Met-enkephalin
[Met5]-enkephalin, opioid growth factor, OGF, YGGFM
Met-enkephalin is one of the two original opioid pentapeptides identified in 1975, derived mainly from proenkephalin. It signals preferentially at delta-opioid receptors and also carries an entirely separate identity as opioid growth factor, a tonic inhibitory regulator of cell proliferation acting at a nuclear-associated OGF receptor. Its therapeutic evidence in humans is thin.
Mechanism
Proenkephalin yields four copies of met-enkephalin plus one leu-enkephalin, with extended forms such as met-enkephalin-Arg-Gly-Leu and met-enkephalin-Arg-Phe; proopiomelanocortin also contributes the YGGFM motif at the N-terminus of beta-endorphin. Met-enkephalin binds delta-opioid receptors with modest preference over mu, both Gi/Go-coupled, inhibiting adenylate cyclase, opening GIRK channels and closing voltage-gated calcium channels. Because it is destroyed within seconds, it functions as a strictly local, synaptically confined modulator rather than a circulating hormone, which is why enzyme inhibition rather than peptide administration has been the practical pharmacological strategy.
Separately, met-enkephalin is identical to opioid growth factor, which acts at the OGF receptor, a nuclear-associated protein distinct from classical opioid receptors and not blocked in the same way. This axis upregulates the cyclin-dependent kinase inhibitors p16 and p21, slowing progression through the cell cycle in epithelial and neoplastic tissue. The dual identity is genuine biology, not marketing, but it also means results attributed to met-enkephalin may reflect either pathway.
What the research shows
The most robust clinical evidence for enkephalin biology comes indirectly, through racecadotril, an enkephalinase (neprilysin) inhibitor that prevents enkephalin breakdown in the gut and reduces intestinal hypersecretion without slowing transit. A Cochrane review of seven randomised trials in around 1,140 children found some evidence of reduced illness duration and stool output versus placebo, though certainty was low and data on the first 48 hours were insufficient for firm conclusions. Racecadotril is approved in several European and Asian countries but not in the United States or United Kingdom.
Direct met-enkephalin work is much weaker. Opioid growth factor was tested in a 24-patient open-label phase 2 study in advanced pancreatic cancer after chemotherapy failure, reporting a clinical benefit response in 53 per cent and a median survival of 65.5 versus 21 days. Crucially, the comparison was with historical controls, not with a randomised concurrent control group, and the trial was open-label; this is hypothesis-generating evidence and nothing more. No adequately powered randomised trial has confirmed it, and the oncology programme has not progressed to registration. Claims of immune enhancement circulating in the peptide market rest on these small studies and on animal work.
Evidence assessment
Limited evidence
Human interventional data on the peptide itself are confined to small open-label oncology studies, the largest of which was a 24-patient single-arm phase 2 trial compared against historical controls. The stronger pathway evidence, a Cochrane review of racecadotril, concerns inhibition of the degrading enzyme rather than administration of the peptide.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Identification of two related pentapeptides from the brain with potent opiate agonist activity Preclinical only
Identified met-enkephalin and leu-enkephalin as the first endogenous opioid peptides, founding the field.
Racecadotril for acute diarrhoea in children Preclinical only
Some evidence of reduced illness duration and stool output versus placebo, with low-certainty evidence for reduced rehydration failure. Validates enkephalin signalling as a target; certainty of evidence was low.
Opioid growth factor improves clinical benefit and survival in patients with advanced pancreatic cancer Preclinical only
Clinical benefit response in 53 per cent versus historical control rates of 23.8 per cent (gemcitabine) and 4.8 per cent (5-fluorouracil); median survival 65.5 versus 21 days. Open-label, uncontrolled, historical comparison only; never confirmed in a randomised trial.
Safety
Met-enkephalin is not a licensed medicine and there is no established human safety profile for repeated administration. The 24-patient pancreatic cancer study reported no adverse effects on haematologic or chemistry parameters, but that is a very small uncontrolled sample. Reported effects in early studies include transient hypotension and flushing. As a delta-preferring opioid agonist, and given that delta agonists have been associated with seizure risk in animals, that remains a relevant unresolved concern. Any material sold direct to consumers is unregulated.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No UK marketing authorisation. Unlicensed substance. Racecadotril, which acts on this pathway, is licensed in several EU countries but is not authorised in the UK. |
| United States | No FDA-approved met-enkephalin or opioid growth factor product. Studied only under investigational applications. Consumer-sold material is an unapproved research chemical. |
| WADA (sport) | Not individually named on the Prohibited List. Prohibited at all times under section S0 as a non-approved substance. |
Questions
Chemically yes, they are the same pentapeptide. The names reflect two distinct pathways: opioid receptor signalling in neurons, and a nuclear-associated OGF receptor that slows cell proliferation. The second is not blocked by conventional opioid antagonism in the same way.
That claim rests on small uncontrolled studies and animal work. No adequately powered randomised trial has demonstrated a clinical immune benefit in humans, and no regulator has approved it for any indication.