5.8–8.1 D
TECH SHEET · 1295.DAC · GHRHR AGONIST
A precision GHRH analog, engineered for a seven-day half-life.
Four protective residue substitutions, a covalent albumin tether, a single Phase 1 dose-escalation, and a halted Phase 2 program. The CJC-1295 evidence base, read as engineering spec.
HALF-LIFE
RESIDUES
30
PHASE 1 COHORTS
4
WADA CLASS
S2
§ 01
Compound
CJC-1295 is a 30-residue synthetic peptide derived from human growth hormone-releasing hormone (GHRH). The backbone is the first 29 amino acids of native hGRF, modified at four positions — D-alanine at position 2, glutamine at position 8, alanine at position 15, and leucine at position 27. Each substitution closes a specific proteolytic vulnerability: position 2 resists dipeptidyl peptidase-4 cleavage, position 8 resists deamidation, position 15 resists trypsin-like proteolysis, and position 27 resists oxidative damage [1].
A 30th residue carries the Drug Affinity Complex (DAC) modification — an N-epsilon-maleimidopropionic acid group that undergoes a Michael addition with the free thiol of cysteine-34 on circulating serum albumin. The product is a covalent peptide-albumin bioconjugate roughly 70 kDa in apparent mass [1]. This single chemical step is what converts a peptide with a native half-life measured in minutes into a peptide with a plasma half-life measured in days.
The non-DAC backbone, sometimes labeled modified GRF(1-29), retains the four amino acid substitutions but lacks the maleimide. Its half-life sits at approximately 30 minutes — a roughly 4-fold extension over native GHRH but two orders of magnitude shorter than the DAC variant. Conflation between the two molecules in lay and vendor literature is endemic; they are pharmacologically distinct.
§ 02
Mechanism
The receptor target is the growth hormone-releasing hormone receptor (GHRHR), a class B G-protein-coupled receptor expressed on anterior pituitary somatotrophs. Receptor engagement triggers a Gs / adenylyl cyclase / cAMP / PKA signaling cascade that drives CREB-mediated transcription of the GH1 gene and the release of stored growth hormone [5]. Downstream hepatic IGF-1 (somatomedin C) production amplifies and biomarks the signal.
The 2020 cryo-electron microscopy structure of the GHRHR-GHRH-Gs complex (PDB 7CZ5, 2.6 Å resolution) showed that GHRH binds as a continuous α-helix engaging all three receptor extracellular loops, the extracellular domain, and every transmembrane helix except TM4 [5]. The structural picture explains atomistically why the four CJC-1295 substitutions preserve receptor activation while resisting peptidase attack — none of the modified residues participates directly in the receptor-binding interface.
A mechanistic point recurs across the recent endocrinology literature: GHRHR agonism produces robust GH stimulation that does not exceed physiological pulse limits, because IGF-1 negative feedback at the hypothalamus continues to regulate peak amplitude even when the GHRH input is sustained [14]. This distinguishes GHRH-axis activation from direct exogenous recombinant GH administration.
§ 03
Pharmacokinetics
The pivotal human pharmacokinetic data come from a single Phase 1 dose-escalation study in 22 healthy adults aged 21-46 years [2]. Single subcutaneous doses of 30, 60, 125, and 250 μg/kg produced mean plasma GH elevations of 2- to 10-fold over baseline persisting at least 6 days, and mean IGF-I elevations of 1.5- to 3-fold persisting 9-11 days. Multiple-dose cohorts maintained IGF-1 elevation for up to 28 days after the final dose. Mean plasma half-life across the dose range fell at 5.8-8.1 days.
A substudy of the same cohort examined whether the multi-day pharmacodynamic profile abolished endogenous GH pulsatility. It did not: trough GH rose approximately 7.5-fold while the discrete pulse architecture — pulse number, amplitude variability, inter-pulse interval — remained intact [3]. Mean GH rose 46% above baseline. The structural picture is a raised floor with the pulses still firing on top, not a flat plateau.
The 2009 proteomic substudy identified five candidate serum biomarkers of CJC-1295 dosing — apolipoprotein A1 and transthyretin isoforms reduced, β-hemoglobin and an albumin C-terminal fragment and immunoglobulin fragments increased, with the immunoglobulin/albumin spot correlating linearly with IGF-1 [6]. The proteomic signature is the most granular dosing readout in the published human record.
§ 04
Clinical development
The sponsor-funded clinical program halted in October 2006. A Phase 2 randomized double-blind trial of CJC-1295 in HIV-associated visceral adiposity (NCT00267527, n=192) terminated after a participant death from an acute coronary event approximately two hours after the 11th weekly dose [8]. An independent review attributed the event to pre-existing undiagnosed coronary artery disease and judged it unrelated to study drug, but the primary efficacy endpoints were never published in peer review and no sponsor-funded clinical development has resumed.
The class-effect benchmark for visceral-fat efficacy comes from a structurally related FDA-approved GHRH analog, tesamorelin: 15-20% reduction in visceral adipose tissue over 26 weeks of daily 2 mg subcutaneous dosing in HIV-associated lipodystrophy [11]. The CJC-1295 Phase 2 program was originally designed against this benchmark; whether it would have hit it remains untested.
A separate randomized trial of tesamorelin in older adults (NCT00257712, the SMART study, n=152, 20 weeks of daily 1 mg SC) produced significant improvement on executive function (P=0.005), a positive trend on verbal memory (P=0.08), 117% IGF-1 elevation, and 7.4% reduction in body fat [9]. This is the strongest class-level evidence that pituitary GHRH-axis activation can yield measurable cognitive effects in older adults — a research signal, not a license to extrapolate to CJC-1295 dosing in any human population.
§ 05
Regulatory chassis
CJC-1295 is not approved for any human therapeutic indication by FDA, EMA, or any other major regulator. On September 20, 2024, the FDA removed CJC-1295 from Category 2 of the interim 503A bulk drug substances list after the original nominators withdrew their nominations [16]. The action unwound the September 2023 'do not compound' designation that had been in place for roughly a year; it did not constitute approval. CJC-1295 remains a research chemical and remains outside legitimate compounding-pharmacy practice.
The World Anti-Doping Code 2025 Prohibited List reaffirms CJC-1295 under Section S2 — Peptide Hormones, Growth Factors, Related Substances and Mimetics — as prohibited at all times, both in-competition and out-of-competition, for any athlete subject to WADA testing [17]. The analytical chassis that supports enforcement is recent: a 2021 metabolism paper characterized 19 in vitro metabolites of CJC-1295 and validated an LC-MS/MS detection method at limits at or below 1 ng/mL in urine [12], and a 2024 nano-LC Orbitrap method validation [15] formalized the routine-testing pipeline.
Forensic identification of seized illicit CJC-1295 in the gray market was confirmed by high-resolution LC-MS/MS sequence determination in 2010 [13]. Counterfeit and impure 'research chemical' CJC-1295 has circulated since; product identity, purity, sterility, and endotoxin burden in non-pharmaceutical channels are not assured.
