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Complete Guide to GHRP-6 Research

Therapeutic uses of the human growth hormones date back to more than 40 years ago (1) and are known to be vital for the bodily developments for young children and adults. As the name suggests, one of the many uses of the hormone is to treat growth hormone deficiency or insufficiency in humans.

Besides this, human growth hormones are a potential candidate that can also be used to treat various catabolic problems including burns, fertility problems, osteoporosis, and Down’s syndrome, to name a few (1).

Considering the importance of the human growth hormones, several research studies have been conducted to understand and synthesize similar compounds, namely peptides, that can help in the medical field. One such peptide is GHRP-6 - which is not the growth hormone itself, instead helps to stimulate the secretion of growth hormones endogenously and maintain their equilibrium in the body.

What is GHRP-6?

Growth hormone releasing hexapeptide or GHRP-6 belongs to a group of synthetic peptides that stimulate the secretion of growth hormones in the body and help regulate their levels in the body. GHRP-6 is a small, low molecular weight, synthetic peptide and is the first in-line synthetic peptide, which showed prominent GH increase both in vivo and in vitro (2).

Background

Initially, in the 1980s, growth hormone releasing peptides (GHRP) were interpreted to be similar to growth hormone releasing hormones (GHRHs). However, when GHRH was first isolated in 1984, it was understood that both these entities are different; what makes GHRP distinct is that they bind to a different receptor, called the ghrelin receptor (3).

In 1999, the growth hormone releasing peptide natural hormone, ghrelin, was discovered and isolated to determine that it possessed the same mechanism as GHRPs. It was then understood that GHRPs, much like endogenously found hormone ghrelin, govern their actions via hypothalamic stimulation and induce various activities, including metabolism and nutrition, in the body (3).

Mode of action

Research was conducted demonstrating that GHRP-6 requires endogenous GHRH presence in order to exert its effects.

In this study (4), 9 healthy men aged between 20 and 30 years were either given GHRH antagonist or saline via intravenous route, followed by GHRP-6 administration after 20 minutes, via an intravenous route of administration. Blood samples were collected every to 10 minutes for the next few hours and the concentrations of growth hormones was measured. After the study, it was noted that HGH levels were lower in candidates who were treated with GHRH antagonist. This study concluded that endogenous GHRH was necessary for GHRP-6 to exert its effects.

While the mechanism of GHRP-6 is uncertain (4), studies have shown that GHRPs produce their effects by binding with two different receptors, namely GHS-R1a and CD36. In addition to HGH release, GHRP-6 also reduces cellular death by binding with CD36 receptors and stimulating the prosurvival cellular pathways (2).

GHRP-6 peptide, through such receptor binding abilities, has also demonstrated its ability to decrease inflammation and increase antioxidant defense mechanisms in the body (2).

Research analysis to understand GHRP-6 way of working

Earlier it was hypothesized that GHRP-6 works through a double mechanism and produces effects at both the pituitary gland and hypothalamus.

In this study (5), 23 subjects - 12 with hypothalamus-pituitary disconnection and 11 healthy candidates - were studied. Every subject was either administered with 100 micrograms of GHRH, 90 micrograms of GHRP-6, or a combination of both, all via an intravenous route of administration.

After administration, the HGH levels were measured in all 23 subjects. In healthy candidates, the highest levels of HGH were found in patients treated with both GHRH and GHRP-6, followed by GHRP-6 treated subjects, and lastly the GHRH treated subjects.

It was opposite in the patients suffering from hypothalamic pituitary disconnection, with the least levels of HGH reported in patients treated with both GHRP-6 and GHRH. The GHRH treated patients had the same levels of HGH as controls, whereas the HGH levels reduced in patients treated with GHRP-6 alone.

Two conclusions were drawn from this study – first, GHRP-6 works best in the presence of GHRH and second, GHRP-6 acts on the hypothalamic pituitary axis in order to produce its effects.

Benefits of GHRP-6

There are several benefits of GHRP-6, including:

  • Elevated levels of growth hormones
  • Treatment in growth hormone deficiency, in children and adults
  • For treating hypothyroidism
  • Induces sleep
  • Stimulates ACTH and cortisol release
  • Elevated energy levels
  • Potential preventative medication for multiple organ failure

GHRP-6 Research and Clinical Studies

In short heighted children

The main aim of this study (6) was to determine the efficacy of orally administered GHRP-6 peptide in the children with short height.

It was known during this time that GHRH, which is a potential GH-releasing agent, exerted maximal GH-releasing effects when administered via intravenous route at the dose of 1 microgram per kg and when co-administered with amino acid arginine. Based on this, the study was conducted with 300 microg per kg oral dose of GHRP-6 (equivalent to 1 microgram per kg i.v dose of GHRH) and co-administration with amino acid arginine, to demonstrate similar effects of GHRP-6 to GHRH.

13 children aged 6 to 11 years were studied.

7 children were administered with 300 microg per kg oral dose of GHRP-6. Upon analysis, it was determined that there was significant rise in their GH levels, similar to the effects of intravenous GHRH.

6 children were administered with GHRP-6 and arginine. Unlike in GHRH, the GHRP-6 induced high growth hormone levels were not affected by the presence of arginine. There was no difference in the GH levels, despite the presence of arginine.

This study concluded that while GHRP-6 may work slightly differently than GHRH, the orally administered GHRP-6 peptide can potentially be used in the clinical treatment of children with short stature.

GHRP-6 Effects in Hypothyroidism

Hypothyroidism leads to reduced levels of growth hormone secretion in the body.

The main aim of this study (7) was to determine whether GHRP-6, a potent HGH release stimulating agent, could be used to treat this condition.

Patients suffering from hypothyroidism were randomly treated with three separate medication doses – first including 100 micrograms of GHRH, second including 1 microgram per kg dose of GHRP-6 and third including the combination of GHRH and GHRP-6 peptides. All compounds were administered via intravenous route.

After the completion of the study, it was noticed that the patients administered with GHRP-6 alone and with combination of GHRP-6 and GHRH induced significantly higher levels of growth hormones than GHRH administration alone.

The probable reasoning behind this is that GHRP-6 differs from GHRH considering that the peptide is a functional antagonist of somatostatin at the pituitary level, which may potentially be why GHRP-6 is able to exert its effects better in patients with hypothyroidism compared to GHRH.

Increased sleep and cortisol hormone release

In this study (8), the effects of GHRP-6 peptide on the hormone release and sleep electroencephalogram (EEG) during the night time was studied.

Healthy male volunteers were treated with four repetitive doses of 50 micrograms of either the GHRP-6 peptide or the placebo.

After the administration, it was noticed that GHRP-6 induced higher secretion of both growth hormones and cortisol (ACTH) hormones. Throughout the night, particularly during the first half, cortisol hormone release and stage 2 sleep was enhanced, while the other sleep EEG variables remained unchanged.

This study demonstrated that not only does GHRP-6 induce growth hormone release, but it also acts on the hypothalamus and pituitary gland axis, enhancing the cortisol hormone release. This research, just like other above-mentioned studies, suggested that GHRP-6 is different from GHRH where GHRH also induces sleep but inhibits cortisol hormone release – thus proving that both GHRH and GHRP-6 act on different receptors despite exerting similar effects (i.e. HGH secretion).

Prevention of Multiple Organ Failure

The main goal of this study (9) was to determine the effects of GHRP-6, either alone or in combination with potent epidermal growth factor (EGF), on multiple organ failure, both in vivo and in vitro.

In vitro study was conducted on the experimental models of injury and multiple organ failure, while in vivo studies on the rat intestine and human colonic cancer cells.

In vitro studies demonstrated that GHRP-6 directly impacted the gut epithelial cells and increased the cell migration by three times its normal rate but showed no impact on cell proliferation.

Whereas in the vivo model, multiple organ failure caused severe hepatic and intestinal damage and lipid peroxidation. Treatment with GHRP-6 reduced these damages by 50-85%, with even more added effects when GHRP-6 was used in combination with EGF.

These findings thus concluded that while further studies were to be conducted, GHRP-6 could potentially be used as a therapeutic agent to reverse multiple organ failure.

Treating diabetes induced delayed GI transit

The main aim of this study (10) was to demonstrate the efficacy of GHRP-6 on delayed gastrointestinal (GI) transit induced by diabetes.

An experimental mouse model, with alloxan drug induced diabetes, was used for this study. Alloxan is a synthetic uric acid derivative compound, commonly used for experiments, which induces diabetes upon administration(14). All these experimental mice were then treated with 6 doses of GHRP-6 at 0, 20, 50, 100 and 200 microg per kg dose, administered via intraperitoneal route of administration.

Based on the study analysis, it was determined that diabetes significantly reduced the levels of gastric emptying (GE), intestinal transit (IT) and colonic transit (CT) in mice. Upon GHRP-6 administration, the levels of GE and IT improved, while there was no effect on CT levels. The most effective GHRP-6 dosage was found to be 200 micrograms per kg.

This study demonstrated that GHRP-6 can potentially be used as a therapeutic agent to treat diabetes induced delayed GI transit in humans, however, additional studies on men are yet to be conducted.

GHRP-6 Side Effects

GHRP-6 induces effects similar to endogenous compound, ghrelin, and hence is a well-tolerated peptide. Needless to say, as with other therapeutic agents, there may be some negative effects on using the peptide, depending on individual body and drug profile.

Some known side effects of GHRP-6 include the following, which are attributed to the high levels of growth hormone secretion (15):

  • Pain, redness and itchiness at the site of administration
  • Lethargy, tiredness, weakness
  • Increased sleep (8,12)
  • Numbness of skin
  • Bloating
  • Flushes
  • Edema

GHRP-6 Peptide Profile

Pharmacokinetic Studies

In order to determine the pharmacokinetic profile for GHRP-6 peptide, this study (11) was conducted on 9 healthy male volunteers who were administered with 100, 200 and 400 micrograms per kg of body weight doses, via the intravenous route.

Blood plasma samples were then collected, and the GHRP-6 levels were quantified using LC-MS method.

Upon averaging the analytical results for all three doses, the distribution rate of GHRP-6 was determined to be approximately 8 minutes and the half-life was approximately 2.5 hours. Furthermore, it was determined that the effects of GHRP-6 are dose dependent, with higher doses resulting in higher effects.

Role of Different Routes of Administration of GHRP-6

Research has demonstrated that oral, intranasal, and sublingual routes of administration are more advantageous than the intravenous route.

This study (12) was conducted to determine the effects of GHRP-6 on sleep and cortisol hormone release when administered via different routes in young healthy male volunteers.

Three routes of administration of GHRP-6 were studied including oral administration of 300 micrograms per kg bodyweight of enteric coated GHRP-6 capsules, intranasal administration of 30 micrograms per kg, and sublingual administration of 30 micrograms per kg.

The study analysis demonstrated that the oral administration of GHRP-6 increased GH and cortisol hormone levels but reduced the sleep stage 2 during the later half of the night. Intranasal administration led to significant increase in GH levels throughout the night, and elevated ACTH hormone release during the first half of the night. What's more, it also improved the sleep stage 2 during the later duration of the night. Lastly, the sublingual administration led to elevated GH levels during the first half of the night.

Thus, GHRP-6 did affect the GH levels, cortisol hormone release, and sleep rate, however these were all dependent on the dose, treatment period and routes of administration.

Summary

GHRP-6 is a potent synthetic peptide composed of six amino acids, analogous to endogenous compounds called ghrelin.

While the mechanism of action of GHRP-6 remains uncertain, there are various theories to support that GHRP-6 acts on different receptors than GHRH, particularly the ghrelin receptor, and acts on the hypothalamus pituitary axis. Once it binds with the receptors, it not only stimulates the release of growth hormones (GH), but also demonstrates cryoprotective effects including reduced inflammation and elevated cell migration.

GHRP-6 has several benefits besides treating growth hormone deficiency. Studies have so far demonstrated promising results from GHRP-6 administration, and clinical studies are ongoing to study further effects on men.

Needless to say, similar to other growth hormone analogs and GH-releasing peptides, GHRP-6 is banned from sports by the World Anti-Doping Agency (WADA)(13). Hence, athletes must ensure not to misuse this peptide for its added advantage of inducing elevated energy levels.

References:

1. Hintz, Raymond L. “Growth hormone: uses and abuses.” BMJ (Clinical research ed.) vol. 328,7445 (2004): 907-8. doi:10.1136/bmj.328.7445.907. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC390151/

2. Berlanga-Acosta, Jorge et al. “Synthetic Growth Hormone-Releasing Peptides (GHRPs): A Historical Appraisal of the Evidences Supporting Their Cytoprotective Effects.” Clinical Medicine Insights. Cardiology vol. 11 1179546817694558. 2 Mar. 2017, doi:10.1177/1179546817694558. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392015/

3. Bowers, C.Y., et al (2012). Ghrelin: A history of its discovery. In Ghrelin in Health and Disaeas (pp. 1-35), Human press Inc. https://mayoclinic.pure.elsevier.com/en/publications/ghrelin-a-history-of-its-discovery

4. Naushira Pandya, Roberta DeMott-Friberg, Cyril Y. Bowers, Ariel L. Barkan, Craig A. Jaffe, Growth Hormone (GH)-Releasing Peptide-6 Requires Endogenous Hypothalamic GH-Releasing Hormone for Maximal GH Stimulation, The Journal of Clinical Endocrinology & Metabolism, Volume 83, Issue 4, 1 April 1998, Pages 1186–1189. https://academic.oup.com/jcem/article/83/4/1186/2865313

5. Popovic V, Damjanovic S, Micic D, Djurovic M, Dieguez C, Casanueva FF. Blocked growth hormone-releasing peptide (GHRP-6)-induced GH secretion and absence of the synergic action of GHRP-6 plus GH-releasing hormone in patients with hypothalamopituitary disconnection: evidence that GHRP-6 main action is exerted at the hypothalamic level. J Clin Endocrinol Metab. 1995 Mar;80(3):942-7. doi: 10.1210/jcem.80.3.7883854. PMID: 7883854. https://pubmed.ncbi.nlm.nih.gov/7883854/

6. Bellone J, Ghizzoni L, Aimaretti G, Volta C, Boghen MF, Bernasconi S, Ghigo E. Growth hormone-releasing effect of oral growth hormone-releasing peptide 6 (GHRP-6) administration in children with short stature. Eur J Endocrinol. 1995 Oct;133(4):425-9. doi: 10.1530/eje.0.1330425. https://pubmed.ncbi.nlm.nih.gov/7581965/

7. Pimentel-Filho FR, Ramos-Dias JC, Ninno FB, Façanha CF, Liberman B, Lengyel AM. Growth hormone responses to GH-releasing peptide (GHRP-6) in hypothyroidism. Clin Endocrinol (Oxf). 1997 Mar;46(3):295-300. doi: 10.1046/j.1365-2265.1997.1270942.x. https://pubmed.ncbi.nlm.nih.gov/9156038/

8. Frieboes RM, Murck H, Maier P, Schier T, Holsboer F, Steiger A. Growth hormone-releasing peptide-6 stimulates sleep, growth hormone, ACTH and cortisol release in normal man. Neuroendocrinology. 1995 May;61(5):584-9. https://doi.org/10.1159/000126883

9. Cibrián D, Ajamieh H, Berlanga J, León OS, Alba JS, Kim MJ, Marchbank T, Boyle JJ, Freyre F, Garcia Del Barco D, Lopez-Saura P, Guillen G, Ghosh S, Goodlad RA, Playford RJ. Use of growth-hormone-releasing peptide-6 (GHRP-6) for the prevention of multiple organ failure. Clin Sci (Lond). 2006 May;110(5):563-73. https://pubmed.ncbi.nlm.nih.gov/16417467/

10. Zheng, Q., Qiu, W. C., Yan, J., Wang, W. G., Yu, S., Wang, Z. G., & Ai, K. X. (2008). Prokinetic effects of a ghrelin receptor agonist GHRP-6 in diabetic mice. World journal of gastroenterology, 14(30), 4795–4799. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739343/

11. Cabrales A, Gil J, Fernández E, Valenzuela C, Hernández F, García I, Hernández A, Besada V, Reyes O, Padrón G, Berlanga J, Guillén G, González LJ. Pharmacokinetic study of Growth Hormone-Releasing Peptide 6 (GHRP-6) in nine male healthy volunteers. Eur J Pharm Sci. 2013 Jan 23;48(1-2):40-6. https://pubmed.ncbi.nlm.nih.gov/23099431/

12. Frieboes RM, Murck H, Antonijevic IA, Steiger A. Effects of growth hormone-releasing peptide-6 on the nocturnal secretion of GH, ACTH and cortisol and on the sleep EEG in man: role of routes of administration. J Neuroendocrinol. 1999 Jun;11(6):473-8. https://pubmed.ncbi.nlm.nih.gov/10336729/

13. 2021 WADA Prohibited list. https://www.wada-ama.org/en/content/what-is-prohibited/prohibited-at-all-times/peptide-hormones-growth-factors-related-substances-and-mimetics

14. Kristina Szabadfi, et al., Therapeutic Areas I: Central Nervous System, Pain, Metabolic Syndrome, Urology, Gastrointestinal and Cardiovascular, in Comprehensive Medicinal Chemistry II, 2007. https://www.sciencedirect.com/topics/medicine-and-dentistry/alloxan

15. HGH Side effects and other hazards. https://www.webmd.com/fitness-exercise/human-growth-hormone


 

Synonyms/Aliases: GHRP-6, Growth Hormone-Releasing Peptide 6, Growth Hormone-Releasing hexapeptide

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