MK-677 or CJC-1295: what is the difference

MK-677 and CJC-1295 are often called “growth hormone stimulators”, but they press different “buttons” of the pituitary. MK-677 mimics the hunger hormone ghrelin, while CJC-1295 mimics the hypothalamic releasing hormone GHRH. The editorial team explains what this difference means in practice: for duration of action, side effects and what is known from clinical studies.

Two paths to growth hormone

The secretion of growth hormone (GH) in the pituitary is regulated by several signals. The main stimulator is somatoliberin (GHRH), released by the hypothalamus. The main inhibitory signal is somatostatin. The third regulator is ghrelin, a hormone produced mainly by the stomach; it acts through the GH secretagogue receptor (GHS-R1a) and enhances both GH release and the sensation of hunger.

CJC-1295 is a synthetic GHRH analog: it binds to the GHRH receptor on pituitary somatotrophs and triggers a signaling cascade through cAMP. MK-677 (ibutamoren) is a non-peptide molecule that activates the ghrelin receptor. In other words, the first substance “presses the gas” through the main channel, and the second through a parallel one.

These pathways interact: GHRH and ghrelin mimetics act synergistically, and ghrelin agonists partly reduce the inhibitory influence of somatostatin. That is precisely why in endocrinological studies they were sometimes combined in order to study the GH secretory reserve.

An important shared feature: both substances work only on condition that the pituitary is able to produce growth hormone. They stimulate one’s own secretion rather than replacing it, as recombinant GH does.

Structure and pharmacokinetics

MK-677 is a small organic molecule developed by Merck. Its main feature is activity when taken by mouth and a prolonged action, which allowed it to be taken once a day in clinical studies. For a peptide hormone that is destroyed in the stomach, such convenience is unattainable.

CJC-1295 is a peptide of 29 amino acids (a modified fragment of GHRH 1–29) to which the so-called DAC is attached — a chemical group that covalently binds to blood albumin. Albumin protects the peptide from rapid breakdown, so the half-life of CJC-1295 with DAC in the study by Teichman and colleagues (2006) was about 6–8 days. The drug was administered subcutaneously.

In the same study a single administration raised the mean GH level several-fold for at least six days, and IGF-1 remained elevated for more than a week. The work of Ionescu and Frohman (2006) showed that the pulsatile nature of GH secretion is preserved, although the baseline level between peaks rises.

On the market, under the name “CJC-1295”, a version without DAC (the so-called modified GRF 1–29) is also sold, which acts far more briefly. These are different compounds, and data from one study cannot be automatically transferred to the other.

What the clinical studies showed

The best-known study of MK-677 is a randomized placebo-controlled trial in healthy elderly people (Nass et al., 2008). Taking 25 mg per day for a year raised GH and IGF-1 levels to values characteristic of young adults and increased lean body mass. At the same time no substantial effect on strength or functional indicators was found.

Earlier, Murphy and colleagues (1998) showed that MK-677 reduced protein catabolism in healthy volunteers on a low-calorie diet. These results shaped interest in ibutamoren as an agent against muscle wasting.

For CJC-1295, mainly pharmacokinetic and pharmacodynamic studies in healthy adults have been published. It was developed for the potential treatment of conditions related to GH deficiency and lipodystrophy, but the drug did not make it to registration.

Neither substance is a registered medicine. Instead, another GHRH analog is registered — tesamorelin — for the treatment of abdominal obesity in patients with HIV-associated lipodystrophy, which shows that stimulation of the GHRH axis has medical use under clear indications.

Side effects

In the study by Nass et al., taking MK-677 was accompanied by increased appetite, a moderate rise in fasting glucose and reduced insulin sensitivity, as well as edema and muscle pain in some participants. For people with prediabetes or diabetes these changes are of particular significance.

In a study of MK-677 in elderly patients after a hip fracture (Adunsky et al., 2011) a signal for heart failure was observed, and the study was stopped early. This is a reminder that in vulnerable groups the effect on water-salt balance may be clinically significant.

For CJC-1295, studies in healthy volunteers described injection-site reactions, a sensation of flushing and headache. There are no long-term safety data. As with any stimulator of the GH/IGF-1 axis, the theoretical risks include fluid retention, carpal tunnel syndrome and an effect on glucose metabolism.

A separate topic is chronically elevated IGF-1. Epidemiological data link high IGF-1 levels with an increased risk of some types of cancer, although a direct causal link for these substances has not been established. That is precisely why the medical use of agents affecting the GH axis is accompanied by monitoring of IGF-1.

• MK-677:hunger, edema, ↑ glucose, ↓ insulin sensitivity.
• CJC-1295:injection-site reactions, flushing, headache; limited data.
• Shared:unknown long-term safety, unregistered status, questionable product quality.

Legal status and control in sport

The WADA Prohibited List assigns to class S2 “Peptide hormones, growth factors and related substances” both GH-releasing factors (GHRH analogs, in particular CJC-1295) and GH secretagogues and ghrelin mimetics, including ibutamoren. Both substances are banned at all times.

The fact that MK-677 is not a peptide does not change its classification: WADA defines the ban by pharmacological action, not by chemical nature.

Products sold as “research peptides” or “SARM MK-677” (although ibutamoren is not a SARM) do not undergo pharmaceutical control. For injectable peptides there are added risks related to sterility and endotoxins.

Any medical intervention in the growth-hormone axis should take place under the supervision of an endocrinologist, taking indications and contraindications into account.

Editorial conclusions

MK-677 and CJC-1295 stimulate the secretion of one’s own growth hormone by different paths: the first through the ghrelin receptor, orally and with a pronounced effect on appetite and glucose metabolism; the second through the GHRH receptor, as an injectable peptide with a prolonged action thanks to binding to albumin.

Clinical studies confirm the ability of both substances to raise GH and IGF-1, but they give no grounds to consider them safe for long-term use by healthy people. Neither is registered, and both are banned in sport.

We also recommend reading “MK-677 vs CJC-1295: what to choose and for whom”, our material on the IGF-1 test and an article on the effect of sleep on growth-hormone secretion.

References

1. Nass R, Pezzoli SS, Oliveri MC, et al. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Ann Intern Med. 2008;149(9):601–611.
2. Murphy MG, Plunkett LM, Gertz BJ, et al. MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. J Clin Endocrinol Metab. 1998;83(2):320–325.
3. Teichman SL, Neale A, Lawrence B, et al. 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;91(3):799–805.
4. Ionescu M, Frohman LA. Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog. J Clin Endocrinol Metab. 2006;91(12):4792–4797.
5. Adunsky A, Chandler J, Heyden N, et al. MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb study. Arch Gerontol Geriatr. 2011.
6. World Anti-Doping Agency. The World Anti-Doping Code International Standard: Prohibited List. Montreal: WADA; чинна редакція.