Enkephalin (Met-enkephalin / Leu-enkephalin)
Also known as: Met-enkephalin, Leu-enkephalin, Opioid Growth Factor (OGF), [Met5]-enkephalin, YGGFM (met-enkephalin sequence), YGGFL (leu-enkephalin sequence), proenkephalin-derived peptides, endogenous opioid pentapeptides
Endogenous opioid pentapeptides; delta-opioid receptor (DOR) primary agonists; mu-opioid receptor (MOR) partial agonists; opioid growth factor (OGF) designation
What it is
Your body makes its own pain-relieving signals — enkephalins are among the most important. These small peptides bind opioid receptors throughout the brain and body to quiet pain, steady mood, and support immune balance. The most clinical data exists for met-enkephalin (also called opioid growth factor, OGF), studied in cancer and autoimmune disease.
The scientific side
enkephalins (met-enkephalin and leu-enkephalin) are endogenous pentapeptides derived from the precursor protein proenkephalin (PENK). They act primarily as agonists at delta-opioid receptors (DOR) and secondarily at mu-opioid receptors (MOR), both of which are G-protein-coupled receptors (GPCRs) that signal through inhibitory Gi proteins. Upon binding to DOR or MOR, enkephalins trigger Gi-mediated inhibition of adenylyl cyclase (reducing cAMP), activation of inwardly rectifying potassium channels (GIRK) causing neuronal hyperpolarization, and inhibition of voltage-gated calcium channels — collectively reducing neuronal excitability and suppressing nociceptive and stress-related neurotransmitter release. High-resolution cryo-EM and single-molecule FRET studies of the DOR demonstrate that met-enkephalin not only stabilizes the receptor's active-state conformation but also catalyzes dynamic transitions between active and inactive conformational states, a property linked to its pharmacological profile and receptor internalization kinetics distinct from synthetic full agonists. DOR allosteric modulator research has identified a lipid-facing binding site in transmembrane helices 2–4 that can be targeted to enhance endogenous enkephalin signaling while preserving natural spatiotemporal activation patterns, offering a potential path to safer analgesia without tolerance. In parallel, met-enkephalin functions as Opioid Growth Factor (OGF) through a distinct nuclear-associated receptor (OGFr) that mediates cell-cycle arrest in the G0/G1 or G2/M phase by upregulating cyclin-dependent kinase inhibitors p16 and p21, suppressing cell proliferation in cancer and immune cells alike (PMIDs: 20890374, 34324868). Enkephalins are rapidly degraded in vivo by two metallopeptidases — neprilysin (enkephalinase/NEP) and aminopeptidase N — providing a therapeutic leverage point: dual enkephalinase inhibitors (DENKIs) that block both enzymes raise synaptic enkephalin concentrations and produce analgesia in human trials with fewer adverse effects than direct opioid agonists (PMIDs: 29722031, 32304400). In the amygdala, met-enkephalin release from the amygdalo-striatal transition zone constrains fear learning and dopamine release via volume transmission, linking enkephalin tone to emotional memory and anxiety (preprint data, 2026). Proenkephalin (PENK) levels in CSF also serve as a validated biomarker of striatal neuron integrity in neurodegenerative disease.
Class: Endogenous opioid pentapeptides; delta-opioid receptor (DOR) primary agonists; mu-opioid receptor (MOR) partial agonists; opioid growth factor (OGF) designation applies to met-enkephalin in context of cell-growth regulation
Administration & storage
- Administration
- Intravenous infusion over 30 minutes — primary route in Phase I and Phase II pancreatic cancer and HCC trialsSubcutaneous injection — evaluated in Phase I; limited by solubility to lower doses (50 µg/kg twice daily maximum)Gene therapy: replication-defective HSV-1 viral vector injection near target tissue (preclinical; not human)
- Storage
- No commercial formulation exists. Investigational OGF was handled as a sterile IV preparation under research pharmacy protocols. Enkephalins are labile peptides subject to rapid enzymatic degradation in biological fluids; storage conditions in trials are not fully reported in the reviewed literature.
- Cautions
- Hypotension: Dose-limiting toxicity for IV OGF in the Phase I pancreatic cancer trial was transient hypotension at doses exceeding 250 µg/kg IV. Patients require cardiovascular monitoring during IV infusion.,No Grade 3 toxicities observed at doses up to 300 µg/kg in the HCC Phase I trial; no adverse effects on oxygen saturation, cardiac rhythm, or laboratory parameters reported in the pancreatic cancer trials (PMIDs: 15014352, 40196893). This is a small dataset; rare events cannot be excluded.,Solubility limitations restrict subcutaneous dosing — the SC route maximum of 50 µg/kg twice daily was imposed by formulation constraints, not by observed toxicity.,Very short in vivo half-life: Enkephalins are rapidly cleaved by neprilysin and aminopeptidase N in plasma and tissue; the peptide has a half-life of seconds to minutes in vivo, which means sustained pharmacological effects require continuous infusion, encapsulation, or an enkephalinase inhibitor strategy.,Unknown long-term safety: All clinical trial data involve small cohorts (n=14–24) with short follow-up. Long-term safety profile in humans is not established.,Exogenous OGF suppresses cell proliferation broadly (including immune and normal cells); theoretical concern regarding impaired wound healing or immune suppression with sustained use, though no such events were reported in the reviewed trials.
Legal & regulatory status
Enkephalins (met-enkephalin and leu-enkephalin) are endogenous peptides, not FDA-approved drugs. Met-enkephalin (OGF) has been studied in Phase I and Phase II investigational clinical trials for pancreatic cancer…
Endogenous enkephalins are not specifically listed on the WADA Prohibited List as prohibited substances, as they are naturally produced by the body. However, synthetic or exogenous administration of met-enkephalin or…
Enkephalin-based therapeutics have not received Health Canada approval. No enkephalin drug product is listed on the Health Canada drug product database as an approved therapeutic. Use is confined to investigational…
What it's studied for
- Advanced pancreatic cancer — met-enkephalin (OGF) as antiproliferative biotherapy Phase I / Phase II clinical trial
- Hepatocellular carcinoma (HCC) — met-enkephalin (OGF) dose escalation and safety Phase I clinical trial
- Autoimmune / neuroinflammatory disease (multiple sclerosis model) — OGF immunomodulation Preclinical (animal model); biomarker data in human-adjacent EAE context
- Pain modulation via delta-opioid receptor (DOR) — mechanistic basis for analgesic development Mechanistic / early translational
- Diabetic ocular complications and wound healing — OGF-OGFr pathway dysregulation Preclinical / translational
- Proenkephalin (PENK) as CSF biomarker of striatal neurodegeneration in Huntington's disease Observational cohort (human, n=57 HD gene-expanded individuals)
- Gene therapy delivery of enkephalin for chronic pain (temporomandibular joint / inflammatory pain) Preclinical (animal model); basis for future gene therapy trials
Safety signals
- Transient hypotension — dose-limiting toxicity at IV doses above 250 µg/kg
- Extremely short plasma half-life — rapid enzymatic degradation limits therapeutic window
- Broad antiproliferative activity via OGFr — potential concern for immune suppression and wound healing with sustained use
- Small trial database — rare adverse events and long-term safety uncharacterized
- Plasma enkephalin levels correlated with disease severity in systemic sclerosis and EAE — dysregulation as a clinical indicator
- DOR agonism — known class effects of delta-opioid receptor activation including seizure risk at high doses
Contraindications
About these dose ranges
Dose ranges below reflect commonly reported community protocols. Where published research cites a specific dose, the PMID is linked. Doses without citations are not clinical recommendations — they reflect what practitioners and researchers commonly report using.
Community-reported dosing
| Route | Dose | Frequency / Duration | Population / context | Source tier |
|---|---|---|---|---|
| Unspecified | Escalating IV doses up to MTD of 250 µg/kg; SC route evaluated at up to 50 µg/kg twice daily | — | Adults with advanced pancreatic cancer — Phase I dose escalation | Research |
| Unspecified | 250 µg/kg IV | — | Adults with advanced pancreatic cancer — Phase II efficacy trial | Research |
| Unspecified | Escalating doses up to 300 µg/kg | — | Adults with unresectable hepatocellular carcinoma and liver disease — Phase I dose escalation | Research |
| Unspecified | 10 mg/kg OGF | — | Mouse EAE model (preclinical — not human) | Research |
| Intravenous infusion over 30 minutes | 250 µg/kg IV (pancreatic cancer Phase II); up to 300 µg/kg IV (HCC Phase I) | Once weekly (pancreatic cancer Phase II); per protocol escalation schedule (HCC Phase I) | Adults with advanced pancreatic or hepatocellular cancer in investigational trial settings |