Which CJC-1295 the question is about
Every human safety datum for "CJC-1295" belongs to the albumin-bound form, the one with the DAC linker and the 5.8 to 8.1-day half-life. The linker-free form that fills most research vials, Mod GRF 1-29, has never been given to people in a published study. So the trial data below describe a molecule that is present for a week; the class data, from GHRH itself and from sermorelin, describe molecules that are present for minutes, which is the better match for the blend. The distinction is explained in CJC-1295 DAC vs no DAC; keep it in mind for every sentence that follows.
| Study | What the authors wrote |
|---|---|
| Teichman et al., 2006 J Clin Endocrinol Metab | No serious adverse reactions were reported. |
| Bowers et al., 1990 J Clin Endocrinol Metab | A side-effect of mild facial flushing of 1- to 3-min duration occurred in 16 of the 18 subjects who received GHRH-(1-44)-NH2. |
| Stanley et al., 2014 JAMA, tesamorelin | Fasting glucose increased in the tesamorelin group at 2 weeks (mean change, 9 mg/dL) but changes at 6 months in fasting glucose were not significant. |
What the two trials recorded
Teichman and colleagues ran two randomized, double-blind, placebo-controlled ascending-dose studies in healthy adults aged 21 to 61, one of 28 days after a single administration and one of 49 days after repeated administration. Their abstract reports the safety outcome in two sentences: "No serious adverse reactions were reported", and the peptide "was safe and relatively well tolerated" [1].
The full text explains the qualifier. In the single-administration study, adverse events were reported in 94 % of subjects on CJC-1295 against 29 % on placebo, all mild to moderate and none needing medical intervention. Injection-site reactions (irritation, redness, induration, pain or itching) lasted up to several hours in about 70 %, with induration up to 5 days in the higher arms; headache (63 %), diarrhoea (43 %) and systemic vasodilatory reactions, meaning flushing, warmth and transient low blood pressure (30 %), were more common in the higher arms. In the repeat study every treated subject had a mild injection-site reaction; flushing rose with the study arm, from 40 % in the lower to 100 % in the higher, and two subjects had transient dizziness and low blood pressure after a first administration. Laboratory values, glucose included, and ECGs showed no consistent change [1]. Ionescu and Frohman's pulsatility study, in men aged 20 to 40, reports hormonal outcomes and no adverse-event data in its abstract [2]. That is the complete published human safety record: two small trials, weeks long, in healthy volunteers.
| Study | Exposure | Safety statement |
|---|---|---|
| Teichman 2006 [1] | single, then repeated administration; 28 and 49 days | no serious adverse reactions; mild to moderate events in 94 % vs 29 % on placebo after a single administration, mostly injection-site reactions |
| Ionescu 2006 [2] | single administration; 1 week | not reported in the abstract |
| ConjuChem phase 2 [9] | 12 weeks, HIV patients, 120 planned | terminated 2006; no results |
Any adverse event in 114 bowel-resection patients, 7 days
- Any treatment-emergent adverse event87.5 %94.8 %
- Ipamorelin IV
- Placebo
Class effects: flushing and local reactions
What a GHRH-receptor agonist does besides releasing GH is well documented for the parent hormone and for sermorelin. In Bowers' 1990 study, GHRH(1-44) produced mild facial flushing lasting one to three minutes in 16 of 18 men, while GHRP-6 did not [3]. In the sermorelin programme reviewed by Prakash and Goa, the most frequently reported adverse events in the clinical trials were transient facial flushing and local pain [4].
In Corpas' 14-day study of GHRH(1-29) in men aged 68, the treatment did not affect fasting glucose, urinary C-peptide, blood pressure, or chemistry and haematology profiles; serum phosphate rose, as it does with GH [5]. Flushing is the signature of the receptor: the DAC form produced it in the trials, and the linker-free form should be expected to share it. Local reactions were the other frequent finding: in the single-administration CJC-1295 trial, injection-site reactions occurred in about 70 % of treated subjects and rarely on placebo, and whether the albumin-binding maleimide of the DAC form adds to them was not studied.
No serious adverse reactions were reported.
Figure 2
Shaded band: the 15-minute infusion. Vertical axis: plasma GH (schematic). Terminal half-life of the peptide: 2 h.
The IGF-1 question
The effect people worry about is not a side effect in the usual sense but the intended effect sustained. In the trial, one CJC-1295 administration raised IGF-1 1.5 to 3-fold for 9 to 11 days, and after repeated administration IGF-1 stayed above baseline for up to 28 days [1]; a week after one administration, trough GH was 7.5-fold higher and IGF-1 45 % higher [2]. Chronic elevation of GH and IGF-1 is the defining feature of acromegaly, and it is why the pulsatile pattern of GH is thought to matter.
The Ionescu study is reassuring on one point, the pulses survived, and silent on the other, what months of a raised trough do, because nobody has looked. In GHRH-knockout mice, five weeks of CJC-1295 increased pituitary GH mRNA and the number of somatotroph cells [8]; that is the expected trophic effect of GHRH on its target cells, and whether it has any human counterpart is unknown.
Glucose, by way of tesamorelin
Raising GH raises hepatic glucose output, so glucose is the metabolic variable to watch with any secretagogue. The CJC-1295 trials do not report it. The best available measurement is for tesamorelin, the GHRH analogue that finished its programme (compared in tesamorelin ipamorelin vs CJC-1295 ipamorelin). In 412 HIV patients treated for 26 weeks, glycaemic measures did not differ from placebo, although more patients on tesamorelin withdrew because of an adverse event [7].
In 50 patients treated for 6 months, fasting glucose rose 9 mg/dl at 2 weeks against 2 mg/dl on placebo (P = .03), and by 6 months the difference was no longer significant [6]. An early, modest, transient rise in fasting glucose is therefore the documented pattern for an approved GHRH analogue in patients; CJC-1295, with a week-long half-life, has no equivalent measurement, and the comparison is drawn out in CJC-1295 ipamorelin versus tesamorelin.
What was never studied
- Exposure beyond 49 days in humans.
- Any patient population: the ConjuChem phase 2 in HIV-associated visceral obesity was terminated in 2006 without results [9].
- Glucose, insulin, lipids, blood pressure or fluid retention on CJC-1295.
- The linker-free form, in any amount, for any duration.
- CJC-1295 combined with ipamorelin or any GHRP.
- Immunogenicity of the albumin conjugate, the concern the FDA raised for ipamorelin in 2023.
The regulatory record
CJC-1295 is not an approved drug anywhere. It was nominated for the FDA's list of bulk substances usable in compounding, and the nomination appears among those subsequently withdrawn on the FDA page that lists substances that "may present significant safety risks", where the FDA states that it "has identified serious adverse events associated with CJC-1295 including increased heart rate and systemic vasodilatory reaction"; ipamorelin acetate, its usual partner, was placed in category 2 of that list on September 29, 2023 with an immunogenicity concern [10]. The WADA Prohibited List names CJC-1295 among GHRH analogues in class S2 [11]. For the other half of the pair, see ipamorelin side effects.
