Abstract
A comprehensive scientific review of CJC-1295, the synthetic GHRH analog peptide, covering the distinction between CJC-1295 with and without DAC, its molecular structure, mechanism of action through the GHRH receptor, clinical trial evidence, pharmacokinetics, and regulatory status.
CJC-1295 is a synthetic analog of growth hormone releasing hormone (GHRH) consisting of the first 29 amino acids of human GHRH with four strategic amino acid substitutions designed to enhance metabolic stability and receptor binding affinity. The compound exists in two distinct forms that are critically important to distinguish: CJC-1295 with DAC (Drug Affinity Complex) and CJC-1295 without DAC, also commonly referred to as modified GRF(1-29) or Mod GRF 1-29. These two forms share the same core peptide sequence but differ dramatically in their pharmacokinetic properties due to the presence or absence of the DAC modification, which covalently bonds the peptide to circulating albumin and extends its half-life from minutes to days.
The development of CJC-1295 originated from the known limitations of native GHRH(1-44) and its truncated bioactive fragment GHRH(1-29), also known as sermorelin. Native GHRH has a plasma half-life of approximately 7 to 10 minutes due to rapid enzymatic degradation, primarily by dipeptidyl peptidase IV (DPP-IV), which cleaves between the second and third amino acids (Ala2-Asp3). This short half-life severely limits the therapeutic utility of native GHRH, requiring frequent injections or continuous infusion to maintain effective plasma levels. The development program at ConjuChem Biotechnologies (Montreal, Canada) systematically addressed this limitation through two complementary strategies: amino acid substitutions to resist enzymatic cleavage, and the DAC bioconjugation technology to extend plasma residence time.
The four amino acid substitutions in CJC-1295 relative to native GHRH(1-29) are: Ala2 replaced by D-Ala (resistance to DPP-IV cleavage), Asn8 replaced by Gln (resistance to asparagine deamidation), Ala15 replaced by Ala with an additional side chain modification (enhanced receptor binding), and Met27 replaced by Leu (resistance to methionine oxidation). The resulting sequence, known as tetrasubstituted GRF(1-29) or Mod GRF 1-29, retains full agonist activity at the GHRH receptor while demonstrating substantially improved metabolic stability. The half-life of CJC-1295 without DAC is approximately 30 minutes—a significant improvement over the 7-minute half-life of native GHRH, though still requiring multiple daily injections for sustained GH axis stimulation.
The Drug Affinity Complex (DAC) technology represents a more radical pharmacokinetic modification. DAC is a reactive chemical moiety (a maleimido group) attached to the lysine residue at position 30 of the peptide. Following subcutaneous injection, this maleimido group spontaneously and irreversibly reacts with a free cysteine residue (Cys34) on circulating serum albumin, forming a stable thioether bond. The resulting CJC-1295-albumin conjugate has a dramatically extended half-life of approximately 6 to 8 days, reflecting albumin's own plasma half-life of approximately 19 days. This means that a single injection of CJC-1295 with DAC produces sustained GHRH receptor stimulation for approximately one to two weeks, fundamentally different from the acute, pulsatile stimulation produced by CJC-1295 without DAC.
CJC-1295 exerts its biological effects through activation of the GHRH receptor (GHRH-R), a G-protein coupled receptor expressed primarily on anterior pituitary somatotroph cells. Upon binding to GHRH-R, the peptide activates the Gs-adenylyl cyclase-cAMP-protein kinase A (PKA) signaling pathway. PKA activation leads to phosphorylation of the transcription factor CREB (cAMP response element binding protein), which drives GH gene expression and GH synthesis. Simultaneously, cAMP elevation opens voltage-gated calcium channels, increases intracellular calcium, and triggers exocytosis of pre-formed GH secretory granules. This dual action—enhanced GH synthesis and enhanced GH release—distinguishes GHRH receptor agonists from GHS-R1a agonists like Ipamorelin, which primarily stimulate release of pre-formed GH stores without directly driving GH gene transcription.
The clinical development of CJC-1295 with DAC was conducted by ConjuChem Biotechnologies through Phase II clinical trials. A pivotal study published in the Journal of Clinical Endocrinology and Metabolism by Teichman and colleagues in 2006 demonstrated that a single subcutaneous injection of CJC-1295 with DAC at doses of 30, 60, or 90 mcg/kg produced dose-dependent elevations in mean GH levels that persisted for 6 to 14 days. IGF-1 levels increased by 1.5 to 3-fold above baseline and remained elevated for 9 to 11 days following a single injection. These pharmacokinetic results confirmed the DAC technology's success in creating a truly long-acting GHRH analog. Repeated weekly or biweekly dosing produced sustained IGF-1 elevations without evidence of tachyphylaxis over the 2 to 3 month study periods.
However, the clinical development of CJC-1295 with DAC encountered a significant safety setback. During extended Phase II clinical trials, several study participants experienced serious adverse events, and the development program was placed on clinical hold. While the specific details of these adverse events were not fully disclosed publicly, concerns about sustained, non-pulsatile GH stimulation and the long biological half-life of the compound were cited as contributing factors. The extended duration of action, while pharmacokinetically elegant, meant that any adverse effects could not be rapidly reversed upon drug discontinuation—a significant safety concern for a compound that was being studied for chronic conditions like GH deficiency and age-related sarcopenia.
CJC-1295 without DAC (Mod GRF 1-29) has a fundamentally different pharmacological profile. Its 30-minute half-life means it produces acute, pulsatile GH release rather than sustained elevation. Following subcutaneous injection, GH levels rise within 15 to 30 minutes, peak at 30 to 60 minutes, and return to baseline within 2 to 3 hours. This acute release pattern closely mimics the natural pulsatile rhythm of endogenous GHRH secretion and may be safer from the perspective of maintaining normal GH receptor sensitivity and somatostatin feedback regulation. The trade-off is the requirement for multiple daily injections (typically 2 to 3) to achieve meaningful cumulative GH axis stimulation.
The synergy between CJC-1295 without DAC and GH secretagogue peptides like Ipamorelin has been extensively documented and represents one of the most important practical findings in GH secretagogue research. The combination produces GH release that is substantially greater than the additive sum of either agent alone. This synergy has a clear mechanistic basis: GHRH receptor activation through CJC-1295 drives cAMP/PKA signaling and GH synthesis, while GHS-R1a activation through Ipamorelin drives phospholipase C/calcium signaling and GH release. Simultaneously, Ipamorelin suppresses somatostatin release from hypothalamic neurons, removing the endogenous inhibitory brake on GH secretion. The convergence of these three mechanisms—stimulation of GH synthesis, stimulation of GH release, and suppression of GH inhibition—explains the observed synergistic potentiation.
Research into CJC-1295's metabolic effects has demonstrated improvements in body composition consistent with enhanced GH/IGF-1 axis activity. Animal studies have shown reductions in visceral adiposity, increases in lean body mass, and improvements in bone mineral density with chronic CJC-1295 administration. The magnitude of these effects is generally proportional to the degree and duration of IGF-1 elevation achieved. Sleep quality improvements have been reported in research settings, consistent with GH's known role in promoting slow-wave deep sleep—the most restorative sleep phase during which the majority of natural GH secretion occurs.
From a regulatory perspective, CJC-1295 in either form has not received FDA or EMA approval for any clinical indication. The clinical development program for CJC-1295 with DAC was suspended and has not been restarted. CJC-1295 without DAC has not been formally evaluated in registration-quality clinical trials. Both forms are classified as research chemicals and are available from peptide synthesis companies for in vitro and animal research. WADA prohibits CJC-1295 under category S2 of the prohibited list. Despite the absence of regulatory approval, CJC-1295 remains one of the most extensively studied and widely used GHRH analogs in the research peptide field, with the CJC-1295/Ipamorelin combination stack representing a particularly well-characterized research paradigm.
The distinction between CJC-1295 with DAC and without DAC cannot be overemphasized for researchers. These are functionally different compounds with dramatically different pharmacokinetic profiles, dosing regimens, and risk-benefit considerations. CJC-1295 with DAC provides convenience (once or twice weekly dosing) but produces sustained, non-pulsatile GHRH receptor stimulation that may lead to GH receptor desensitization and has been associated with clinical safety concerns. CJC-1295 without DAC requires multiple daily injections but preserves physiological pulsatile GH release patterns and provides greater temporal control over GH axis stimulation. The majority of current research literature favors CJC-1295 without DAC, particularly in combination with Ipamorelin, as the preferred approach for optimizing the benefit-risk ratio of GHRH analog-based GH axis stimulation.
