GHRH?

GRF and modified GRF are the shortest fully functional fragments of GHRH. GHRH (aka somatorelin) is generated in the hypothalamus of most mammals, including humans, and acts to regulate the production of growth hormone in the anterior pituitary gland. In essence, GHRH is responsible for regulating levels of growth hormone and thus is responsible for regulating growth. GHRH is 44 amino acids long.
Origin of Modified GRF (1-29)

Research performed in the early 1980s, on both animals and humans, found that the first 29 amino acids of the growth hormone molecule, dubbed GRF (1-29), were capable of causing all of the same effects as the full 44-amino-acid protein1,2 . Unfortunately, the therapeutic potential of the shortened peptide was limited due to rapid metabolic clearance. To make the molecule more useful, analogues were created by substituting one amino acid for another in an effort to preserve function while improving the lifespan of the molecule. The result was modified GRF (1-29), which is the same as GRF (1-29) except that four amino acids have been altered (hence the alternative name tetrasubstituted GRF (1-29)).

Modified GRF (1-29) has substitutions at the 2, 8, 15, and 27 positions that make it a slightly different molecule than GRF (1-29). Each substitution prevents a specific type of metabolic degradation. At position 2, the substitution of D-alanine for alanine provides resistance against DPP-IV cleavage. The substitution of glutamine for asparagine at position 8 protects against asparagine rearrangement and amide hydrolysis. The use of alanine in place of glycine at position 15 enhances receptor binding and makes modified GRF (1-29) more potent. Finally, the use of leucine in place of methionine at position 27 prevents methionine oxidation from occurring3,4 .

Effects of Modified GRF (1-29)

Because mod GRF (1-29) acts on growth-hormone releasing hormone receptors in exactly the same way that GHRH does, its effects are identical to those of GHRH. The major effect of both molecules is the release of growth hormone, which in turn

.    promotes muscle growth through muscle cell hypertrophy,
.    promotes healing,
.    alters glucose (blood sugar) regulation,
.    regulates temperature,
.    increases calcium retention and thus bone growth,
.    increases fat metabolism (lipolysis),
.    stimulates the immune system, and
.    increases the breakdown of thyroid hormones.

Modified GRF (1-29) Analogues

Modified GRF (1-29) comes in two basic forms. The first is referred to as CJC-1295 DAC and the second is referred to as CJC-1295 No DAC. Without DAC (drug affinity complex), the half-life of mod GRF (1-29) is about 30 minutes. With DAC, the half-life of mod GRF (1-29) increases to close to 8 hours. DAC promotes binding of mod GRF (1-29) to albumin in the blood. Albumin binding protects mod GRF (1-29) from degradation in the bloodstream and thus allows more of the molecule to reach GHRH receptor sites5 .


1. Wehrenberg, W. B. & Ling, N. In vivo biological potency of rat and human growth hormone-releasing factor and fragments of human growth hormone-releasing factor. Biochem. Biophys. Res. Commun.115, 525-530 (1983).

2. Grossman, A. et al. Responses to analogues of growth hormone-releasing hormone in normal subjects, and in growth-hormone deficient children and young adults. Clin. Endocrinol. (Oxf.)21, 321-330 (1984).

3. Frohman, L. A. et al. Rapid enzymatic degradation of growth hormone-releasing hormone by plasma in vitro and in vivo to a biologically inactive product cleaved at the NH2 terminus. J. Clin. Invest.78, 906-913 (1986).

4. Izdebski, J. et al. New potent hGH-RH analogues with increased resistance to enzymatic degradation. J. Pept. Sci. Off. Publ. Eur. Pept. Soc.8, 289-296 (2002).

5. Drug Affinity Complex (DAC tm) technology | ConjuChem. at <http://www.conjuchem.com/technology/dac>

How Does Epithalon Work?

The epithalon tetrapeptide is capable of regulating the cell cycle, improving immune system function, fighting the effects of aging, and regulating circadian rhythm. How does a single molecule have such profoundly diverse effects? The answer is DNA.

Epithalon at a Glance

Epithalon (a.k.a. epithalone, epitalone, LS-72251, and CID2192042) is just four amino acids in length (Alanine-Glutamate-Asparagine-Glycine).  Epithalon was first isolated from the pineal gland of cows but is easily synthesized using recombinant techniques in a laboratory. Though small, epithalon does have some limited secondary structure and is an effective transcription, regulator.

Transcription Regulation and DNA

Short peptides, because they lack substantial secondary and tertiary structure, were previously thought to be ineffective as biological molecules unless assisted by a larger molecule. Recent research in rats, however, has suggested that small peptides are not only biologically active, but that they may be ideal exogenous transcription factors.

One of the problems with gene therapy is getting effective treatments through the tough-to-permeate cell membrane and then through the similarly tough nuclear membrane. Short peptides, like epithalon, are highly effective at crossing into cells and nuclei to then bind to and manipulate the transcription of DNA1. It turns out that most of the effects of epithalon result from its manipulation of DNA transcription and not as a direct result of the molecule interacting with hormone feedback mechanisms2,3. Simply put, epithalon and other short peptides can active and deactivate genes to produce some astounding results.

Known Roles of Epithalon

To date, epithalon has been found to have the following DNA interactions.

1.       CD5 promoter region binding – Leads to immune cell differentiation
2.       IL-2 promoter region binding – Increases IL-2 production, which regulates white blood cells
3.       MMP2 promoter region binding – Enhances MMP activation and decreases inflammation
4.       Tram1 promoter region binding – Enhances protein production
5.       Arylalkylamine-N-acetyltransferase activation – Enhances melatonin production
6.       pCREB transcription factor activation – Circadian rhythm regulation and anti-neoplastic effects
7.       Telomerase gene activation – Telomerase activity increases cell longevity

Epithalon appears to bring about the vast majority of its effects by altering DNA transcription. Though the full effects of such manipulation are not yet known, testing in rats, mice, and birds has shown encouraging results. Scientists are not only testing epithalon now as a potential therapeutic agent but are testing a whole variety of short peptides in an effort to provide targeted gene therapy.


1. Fedoreyeva, L. I., Kireev, I. I., Khavinson, V. K. & Vanyushin, B. F. Penetration of short fluorescence-labeled peptides into the nucleus in HeLa cells and in vitro specific interaction of the peptides with deoxyribooligonucleotides and DNA. Biochem. Biokhimii͡a76, 1210-1219 (2011).

2. Khavinson, V. K. et al. Short cell-penetrating peptides: a model of interactions with gene promoter sites. Bull. Exp. Biol. Med.154, 403-410 (2013).

3. Khavinson, V. K., Linkova, N. S., Chalisova, N. I., Dudkov, A. V. & Koncevaya, E. A. Effect of short peptides on the expression of signaling molecules in organotypic pineal cell culture. Bull. Exp. Biol. Med.152, 138-141 (2011).

Is GHRP-6 Similar to Other Human Growth Hormone Secretagogues?

The world of growth hormone secretagogues has undergone a sort of revolution in the last decade or so with the advent of some different peptides that can stimulate growth hormone secretion. All of these peptides are currently being researched, primarily in animals, to determine both their efficacy and their downstream effects on other body tissues. This research is revealing that not all growth hormone secretagogues are the same … and that is a good thing.

Receptor Selection

Growth hormone secretion is controlled by a vast array of molecules from the very specific growth hormone releasing hormone (GHRH) to less specific alternatives like ghrelin and catecholamines (e.g. norepinephrine). The interaction of these molecules with one another and with molecules that inhibit growth hormone (GH) secretion ultimately determines GH levels.

GHRH has its own receptor on the anterior pituitary gland and is the primary driver of GH release. Studies show, however, that ghrelin and its analogues interact with the anterior pituitary gland through a unique receptor. Catecholamines also interact with an as-of-yet-unidentified receptor on the anterior pituitary gland. In short, GH release is subject to a number of different receptor interactions.

GH Release Is Complicated

When GHRH interacts with the anterior pituitary, the response is immediate growth hormone release followed by negative feedback that suppresses the actions of GHRH. Suppression happens when GH and IGF-1 (insulin-like growth factor-1) levels rise high enough. This is the standard pathway for control of GH levels, but the pathway can be subverted, at least partially, by other molecules.

GHRP-6, which is a ghrelin analogue, is capable of producing GH release on its own. The response, however, is minimal. The main function of ghrelin (and thus GHRP-6) is to interact synergistically with GHRH to produce an augmented GH release. When both molecules bind to their respective receptors, the result is a massive increase in GH release. What is interesting, however, is that GH release secondary to ghrelin is not subject to feedback the way that GHRH-induced release is. Simply put, ghrelin causes GH release no matter what else is going on in terms of hormonal feedback in the rest of the body.

One might speculate that catecholamines would work similarly to GHRP-6/ghrelin in producing a feedback-free elevation of GH. This turns out not to be the case. While catecholamine-induced GH release is not opposed by a direct feedback mechanism, there are several indirect mechanisms that serve to suppress GH release. The net result is that catecholamines do not produce an increase in GH levels.

Why Does It Matter?

GH release secondary to GHRH has different total-body effects than does GH release secondary to ghrelin analogues. The reason for these differences is that ghrelin analogues also stimulate additional receptors throughout the body that are not stimulated by GHRH, which is strictly active in the anterior pituitary.

With ghrelin analogues, it is possible to derive effects from GH that would not otherwise arise. An example of such an effect is increased lean body mass accumulation and simultaneous loss of fat mass. This arises because GHRP-6 stimulates the uptake of glucose by muscle cells while inducing fat cells to burn energy. Thus, calories are selectively shunted to muscle growth and away from fat growth. So, despite the fact that GHRP-6 causes increased hunger, it tends not to lead to obesity, but rather to a gain in lean body mass. Note that this effect is not consistent across all ghrelin analogues, so it is not safe to assume that they all leads to improvements in adiposity.

The Bottom Line

GHRP-6 is similar to some GH secretagogues, but very different from others. This, of course, does not mean that it doesn’t interact with other secretagogues or that its actions are separate. GHRP-6 is a unique peptide with unique effects and is currently be investigated as a potential weight loss and immune-boosting supplement using animal models.

How Relevant Is Epithalon?

Interest in epithalon, at least in some circles, waned during the early part of the twenty-first century. Very little research trickled in during the early 2000s, but interest in the molecule has picked up again. Scientists have begun to realize that the little four-amino-acid peptide epithalon may offer some insight into the regulation of DNA and may even be an effective tool in the fight against cancer and several other diseases.

The Relevance of Epithalon in Cancer

Research suggests that epithalon can actively decrease tumor size and even prevent metastasis. In rat studies, epithalon was effective in reducing the expression of mRNA (messenger RNA) from oncogenes (cancer-causing genes)1. In another study, epithalon was found to decrease proliferation of tumors of the epithelial cells in the colons of rats2. In yet another study, epithalon was found to decrease the rate of adenocarcinoma (breast cancer) development in female rats3.


At least some of the effect of epithalon in tumor suppression results from its ability to manipulate the transcription of DNA. It appears that, in general, epithalon can increase the transcription of anti-cancer tumor suppressor genes while simultaneously decreasing the transcription of cancer-causing oncogenes. In addition to its direct effects on tumor suppressor genes and oncogenes, epithalon also appears to have an indirect effect on cancer through the regulation of various hormones like melatonin and norepinephrine.

The Relevance of Epithalon in Circadian Regulation

Disruptions in the normal sleep/wake cycle (circadian rhythm) have been associated with depression, mental illness, Alzheimer’s disease, cancer, and even premature aging. Epithalon has been shown, in several animal studies, to help regulate sleep cycles and improve melatonin secretion. In experiments on rats, epithalon was able to restore normal circadian function in the female rat after their sleep/wake cycles were intentionally disturbed4 .

The Relevance of Epithalon in Aging

Aging is a cumulative process in which cells in the body slowly, but surely undergo programmed cell death (apoptosis). At least part of the aging process results from the progressive loss of telomeres, little protective caps that sit on the end of chromosomes. There is an enzyme that can repair telomeres, called telomerase, but it isn’t active in the vast majority of cells. Epithalon can activate telomerase and thus slow at least some of the aging process. A lot more work needs to go into understanding how epithalon affects aging, but early animal studies are encouraging.

Ebb and Flow

There are an inevitable ebb and flow in the ide of scientific interest. As is commonly said, science progresses one funeral at a time. In other words, even good ideas may not get a foothold if the environment isn’t right. In the early days after its discovery, the scientific establishment wasn’t ready to acknowledge epithalon and its effects. Now, the molecule is becoming a focal point of an entire branch of science known as small peptide genomic regulation. The near future should produce some astounding insights into the workings of epithalon.


1. Anisimov, V. N. et al. Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Int. J. Cancer J. Int. Cancer101, 7-10 (2002).

2. Kossoy, G. et al. Epitalon and colon carcinogenesis in rats: proliferative activity and apoptosis in colon tumors and mucosa. Int. J. Mol. Med.12, 473-477 (2003).

3. Anisimov, V. N. The role of pineal gland in breast cancer development. Crit. Rev. Oncol. Hematol.46, 221-234 (2003).

4. Arutjunyan, A. et al. Melatonin and pineal gland peptides are able to correct the impairment of reproductive cycles in rats. Curr. Aging Sci.5, 178-185 (2012).