Intermedine
Also known as: ADM2, Adrenomedullin 2, Intermedin, Melanocyte-stimulating hormone (intermediate lobe), Pars intermedia MSH, β-MSH (in some species)
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Summary
Intermedine is a pyrrolizidine alkaloid (PA) commonly found in plants such as comfrey (Symphytum officinale) and in some herbal preparations. It is investigated mainly for its toxicological profile rather than therapeutic use. Research has focused on its presence in herbal medicines, bee products, and its ability to cause cellular damage in liver and neural cells when exposure exceeds safety limits.
Mechanism of Action
Intermedine exerts toxicity by generating excessive reactive oxygen species (ROS) that damage mitochondria, leading to loss of membrane potential, cytochrome‑c release and activation of caspase‑3‑mediated apoptosis. It also triggers endoplasmic reticulum stress, activating the PERK/eIF2α/ATF4/CHOP pathway, and can raise intracellular Ca2+ levels. In neural progenitor cells, it reduces viability and impairs oligodendrogenesis, suggesting interference with cell proliferation and differentiation pathways.
What the Research Shows
In vitro studies have shown that intermedine, alone or combined with the related PA lycopsamine, reduces viability of mouse neural progenitor cells and human hepatocytes at micromolar concentrations. Hepatocyte experiments demonstrate dose‑dependent inhibition of proliferation, colony formation, migration, and induction of apoptosis via ROS, mitochondrial dysfunction, and ER‑mediated pathways. Electron microscopy confirmed mitochondrial structural damage. Analytical work has identified intermedine in Eupatorium fortunei herbs, comfrey roots, and bee products, often exceeding recommended intake limits. No clinical trials of isolated intermedine have been reported; the focus remains on risk assessment and detection methods.
Reported Benefits
No therapeutic benefit of isolated intermedine has been demonstrated in the literature. Its significance lies in its role as a marker of toxic pyrrolizidine alkaloid exposure in herbal and food products, informing safety monitoring and formulation strategies that aim to remove or reduce PA content.
Limitations of the Evidence
Evidence is confined to cell‑culture models and analytical surveys; there are no in vivo or human efficacy studies. Toxicity data are dose‑dependent and may not translate directly to real‑world exposure levels. The stereochemical complexity of intermedine limits extrapolation of findings to other PAs, and long‑term effects in humans remain uncertain.
Safety Considerations
Intermedine is hepatotoxic and neurotoxic at micromolar concentrations, causing ROS‑mediated apoptosis, mitochondrial damage, and ER stress. Chronic dietary exposure from herbal medicines or contaminated bee products may increase risk of hepatic sinusoidal obstruction syndrome. Topical use of PA‑depleted plant extracts is considered safer because systemic absorption is minimal. No safe internal dosage has been established.
How It Is Administered
Research on intermedine has employed intravenous and subcutaneous routes in experimental settings, but the compound is not approved for clinical use. Current applications are limited to analytical testing and toxicology assays rather than therapeutic administration.
Routes of Administration
Goals & Uses
- Heart failure treatmentCardiovascularLow
- Energy homeostasis / Feeding behaviorMetabolicLow
- Metabolic regulationEndocrineLow
- Melanogenesis / Skin PigmentationPigmentationModerate
- Cardiovascular modulationCardiovascularLow
- Anti-inflammatory effectsInflammationLow
- VasodilationCardiovascular SupportModerate
Contraindications
- Known hypersensitivity to melanocortin peptidesAllergy/ImmunologyHigh
- Melanoma or pigmented lesion historyOncologyHigh
Adverse Effects
- Injection site reactionsLocalUnknown
- HeadacheNeurologicUnknownPain in the head or upper neck
- HypotensionCardiovascularUnknownLow blood pressure
- Cardiovascular effects (blood pressure changes)CardiovascularUnknown
- NauseaGastrointestinalUnknownFeeling of sickness or urge to vomit
- HyperpigmentationDermatologicUnknown
Drug Interactions
- Other melanocortin receptor agonists/antagonistsModerate
Population Constraints
- PregnancyReproductive SafetyRelative
- Patients with active malignancyOncologyRelative
- Pediatric populationsAgeRelative
Regulatory Status
- European UnionUnapprovedNo EMA approval
- United StatesUnapprovedNo FDA approval
- United KingdomUnapprovedNo MHRA approval
Not approved for any therapeutic indication; used only in experimental and pre‑clinical settings.
Evidence & Sources
- Journal ArticleLowZhang Y, et al.2021-01-01T00:00:00.000000Z
- Journal ArticleLowWang Z, et al.2022-01-01T00:00:00.000000Z
- Journal ArticleModerateLiu X, Huang X, Song X2026-01-01T00:00:00.000000Z
- Journal ArticleLowColegate SM, et al.2014-01-01T00:00:00.000000Z
- Journal ArticleLowWang Z, et al.2021-01-01T00:00:00.000000Z
- Journal ArticleModerateBrugnerotto P, et al.2025-01-01T00:00:00.000000Z
Frequently Asked Questions
What is intermedine?
Intermedine is a naturally occurring pyrrolizidine alkaloid found in certain plants, especially comfrey, and can appear in herbal medicines and bee products. It is studied mainly for its toxic potential rather than as a drug.
Is intermedine safe for internal use?
No. In vitro studies show that intermedine can cause liver cell death and damage neural progenitor cells. Regulatory bodies consider pyrrolizidine alkaloids hepatotoxic, and internal exposure above low limits is discouraged.
Can intermedine be used therapeutically?
There is no evidence of therapeutic benefit. All published work focuses on its toxicity and on detecting it to avoid harmful exposure.
How is intermedine detected in products?
Most studies use liquid chromatography‑tandem mass spectrometry (LC‑MS/MS) after solvent extraction, sometimes with solid‑phase extraction or QuEChERS, to quantify intermedine and related alkaloids in herbs, honey, pollen, and other matrices.
Why do some reviews mention topical use of comfrey?
Comfrey contains intermedine, but topical formulations can be processed to remove pyrrolizidine alkaloids, minimizing systemic absorption. Such PA‑depleted products have shown safety in skin applications, whereas internal use remains risky.
What is Intermedine used for?
Intermedine is educationally associated with: Heart failure treatment, Energy homeostasis / Feeding behavior, Metabolic regulation, Melanogenesis / Skin Pigmentation, Cardiovascular modulation, Anti-inflammatory effects, Vasodilation. Educational only — not medical advice.
How is Intermedine administered?
Recorded routes of administration: Intraperitoneal, Intravenous, Subcutaneous.
What are the potential side effects of Intermedine?
Reported adverse effects include: Injection site reactions, Headache, Hypotension, Cardiovascular effects (blood pressure changes), Nausea, Hyperpigmentation. This list is not exhaustive — consult a qualified clinician.
Who should avoid Intermedine?
Recorded contraindications: Known hypersensitivity to melanocortin peptides, Melanoma or pigmented lesion history. Consult a qualified clinician before use.