Research Dossier on CJC-1295 (NO DAC) + Ipamorelin

(Growth Hormone Secretagogue)

Classification & Molecular Identity

Overview

• CJC-1295 (without DAC) (often called modified GRF(1-29) or mod-GRF(1-29)) is a stabilized, tetrasubstituted analog of the 1–29 N-terminal fragment of human growth hormone-releasing hormone (GHRH, a.k.a. GRF). The four canonical substitutions reported for the “CJC-1295 family” are D-Ala², Gln⁸, Ala¹⁵, and Leu²⁷, introduced to improve resistance to endo/exopeptidases (notably DPP-IV cleavage at the Tyr¹–Ala² bond) and to enhance receptor affinity/stability. In the “without DAC” form there is no albumin-reactive maleimide; the molecule therefore behaves like a short-acting GHRH analog rather than an albumin conjugate. PMC+2Oxford Academic+2

• Ipamorelin is a pentapeptide and selective agonist of the ghrelin/“growth-hormone secretagogue” receptor (GHSR1a). It is widely cited as selective for GH release with minimal effect on ACTH/cortisol or prolactin in the dose ranges tested in early human/animal work. A representative sequence description is Aib-His-D-2-Nal-D-Phe-Lys-NH₂. PubMed+1

Chemical class:
• CJC-1295 (w/o DAC): 29-aa linear peptide, amidated C-terminus; GHRH-receptor (GHRHR) agonist.
• Ipamorelin: 5-aa peptide; GHSR1a agonist (ghrelin mimetic).

Molecular formulae, size & motifs

• CJC-1295 (w/o DAC): Peptide of 29 residues (GHRH 1–29 backbone) with substitutions noted above; typical molar mass ~3.3 kDa (varies by exact sequence microvariants reported in analytical literature). Protease-liability is reduced primarily by the D-Ala² substitution and additional changes at 8/15/27. Oxford Academic+1

• Ipamorelin: C₃₈H₄₉N₉O₅, Mᵣ ≈ 711 g·mol⁻¹ (free base). Motifs include Aib (α-aminoisobutyric acid) and D-2-naphthylalanine, conferring receptor selectivity and metabolic stability among first-generation GHSs. PubMed

Discovery history (lab, year, species)

• Stabilized GHRH analogs: Resistance to plasma degradation via D-Ala² and other substitutions was explored since the late 1980s–1990s; later work cataloged tetrasubstituted GRF(1-29) analogs and related modifications, establishing the CJC lineage. PubMed+1

• Ipamorelin: Developed in the 1990s (Novo Nordisk), identified as the first GHS with GH-selective secretagogue profile, and advanced to human PK/PD characterization. PubMed+1

Endogenous vs. synthetic origin

Both components are fully synthetic peptide ligands that target endogenous endocrine pathways: CJC-1295 (w/o DAC) acts at GHRHR on pituitary somatotrophs; ipamorelin acts at GHSR1a expressed centrally and in pituitary, mimicking the action of ghrelin. Karger+1

Homologs, analogs, derivatives

• Within the GHRH class:

  • Sermorelin (GRF(1-29)) – the unmodified reference agonist (short half-life).

  • Tesamorelin (TH9507) – stabilized GHRH analog (distinct substitutions; separate clinical program). New England Journal of Medicine+1

• Within the GHSR/ghrelin mimetic class: hexarelin, GHRP-2, GHRP-6, and relamorelin (RM-131; advanced for GI indications). Ipamorelin is distinct for GH selectivity in early work. PubMed+1

Historical Development & Research Trajectory

Key milestones

• 1980s–1990s (GHRH analogs): Strategic substitutions (e.g., D-Ala², Ala¹⁵) shown to prolong half-life and preserve potency of GRF(1-29) in humans/animals; multiple labs explored cyclization, PEGylation, and later albumin-binding chemistries (the latter relevant to CJC-1295 with DAC, not the present “without DAC” construct). PubMed+1

• 1998–1999 (Ipamorelin): First reports establish selective GH secretagogue profile and human PK/PD (short terminal half-life; dose-proportional PK; single GH pulse with peak ≈0.67 h after dosing). PubMed+1

• 1990s–2000s (synergy concept): Multiple studies in humans and animals document synergistic GH release when a GHRH agonist is combined with a GHSR agonist (e.g., GHRH + GHRP-2/GHRP-6), establishing a mechanistic rationale for pairing GHRH analogs with ghrelin mimetics. PubMed+2Oxford Academic+2

• 2000s–2010s: GHRH analogs such as tesamorelin demonstrate clinical outcomes in disease-specific contexts (e.g., HIV-associated visceral adiposity), while ipamorelin is explored clinically for postoperative ileus as a prokinetic GHSR agonist. (Programs are separate and not designed to test the combined regimen.) New England Journal of Medicine+1

Paradigm shifts & controversies

• Shift to physiology-mimicry: Instead of exogenous GH, investigators examined endogenous axis stimulation (GHRH and/or GHSR agonism) to preserve pulsatility and downstream regulation. Synergy studies underpinned the dual-pathway approach. PubMed+1

• Controversy/data gaps: CJC-1295 without DAC itself has limited modern, named clinical literature (much of the clinical literature names sermorelin or tesamorelin, or CJC-1295 with DAC). Human trials explicitly testing the combination of “CJC-1295 (without DAC) + ipamorelin” are not established in indexed registries to date. (Evidence for co-administration relies on class-based synergy between GHRH agonists and GHSR agonists.) PubMed+1

Evolution of scientific interest

Interest broadened from endocrine physiology into metabolism, body composition, and GI motility (for GHSR agonists). In parallel, analytical and anti-doping sciences cataloged GHRH analog microvariants such as [D-Ala²,Gln⁸,Ala¹⁵,Leu²⁷]sermorelin—consistent with the “CJC-1295 without DAC” tetrasubstitution pattern. PMC

Mechanisms of Action

Primary receptor interactions

• CJC-1295 (w/o DAC): Full agonist at the GHRH receptor (GHRHR) on pituitary somatotrophs → Gs–adenylyl cyclase–cAMP–PKA–CREB activation → GH gene transcription and regulated exocytosis of GH. Substitutions mainly improve metabolic stability; pharmacophore remains the GHRH(1–29) N-terminal domain. (Mechanism inferred from GHRH biology and stabilized analog literature.) PubMed

• Ipamorelin: Agonist at the ghrelin (GHSR1a) receptor, triggering Gq/Gi and Ca²⁺-dependent secretagogue signaling upstream of somatotroph GH release; selective for GH with minimal ACTH/cortisol co-release in early work. PubMed

Complementarity & synergy

GHRH and GHSR pathways are partly independent and convergent at the somatotroph; co-administration yields supra-additive (synergistic) GH release across studies in humans and animals (e.g., GHRH + GHRP-2/GHRP-6). This synergy is one principal scientific rationale for examining GHRH analog + ghrelin mimetic pairs. PubMed+2Oxford Academic+2

Intracellular signaling & downstream biology

• GHRHR (CJC-1295 w/o DAC): cAMP–PKA → increased GH synthesis; enhances amplitude of physiologic GH pulses.

• GHSR (Ipamorelin): PLC–IP₃/Ca²⁺ and additional signaling that sensitizes somatotrophs to GHRH; induces a rapid GH pulse after dosing.

• Downstream axis: GH → hepatic IGF-1 (JAK2–STAT5); proteomic readouts of GH-axis activation after GHRH analog exposure have been described in related settings. Antiaging Systems

CNS vs peripheral effects

• Primary site of action: anterior pituitary somatotrophs (outside the classic BBB).

• GHSR expression extends to hypothalamus and peripheral tissues; ipamorelin (as a ghrelin mimetic) can exert central and peripheral actions, although endocrine GH release is the principal measured pharmacodynamic effect in human PK/PD studies. PubMed

Hormonal, metabolic, immune interactions

Activation of the GH–IGF-1 axis via these pathways influences protein synthesis, lipolysis, and glucose metabolism, with context-dependent changes in insulin sensitivity reported in the broader GHS literature. (Direction/magnitude are model-dependent.) Europe PMC

Evidence grading (A–C)

• A (replicated PD concept): Synergistic GH release when GHRH agonism is paired with GHSR agonism; selective GH secretagogue profile of ipamorelin; improved stability of tetrasubstituted GHRH analogs vs native GRF(1-29). PubMed+2Oxford Academic+2

• B (limited translation for this exact pair): Individual clinical programs exist (tesamorelin for HIV adiposity; ipamorelin for ileus), but no large, modern trials specifically of CJC-1295 (w/o DAC) + ipamorelin. Not established. New England Journal of Medicine+1

• C (hypothesis): That this exact combination confers superior body-composition, metabolic, or functional outcomes vs single agents in humans—Unknown/Not established.

Pharmacokinetics & Stability

ADME profile — CJC-1295 (without DAC)

• Absorption & distribution: As a short-acting GHRH analog, it is expected to show rapid systemic availability after parenteral administration and wide extracellular distribution typical of small peptides.

• Metabolism: Proteolytic cleavage is reduced vs native GRF(1-29) by D-Ala² and additional substitutions (Gln⁸, Ala¹⁵, Leu²⁷), which together slow DPP-IV and endopeptidase attack; published analog studies (and PEGylation/cyclization work) document longer in-plasma persistence than unmodified sermorelin but far shorterthan albumin-conjugated variants. PubMed+1

• Excretion: Renal and proteolytic; half-life in humans for short-acting GHRH analogs is minutes to tens of minutes (sequence- and formulation-dependent). (Direct head-to-head, named PK for “CJC-1295 without DAC” under that exact name is limited in indexed literature; stability inferences come from the analog class.) PubMed

ADME profile — Ipamorelin

• Absorption: Rapid systemic appearance when infused or injected.

• Distribution: Modest volume of distribution (~0.22 L·kg⁻¹ in healthy volunteers).

• Metabolism & excretion: Primarily renal, with a short terminal half-life ~2 h reported in human PK/PD modeling after 15-min IV infusion (dose-proportional PK). In some reports (non-human, bolus), shorter apparent half-lives are noted; human PK/PD consistently characterizes brief exposure with a single GH pulse peaking ≈0.67 h. PubMed+1

Plasma half-life & degradation

• CJC-1295 (w/o DAC): Short-acting (minutes–tens of minutes) relative to the days-long effective half-life of CJC-1295 with DAC; enzymatic liabilities are mitigated but not abolished. (Not established precisely for all commercial microvariants; the literature supports the directionality vs native GRF.) PubMed

• Ipamorelin: t½ ≈ 2 h (humans); GH pulse temporally linked to exposure. PubMed

Stability (in vitro & in vivo)

• CJC-1295 (w/o DAC): Substitutions increase plasma stability in vitro; in vivo duration remains short, aligning with the design goal to mimic physiologic, pulsatile GHRH. PubMed

• Ipamorelin: Stable enough to permit linear PK and predictable PD in humans; no major active metabolitesdominate exposure in clinical PK publications. PubMed

Storage/reconstitution considerations

Peer-reviewed monographs provide general peptide handling guidance; formal, peer-reviewed reconstitution/stability studies specific to commercial research vials are not established. (Data gap.)

Preclinical Evidence

CJC-1295 (without DAC) — animal/in vitro

• Stabilized GHRH analogs with D-Ala² (± additional positions) show enhanced half-life and potent GH releasein rodent pituitary and in vivo models; older studies also explored PEGylation and cyclization to prolong action. PubMed+1

Ipamorelin — animal/in vitro

• Endocrine selectivity: Ipamorelin selectively triggers GH release in animals without significant ACTH/cortisolincreases at pharmacologic exposures. PubMed

• GI motility models: In rodent postoperative ileus, ipamorelin accelerated gastric emptying and improved transit measures (preclinical rationale for clinical GI trials). PMC

Combination rationale — preclinical physiology

Multiple studies demonstrate synergy between GHRH analogs and GHSR agonists in vivo (rat, human) at the level of GH pulse amplitude and area-under-curve—a principle that motivates combination experiments even where named products were not paired in formal trials. PubMed+1

Dose ranges tested (investigational, selected exemplars)

• GHRH analogs: wide range in animals (µg·kg⁻¹, model-specific); short-acting constructs dose near physiologic testing paradigms. (Heterogeneous; not standardized.)

• Ipamorelin: human PK used 4.21–140.45 nmol·kg⁻¹ IV over 15 min in healthy males (investigational doses used in study Gobburu 1999). PubMed

Comparative efficacy/safety (preclinical)

• CJC-1295 (w/o DAC) outlasts native GRF(1-29) but remains short-acting;

• Ipamorelin shows rapid, selective GH release with a concise PK window;

• Combined pathway activation yields greater GH output than either alone in synergy paradigms. PubMed+1

Limitations

• Limited modern, peer-reviewed preclinical head-to-head studies naming “CJC-1295 without DAC”; many reports discuss the class (stabilized GRF analogs).

• Combination studies with this exact pair are not established; preclinical synergy derives from class archetypes(e.g., GHRH + GHRP-2/-6). PubMed

Human Clinical Evidence

Important: No indexed, peer-reviewed Phase II/III clinical trial was found that tests the combined regimen “CJC-1295 (w/o DAC) + ipamorelin.” Evidence below summarizes each component’s human literature and class synergy observations.

GHRH analogs (context for CJC-1295 w/o DAC)

• Stability substitutions (e.g., D-Ala²) increased half-life and reduced clearance of GRF(1-29) in humans (older PK/PD work). PubMed

• Tesamorelin, a distinct stabilized GHRH analog, produced clinically significant reductions in visceral adipose tissue and lipid improvements in HIV-associated lipodystrophy (investigational regimen used in study Falutz 2007; NCT00123253). This demonstrates translational potential of stabilized GHRH agonism, not of the present named analog. New England Journal of Medicine

Ipamorelin — human PK/PD & trials

• Healthy volunteers (PK/PD): Randomized dose-escalation trial characterized dose-proportional PK, t½ ~ 2 h, Vss ~ 0.22 L·kg⁻¹, and a single GH pulse peaking ~0.67 h after infusion (investigational doses used in study Gobburu 1999). PubMed

• Postoperative ileus (Phase 2 proof-of-concept): In bowel resection patients (NCT00672074), ipamorelin 0.03 mg·kg⁻¹ twice daily for ≤7 days (investigational dose used in study Beck 2014) was well tolerated but did notsignificantly improve primary efficacy endpoints vs placebo. PubMed

• Additional registry: NCT01280344 evaluated ipamorelin for GI recovery after bowel resection (safety/efficacy; status per registry). ClinicalTrials.gov

Combination (GHRH agonist + GHSR agonist) — human physiology

Multiple independent physiological studies demonstrate synergy (greater-than-additive GH output) when GHRH and GHSR agonists are co-administered in humans under various endocrine conditions (e.g., GHRH + GHRP-2). These support the biological plausibility of pairing a short-acting GHRH analog (like CJC-1295 without DAC) with ipamorelin, although no registered clinical trials specifically test this named pair for efficacy outcomes. Confounding variables (age, sex, gonadal status, somatostatin tone) modulate synergy magnitude. PubMed+2Oxford Academic+2

Safety signals/adverse events (component-wise)

• GHRH analog class: Generally injection-site reactions, flushing, and transient symptoms have been described (agent- and dose-dependent).

• Ipamorelin: In Phase 2 ileus study, well tolerated, no major safety signals; broader GHS literature notes potential glycemic effects via insulin sensitivity modulation (context dependent; not definitive for ipamorelin). PubMed+1

ClinicalTrials.gov IDs (illustrative, component-level)

• Ipamorelin: NCT00672074, NCT01280344. ClinicalTrials.gov+1

• GHRH agonist (tesamorelin): NCT00123253 (for context; distinct molecule). PubMed

Comparative Context

Related peptides & classes

• GHRH analogs: sermorelin (short-acting), tesamorelin (stabilized; clinically validated for HIV-associated VAT reduction). New England Journal of Medicine

• GHSR agonists: ipamorelin (GH-selective), hexarelin/GHRP-2/-6 (differing selectivity/adrenal effects); newer relamorelin advanced in GI motility. PMC

Advantages (research perspective)

• Physiologic mimicry: pairing GHRH and GHSR agonism tests natural dual-pathway control of GH secretion with documented synergy. PubMed

• Temporal control: Short-acting agents (CJC-1295 w/o DAC; ipamorelin) can be used to probe pulse timing and somatostatin tone interactions in mechanistic studies. Physiology Journals

Disadvantages / constraints

• Evidence gap: No large modern RCTs of this specific named combination for clinical outcomes; Unknowncomparative benefit vs. single agents.

• PK mismatch: Ipamorelin (t½ ~2 h) vs CJC-1295 w/o DAC (minutes–tens of minutes) may require designs that control timing to exploit synergy; Not established in controlled trials. PubMed+1

Research category placement

• Axis-modulating duo: Short-acting GHRH receptor agonist + short-acting GHSR agonist for GH pulse physiology and endocrine systems biology experiments. PubMed

Research Highlights

• Selective GHSR agonism: Ipamorelin demonstrated GH-selective secretagogue activity with minimal ACTH/cortisol effect in early literature. PubMed

• Stabilized GHRH analogs: D-Ala² and other substitutions extend GRF(1-29) stability vs native peptide in human/animal models. PubMed

• Synergy is robust: Independent labs show supradditive GH release to combined GHRH + GHSR agonists under varied physiologic states. PubMed

Conflicting evidence / open questions

• Translational outcomes for this exact pair are unknown; ipamorelin failed to improve primary endpoints in one Phase 2 GI study despite a solid preclinical rationale. PubMed

Potential Research Applications (No clinical claims; research-only framing)

• Endocrine physiology:

  • Mapping GH pulsatility under dual-pathway stimulation; testing somatostatin brake interactions; endocrine systems modeling. Physiology Journals

• Proteomic/biomarker mapping:

  • Time-resolved serum proteomics to dissect GHRH vs GHSR signatures and their interaction, drawing on prior GH-axis biomarker paradigms. Antiaging Systems

• Comparative pharmacology:

  • Short-acting GHRH analogs vs GHSR agonists; determining dose–response windows that maximize synergy while preserving physiologic pulse architecture. PubMed

• Metabolism & body composition (preclinical):

  • Class literature explores how GH-axis modulation shapes protein turnover and lipid flux; directionalitydepends on model and exposure pattern (Not established for this pair). Europe PMC

Safety & Toxicology

Preclinical / mechanistic considerations

• CJC-1295 (w/o DAC): As a short peptide, expected liabilities are proteolysis and immune recognition risk common to peptide hormones; no specific long-term tox dossier for this named analog is established in the peer-reviewed domain. (Data gap.)

• Ipamorelin: Early human PK/PD and Phase 2 data indicate good short-term tolerability; broader GHS class shows context-dependent glycemic effects (insulin sensitivity). PubMed+1

Known/theoretical risks (class-based)

• GH–IGF-1 axis activation can influence insulin sensitivity, fluid balance, soft-tissue growth; magnitude relates to exposure pattern (pulsatile vs sustained). Not established for the present pair in controlled trials. Europe PMC

Data gaps

• Chronic exposure safety for CJC-1295 (w/o DAC) and combined administration with ipamorelin—Unknown.

• Drug–drug interactions (pharmacodynamic) with other endocrine modulators—Not established.

• Immunogenicity specific to repeatedly dosed short GHRH analog microvariants—Not established.

Limitations & Controversies

• Nomenclature ambiguity: “CJC-1295 without DAC” is a market vernacular for tetrasubstituted GRF(1-29) congeners; peer-reviewed articles may not consistently use this exact name even when the D-Ala²/Gln⁸/Ala¹⁵/Leu²⁷ pattern is present. Analytical/anti-doping papers help anchor identity. PMC

• Evidence gap for the pair: Despite clear physiologic synergy between GHRH and GHSR pathways, no large RCTs evaluate this named combination for clinical outcomes. Conclusions must therefore remain conservative (Not established). PubMed

• Generalizability: Findings from tesamorelin (distinct GHRH analog) or ipamorelin in ileus do not directly translate to CJC-1295 (w/o DAC) + ipamorelin without dedicated trials. New England Journal of Medicine+1

Future Directions

• Controlled human physiology studies to quantify synergy (pulse amplitude, frequency, IGF-1 dynamics) using short-acting GHRH analog + ipamorelin, with model-based PK/PD (e.g., deconvolution, approximate entropy of GH patterns). (Planned/ongoing trials: none located for this exact pair as of September 26, 2025.)

• Mechanistic omics: Proteomic and transcriptomic mapping to distinguish GHRH-only vs GHSR-only vs combination signatures—extending prior GH-axis biomarker frameworks. Antiaging Systems

• Comparative endocrine systems modeling: Explore timing/sequence (e.g., GHSR priming followed by GHRH) to resolve state-dependent synergy under varying somatostatin tone. Physiology Journals

References (peer-reviewed / registries)

GHRH analogs (stability & identity)

1. Su CM, et al. In vitro stability of growth hormone-releasing factor (GRF) analogs. Peptides. 1991. PMID: 1826667. (Ala¹⁵ and proteolysis). PubMed

2. Campbell RM, et al. Enhanced stability and potency of novel GRF analogues derived from rodent and human GRF sequences. Peptides. 1994;15:489-495. PMID: 7937325; doi:10.1016/0196-9781(94)90211-9. PubMed

3. Soule S, et al. Incorporation of D-Ala² in GHRH(1-29) increases half-life and decreases clearance in normal men.JCEM. 1994;79:1208-1211. doi:10.1210/jcem.79.4.7962295. PubMed

4. Knoop A, et al. Qualitative identification of GHRH analogs & metabolites in human plasma. Drug Test Anal. 2016;8:1036-1046. PMCID: PMC4830873. (Notes [D-Ala²,Gln⁸,Ala¹⁵,Leu²⁷] pattern). PMC

5. Thomas A, et al. Chromatographic–mass spectrometric analysis of peptidic doping agents (includes CJC-1295 & CJC-1293 annotations). J Mass Spectrom. 2024. doi:10.1002/jms.4996. Analytical Science Journals

Ipamorelin (pharmacology & PK/PD)
6. Raun K, et al. Ipamorelin, the first selective GH secretagogue. Eur J Endocrinol. 1998;139:552-561. PMID: 9849822. PubMed
7. Gobburu JV, et al. PK-PD modeling of ipamorelin in healthy volunteers. Pharm Res. 1999;16:1412-1416. PMID: 10496658. (t½ ≈ 2 h; GH pulse at ≈0.67 h). PubMed

Combination rationale (synergy)
8. Bowers CY, et al. GHRP-2, GHRH and SRIF interrelationships during chronic administration; synergy observations.Neuroendocrinology. 1996. PMID: 8887169. PubMed
9. Arvat E, et al. Endocrine activities of ghrelin: synergistic effect with GHRH on GH secretion in humans. JCEM. 2001;86:1169-1174. Oxford Academic
10. Norman C, et al. Differential pulsatile secretagogue control of GH secretion in men; synergy quantification. AJP-Regul Integr Comp Physiol. 2013. doi:10.1152/ajpregu.00069.2013. Physiology Journals

Clinical programs (context)
11. Falutz J, et al. Tesamorelin (stabilized GHRH analog) in HIV-associated visceral adiposity—26-week RCT. NEJM. 2007;357:2359-2370. ClinicalTrials.gov NCT00123253. New England Journal of Medicine
12. Beck DE, et al. Ipamorelin for postoperative ileus—Phase 2 proof-of-concept RCT. Int J Colorectal Dis. 2014;29:1527-1534. ClinicalTrials.gov NCT00672074. PubMed
13. ClinicalTrials.gov record for NCT01280344 (Ipamorelin: GI recovery after bowel resection). ClinicalTrials.gov

GHS class safety/physiology
14. Sigalos JT, Pastuszak AW. The safety and efficacy of GH secretagogues—review. Transl Androl Urol. 2017;6:S37–S43. PMCID: PMC5632578. PMC

Notes on identity: In peer-reviewed sources, “CJC-1295 without DAC” may appear as [D-Ala²,Gln⁸,Ala¹⁵,Leu²⁷]-GRF(1-29) amide or similar tetrasubstituted sermorelin; naming conventions vary across analytical vs pharmacology papers. PMC

⚠️ Disclaimer

This peptide combination is intended strictly for laboratory research use. It is not FDA-approved or authorized for human use, consumption, or therapeutic application.