A comprehensive, citation-backed review of the GHRH analog CJC-1295 — comparing the DAC and no-DAC (MOD GRF 1-29) forms, examining the pharmacological basis for CJC-1295 Ipamorelin synergy, and summarizing key clinical and preclinical data.
Introduction: What Is CJC-1295?
CJC-1295 is a synthetic, tetrasubstituted analog of growth hormone-releasing hormone (GHRH), originally developed by ConjuChem Biotechnologies (Montréal, Canada). It was engineered to overcome the severe pharmacokinetic limitations of native GHRH, which has a plasma half-life of only ~7 minutes due to rapid degradation by dipeptidyl peptidase IV (DPP-IV) and other serum proteases.
The compound exists in two research-relevant forms that differ dramatically in their pharmacokinetics:
- CJC-1295 with DAC (Drug Affinity Complex): The original compound bearing a reactive maleimidopropionyl-Lysine at the C-terminus that covalently binds serum albumin in vivo, extending the half-life to 5.8–8.1 days in humans.
- CJC-1295 without DAC (also called Modified GRF 1-29 or MOD GRF 1-29): The same tetrasubstituted GHRH(1-29) core without the DAC appendage, yielding a half-life of approximately 30 minutes and producing physiological, pulsatile GH release.
CJC-1295 reached Phase II clinical trials for lipodystrophy and growth hormone deficiency before development was discontinued. In the foundational human clinical trial, a single injection produced dose-dependent GH increases of 2- to 10-fold lasting 6+ days and IGF-1 increases of 1.5- to 3-fold lasting 9–11 days, with no serious adverse events reported (Teichman et al., 2006). The compound remains an active subject of basic and translational peptide research as a GHRH analog with a well-characterized mechanism.
Mechanism of Action
CJC-1295 functions as a selective agonist of the GHRH receptor (GHRHR), a G protein-coupled receptor (GPCR) located on somatotroph cells in the anterior pituitary gland. The four amino acid substitutions (D-Ala², Gln&sup8;, Ala¹&sup5;, Leu²&sup7;) protect the peptide from enzymatic cleavage while preserving receptor binding geometry, dramatically extending the duration of receptor engagement versus native GHRH.
Signaling Cascade
Upon binding to the GHRH receptor, CJC-1295 triggers the following intracellular signaling cascade within pituitary somatotrophs:
- Gs protein activation → stimulation of adenylyl cyclase
- cAMP accumulation → activation of Protein Kinase A (PKA)
- PKA phosphorylation → GH gene transcription via the CREB pathway
- Phospholipase C activation → generation of IP₃ and DAG
- IP₃-mediated Ca²⁺ release from the endoplasmic reticulum
- DAG → Protein Kinase C (PKC) activation → GH vesicle exocytosis
- GH secretion into systemic circulation
DAC-Mediated Albumin Binding (CJC-1295 with DAC Only)
In the DAC form, after subcutaneous injection, the maleimidopropionyl group at Lys³⁰ reacts with the free thiol on Cys34 of serum albumin within minutes. At least 90% of injected CJC-1295 covalently binds albumin, with trace amounts binding fibrinogen and IgG (Jetté et al., 2005). This covalent conjugation dramatically reduces renal clearance (leveraging albumin’s ~19-day half-life), protects against proteolytic degradation, and creates a sustained-release depot yielding a compound half-life of 5.8–8.1 days.
GH/IGF-1 Axis Activation
Released GH acts on multiple peripheral tissues: the liver (primary site of IGF-1 synthesis), adipose tissue (lipolysis via hormone-sensitive lipase), muscle (protein synthesis via mTOR and PI3K/Akt), and bone (osteoblast activity). IGF-1 in turn exerts negative feedback on both the hypothalamus (increasing somatostatin) and pituitary (reducing GH sensitivity), maintaining endocrine homeostasis.
Pulsatility Is Preserved
A critical finding by Ionescu & Frohman (2006) demonstrated that pulsatile GH secretion is preserved even during continuous CJC-1295 with DAC treatment. GH pulse frequency (3.5 vs. 3.6 pulses/period, p = NS) and peak pulse height were unchanged. What increased was the trough GH level (0.058 → 0.435 ng/mL, 7.5-fold, p < 0.0001) and mean GH (46% increase, p < 0.01). This distinguishes CJC-1295 from exogenous GH therapy, which suppresses endogenous pulsatility entirely.
CJC-1295 with DAC vs. Without DAC (MOD GRF 1-29)
The two research forms of CJC-1295 share the same tetrasubstituted GHRH(1-29) core and identical GHRH receptor mechanism, but differ dramatically in pharmacokinetics and the pattern of GH release they produce.
| Parameter | CJC-1295 with DAC | CJC-1295 no DAC (MOD GRF 1-29) |
|---|---|---|
| Half-life | 5.8–8.1 days | ~30 minutes |
| Albumin binding | Yes — covalent via maleimide-Cys34 | No |
| Peak plasma concentration | 0.5–2.0 h post-injection | ~15–30 min post-injection |
| Duration of detectable drug | 10–14 days | 1–2 hours |
| GH elevation pattern | Sustained baseline elevation for 6+ days | Sharp physiological pulse, 1–3 hours |
| IGF-1 elevation | 9–11 days (single dose) | Transient (~hours) |
| DPP-IV resistant | Yes (D-Ala² substitution) | Yes (D-Ala² substitution) |
| Typical dosing interval (research) | Weekly to biweekly | Daily or multiple times daily |
| Ipamorelin combination | Less common (hard to control pulse timing) | Preferred — pulse timing aligns with Ipamorelin |
CJC-1295 with DAC: Key Characteristics
- Sustained, continuous GH/IGF-1 elevation for days per dose
- Raises the “floor” of GH secretion (trough GH 7.5× higher)
- Preserves natural pulse frequency but elevates baseline
- Weekly or biweekly dosing — fewer injections needed
- More suitable for sustained-exposure research designs
CJC-1295 no DAC (MOD GRF 1-29): Key Characteristics
- Sharp, physiological GH pulse mimicking natural GHRH release
- Minimizes GHRH receptor desensitization risk
- Preserves natural GH axis feedback architecture
- Allows precise pulse timing in experimental protocols
- Preferred for co-administration with Ipamorelin (the 2X Blend)
Nomenclature Note
“CJC-1295 without DAC” in standard research usage refers to Modified GRF (1-29) — the tetrasubstituted 29-amino-acid peptide without the Lys³⁰-maleimidopropionyl appendage. This is the commercially and research-relevant form. It should not be confused with a literal “CJC minus the DAC group” (retaining Lys³⁰), which would actually have a shorter half-life than Sermorelin due to the exposed lysine residue.
Research-Grade CJC-1295
Third-party tested, ≥98% purity. Available as CJC-1295 no DAC (MOD GRF 1-29) and CJC-1295 with DAC.
CJC-1295 No DAC
CJC-1295 With DAC
Peptide Calculator
Chemical Profile
| Property | CJC-1295 no DAC (MOD GRF 1-29) | CJC-1295 with DAC |
|---|---|---|
| Common Names | CJC-1295 no DAC, Mod GRF (1-29), Modified GRF 1-29 | CJC-1295 DAC, DAC:GRF |
| CAS Number | 446036-97-1 | 446262-90-4 |
| Molecular Formula | C₁₅₂H₂₅₂N₄₄O₄₂ | C₁₆₅H₂₆₉N₄₇O₄₆ |
| Molecular Weight | 3,367.9 g/mol | ~3,647 g/mol |
| PubChem CID | 91976842 | — |
| Chain Length | 29 amino acids | 30 amino acids + DAC appendage |
| C-terminus | Amidated (–NH₂) | Nε-maleimidopropionyl-Lys³⁰-NH₂ |
| Physical Form | White to off-white lyophilized powder | White to off-white lyophilized powder |
| Half-life | ~30 minutes | 5.8–8.1 days (albumin-bound) |
The Four Stabilizing Substitutions
CJC-1295 differs from native GHRH/Sermorelin by four amino acid substitutions that confer dramatically improved stability and receptor binding:
| Position | Native GHRH | CJC-1295 | Purpose |
|---|---|---|---|
| Position 2 | Ala | D-Ala | Prevents DPP-IV cleavage (key stability modification) |
| Position 8 | Asn | Gln | Reduces asparagine rearrangement / amide hydrolysis |
| Position 15 | Gly | Ala | Enhances bioactivity and receptor binding affinity |
| Position 27 | Met | Leu | Prevents methionine oxidation during storage and in vivo |
Amino acid sequence (CJC-1295 no DAC): H-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
The DAC version adds a Lys at position 30 bearing an N-ε-maleimidopropionyl group, which reacts with the free thiol on Cys34 of serum albumin to form a covalent bond in vivo, extending half-life from minutes to days.
Key Research Studies (PubMed Citations)
The following studies represent the core peer-reviewed evidence base for CJC-1295. All studies are available through PubMed or major academic databases.
1. Foundational Human Pharmacokinetics & Pharmacodynamics
Teichman et al. (2006) — Journal of Clinical Endocrinology & Metabolism, 91(3):799–805. (PMID: 16352683)
Two randomized, double-blind, placebo-controlled ascending-dose trials in healthy adults. Single CJC-1295 injection produced dose-dependent GH increases of 2- to 10-fold for 6+ days and IGF-1 increases of 1.5- to 3-fold for 9–11 days. Half-life: 5.8–8.1 days. Multiple doses showed cumulative IGF-1 elevation through Day 28. No serious adverse events at 30–60 μg/kg doses. Common effects: injection site reactions (70%), headache (63%), diarrhea (43%), flushing (30%).
2. GH Pulsatility Preservation
Ionescu & Frohman (2006) — Journal of Clinical Endocrinology & Metabolism, 91(12):4792–4797.
Randomized controlled study with 12-hour GH sampling and pulse analysis. GH pulse frequency unchanged (3.5 vs. 3.6 pulses/period); trough GH increased 7.5-fold (p < 0.0001); mean GH increased 46% (p < 0.01); IGF-1 increased 44% (p < 0.001). Demonstrated that CJC-1295 does not disrupt normal GH pulsatility — a critical distinction from exogenous GH therapy.
3. Albumin Binding Mechanism (Preclinical Identification)
Jetté et al. (2005) — Endocrinology, 146(7):3052–3058.
In vitro and in vivo studies in rats. CJC-1295-HSA conjugate showed 90.3% stability after 24h vs. DPP-IV (vs. 0% for native hGRF1-29). SC injection produced 4-fold GH AUC increase. CJC-1295 detectable in plasma for >72 hours vs. <1 hour for native peptide. Confirmed the molecular basis of DAC-mediated albumin bioconjugation.
4. Growth Normalization in GHRH Knockout Mice
Alba et al. (2006) — American Journal of Physiology — Endocrinology and Metabolism, 291(6):E1290–E1294. (PMID: 16822960)
GHRH knockout mice treated with CJC-1295 for 5 weeks. Daily dosing normalized body weight, length, femur/tibia length, lean mass, and fat mass. Increased total pituitary RNA and GH mRNA with confirmed somatotroph cell proliferation — indicating effects beyond simple GHRH receptor agonism, including trophic effects on pituitary cells.
5. Serum Proteomic Changes
Sackmann-Sala et al. (2009) — Growth Hormone & IGF Research, 19(6):471–477. (PMID: 19386527)
Proteomic analysis (2D-PAGE and MALDI-TOF/MS) of serum from 11 healthy men after CJC-1295 (60–90 μg/kg). Identified 5 significant protein changes including decreased apolipoprotein A1 and transthyretin isoforms. Significant correlation (r² = 0.668, p = 0.002) between protein spot intensity and IGF-1 levels — identifying potential biomarkers for GH/IGF-1 axis monitoring.
6. Ipamorelin Selectivity (Combination Partner Study)
Raun et al. (1998) — European Journal of Endocrinology, 139(5):552–561. (PMID: 9849822)
Established Ipamorelin as the first selective growth hormone secretagogue. GH potency comparable to GHRP-6 (EC50 = 1.3 vs. 2.2 nmol/L), but Ipamorelin did not release ACTH or cortisol even at doses >200-fold above GH ED50. No effect on FSH, LH, prolactin, or TSH. This selectivity profile is the key pharmacological rationale for combining Ipamorelin with CJC-1295.
7. GH Secretagogue Safety & Synergy Review
Sigalos & Pastuszak (2018) — Sexual Medicine Reviews, 6(1):45–53. (PMID: 28400207)
Systematic review of GHS clinical and preclinical data. GHRH analogs and GHRPs act synergistically when co-administered, with combination regimens reducing time to peak GH by 43%. IGF-1 improvements sustained at 90, 180, and 270 days. GHS compounds increase GH and IGF-1 without exceeding physiologic norms.
CJC-1295 and Ipamorelin Synergy
The combination of CJC-1295 (typically the no-DAC / MOD GRF 1-29 form) with Ipamorelin is among the most studied peptide pairings in GH secretagogue research. The scientific basis rests on receptor complementarity: the two compounds act on distinct but convergent intracellular pathways within the same somatotroph cells.
CJC-1295 Pathway (GHRH Receptor)
- Activates Gs protein → adenylyl cyclase → cAMP → PKA
- Promotes GH gene transcription and vesicle priming
- Provides the sustained “permissive state” for GH release
- Acts as the “primer” that loads the secretory apparatus
Ipamorelin Pathway (GHS-R1a / Ghrelin Receptor)
- Activates Gq protein → PLC → IP₃ + DAG → Ca²⁺ + PKC
- Triggers rapid exocytosis of GH-containing secretory granules
- Provides the acute “trigger” for GH pulse release
- Partially suppresses somatostatin tone, amplifying GH response
The Synergistic Mechanism
When co-administered, CJC-1295 activates the cAMP/PKA cascade (loading vesicles and elevating baseline GH synthesis) while Ipamorelin simultaneously activates the Ca²⁺/PKC cascade (triggering rapid granule exocytosis). Research in the GHS literature found that pairing a GHRH analog with a GHS produced approximately 54-fold GH elevation over saline — compared to ~20-fold for GHRH analog alone and ~47-fold for GHS alone (Sigalos & Pastuszak, 2018). The combination exceeded additive predictions, suggesting true pharmacological synergy.
An additional dimension of synergy: Ipamorelin partially suppresses somatostatin tone at the hypothalamic level. Since somatostatin is the natural inhibitor of GH release, this disinhibition amplifies the pituitary response to CJC-1295’s GHRH receptor stimulation (Lengyel, 2006).
Why CJC-1295 No DAC (Not With DAC) for the Combination
- The short half-life (~30 min) produces a controlled, time-limited pulse that aligns with Ipamorelin’s ~2-hour window
- Natural pulsatile GH dynamics are preserved, reducing receptor desensitization risk
- Researchers can time administration relative to specific experimental endpoints (e.g., sleep onset, post-exercise)
- Both peptides can be co-administered in the same syringe, simplifying protocols
- The DAC form’s 7-day half-life makes it harder to control GH exposure in time-sensitive designs
Current Evidence Limitations
Note: Most CJC-1295/Ipamorelin synergy data is modeled from individual compound pharmacodynamics and extrapolated from GHRH + GHS combination research using related compounds. Direct head-to-head human clinical trial data comparing the fixed combination to individual components remains limited. This represents an active research gap in the field.
CJC-1295 / Ipamorelin 2X Blend
Our 2X Blend combines research-grade CJC-1295 no DAC (MOD GRF 1-29) with Ipamorelin in a single lyophilized formulation — designed for researchers studying the synergistic GHRH + GHS pathway.
- Dual-pathway GH stimulation: cAMP/PKA + Ca²⁺/PKC
- Third-party tested, ≥98% purity per component
- Pre-combined for research convenience
Comparison with Other GH Secretagogues
Understanding CJC-1295’s pharmacological position relative to other GH-stimulating peptides is essential for research design. The table below compares the major compounds in this class.
| Compound | Receptor | Half-Life | GH Pattern | Cortisol | Appetite | Specificity |
|---|---|---|---|---|---|---|
| CJC-1295 with DAC | GHRHR | ~7 days | Sustained ↑↑ | None | None | High |
| CJC-1295 no DAC | GHRHR | ~30 min | Pulsatile ↑ | None | None | High |
| Sermorelin | GHRHR | ~15 min | Brief pulse ↑ | None | None | High |
| Ipamorelin | GHS-R1a | ~2 hr | Acute spike ↑↑ | None | Minimal | Very High |
| GHRP-6 | GHS-R1a | ~15–30 min | Acute spike ↑↑ | ↑ | Significant | Low |
| GHRP-2 | GHS-R1a | ~15–30 min | Acute spike ↑↑↑ | ↑ | Moderate | Low–Moderate |
| Tesamorelin | GHRHR | ~26 min | Pulsatile ↑ | None | None | High |
Key takeaway: CJC-1295 no DAC and Ipamorelin are the only two compounds in this table that combine high GH specificity (no cortisol, no appetite effects) with different receptor targets (GHRHR vs. GHS-R1a) — making them the pharmacologically optimal pairing for isolated, synergistic GH axis stimulation in research settings (Raun et al., 1998).
Storage & Handling
Lyophilized Powder (Pre-Reconstitution)
| Storage Condition | Duration | Notes |
|---|---|---|
| −20°C (optimal) | 24–36 months | Sealed, nitrogen-purged vials; preferred for long-term storage |
| 4°C (refrigerated) | 6–12 months | Suitable for active inventory |
| Room temperature | 2–4 weeks max | Emergency only; protect from light and moisture |
Reconstituted Solution
| Solvent | Temperature | Stability |
|---|---|---|
| Bacteriostatic water | 2–8°C | 4–6 weeks |
| Sterile water | 2–8°C | 3–7 days |
| Either (frozen aliquots) | −20°C | 3–6 months |
| Either | Room temperature | 4–6 hours maximum |
Handling Best Practices
- Allow sealed vials to reach room temperature before opening to prevent condensation and moisture uptake.
- Reconstitute carefully: Direct bacteriostatic water gently against the vial wall — never inject directly onto the powder. Allow 2–3 minutes for dissolution; do not shake or vortex.
- Aliquot immediately into single-use volumes; freeze unused aliquots at −20°C to avoid repeated freeze-thaw cycles.
- Filter for administration: Use a 0.2 μm syringe filter for in vivo or cell culture applications.
- Protect from light: Use amber or foil-wrapped vials.
- DAC form note: The maleimidopropionyl group may hydrolyze under alkaline conditions. Keep reconstituted DAC solutions at pH 4.5–6.5 and refrigerated.
Stability advantage: CJC-1295’s Leu²⁷ substitution (replacing methionine) specifically eliminates oxidation susceptibility, making it more stable during long-term storage than Sermorelin or native GHRH.
Use our Peptide Calculator to determine accurate reconstitution volumes and concentrations for your research protocol.
Research Applications
CJC-1295 is utilized across multiple preclinical and translational research domains:
GH Axis Physiology
Studying GHRH receptor signaling, pulsatile GH dynamics, and feedback architecture of the hypothalamic–pituitary–somatotroph axis. CJC-1295’s preservation of pulsatility makes it superior to exogenous GH for physiological research.
Metabolic Research
Investigating GH-mediated lipolysis, fat oxidation, and body composition changes. The DAC form’s sustained IGF-1 elevation is particularly relevant for long-duration metabolic studies.
Growth & Development
GH deficiency models, somatotroph proliferation research, and bone metabolism studies. Alba et al. (2006) demonstrated full growth normalization in GHRH knockout mice.
Receptor Pharmacology
GHRH receptor desensitization, cross-talk with the ghrelin/GHS-R1a pathway, and combination pharmacology with GHRPs. The no-DAC form is preferred for controlled pulse-timing experiments.
Biomarker Discovery
Identifying serum protein biomarkers of GH/IGF-1 axis activation for anti-doping and clinical monitoring, building on Sackmann-Sala et al. (2009).
Analytical Chemistry
Detection methods for GHRH analogs in biological matrices: LC-MS/MS, immuno-PCR, and WADA-compliant urinary assays for anti-doping research.
Frequently Asked Questions
Research-Grade CJC-1295 Peptides
Third-party tested, ≥98% purity. Available individually or as the CJC-1295 / Ipamorelin 2X Blend.
CJC-1295 No DAC
CJC-1295 With DAC
2X Blend
Peptide Calculator
References
- 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. J Clin Endocrinol Metab. 2006;91(3):799–805. PMID: 16352683.
- 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. DOI: 10.1210/jc.2006-1702.
- Jetté L, Léger R, Thibaudeau K, et al. 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.
- Alba M, Fintini D, Sagazio A, et al. Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse. Am J Physiol Endocrinol Metab. 2006;291(6):E1290–E1294. PMID: 16822960.
- Sackmann-Sala L, Ding J, Frohman LA, Kopchick JJ. Activation of the GH/IGF-1 axis by CJC-1295, a long-acting GHRH analog, results in serum protein profile changes in normal adult subjects. Growth Horm IGF Res. 2009;19(6):471–477. PMID: 19386527.
- Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998;139(5):552–561. PMID: 9849822.
- Sigalos JT, Pastuszak AW. The safety and efficacy of growth hormone secretagogues. Sex Med Rev. 2018;6(1):45–53. PMID: 28400207.
- Henninge J, Pepaj M, Hullstein I, Hemmersbach P. Identification of CJC-1295, a growth-hormone-releasing peptide, in an unknown pharmaceutical preparation. Drug Test Anal. 2010;2(11):647–650. DOI: 10.1002/dta.233.
- Lengyel AMJ. Novel mechanisms of growth hormone regulation: growth hormone-releasing peptides and ghrelin. Braz J Med Biol Res. 2006;39(8):1003–1011. DOI: 10.1590/S0100-879X2006000800002.
- Al Musaimi O. Exploring FDA-approved frontiers: insights into natural and engineered peptide analogues in the GLP-1, GIP, GHRH, CCK, ACTH, and α-MSH realms. Biomolecules. 2024;14(3):264. DOI: 10.3390/biom14030264.
