Modified GRF(1–29)

Modified GRF(1–29) is an amidated, 29-residue analogue of growth hormone-releasing hormone (GHRH), with four substituted amino acids. It is commonly called CJC-1295 no DAC. DAC is the added chemical group that allows the original long-acting CJC-1295 molecule to bind albumin, a blood protein; modified GRF(1–29) lacks this group. Published analytical studies have identified preparations of the DAC-free peptide and examined its breakdown products, but the reviewed sources do not establish its human blood-concentration profile, treatment benefit or safety. Distinguishing the two molecules is therefore essential when deciding which human results apply.

Overview

GRF is short for growth hormone releasing factor, another name for GHRH. The four substitutions are D-alanine at position 2, glutamine at position 8, alanine at position 15 and leucine at position 27. The chain ends in an amide. These changes distinguish it from sermorelin, which contains the natural first 29 residues with the same type of terminal amidation. The FDA chemistry assessment (2024) records the DAC free sequence and molecular formula separately from CJC-1295 with DAC.

Molecular profile

Peptide length: 29 residues with an amidated C terminus Source
Core substitutions: D-alanine 2, glutamine 8, alanine 15 and leucine 27 Source
Sequence: Tyr-D-Ala-Asp-Ala-Ile-Phe-Thr-Gln-Ser-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Leu-Ser-Arg-NH2 Source
Molecular formula: C152H252N44O42, DAC free base Source
Molecular weight: 3367.95 g/mol, DAC free base Source

Forms and derivatives

CJC-1295 no DAC and tetrasubstituted GRF(1–29)

Common names for the four substitution amidated 29 residue fragment. The bare CJC-1295 name also appears in DAC papers, so the sequence and extension determine which findings apply.

Acetate form

A salt of the DAC free peptide. Acetate identifies a counterion and does not indicate an albumin binding unit. FDA evaluates the DAC free and DAC salt forms separately.

N terminal glycine extended modified GRF

Gajda and colleagues identified an extra glycine in seized material. The longer chain has a distinct analytical identity; that study measured no clinical outcome.

CJC-1295 with DAC

The related development molecule adds modified lysine and an albumin binding group. Early human exposure and GH/IGF-1 findings belong to that complete preparation.

Names and derivative identities

Modified GRF(1–29), tetrasubstituted GRF(1–29) and CJC-1295 no DAC often identify this peptide. The bare name CJC-1295 is ambiguous because it has been used for both DAC and DAC free material. The presence of an acetate counterion establishes a salt form but does not answer whether the albumin binding unit is present. A glycine extended analogue is another distinct molecule: it adds a residue at the N terminus and is discussed below with the study that identified it.

Uses and research areas

The design comes from attempts to preserve the GH releasing activity of a short GHRH fragment while changing its susceptibility to degradation. The exact DAC free preparation has appeared in forensic identification and anti-doping analytical research. Investigators in those studies asked what a sample contained, what breakdown products formed and whether a laboratory method could detect them.

Claims about adult body composition, recovery or aging require treated human participants and relevant outcomes. The primary analytical reports supply neither a clinical comparator nor follow-up of such effects. There is no FDA approved medicinal product for modified GRF(1–29).

Mechanism of action

Natural releasing hormone stimulates receptors on GH producing cells in the anterior pituitary. The first 29 residues retain substantial activity, as shown in the human fragment comparison by Losa and colleagues (1984). Modified GRF's design uses that active core and introduces substitutions intended to alter degradation or stability. D-alanine reverses the usual stereochemical configuration at the second residue, which can change how an enzyme recognizes that part of the peptide.

The original CJC development experiments by Jetté and colleagues (2005) combined substituted fragments with albumin binding extensions and tested the resulting material in cells and rats. Those results provide development context. A demonstrated GH releasing response to the complete DAC preparation cannot isolate the exact DAC free fragment's response, and FDA's material specific assessment explicitly leaves its pharmacological activity unresolved.

Pharmacokinetics

Human pharmacokinetics for the exact four substitution DAC free fragment remain unresolved in these primary studies. They characterize chemical identity and laboratory breakdown products without a human concentration time course. The multi-day estimate in Teichman and colleagues (2006) belongs to the albumin binding DAC material. The absence of that extension does not provide a numerical estimate for the shorter peptide.

Soule, King and Millar (1994) measured a longer disappearance half-time after replacing only the second residue of GHRH(1–29)-amide with D-alanine. That singly substituted analogue has different chemistry from the four substitution fragment on this page. Laboratory metabolism can identify cleavage products, but it supplies no human blood concentration time course or duration of GH secretion for this exact peptide.

Research findings

Identification of a seized preparation

Henninge and colleagues (2010) analyzed an unknown pharmaceutical preparation submitted by Norwegian police and customs authorities. High resolution tandem mass spectrometry supported a 29 amino acid sequence with a C terminal amide. The paper described it as consistent with material marketed as CJC-1295; FDA's later assessment identifies the report with the DAC free form. The study's finding concerns chemical identity and illustrates how the common name can lead to the wrong pharmacology paper.

Breakdown products and analytical detection

Memdouh and colleagues (2021) separately examined sermorelin, tesamorelin, CJC-1295 without DAC and CJC-1295 with DAC. They identified 19 major metabolites across the four peptide set and developed a liquid chromatography tandem mass spectrometry method using fortified urine. Detection limits were generally at or below 1 ng/mL. Fortified urine is a sample supplemented with known reference material. It allows the investigators to test how reliably the assay detects a peptide among other sample constituents.

What the DAC human studies measured

Teichman and colleagues (2006) reported prolonged increases in GH and IGF-1 after CJC-1295 with DAC in healthy adults. Ionescu and Frohman (2006) sampled blood overnight after the same type of long-acting material. Growth hormone still rose in pulses, but its concentration between pulses—the trough—was higher. The albumin-binding addition changes how the peptide associates with blood proteins and how long it persists. Those human hormone measurements therefore cannot supply the missing measurements for modified GRF(1–29) without DAC.

A glycine extended analogue

Gajda and colleagues (2019) identified growth hormone secretagogue analogues in preparations seized by Danish customs. The materials included a modified GRF related peptide with an extra glycine at its N terminus. Comparison with reference standards supported the added residue. This derivative provides another example of how small sequence changes create a different analytical identity. The paper did not measure clinical efficacy or establish that the extended molecule behaves like the unextended fragment.

Safety and tolerability

Clinical harms for the exact DAC free fragment are poorly characterized. The chemical identification and fortified urine studies did not administer it to participants. FDA's assessment raises concerns about peptide impurities, aggregation and potential immune reactions in injectable preparations and identifies gaps in the nonclinical and clinical evidence. These concerns apply to preparation quality as well as the uncertainty around prolonged endocrine stimulation.

The heart rate and vasodilatory reactions reported in the DAC clinical program are described on the CJC-1295 with DAC profile. Different exposure leaves the magnitude of corresponding risks for the DAC free fragment undetermined. Likewise, a shorter presumed duration cannot establish fewer side effects without an actual comparison.

What the research means

The primary findings establish that a DAC free modified fragment has appeared in analyzed preparations and can be distinguished from related analogues. Laboratory metabolism adds information about possible breakdown products and detection. This evidence is useful because chemical identity determines which findings a reader can reasonably apply.

The central clinical gaps remain direct human pharmacokinetics, a measured GH response to the exact material, patient outcomes and safety follow-up. The related GHRH literature offers biological context for those questions. It also shows that a residue substitution, albumin binding addition or delivery change can alter the result enough to require separate measurement.

FAQs

What does no DAC mean?

It indicates absence of the modified lysine and reactive albumin binding unit in original CJC-1295. The remaining four substitution fragment is commonly called modified GRF(1–29). Its exact sequence and terminal modification still matter when identifying a preparation.

Is a short human half-life established?

The available primary studies do not establish a value for the exact four substitution DAC free fragment. The Teichman estimate belongs to DAC material; the Soule study used a singly substituted analogue. Neither supplies the missing value.

What did the identification study establish?

Henninge and colleagues (2010) characterized an unknown preparation by mass spectrometry. It supported an amidated 29 residue identity later assigned by FDA to the DAC free form. The experiment measured no human GH response or clinical outcome.

Does fortified urine show human excretion?

Memdouh and colleagues (2021) added reference peptides and metabolites to urine for detection testing. The experiment assessed analytical performance. A human excretion time course needs samples obtained after defined human exposure.

Can the DAC trials establish preserved pulses for this fragment?

The Ionescu and Frohman study tested albumin-binding CJC-1295 with DAC. GH concentrations between pulses increased while the pulses continued. Modified GRF (1–29) lacks that albumin-binding component, and these sources do not provide corresponding human hormone-sampling results for the DAC-free peptide.

Is the glycine extended derivative the same peptide?

Gajda and colleagues (2019) identified added N terminal glycine in modified GRF related material. That residue changes the chain and its analytical identity. The report provides no comparison establishing equivalent pharmacology.

Sermorelin provides the unmodified amidated 29 residue comparison. CJC-1295 with DAC supplies the long acting development program, while tesamorelin links a modified full length releasing hormone to clinical visceral fat outcomes. These comparisons explain the family without assuming that shared receptor biology produces equivalent exposure or clinical benefit.

References

Henninge J, Pepaj M, Hullstein I, Hemmersbach P. Identification of CJC-1295, a growth-hormone-releasing peptide, in an unknown pharmaceutical preparation. Drug testing and analysis. 2010;2(11-12):647–650. DOI: 10.1002/dta.233. PMID: 21204297.
Mass spectrometry identified an amidated 29 residue preparation; FDA assigns this record to the DAC free form.
Memdouh S, Gavrilović I, Ng K, Cowan D, Abbate V. Advances in the detection of growth hormone releasing hormone synthetic analogs. Drug testing and analysis. 2021;13(11-12):1871–1887. DOI: 10.1002/dta.3183. PMID: 34665524.
Researchers studied peptide breakdown in laboratory systems and developed a urine-detection method using samples with known peptides added. Sermorelin, tesamorelin and CJC-1295 with and without DAC were analyzed separately; this was not a human treatment or excretion study.
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;146(7):3052–3058. DOI: 10.1210/en.2004-1286. PMID: 15817669.
Pituitary cell and rat experiments characterized GH releasing activity and prolonged circulation of albumin binding CJC-1295.
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. The Journal of clinical endocrinology and metabolism. 2006;91(3):799–805. DOI: 10.1210/jc.2005-1536. PMID: 16352683.
Two randomized healthy adult trials measured prolonged DAC peptide exposure and sustained GH and IGF-1 responses.
Ionescu M, Frohman LA. Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog. The Journal of clinical endocrinology and metabolism. 2006;91(12):4792–4797. DOI: 10.1210/jc.2006-1702. PMID: 17018654.
Overnight sampling found preserved pulses alongside increased trough and mean GH after DAC material.
Losa M, Schopohl J, Müller OA, von Werder K. Stimulation of growth hormone secretion with human growth hormone releasing factors (GRF1-44, GRF1-40, GRF1-29) in normal subjects. Klinische Wochenschrift. 1984;62(23):1140-1143. DOI: 10.1007/BF01782473. PMID: 6240568.
A healthy volunteer comparison demonstrated acute GH releasing activity of three fragment lengths, including GRF(1-29).
Soule S, King JA, Millar RP. Incorporation of D-Ala2 in growth hormone-releasing hormone-(1-29)-NH2 increases the half-life and decreases metabolic clearance in normal men. The Journal of Clinical Endocrinology and Metabolism. 1994;79(4):1208-1211. DOI: 10.1210/jcem.79.4.7962295. PMID: 7962295.
Primary pharmacokinetics measured disappearance half-times of the natural amidated fragment and its singly substituted D-Ala2 analogue in ten men.
Gajda PM, Holm NB, Hoej LJ, Rasmussen BS, Dalsgaard PW, Reitzel LA, Linnet K. Glycine-modified growth hormone secretagogues identified in seized doping material. Drug Testing and Analysis. 2019;11(2):350-354. DOI: 10.1002/dta.2489. PMID: 30136411.
Seized materials included a modified GRF related molecule with an extra N terminal glycine.
U.S. Food and Drug Administration. FDA Briefing Document: Pharmacy Compounding Advisory Committee Meeting, December 4, 2024. CJC-1295-related bulk drug substances. 2024.
Agency assessment separates DAC and DAC free identities and reviews pharmacology, human studies and safety.

Glossary

GHRH: Growth hormone releasing hormone, a hypothalamic peptide that stimulates GH producing pituitary cells.
IGF-1: Insulin-like growth factor 1, produced in liver and other tissues and mediating part of the GH response.
Pharmacokinetics: The study of how a compound enters, moves through and leaves the body.
Half-life: Time for an assayed concentration to fall by half during a specified disappearance or elimination phase.
Amidation: A chemical modification at the end of a peptide chain, indicated by NH2 in these names.
Mass spectrometry: Measurement of molecular ions and fragments to help identify a compound.
Fortified urine: Urine supplemented with a known material for analytical testing.
Counterion: An ion associated with a charged molecule in a salt.
DAC: The reactive albumin binding addition in original CJC-1295.