Coumarin

Coumarin at a Glance

Coumarin, or 2H-chromen-2-one, is the simplest member — and the structural parent — of the large coumarin family of plant benzopyranones. On its own it is a colourless crystalline solid with a sweet, warm scent usually described as new-mown hay or vanilla-almond: the smell of drying grass, tonka bean, sweet clover and cassia cinnamon. That aroma made it one of the first materials of modern perfumery.

Two things dominate its story, and both are widely misunderstood. The first is a genuine dose-dependent liver toxicity that appears in a susceptible minority of people — the reason coumarin is banned as a direct food additive in the United States, restricted in the EU, and the basis of the standing warning about heavy cassia (vs. Ceylon) cinnamon consumption ^{7,8,9Reference 7Woehrlin F et al. · 2010Quantification of flavoring constituents in cinnamon: high variation of coumarin in cassia bark from the German retail market and in authentic samples from IndonesiaView study →Reference 8Abraham K et al. · 2010Toxicology and risk assessment of coumarin: focus on human dataView study →Reference 9Pitaro M et al. · 2022ReviewCoumarin-induced hepatotoxicity: a narrative reviewView study →}. The second is a myth: because “coumarin” lends its name to the coumarin anticoagulants, coumarin itself is often assumed to thin the blood. It does not. The anticoagulants — warfarin, dicoumarol — are chemically distinct 4-hydroxycoumarin derivatives, and coumarin has no meaningful anticoagulant activity of its own ^{17,20Reference 17Norn S et al. · 2014Norn S, Permin H, Kruse PR, Kruse E (2014). [On the history of vitamin K, dicoumarol and warfarin]. Dansk Medicinhistorisk Årbog. https://pubmed.ncbi.nlm.nih.gov/25639072/View study →Reference 20Gómez-Outes A et al. · 2012Discovery of anticoagulant drugs: a historical perspectiveView study →}.

Everything below keeps the isolated molecule distinct from the plants that carry it, and keeps coumarin distinct from its more pharmacologically active relatives — the anchoring hubs scopoletin, umbelliferone, imperatorin and osthole are all substituted descendants of this parent scaffold.

Established Uses: Fragrance & Flavour

Coumarin’s one truly established, large-scale human use is non-medical: it is a workhorse fragrance ingredient. It was among the first aroma chemicals used in perfumery (Houbigant’s Fougère Royale, 1882) and remains a defining note of the fougère and oriental families, valued for its sweet, hay-like, tobacco-and-almond warmth. It is a declared, restricted fragrance allergen in the EU.

As a food flavouring its history is more cautionary. Coumarin was once added directly to foods, but the United States FDA prohibited it as a direct food additive in 1954 after the rodent hepatotoxicity emerged, and the EU restricts it: coumarin may enter food only naturally (via flavourings such as cinnamon, tonka or woodruff), with maximum levels set for specific food categories ^{21Reference 21EFSA Panel on Food Additives et al. · 2008Coumarin in flavourings and other food ingredients with flavouring properties — Scientific OpinionView study →}. So most human coumarin exposure today is indirect — inhaled from fragrance or eaten as a natural constituent of spices and flavourings, not added as pure coumarin.

Coumarin Is Not an Anticoagulant

This is the single most common error about the molecule, so it is worth stating plainly: coumarin (1,2-benzopyrone) is not a blood thinner.

The confusion is historical. In the 1920s, cattle in North America and Canada began dying of uncontrolled internal bleeding — “sweet clover disease” — after eating spoiled sweet-clover (Melilotus) hay. In 1940–41, Karl Paul Link’s laboratory in Wisconsin isolated the culprit: dicoumarol (dicumarol), a compound formed by mould fermentation of the plant’s coumarin/coumarinic-acid glucosides in the rotting hay. Dicoumarol is 3,3′-methylene-bis(4-hydroxycoumarin) — two 4-hydroxycoumarin units bridged together — and it, not the parent coumarin, is the anticoagulant. Link’s group went on to develop warfarin (also a 4-hydroxycoumarin derivative) as a rodenticide and then a human anticoagulant drug ^{17,20Reference 17Norn S et al. · 2014Norn S, Permin H, Kruse PR, Kruse E (2014). [On the history of vitamin K, dicoumarol and warfarin]. Dansk Medicinhistorisk Årbog. https://pubmed.ncbi.nlm.nih.gov/25639072/View study →Reference 20Gómez-Outes A et al. · 2012Discovery of anticoagulant drugs: a historical perspectiveView study →}.

The mechanistic point that resolves the myth: warfarin and dicoumarol work as vitamin K antagonists, blocking the enzyme VKOR (vitamin-K epoxide reductase) and thereby the synthesis of clotting factors II, VII, IX and X. That activity depends on the 4-hydroxy substituent and the specific side chains of these molecules. Plain coumarin lacks the 4-hydroxyl group, is not a vitamin K antagonist, and does not reproduce their anticoagulant effect ^{17,20Reference 17Norn S et al. · 2014Norn S, Permin H, Kruse PR, Kruse E (2014). [On the history of vitamin K, dicoumarol and warfarin]. Dansk Medicinhistorisk Årbog. https://pubmed.ncbi.nlm.nih.gov/25639072/View study →Reference 20Gómez-Outes A et al. · 2012Discovery of anticoagulant drugs: a historical perspectiveView study →}. Calling this class the “coumarins” is a naming accident of their shared benzopyrone skeleton — not evidence that the fragrant parent thins blood.

The Hepatotoxicity Story

Coumarin’s safety profile is a textbook case of metabolism deciding toxicity, and of why an animal result does not transfer cleanly to humans.

In the rat and mouse, coumarin is a liver (and lung) toxin and, at high doses, a carcinogen — but the tumours are non-genotoxic, appearing only at doses high enough to cause tissue damage first, with a non-linear, threshold dose-response ^{2Reference 2Lake BG · 1999Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessmentView study →}. The reason is the metabolic branch point:

• 7-hydroxylation — via cytochrome P450 2A6 (CYP2A6) — converts coumarin to 7-hydroxycoumarin (umbelliferone), which is glucuronidated and excreted. This is a detoxification pathway, and it is the major route in most humans ^{1,2Reference 1Egan D et al. · 1990The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compoundsView study →Reference 2Lake BG · 1999Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessmentView study →}.
• 3,4-epoxidation produces an unstable coumarin 3,4-epoxide, which breaks down to the reactive, hepatotoxic aldehyde o-hydroxyphenylacetaldehyde (o-HPA). This is the toxic pathway, and it dominates in the rat and mouse ^{3,4,5Reference 3Born SL et al. · 2000o-Hydroxyphenylacetaldehyde is a hepatotoxic metabolite of coumarinView study →Reference 4Born SL et al. · 2000In vitroIn vitro kinetics of coumarin 3,4-epoxidation: application to species differences in toxicity and carcinogenicityView study →Reference 5Born SL et al. · 1997Synthesis and reactivity of coumarin 3,4-epoxideView study →}.

Most people are efficient 7-hydroxylators and route coumarin down the safe path. But CYP2A6 is genetically variable, and a poor-metaboliser subgroup shunts relatively more coumarin toward the toxic epoxide route — the biological basis for the observation that a proportion of people are susceptible to coumarin liver injury ^{1,2,9Reference 1Egan D et al. · 1990The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compoundsView study →Reference 2Lake BG · 1999Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessmentView study →Reference 9Pitaro M et al. · 2022ReviewCoumarin-induced hepatotoxicity: a narrative reviewView study →}. In the clinical trials that used coumarin as a drug, reversible liver-enzyme rises appeared in a small but consistent fraction of patients — about 6% in one large randomised lymphoedema trial at 400 mg/day ^{12Reference 12Loprinzi CL et al. · 1999Lack of effect of coumarin in women with lymphedema after treatment for breast cancerView study →}.

This is what underlies the regulatory limits. The EFSA tolerable daily intake (TDI) is 0.1 mg/kg body weight, derived from the animal liver toxicity with uncertainty factors and cross-checked against human data ^{8,21Reference 8Abraham K et al. · 2010Toxicology and risk assessment of coumarin: focus on human dataView study →Reference 21EFSA Panel on Food Additives et al. · 2008Coumarin in flavourings and other food ingredients with flavouring properties — Scientific OpinionView study →}. Ordinary dietary-plus-fragrance exposure is normally well below it (estimated ~0.06 mg/kg/day) ^{2Reference 2Lake BG · 1999Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessmentView study →} — but cassia cinnamon can carry so much coumarin (undetectable up to ~10,000 mg/kg, varying wildly even within a single tree) that a heavy consumer, or a small child, can exceed the TDI from cinnamon alone ^{7,8Reference 7Woehrlin F et al. · 2010Quantification of flavoring constituents in cinnamon: high variation of coumarin in cassia bark from the German retail market and in authentic samples from IndonesiaView study →Reference 8Abraham K et al. · 2010Toxicology and risk assessment of coumarin: focus on human dataView study →}. Ceylon cinnamon (Cinnamomum verum) contains far less and is the low-coumarin alternative ^{8Reference 8Abraham K et al. · 2010Toxicology and risk assessment of coumarin: focus on human dataView study →}. This is a cassia-specific caution; it does not generalise to all “cinnamon.”

What It's Used For

Beyond fragrance, coumarin has been investigated as a drug — chiefly for high-protein oedema/lymphoedema and as an adjuvant in oncology — and, as the parent scaffold, in countless in-vitro screens. The honest summary is that the human clinical record is old, mixed, and largely abandoned, weighed down by the same hepatotoxicity described above.

Evidence by IndicationStrength of support · Beta

Support is an experimental score — weighted by study type (human > animal > in vitro) and volume. A beta, not a validated metric. These scores rate clinical drug uses (mostly negative or abandoned) alongside scaffold bioactivity; read the per-row basis.

01Fragrance & flavour (established, non-medical)Promising68%Century-plus of established perfumery/flavour use; regulated allergen ^{21Reference 21EFSA Panel on Food Additives et al. · 2008Coumarin in flavourings and other food ingredients with flavouring properties — Scientific OpinionView study →}

02Lymphoedema / high-protein oedemaShaky30%Positive early trials ^{11Reference 11Casley-Smith JR et al. · 1993Treatment of lymphedema of the arms and legs with 5,6-benzo-[alpha]-pyroneView study →} overturned by the pivotal RCT ^{12Reference 12Loprinzi CL et al. · 1999Lack of effect of coumarin in women with lymphedema after treatment for breast cancerView study →}

03Antitumour / adjuvant oncologyShaky22%Small phase trials, weak/inconsistent signal ^{14,15Reference 14Marshall ME et al. · 1994ReviewAn updated review of the clinical development of coumarin (1,2-benzopyrone) and 7-hydroxycoumarinView study →Reference 15Sagaster P et al. · 1995RCTRandomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancerView study →}

04Antioxidant / antimicrobial (scaffold)Shaky18%In-vitro; activity belongs to substituted coumarins, not the parent ^{1Reference 1Egan D et al. · 1990The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compoundsView study →}

Mechanisms

The load-bearing rows are the top two: whether coumarin is safe or toxic is decided by how much goes down the CYP2A6 7-hydroxylation (safe) versus the 3,4-epoxidation (toxic) branch — which is why a CYP2A6 poor-metaboliser subgroup carries the risk.

Pharmacokinetics

Coumarin is small and lipophilic, absorbed readily from the gut and distributed quickly (it crosses into brain tissue, correlating with a transient sedative effect in animal models) ^{16Reference 16Ritschel WA · 1983Pharmacokinetics of coumarin, 7-hydroxycoumarin and 7-hydroxycoumarin glucuronide in the blood and brain of gerbils following intraperitoneal administration of coumarinView study →}. Its defining PK feature is near-complete first-pass metabolism: after an oral dose the great majority is converted on first liver pass to 7-hydroxycoumarin, so the systemic bioavailability of intact coumarin is very low — on the order of a few percent — and plasma is dominated by the 7-hydroxycoumarin glucuronide rather than the parent ^{1,16Reference 1Egan D et al. · 1990The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compoundsView study →Reference 16Ritschel WA · 1983Pharmacokinetics of coumarin, 7-hydroxycoumarin and 7-hydroxycoumarin glucuronide in the blood and brain of gerbils following intraperitoneal administration of coumarinView study →}. The elimination half-life of coumarin is short (~1 hour) ^{1Reference 1Egan D et al. · 1990The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compoundsView study →}. Two consequences follow: (1) in-vitro potencies of “coumarin” are misleading, because so little parent molecule survives to circulate; and (2) individual differences in CYP2A6 activity change the balance of detox versus toxic metabolites, which is the crux of the safety story ^{1,2Reference 1Egan D et al. · 1990The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compoundsView study →Reference 2Lake BG · 1999Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessmentView study →}.

Clinical Trials

Human trials exist, but they are mostly historical and mostly negative or inconclusive. The best-quality study is the pivotal lymphoedema RCT, which was negative and flagged hepatotoxicity ^{12Reference 12Loprinzi CL et al. · 1999Lack of effect of coumarin in women with lymphedema after treatment for breast cancerView study →}; oncology trials were small phase I/II efforts with weak signals ^{14,15Reference 14Marshall ME et al. · 1994ReviewAn updated review of the clinical development of coumarin (1,2-benzopyrone) and 7-hydroxycoumarinView study →Reference 15Sagaster P et al. · 1995RCTRandomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancerView study →}.

Last checked: July 2026.

Isolate vs. Plant Studies

Coumarin sits at an unusual place on the isolate-vs-plant axis. Its direct human exposure is as the isolated molecule — in fragrance, and historically as a pure oral drug — so the negative lymphoedema and inconclusive oncology data are genuinely about the isolate ^{12,14Reference 12Loprinzi CL et al. · 1999Lack of effect of coumarin in women with lymphedema after treatment for breast cancerView study →Reference 14Marshall ME et al. · 1994ReviewAn updated review of the clinical development of coumarin (1,2-benzopyrone) and 7-hydroxycoumarinView study →}. That is a strength for interpreting the safety and efficacy record: there is no “whole plant is different” escape hatch for the liver-toxicity finding, which comes straight from dosing the pure compound ^{2,12Reference 2Lake BG · 1999Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessmentView study →Reference 12Loprinzi CL et al. · 1999Lack of effect of coumarin in women with lymphedema after treatment for breast cancerView study →}.

Conversely, the health claims people attach to coumarin-containing plants — cinnamon, tonka, sweet clover, woodruff — are almost never about coumarin as an active. In cinnamon the metabolic and antimicrobial activity tracks cinnamaldehyde and procyanidins, with coumarin present as a hepatotoxic contaminant to be limited, not a benefit ^{7,8Reference 7Woehrlin F et al. · 2010Quantification of flavoring constituents in cinnamon: high variation of coumarin in cassia bark from the German retail market and in authentic samples from IndonesiaView study →Reference 8Abraham K et al. · 2010Toxicology and risk assessment of coumarin: focus on human dataView study →}. So the honest framing inverts the usual caveat: for efficacy, coumarin is a bystander in its plants; for safety, the isolate data are exactly what matter.

Its Role in Plants

In plants, coumarin is stored largely as an odourless, water-soluble glucoside (coumarinic-acid glucoside / melilotoside). When tissue is crushed or wilts, enzymes release the aglycone, which lactonises to the fragrant free coumarin — the reason freshly cut hay, sweet clover and woodruff develop their sweet smell as they dry ^{1Reference 1Egan D et al. · 1990The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compoundsView study →}.

Biosynthetically, coumarin derives from the phenylpropanoid pathway: ortho-hydroxylation of a cinnamic-acid derivative (via a 2-oxoglutarate-dependent feruloyl/p-coumaroyl-CoA 2′-hydroxylase, F6′H/C2′H) gives an ortho-hydroxycinnamoyl unit that cyclises to the lactone ^{18Reference 18Shimizu B · 2014Shimizu B (2014). 2-Oxoglutarate-dependent dioxygenases in the biosynthesis of simple coumarins. Frontiers in Plant Science. https://pubmed.ncbi.nlm.nih.gov/25404933/View study →}. The same 2-oxoglutarate-dependent dioxygenase machinery feeds the simple coumarins generally ^{18Reference 18Shimizu B · 2014Shimizu B (2014). 2-Oxoglutarate-dependent dioxygenases in the biosynthesis of simple coumarins. Frontiers in Plant Science. https://pubmed.ncbi.nlm.nih.gov/25404933/View study →}.

Ecologically, coumarins function in defence — deterring herbivores and inhibiting the growth of competing plants and microbes (allelopathy) — and, in the ortho-hydroxylated iron-mobilising coumarins (fraxetin, esculetin), in iron acquisition from soil ^{18Reference 18Shimizu B · 2014Shimizu B (2014). 2-Oxoglutarate-dependent dioxygenases in the biosynthesis of simple coumarins. Frontiers in Plant Science. https://pubmed.ncbi.nlm.nih.gov/25404933/View study →}. These are plant-biology roles and should not be read as human pharmacology.

Prevalence in Nature

Coumarin occurs across many plant families but is concentrated in a handful of famously fragrant species. The richest common source is the tonka bean (Dipteryx odorata), whose seeds are roughly 1–3% coumarin by weight and are used (where permitted) as a vanilla-like flavouring ^{19Reference 19Moraes MLL et al. · 2022Experimental mixture design as a tool to evaluate coumarin (1,2-benzopyrone) extraction from Dipteryx odorataView study →}. Sweet clover / melilot (Melilotus) and sweet woodruff (Galium odoratum) are the classic hay-scented herbs; deertongue and several sweet grasses (sweet vernal grass) also carry it.

The nutritionally important source is cassia cinnamon (Cinnamomum cassia and related C. aromaticum/C. loureiroi), where coumarin is a highly variable constituent of the bark — measured from undetectable up to ~10,000 mg/kg, with large variation between samples and even within a single tree ^{7Reference 7Woehrlin F et al. · 2010Quantification of flavoring constituents in cinnamon: high variation of coumarin in cassia bark from the German retail market and in authentic samples from IndonesiaView study →}. Ceylon cinnamon (Cinnamomum verum) contains only trace amounts and is the low-coumarin choice ^{8Reference 8Abraham K et al. · 2010Toxicology and risk assessment of coumarin: focus on human dataView study →}. Trace coumarin also appears in lavender, licorice and other aromatics.

Major Natural Sources

Source	Part	Typical coumarin level	Note
Tonka bean (Dipteryx odorata)	seed	~1–3% dry wt 19Reference 19Moraes MLL et al. · 2022Experimental mixture design as a tool to evaluate coumarin (1,2-benzopyrone) extraction from Dipteryx odorataView study →	richest common source; restricted as a food flavouring
Cassia cinnamon (Cinnamomum cassia)	bark	undetectable–~1% (up to ~10,000 mg/kg) 7Reference 7Woehrlin F et al. · 2010Quantification of flavoring constituents in cinnamon: high variation of coumarin in cassia bark from the German retail market and in authentic samples from IndonesiaView study →	wildly variable; the dietary-exposure driver
Sweet clover / melilot (Melilotus officinalis)	dried herb	fractions of a percent 1Reference 1Egan D et al. · 1990The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compoundsView study →	source of “sweet clover disease” → dicoumarol
Sweet woodruff (Galium odoratum)	herb	low percent on drying 1Reference 1Egan D et al. · 1990The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compoundsView study →	traditional May-wine flavouring
Ceylon cinnamon (Cinnamomum verum)	bark	~0.001–0.02% dry wt 8Reference 8Abraham K et al. · 2010Toxicology and risk assessment of coumarin: focus on human dataView study →	the low-coumarin alternative to cassia

Discovery & Synthesis

Coumarin was first isolated in 1820 from the tonka bean (from the French coumarou, the local name for the tree — the origin of the compound’s name) by the Munich chemist A. Vogel, who initially mistook it for benzoic acid. Its structure as the lactone of ortho-coumaric acid was established over the following decades.

The molecule’s landmark in synthetic chemistry is the Perkin synthesis: William Henry Perkin prepared coumarin in 1868 by condensing salicylaldehyde with acetic anhydride and sodium acetate (the Perkin reaction) — one of the first commercially significant syntheses of an aroma chemical and a foundation of the synthetic-fragrance industry. Manufacture today is overwhelmingly synthetic (Perkin-type and related routes, e.g. from salicylaldehyde or phenol derivatives): commercial coumarin is a made molecule, cheaper and more consistent than tonka extraction, and extraction from plants is now marginal.

Patents: not yet researched.

Toxicity & Safety

Coumarin carries a moderate flag — not because ordinary exposure is dangerous, but because it is a genuine dose-dependent hepatotoxin in a susceptible human subgroup, it is a rodent liver/lung carcinogen at high doses (albeit by a non-genotoxic, threshold mechanism), and it is a regulated fragrance allergen ^{1,2,9,21Reference 1Egan D et al. · 1990The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compoundsView study →Reference 2Lake BG · 1999Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessmentView study →Reference 9Pitaro M et al. · 2022ReviewCoumarin-induced hepatotoxicity: a narrative reviewView study →Reference 21EFSA Panel on Food Additives et al. · 2008Coumarin in flavourings and other food ingredients with flavouring properties — Scientific OpinionView study →}. Crucially, the anticoagulant risk that people fear does not exist for this molecule — that belongs to the 4-hydroxycoumarin drugs ^{17,20Reference 17Norn S et al. · 2014Norn S, Permin H, Kruse PR, Kruse E (2014). [On the history of vitamin K, dicoumarol and warfarin]. Dansk Medicinhistorisk Årbog. https://pubmed.ncbi.nlm.nih.gov/25639072/View study →Reference 20Gómez-Outes A et al. · 2012Discovery of anticoagulant drugs: a historical perspectiveView study →}.

Safety at a Glance

⚠️ Moderate toxicity

• Ordinary exposure is generally low-risk. Typical dietary-plus-fragrance intake sits below the EFSA TDI of 0.1 mg/kg/day, and coumarin is not genotoxic ^{1,2Reference 1Egan D et al. · 1990The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compoundsView study →Reference 2Lake BG · 1999Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessmentView study →}.
• Not a blood thinner. Coumarin does not inhibit vitamin-K clotting-factor synthesis; warfarin/dicoumarol are different 4-hydroxycoumarin molecules ^{17,20Reference 17Norn S et al. · 2014Norn S, Permin H, Kruse PR, Kruse E (2014). [On the history of vitamin K, dicoumarol and warfarin]. Dansk Medicinhistorisk Årbog. https://pubmed.ncbi.nlm.nih.gov/25639072/View study →Reference 20Gómez-Outes A et al. · 2012Discovery of anticoagulant drugs: a historical perspectiveView study →}.
• Dose-dependent liver toxicity in a susceptible minority. Reversible transaminase rises (≈6% at 400 mg/day in trials); CYP2A6 poor-metabolisers are more at risk ^{9,12Reference 9Pitaro M et al. · 2022ReviewCoumarin-induced hepatotoxicity: a narrative reviewView study →Reference 12Loprinzi CL et al. · 1999Lack of effect of coumarin in women with lymphedema after treatment for breast cancerView study →}.
• Heavy cassia-cinnamon intake can exceed the TDI — especially for small children or daily high-dose “cinnamon” supplement users; Ceylon cinnamon is the low-coumarin alternative ^{7,8Reference 7Woehrlin F et al. · 2010Quantification of flavoring constituents in cinnamon: high variation of coumarin in cassia bark from the German retail market and in authentic samples from IndonesiaView study →Reference 8Abraham K et al. · 2010Toxicology and risk assessment of coumarin: focus on human dataView study →}.
• Fragrance contact allergen. A declarable EU fragrance allergen; can cause allergic contact dermatitis in sensitised individuals ^{21Reference 21EFSA Panel on Food Additives et al. · 2008Coumarin in flavourings and other food ingredients with flavouring properties — Scientific OpinionView study →}.
• Rodent carcinogenicity does not transfer directly. Tumours in rats/mice arise via toxic 3,4-epoxide metabolites at high doses — a species-specific, threshold effect, not evidence of human genotoxic carcinogenicity ^{1,2Reference 1Egan D et al. · 1990The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compoundsView study →Reference 2Lake BG · 1999Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessmentView study →}.

Full Safety & Interactions Detail

Hepatotoxicity. The principal human concern is reversible, idiosyncratic liver injury: cholestatic/hepatocellular enzyme rises that resolve on stopping. In the lymphoedema RCT, ~6% of women on 400 mg/day showed serologic liver toxicity ^{12Reference 12Loprinzi CL et al. · 1999Lack of effect of coumarin in women with lymphedema after treatment for breast cancerView study →}; case reports link cassia-cinnamon supplements to acute hepatitis, plausibly via coumarin in susceptible individuals ^{10Reference 10Brancheau D et al. · 2015Case reportDo cinnamon supplements cause acute hepatitis? American Journal of Case Reports. https://pubmed.ncbi.nlm.nih.gov/25923145/View study →}. Risk is concentrated in the CYP2A6 poor-metaboliser subgroup, who route more coumarin toward the toxic 3,4-epoxide/o-HPA pathway ^{3,4,5,9Reference 3Born SL et al. · 2000o-Hydroxyphenylacetaldehyde is a hepatotoxic metabolite of coumarinView study →Reference 4Born SL et al. · 2000In vitroIn vitro kinetics of coumarin 3,4-epoxidation: application to species differences in toxicity and carcinogenicityView study →Reference 5Born SL et al. · 1997Synthesis and reactivity of coumarin 3,4-epoxideView study →Reference 9Pitaro M et al. · 2022ReviewCoumarin-induced hepatotoxicity: a narrative reviewView study →}.

Regulatory limits. The EFSA TDI is 0.1 mg/kg body weight ^{8,21Reference 8Abraham K et al. · 2010Toxicology and risk assessment of coumarin: focus on human dataView study →Reference 21EFSA Panel on Food Additives et al. · 2008Coumarin in flavourings and other food ingredients with flavouring properties — Scientific OpinionView study →}; the US FDA has prohibited coumarin as a direct food additive since 1954. Ordinary combined exposure is estimated around 0.06 mg/kg/day ^{2Reference 2Lake BG · 1999Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessmentView study →}, but cassia cinnamon is the realistic way to exceed the TDI given its high and variable content ^{7,8Reference 7Woehrlin F et al. · 2010Quantification of flavoring constituents in cinnamon: high variation of coumarin in cassia bark from the German retail market and in authentic samples from IndonesiaView study →Reference 8Abraham K et al. · 2010Toxicology and risk assessment of coumarin: focus on human dataView study →}.

The anticoagulant myth (interactions). Because coumarin is not a vitamin-K antagonist, it does not carry warfarin-type bleeding interactions in its own right ^{17,20Reference 17Norn S et al. · 2014Norn S, Permin H, Kruse PR, Kruse E (2014). [On the history of vitamin K, dicoumarol and warfarin]. Dansk Medicinhistorisk Årbog. https://pubmed.ncbi.nlm.nih.gov/25639072/View study →Reference 20Gómez-Outes A et al. · 2012Discovery of anticoagulant drugs: a historical perspectiveView study →}. (Distinct issue: some plant sources — and separately the furanocoumarins in grapefruit — can affect drug-metabolising enzymes, but that is a property of those specific molecules/matrices, not of unsubstituted coumarin.)

Carcinogenicity in context. Coumarin causes liver and lung tumours in rats and mice, but the weight of genotoxicity testing is negative, and tumours appear only at hepatotoxic doses with a non-linear threshold dose-response — a metabolism-mediated, species-specific mechanism that risk assessors — accounting for the species-specificity of coumarin toxicokinetics — conclude does not indicate a genotoxic cancer risk to humans at dietary/fragrance exposures ^{1,2,6Reference 1Egan D et al. · 1990The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compoundsView study →Reference 2Lake BG · 1999Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessmentView study →Reference 6Felter SP et al. · 2006A safety assessment of coumarin taking into account species-specificity of toxicokineticsView study →}.

Reproductive note (prose only). No robust human reproductive-toxicity dataset exists for isolated coumarin; pregnancy/lactation decisions belong to the specific herb or product where intake is decided, not to this molecule page. The safety ceiling for the general population is set by the hepatotoxicity endpoint and the TDI above.

Dosage

There is no recommended intake of coumarin, and no current medical use that calls for dosing the isolated molecule. The figures below are for context only:

The clinical doses are exactly the exposures at which liver toxicity was seen, which is why they were abandoned. For everyday life the practical guidance is simpler: prefer Ceylon over cassia cinnamon if you consume cinnamon in quantity, and treat coumarin as a fragrance/flavour constituent to keep within regulatory limits rather than a supplement to take ^{7,8Reference 7Woehrlin F et al. · 2010Quantification of flavoring constituents in cinnamon: high variation of coumarin in cassia bark from the German retail market and in authentic samples from IndonesiaView study →Reference 8Abraham K et al. · 2010Toxicology and risk assessment of coumarin: focus on human dataView study →}. These are regulatory and historical-research figures, not a personal recommendation.

References

1. Egan D, O’Kennedy R, Moran E, et al. (1990). The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compounds. Drug Metabolism Reviews. https://pubmed.ncbi.nlm.nih.gov/2078993/
2. Lake BG (1999). Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessment. Food and Chemical Toxicology. https://pubmed.ncbi.nlm.nih.gov/10418958/
3. Born SL, Hu JK, Lehman-McKeeman LD (2000). o-Hydroxyphenylacetaldehyde is a hepatotoxic metabolite of coumarin. Drug Metabolism and Disposition. https://pubmed.ncbi.nlm.nih.gov/10640521/
4. Born SL, Caudill D, Smith BJ, Lehman-McKeeman LD (2000). In vitro kinetics of coumarin 3,4-epoxidation: application to species differences in toxicity and carcinogenicity. Toxicological Sciences. https://pubmed.ncbi.nlm.nih.gov/11053537/
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