Met-Enkephalin

An endogenous opioid pentapeptide (Tyr-Gly-Gly-Phe-Met), also called Opioid Growth Factor, studied as a tonic inhibitor of cell proliferation through a non-classical receptor; its small human trials in cancer and autoimmune disease were open-label or terminated, and the one industry development program was abandoned over pharmacokinetics.

Also referenced as: Opioid Growth Factor, OGF, [Met5]-enkephalin, Methionine enkephalin, Met-Enk, Metenkefalin, Tyr-Gly-Gly-Phe-Met, YGGFM

Also appears in: Neuroprotection

What is Met-Enkephalin?

Met-enkephalin is an endogenous opioid pentapeptide with the sequence Tyr-Gly-Gly-Phe-Met (YGGFM), molecular formula C27H35N5O7S, a molecular weight near 573.7 Da, and CAS number 58569-55-4. It was one of the two enkephalins isolated from pig brain and sequenced by Hughes, Kosterlitz and colleagues in December 1975 — the other, Leu-enkephalin, differs only at the fifth residue (Hughes et al., Nature, 1975, 258(5536):577–580). It is produced by proteolytic processing of the precursor protein proenkephalin, whose human form carries six Met-enkephalin sequences against a single Leu-enkephalin sequence: four as the free pentapeptide, plus the C-terminally extended heptapeptide Met-enkephalin-Arg-Phe and octapeptide Met-enkephalin-Arg-Gly-Leu (Comb et al., Nature, 1982, 295(5851):663–666; gene organization in Noda et al., Nature, 1982, 297(5865):431–434).

The same molecule carries a second name that has nothing to do with opioid analgesia. Ian Zagon and Patricia McLaughlin at Penn State designated it Opioid Growth Factor (OGF) to describe a different role: a tonically active, inhibitory signal that restrains cell proliferation. Vendors sell the peptide under both names, and the two names index two largely separate bodies of literature — classical opioid pharmacology on one side, cell-cycle and autoimmune research on the other. Reading a claim about this compound requires knowing which literature it came from.

It appears in the research-peptide market mostly through the OGF framing, helped by adjacency to low-dose naltrexone, which is popular in the same communities and is proposed to work by raising endogenous met-enkephalin levels.

How it works

• Preferential delta-opioid receptor agonism. In classical opioid pharmacology, met-enkephalin is an agonist at opioid receptors with a preference for the delta subtype — the receptor class that the enkephalins were used to define, through the peptide’s relative potency in the mouse vas deferens versus the guinea-pig ileum (Lord et al., Nature, 1977, 267(5611):495–499). It retains lower-affinity activity at mu receptors, so it is delta-preferring rather than delta-selective. This is a receptor-mediated opioid effect and is distinct from the growth-related mechanism below.
• A separate, non-classical receptor (OGFr). Zagon and colleagues cloned a 2.1-kb cDNA encoding a 580-amino-acid receptor for [Met5]-enkephalin whose prominent structural feature is eight imperfect repeats of nine amino acids each, and whose molecular organization has no homology to the mu, delta, or kappa opioid receptors (Brain Research, 1999, 849(1–2):147–154). OGFr is described as an integral membrane protein associated with the nucleus rather than a conventional cell-surface GPCR — detected on the outer nuclear envelope, and carrying no significant homology to known functional motifs apart from a bipartite nuclear localization signal (Zagon et al., Brain Research Reviews, 2002, 38(3):351–376). The growth literature and the analgesia literature therefore describe two different targets.
• Cell-cycle arrest through cyclin-dependent kinase inhibitors. The OGF-OGFr interaction upregulates p16INK4a and p21WAF1/CIP1, delaying the G1/S transition and slowing proliferation (Cheng et al., Molecular Biology of the Cell, 2009, 20(1):319–327). The direction matters: despite the “growth factor” name, the described action is inhibitory, not anabolic.
• Suppression of T-lymphocyte proliferation. OGF acting through OGFr reduced T-cell proliferation in vitro, which is the stated rationale for testing it in autoimmune disease (Zagon et al., Immunobiology, 2011, 216(5):579–590); a companion paper reports the same for B lymphocytes (Immunobiology, 2011, 216(1–2):173–183). The broader axis is reviewed in McLaughlin & Zagon, Biochemical Pharmacology, 2012, 84(6):746–755. Note that essentially this entire mechanistic literature comes from one laboratory.
• Rapid enzymatic degradation. Enkephalins are cleaved within minutes in biological fluids — aminopeptidase N removes the N-terminal tyrosine that receptor binding requires, neprilysin cleaves the Gly3–Phe4 bond, and angiotensin-converting enzyme and dipeptidyl peptidase 3 contribute as well. This is the reason an entire drug class of enkephalinase inhibitors exists (reviewed in García-Domínguez, Biomolecules, 2024, 14(8):926). Every human study of the peptide used parenteral infusion rather than any depot or oral format, and as set out below, this constraint is what ended the one commercial development program.

Research status

Met-enkephalin has a very large basic-science literature and a small, mostly uncontrolled, and substantially failed clinical record.

Pancreatic cancer. A Phase I trial in advanced unresectable pancreatic adenocarcinoma established a maximum tolerated dose of 250 µg/kg intravenously over 30 minutes, with hypotension as the dose-limiting toxicity; subcutaneous dosing was capped at 50 µg/kg twice daily by the peptide’s solubility. No adverse events were reported for cardiac rhythm, oxygen saturation, laboratory values, or neurological status. In the uncontrolled chronic-dosing phase, two subjects had resolution of liver metastases and one showed regression of the pancreatic tumor (Smith et al., Anti-Cancer Drugs, 2004, 15(3):203–209). The follow-on study (NCT00109941) was a prospective open-label Phase II in 24 treated subjects who had failed standard chemotherapy, dosed weekly at 250 µg/kg intravenously over 45 minutes. It reported a clinical benefit response in 53% versus historical control rates of 23.8% for gemcitabine and 4.8% for 5-fluorouracil, and a median survival “three times” that of untreated patients — which in absolute terms was 65.5 days versus 21 days (Smith et al., Open Access Journal of Clinical Trials, 2010, 2010(2):37–48). The authors state the limitation plainly: there was no concurrent randomized control arm, and the benefit comparisons were made against historical controls.

The one industry program, and the reason it stopped. In March 2005 Innovive Pharmaceuticals licensed the peptide from Penn State as INNO-105 and ran its own Phase I dose-escalation study in adults with advanced solid malignancies (NCT00255333, 24 participants), beginning in November 2005. The program was terminated. Innovive’s own SEC filing gives the reason in plain terms: the trial results showed that INNO-105 “appeared unlikely to achieve targeted plasma levels without demonstrating adverse side effects.” Development was discontinued in late September 2006 and the Penn State license was returned that December. This is the only time a commercial sponsor took the peptide into the clinic, and it failed on exactly the pharmacokinetic ceiling the mechanism section describes.

Other trials that stopped. A Phase II study of OGF in advanced head and neck squamous cell carcinoma (NCT00982696) ran from 2008, enrolled 5 patients, and was terminated in 2011 with the registry recording the reason verbatim as “Deemed ineffective.” A Phase I of OGF combined with gemcitabine in pancreatic cancer (NCT00783172) was terminated after 4 patients, with the registry reason recorded as “Problems with IRB.” No randomized controlled trial of OGF has demonstrated a survival benefit in any cancer, and no Phase III of the peptide alone has been run.

Hepatocellular carcinoma — completed in 2013, published in 2025. A Phase I dose-escalation study in unresectable hepatocellular cancer with concomitant liver disease (NCT00706576, sponsored by the University of Missouri–Columbia and conducted at Penn State Hershey) completed in July 2013 and posted no results to the registry. It was eventually reported twelve years later: 15 doses were administered to 14 patients up to a maximum of 300 µg/kg, no Grade 3 toxicities were encountered, and that dose exceeds the 250 µg/kg maximum tolerated dose from the earlier pancreatic trial (Kimchi et al., Cancer Investigation, 2025, 43(3):224–235). The study was a toxicity and pharmacokinetic exercise; it makes no efficacy claim.

HIV. An early immunomodulation study infused methionine-enkephalin at 10 µg/kg three times weekly for up to 12 weeks in seven patients at various stages of HIV infection. Increases in interleukin-2 receptor expression were seen on one occasion in each of two patients, and increased interleukin-2 production in one, but there were no significant pre-versus-post changes in circulating T-cell subsets or T-cell responses to mitogens and antigens, and no Kaposi’s sarcoma regression. The authors concluded that the peptide appeared to enhance selected immune responses temporarily, but that on the schedule used it was not clinically efficacious (Zunich & Kirkpatrick, Journal of Clinical Immunology, 1988, 8(2):95–102). No toxicity was observed.

Multiple sclerosis and the one approved product. The only marketed medicine built on this peptide is a two-peptide combination — metenkefalin acetate plus tridecactide acetate — sold by Bosnalijek as ENKORTEN, a lyophilizate for injection at 5 mg + 1 mg, classified as an immunostimulant for use in health institutions. It is authorized in Bosnia and Herzegovina for relapsing-remitting multiple sclerosis in adults, and has held a Bosnian marketing authorization since at least December 2013; the current authorization (04-07.3-2-11456/22) dates from March 2024 and is a renewal rather than a first approval. A Phase IIIb assessor-blind trial (NCT03283397) compared the combination — dosed at 10 mg metenkefalin + 2 mg tridecactide, twice the marketed strength — against interferon beta-1a in 301 patients with relapsing-remitting MS, aiming to show superiority on annualized relapse rate at 144 weeks; it is listed as terminated because further patients could not be enrolled during the COVID-19 pandemic, and no results are posted on the registry. The same sponsor ran an open-label randomized COVID-19 study of ENKORTEN added to standard care in 120 patients (NCT04374032), completed in November 2020, also with no registry results.

Indirect evidence via low-dose naltrexone. Much of what circulates as met-enkephalin evidence is actually naltrexone evidence, and the two Crohn’s studies are often quoted as one. The first was an open-label pilot with no control arm: 17 patients on 4.5 mg naltrexone daily for 12 weeks, of whom 89% showed a response and 67% achieved remission (Smith et al., American Journal of Gastroenterology, 2007, 102(4):820–828). The controlled figures come only from the later randomized double-blind placebo-controlled trial in 40 subjects, where 88% of naltrexone-treated patients had at least a 70-point decline in CDAI versus 40% on placebo, and 78% showed an endoscopic response versus 28% (Smith et al., Digestive Diseases and Sciences, 2011, 56(7):2088–2097). In MS, a crossover pilot of low-dose naltrexone enrolled 80 subjects, of whom 60 completed; high dropout and data-management errors substantially reduced statistical power, and the significant improvements were confined to mental-health quality-of-life indices, not disability measures (Cree et al., Annals of Neurology, 2010, 68(2):145–150). Separately, serum [Met5]-enkephalin was reported to be lower in MS patients than in non-MS neurologic patients and restored by low-dose naltrexone (Ludwig et al., Experimental Biology and Medicine, 2017, 242(15):1524–1533). All of these studies administer an oral opioid antagonist, not the peptide.

No regulatory authority in the United States or the European Union has approved met-enkephalin for any indication. A DailyMed search for “enkephalin” returns no labeled drug products at all, and the Bosnian authorization of a fixed combination does not change that.

Common dosage forms

• Lyophilized powder in vials sold for reconstitution, labeled either Met-Enkephalin or OGF, in milligram-scale presentations typically ranging from about 1 mg to 10 mg.
• Analytical and biochemical reagent grade from life-science peptide suppliers, usually as an acetate or trifluoroacetate salt intended for assay and receptor-binding work rather than administration.
• The approved combination product is a lyophilizate for solution for injection pairing 5 mg metenkefalin with 1 mg tridecactide, supplied as six vials with six 2 mL ampoules of 0.9% sodium chloride as solvent — a fixed hospital-use combination, not met-enkephalin alone.
• Routes used in the human studies were intravenous infusion over 30 to 45 minutes and, in the pancreatic Phase I only, subcutaneous injection limited by solubility. No oral, nasal, or transdermal format has been tested clinically.
• Closely named neighbours appear across the same catalogs and are different molecules with different pharmacology: the proenkephalin-derived extended forms Met-enkephalin-Arg-Phe and Met-enkephalin-Arg-Gly-Leu, the C-terminally amidated met-enkephalinamide, and D-amino-acid analogs such as DADLE. Identity should be confirmed by sequence rather than by label.

This section describes formats only and is not dosing guidance.

Key considerations

• One molecule, two names, two literatures. A source discussing “OGF” is usually reporting cell-cycle or autoimmune work from a single research group; a source discussing “met-enkephalin” is usually reporting opioid, pain, or neuroendocrine work spanning fifty years. Marketing material routinely mixes findings across the two without saying so.
• The cancer program did not succeed, and one failure is more informative than the rest. The head and neck Phase II was terminated with “deemed ineffective” recorded as the reason, the combination Phase I stopped at four patients, and the pancreatic result everyone cites is an open-label study against historical controls where the frequently repeated “three times the survival” figure is 65.5 days versus 21 days in patients who had already failed chemotherapy. The most decision-relevant data point is the one rarely quoted: the only commercial sponsor to test the peptide dropped it in 2006 because it could not reach target plasma levels without adverse effects.
• Investigator conflicts are disclosed and material. The Penn State Research Foundation holds patents covering OGF in cancer with Zagon, McLaughlin and Jill Smith named as inventors, and separately covering naltrexone in inflammatory bowel disease; that cancer portfolio was licensed commercially, first to Innovive in 2005 and later to another developer. The papers disclose this — the 2011 Crohn’s trial states outright that two authors hold a patent for the use of naltrexone in IBD — and it is worth weighting when nearly all the positive clinical literature comes from one group.
• It is an opioid agonist, not an inert growth signal. The “growth factor” name obscures that met-enkephalin acts at delta-preferring opioid receptors and retains mu activity. Hypotension was the dose-limiting toxicity in the pancreatic Phase I, which is a cardiovascular signal rather than a theoretical one; the later hepatocellular Phase I reached 300 µg/kg without Grade 3 toxicity in a different patient population, so the ceiling is not fixed, but neither dataset is large.
• Pharmacokinetics contradict most of what is sold. Enkephalins are cleaved by multiple peptidases on a minutes timescale, which is why every human study used infusion and why the commercial program was abandoned. Formats that imply sustained systemic exposure have no support in the clinical record.
• Low-dose naltrexone data is not met-enkephalin data. The Crohn’s and MS trials most often cited in support of this peptide tested an oral opioid antagonist, and the widely quoted 88%-versus-40% Crohn’s figure belongs to the randomized trial, not to the uncontrolled pilot it is often merged with. Whether raising endogenous enkephalin tone explains those results remains a hypothesis from the same investigators, and the one direct MS biomarker finding is a small serum-level comparison, not an outcome trial.
• A foreign approval is not a US approval, and it is not this peptide alone. ENKORTEN is a fixed combination of metenkefalin with a second peptide, authorized in one country for one indication and administered in a hospital setting. Nothing in that authorization transfers to single-agent met-enkephalin sold as a research compound.