Cyclo(His-Pro)

CHP, cyclo-histidyl-proline, histidyl-proline diketopiperazine, cyclo(L-His-L-Pro); with zinc: Cyclo-Z, NovDB2

Cognitive & neuro

Awaiting medical reviewEN ES DE FR PT ZH+ Follow for updates

Summary

Class: Naturally occurring cyclic dipeptide (diketopiperazine) formed when the hormone TRH (thyrotropin-releasing hormone) is broken down; also present in foods (soy sauce, some fermented foods, prostate extracts); cyclic structure makes it unusually stable
Mechanism: Enhances cellular zinc uptake and acts on zinc-dependent pathways; activates Nrf2 antioxidant responses; modulates dopamine and appetite signalling in rodents; recently described as a modulator of the chloride channel CLIC1
Routes studied: Oral (with zinc, in human trials); intraperitoneal and intranasal (rodents)
Half-life: Resistant to peptidases because of its cyclic structure; plasma half-life reported in hours in animals; crosses the blood–brain barrier
Storage: Research powder: room temperature or refrigerated, dry; stable compound
Regulatory status: Investigational; not approved anywhere; present in some foods at trace levels

Doses are as reported in studies or by the community — never recommendations.

1What it is

Cyclo(His-Pro) is what is left when the body degrades TRH, the hypothalamic hormone that drives thyroid-stimulating hormone release. The enzyme pyroglutamyl peptidase removes TRH's first residue and the remaining His-Pro spontaneously curls into a ring. Unlike most peptides, that ring makes it resistant to digestion, which is why it is found intact in gut, brain, blood and even in foods such as soy sauce and aged cheese. It was identified in the 1970s and has been studied mainly by a few groups in the US and Korea, most notably for its ability to improve zinc handling and blood glucose in diabetic animals when given with zinc.

A zinc-plus-CHP combination has been through Phase 1 and Phase 2 trials for type 2 diabetes in Korea and the US. It is an endogenous molecule and food constituent, not a synthetic research compound, though the material in trials is synthetic.

2How it's thought to work

Zinc transport. CHP increases cellular uptake of zinc, including into pancreatic β-cells and muscle; zinc is essential for insulin storage and signalling, and the glucose-lowering effect in rodents requires both CHP and zinc together (Song 1998; Song 2003).

Antioxidant signalling. activates Nrf2 and increases glutathione and SOD in neuronal cultures, protecting against oxidative stress (Minelli 2009).

Neuromodulation. inhibits dopamine reuptake and modulates appetite and body temperature in rodents; proposed anorexigenic and ethanol-related effects.

CLIC1 modulation. a 2026 preclinical report describes CHP as a conformational modulator of chloride intracellular channel 1, proposed to explain metabolic and muscle effects †.

NAD+/SIRT1. a 2023 diabetic mouse study attributed improved glucose and lipid control to increased NAD+ and Sirt1 activity.

Proposed: a cyclic dipeptide formed when TRH is broken down. The ring makes it far more stable than its parent and it crosses into the brain, where it is reported to have effects on appetite and glucose handling of its own rather than as a step on the thyroid axis.Schematic — not to scale

3What the research shows

Graded B (Phase 2 completed, results not fully published)

Type 2 diabetes (CHP + zinc)

A Phase 2 randomised, placebo-controlled trial of three dose levels of zinc-plus-CHP in about 64 obese adults with type 2 diabetes over 12 weeks (NCT02784275, US) is recorded as completed; no peer-reviewed results have been published as of review date. An earlier Korean Phase 2 (started 2016) and a Phase 1 safety/PK study in healthy volunteers (Australia) are also listed as completed without published results. A small earlier pilot reported reduced fasting glucose in people with diabetes given CHP with zinc (Song 2003 — small, uncontrolled). Grade reflects unpublished primary data. [3]

Glucose, lipids and body weight in rodents

Zinc plus CHP lowered glucose, improved insulin sensitivity and reduced weight gain in genetically diabetic and aged rats and mice (Song 1998, Diabetes Care? †; Hwang 2003; Choi 2023, KK-Ay mice). Effects consistently depend on co-administration with zinc. [2][4]

Graded C/D

Neuroprotection, Alzheimer's and Parkinson models

CHP protected neurons from oxidative and glutamate toxicity in culture and reduced neurodegeneration in rodent Parkinson and Alzheimer models (Minelli 2009; Grottelli 2016; Bellezza 2014). Rat Alzheimer-model studies in 2024–2025 examined liver and pancreatic lipid metabolism and oxidative stress. No human data. [5][6][7]

Appetite, body temperature, ethanol intake

Older rodent literature (Prasad 1988 review) reports anorexigenic and hypothermic effects; no human confirmation. [1]

Graded D (preclinical, announced 2026)

Facioscapulohumeral muscular dystrophy

A preclinical collaboration for FSHD was announced in 2026 based on the CLIC1 mechanism †.

4Reported side effects and interactions

Literature-reported

Phase 1 reported no serious safety concerns in healthy volunteers †; detailed adverse-event data from Phase 2 have not been published. Dietary CHP exposure (foods) has no known adverse effects.

Community-reported

essentially none documented; CHP is not a commonly sold research peptide.

Theoretical. zinc co-administration at 30 mg/day or more over months can induce copper deficiency; CHP's dopaminergic effects in rodents raise questions in people on dopaminergic medicines; as a TRH metabolite it could in principle affect prolactin or TSH, though it does not act on TRH receptors.

Interactions. none established; zinc component interacts with tetracyclines, quinolones and may reduce copper absorption.

Markers researchers commonly monitor

Based on the trial design and mechanism:

Marker	Why it's watched
Fasting glucose, HbA1c, fasting insulin	the Phase 2 outcomes.
Serum zinc and copper, ceruloplasmin	the formulation delivers zinc daily; copper deficiency is the realistic long-term risk.
Lipid panel and weight	secondary metabolic endpoints in rodent and human studies.
TSH and prolactin	a baseline for a TRH metabolite, though no effect is expected.
CBC and CMP	general baseline for an investigational compound with little published human safety data.

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Clinical material is an oral capsule or tablet combining CHP with zinc gluconate. Research-grade CHP is a stable crystalline powder soluble in water; it is not an injectable product and no community protocol exists. If a calculator is used at all it is for solution preparation in a laboratory context only. (research use only)

6Commonly studied alongside

Zinc (the obligate partner in every metabolic study), TRH (its parent hormone), metformin (background therapy in the diabetes trials), carnosine and anserine (profiles 10 and 177 — other zinc-chelating histidine dipeptides).

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	Investigational (Phase 2 completed, no NDA); not approved; not a lawful dietary-supplement ingredient as an isolated synthetic peptide †
European Union	Not authorised; isolated CHP would be a Novel Food if marketed as a supplement
United Kingdom	Not licensed
Australia	Not approved; Phase 1 conducted under CTN scheme
South Africa	Not registered
Sport	Not specifically listed by WADA; as a non-approved pharmacological substance could fall under S0 †

8Open questions

Publication of the completed Phase 2 trials: do the rodent glucose effects hold in humans?
How much of any effect is zinc alone versus CHP enhancing zinc delivery?
The CLIC1 mechanism and its relevance to muscle disease.
Whether dietary CHP (soy sauce, fermented foods) has any physiological significance.

9References

1Prasad C (1988). Cyclo(His-Pro): its distribution, origin and function in the human. Neurosci Biobehav Rev. PubMed · DOI
2Song MK et al. (1998). Cyclo (His-Pro) plus zinc induces an anti-hyperglycemic effect in genetically diabetic Goto-Kakizaki rats [verify title]. Diabetes Res Clin Pract [verify]. PubMed
3Song MK, Rosenthal MJ, Hong S et al. (2003). Synergistic antidiabetic activities of zinc, cyclo (his-pro), and arachidonic acid. Metabolism. PubMed
4Hwang IK et al. (2003). Zinc plus cyclo-(His-Pro) treatment improves glucose tolerance in aged and genetically diabetic rats [verify]. Exp Biol Med. PubMed
5Minelli A et al. (2009). Cyclo(His-Pro) up-regulates heme oxygenase 1 via activation of Nrf2-ARE signalling. J Neurochem. PubMed · DOI
6Bellezza I et al. (2014). Cyclo(His-Pro) exerts protective carbonyl quenching effects through its peptide binding and antioxidant properties [verify]. Free Radic Biol Med. PubMed
7Grottelli S et al. (2016). The role of cyclo(His-Pro) in neurodegeneration. Int J Mol Sci. PubMed · DOI
8ClinicalTrials.gov NCT02784275 (completed). A Phase 2 study of zinc plus cyclo-(His-Pro) in obese patients with type 2 diabetes. PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

10Community

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Self-reported side effects Phase 2

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11Page history

31 Oct 2026Profile published — awaiting medical review

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