Peptide Schedule
Cyclic Glycine-Proline (cGP)2 residuesGPEach bubble = one amino acid. Size = residue mass. Color = chemical class.Cyclic Glycine-Proline (cGP)
Benefits
About Cyclic Glycine-Proline (cGP)
Cyclic Glycine-Proline (cGP) is a naturally occurring cyclic dipeptide derived from the enzymatic cleavage of insulin-like growth factor-1 (IGF-1). When IGF-1 is metabolized, it first produces glycine-proline-glutamate (GPE) from its N-terminal tripeptide. GPE is highly unstable in plasma (half-life under 4 minutes) and is rapidly converted into cGP, a stable 2,5-diketopiperazine with a molecular weight of just 154.2 Da. This small, lipophilic molecule is endogenous to the human body and has been detected in plasma, cerebrospinal fluid, and breast milk. cGP's primary function is regulating IGF-1 bioavailability. It competes with IGF-1 for binding to insulin-like growth factor binding protein-3 (IGFBP-3), the main carrier protein that sequesters IGF-1 in an inactive state. By displacing IGF-1 from IGFBP-3, cGP increases the pool of free, bioactive IGF-1 available to tissues. What makes this mechanism particularly interesting is its bidirectional nature — cGP promotes IGF-1 activity when it's insufficient but can inhibit it when it's excessive, functioning as a true homeostatic regulator. The cGP/IGF-1 molar ratio has emerged as a biomarker of functional IGF-1 status. Research shows that a healthy increase in this ratio with age correlates with normal cognition, while a declining ratio is associated with dementia in Parkinson's disease patients. Stroke patients with higher baseline cGP/IGF-1 ratios demonstrate better neurological recovery at 90 days. In preclinical studies, cGP administration has reduced amyloid plaque burden and improved spatial memory in Alzheimer's mouse models, normalized systolic blood pressure in diet-induced obese rats, and protected neural tissue from hypoxic-ischemic injury. It also acts as a positive allosteric modulator of AMPA receptors and upregulates brain-derived neurotrophic factor (BDNF) signaling.
Who Should Consider Cyclic Glycine-Proline (cGP)
- Adults with age-related cognitive decline
- Stroke recovery patients seeking neuroprotective support
- Individuals with impaired IGF-1 signaling or low bioavailable IGF-1
- Older adults looking to maintain cognitive function
- Researchers studying IGF-1 homeostasis and neuroprotection
How Cyclic Glycine-Proline (cGP) Works
cGP's primary mechanism centers on regulating IGF-1 homeostasis through competitive displacement. IGF-1 circulates largely bound to IGFBP-3, which keeps it inactive. cGP retains affinity for IGFBP-3's binding pocket and competes with IGF-1 for this site, freeing IGF-1 to interact with its receptor (IGF-1R) on target cells. This activates the PI3K/Akt signaling cascade, which promotes neuronal survival, synaptic plasticity, and anti-apoptotic pathways. At the receptor level, cGP functions as a positive allosteric modulator of AMPA-type glutamate receptors, enhancing excitatory neurotransmission and long-term potentiation — the cellular basis of memory formation. cGP also upregulates brain-derived neurotrophic factor (BDNF) signaling, which supports dendritic growth, synaptogenesis, and neuronal resilience. cGP provides direct cytoprotection by alleviating oxidative stress in neural cells. Studies in human fetal neural stem cells showed dose-dependent reductions in apoptosis. Its small size (154.2 Da), cyclic stability, and favorable topological polar surface area (49.4 angstroms squared) allow efficient BBB penetration and CNS accumulation.
What to Expect
Minimal noticeable effects. cGP begins accumulating in plasma and CSF. The compound is building toward effective tissue concentrations.
Some users report subtle improvements in mental clarity, focus, and sleep quality as cGP/IGF-1 ratios begin to shift and IGF-1 bioavailability increases.
More consistent cognitive benefits become apparent. Improved memory recall, better stress resilience, and enhanced mental sharpness. Blood pressure normalization may be measurable in those with elevated levels.
Full accumulation effects. Sustained improvements in cognitive performance, neuroprotective benefits ongoing. The cGP/IGF-1 ratio should be normalized, supporting healthy IGF-1 function long-term.
Dosing Protocol
| Level | Dose / Injection | Frequency |
|---|---|---|
| Beginner | 0.04mg | Daily |
| Moderate | 0.04mg | 2x Daily |
| Aggressive | 0.08mg | Daily |
Note: cGP is an endogenous cyclic dipeptide metabolite of IGF-1, belonging to the 2,5-diketopiperazine class. It's found naturally in human plasma, cerebrospinal fluid, and breast milk. Unlike its precursor GPE (half-life <4 min), cGP is enzymatically stable due to its rigid cyclic structure. It's orally bioavailable, crosses the blood-brain barrier efficiently, and is commercially available as the supplement cGPMAX at 40 mcg/day. NNZ-2591, a synthetic cGP analog, is in Phase 2 clinical trials for neurodevelopmental disorders at doses of 4-12 mg/kg twice daily.
How to Inject Cyclic Glycine-Proline (cGP)
Take one capsule (40 mcg cGP) by mouth once daily with or without food. Some individuals with more pronounced age-related symptoms may take up to two capsules daily. Consistency is key — cGP works through gradual accumulation, so daily dosing without skipping is recommended. Allow at least 90 days before assessing full effects. No reconstitution or injection is required.
Cycling Protocol
The commercial supplement cGPMAX recommends at least 90 days of consistent daily use to build cGP reserves. cGP works on an accumulation basis — levels need to be gradually topped up and then maintained. There's no established cycling protocol from clinical research. Given its endogenous nature and safety profile, continuous daily use appears to be the standard approach.
Pharmacokinetics
Source: Estimated from diketopiperazine class stability data; cGP is enzymatically stable unlike precursor GPE (t½ <4 min). Specific cGP plasma half-life not yet characterized in published human PK studies.
Loading the interactive decay curve.
Side Effects
cGP has an outstanding safety profile based on available research. As an endogenous compound naturally present in human plasma, CSF, and breast milk, it's generally very well tolerated. No significant adverse events have been reported in published studies. The commercial supplement cGPMAX has been used without notable side effect reports. Mild headache or GI discomfort are theoretically possible at higher doses. Because cGP modulates IGF-1 bioavailability, individuals with IGF-1-sensitive conditions (such as active cancers) should exercise caution. Long-term safety data from controlled clinical trials is still limited for cGP itself, though the synthetic analog NNZ-2591 has completed Phase 2 trials with an acceptable safety profile.
Contraindications
- Pregnancy and breastfeeding (insufficient controlled safety data)
- Active or suspected IGF-1-dependent cancers
- Known hypersensitivity to cyclic dipeptides or diketopiperazines
- Individuals on exogenous IGF-1 or growth hormone therapy (potential interaction)
- Children under 18 without medical supervision
Drug Interactions
- May potentiate the effects of exogenous IGF-1 or growth hormone by increasing free IGF-1 levels
- Theoretical interaction with IGFBP-3 modulators — could amplify IGF-1 displacement
- Use caution when combining with other AMPA receptor modulators (ampakines, racetams) due to possible additive excitatory effects
Storage & Stability
Molecular Profile
Related Peptides
References
- Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1PubMed 24633053
- Cyclic Glycine-Proline (cGP) Normalises Insulin-Like Growth Factor-1 (IGF-1) Function: Clinical Significance in the Ageing BrainPubMed 36770687
- Cyclic Glycine-Proline Improves Memory and Reduces Amyloid Plaque Load in APP/PS1 Transgenic Mouse ModelPubMed 36909366
- Plasma cyclic glycine proline/IGF-1 ratio predicts clinical outcome and recovery in stroke patientsPubMed 31019991
- Cyclic glycine-proline normalizes systolic blood pressure in high-fat diet-induced obese male ratsPubMed 31753784
- Supplementation of Blackcurrant Anthocyanins Increased Cyclic Glycine-Proline in the Cerebrospinal Fluid of Parkinson PatientsPubMed 29865234