Carvone

Carvone

1. Identity and Chemical Characterization

1.1 Names and Classification

Carvone is a monoterpenoid ketone, a naturally occurring organic compound with the molecular formula C₁₀H₁₄O and a molar mass of 150.22 g/mol. It is a monoterpene, belonging to the terpenoids, a large and structurally diverse family of natural products derived from C5 isoprene units, generally joined in a head-to-tail fashion. Its IUPAC name is 2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one. Carvone carries the CAS Registry Numbers 99-49-0 (racemic), 6485-40-1 (R-form, l-carvone), and 2244-16-8 (S-form, d-carvone).

Its stereochemistry is coupled with rich functionality including a cyclic ketone, an endocyclic double bond, and an isopropenyl group. It displays properties characteristic of unsaturated ketones, including the presence of a polar carbonyl group which makes it partially soluble in water.

1.2 Chirality and Enantiomers

Like limonene, carvone is a monoterpene that exists in nature as two enantiomers: (R)-carvone [also known as (–)-carvone or L-carvone] and (S)-carvone [also known as (+)-carvone or D-carvone]. The (R)-(-)-carvone has a characteristic sweet, minty aroma of spearmint, and (S)-(+)-carvone possesses a spicy, caraway-like scent. Most monoterpenes are optically active, and carvone is a prime example: S-(+)-carvone (or d-carvone) is present in relevant amounts in caraway and dill, whereas R-(−)-carvone (or l-carvone) can be found in spearmint.

At approximately 3800 tonnes per year, the worldwide market for (R)-carvone is much larger than that of its (S)-isomer (approximately 10 tonnes per year). Much (R)-carvone is extracted from natural mint, but about half of the commercial product is synthesized from (R)-limonene.

1.3 Natural Sources and Botanical Origins

Carvone is found naturally in many essential oils, but is most abundant in the oils from seeds of caraway (Carum carvi), spearmint (Mentha spicata), and dill. The R-(−)-carvone isomer is also the most abundant compound in the essential oil from several species of mint, particularly spearmint oil (Mentha spicata), which is composed of 50–80% R-(−)-carvone. The R-(−)-carvone isomer also occurs in kuromoji oil. Some oils, like gingergrass oil, contain a mixture of both enantiomers. Many other natural oils, for example peppermint oil, contain trace quantities of carvones.

Carvone is the major compound of the essential oil of many species of the Lamiaceae family, including Mentha, Mentha spicata, Mentha × villoso-nervata, Mentha piperita L., Mentha crispa L., and Mentha cardiaca L. Moreover, carvone is the major compound of the essential oil of Anethum graveolens (dill), Thymus vulgaris, Majorana hortensis, Carum carvi, Anethum sowa, and Solanum tuberosum L. The monoterpene has also been identified in Lippia alba, Anethum graveolens L., and Mentha cardiaca L.

Caraway contains 3–7% volatile oil, with the main components divided into carvone (50–60%) and limonene (40%). The fruit also contains approximately 10% fixed oil along with 20% carbohydrate and 20% protein.

1.4 Common Forms and Preparations

Carvone is produced by both extraction and purification of essential oils from caraway, dill, and spearmint seeds and by chemical and biotechnological synthesis. Synthetic carvone, produced via chemical synthesis from precursors like limonene, offers a cost-effective alternative with comparable purity levels exceeding 99%, enabling consistent supply for large-scale flavor formulations.

Commercial and medicinal forms include: isolated essential oils of caraway, dill, or spearmint (used in capsules, teas, and topical preparations); standardized enteric-coated capsules combining caraway oil with peppermint oil; food-grade flavoring agents; and fragrance-grade isolates for cosmetic and aromatherapy use. S-(+)-Carvone is also used to prevent premature sprouting of potatoes during storage, being marketed in the Netherlands for this purpose under the name Talent. R-(−)-Carvone has been approved by the U.S. Environmental Protection Agency for use as a mosquito repellent.

2. Historical and Traditional Use

2.1 Ancient and Classical Antiquity

Caraway was used for medicinal purposes by the ancient Romans, but carvone was probably not isolated as a pure compound until Franz Varrentrapp (1815–1877) obtained it in 1849. It was originally called "carvol" by Schweizer. Caraway is one of the oldest herbs cultivated in Europe and was used for medicinal purposes by the ancient Romans without knowing about the specifics of carvone. As the compound most responsible for the flavour of caraway, dill, and spearmint, carvone has been used for millennia in food.

Caraway's use as a digestive aid was first mentioned in the Egyptian Ebers Papyrus about 1500 B.C. In Shakespeare's Henry IV, the character Falstaff is invited to have a serving of baked apples and caraway to aid the digestion and relieve gas. Nineteenth-century American Eclectic physicians, such as Harvey Felter, pointed out the seeds not only promote digestion but also ease the symptoms of children suffering from digestive colic.

2.2 Traditional European and Middle Eastern Use

Carvone is utilized as a component of caraway and dill, two of the oldest cultivated spices, and the worldwide-used aromatic plant spearmint. Caraway and dill are used as flavorings for several traditional foods. The spearmint plant (Mentha spicata), sometimes called Garden Mint, has been used in folk medicine as a carminative, in oil to flavor condiments, and the leaves to make herbal teas. Both dill and caraway seeds have been used as spices in foodstuffs for centuries.

Caraway belongs to a class of herbs called carminatives, which are plants helpful in easing gastrointestinal discomfort, including gas. This carminative and antispasmodic use is one of the most consistently documented traditional applications across European herbal traditions, from medieval herbalism through 19th-century botanical medicine.

2.3 Traditional Use in Latin America

The plant Lippia turbinata Griseb., a native aromatic shrub commonly known as "poleo," "té del país," "té criollo," or "poleo fino," is widely used in traditional medicine of Northern and Central Argentina. Research has demonstrated the anxiolytic effects of (R)-(−)-carvone extracted from Lippia alba essential oil, which is widely used in the regions of Central and South America as a tranquilizer.

2.4 Historical Isolation and Chemical Elucidation

In 1841, Swiss chemist Eduard Schweizer isolated what eventually became known as (S)-carvone from oil extracted from caraway seeds (Carum carvi), from which carvone gets its name. Fifty years later, German chemist W. Kwaenick discovered its enantiomer in the oils of spearmint (Mentha spicata) and kuromoji (Lindera umbellata, a deciduous Asian shrub). Goldschmidt and Zürrer identified it as a ketone related to limonene, and the structure was finally elucidated by Georg Wagner (1849–1903) in 1894.

3. Key Constituents and Mechanisms of Action

3.1 Structural Basis of Biological Activity

The antimicrobial effects of carvone are related to its action on the cell membrane and to ultrastructural changes, while the anti-inflammatory, antidiabetic, and anticancer effects involve action on cellular and molecular targets such as the induction of apoptosis, autophagy, and senescence. The presence of the α,β-unsaturated ketone moiety is considered central to carvone's reactivity and biological interactions, as this functional group allows Michael-type addition reactions with cellular nucleophiles.

The monoterpenoids are 10-carbon compounds chemically synthesized from the mevalonate pathway in plants and documented to have a myriad of pharmacological properties such as anti-inflammatory, antibacterial, neuroprotective, antihypertensive, antidiabetic, and antihyperlipidemic effects.

3.2 Antimicrobial Mechanisms

Carvone can be used as an antibacterial agent against many strains of bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Its antibacterial effects are often related to its capacity to penetrate into bacterial cells, thus inducing an increase in cell permeability and a decrease in cell membrane integrity. The action of carvone on germ tube formation and fungal biofilm has also been reported.

3.3 Anti-inflammatory Mechanisms

To explore the molecular mechanisms underlying the anti-inflammatory activity of (R)-(-)-carvone, researchers evaluated its ability to inhibit signaling pathways involving mitogen-activated protein kinases (MAPKs) and the transcription factor NF-κB. (R)-(-)-carvone significantly decreased c-Jun N-terminal kinase (JNK) 1 phosphorylation, but not that of the other MAPKs, induced by bacterial lipopolysaccharides (LPS) in the RAW 264.7 macrophage cell line. The molecular mechanisms underlying the anti-inflammatory effects of the two carvone enantiomers were found to be dissimilar; (S)-(+)-carvone's anti-inflammatory activity is mediated, at least in part, by the activation of Sirtuin-1 (SIRT1).

3.4 Antispasmodic Mechanisms

The antispasmodic effects of carvone have been confirmed on smooth muscle of the guinea pig ileum. The anti-spasmodic effects of carvone in the presence of histamine, carbachol, and BaCl₂ were compared with verapamil as a calcium channel blocker. Research showed that carvone could act on an allosteric site of GABA-A receptors, different from the site of action of benzodiazepines.

3.5 Antinociceptive (Pain-Reducing) Mechanisms

The hypothesis for antinociceptive effects of carvone involves Na⁺ channel blocking mechanisms of the central and peripheral nervous system that ultimately reduce peripheral nerve excitability. Carvone impacts pain reduction, as demonstrated by Gonçalves et al., who observed that mice treated with 100 and 200 mg/kg of R-(−)-carvone showed a significant decrease in the number of writhes. Additionally, it is known that the analgesic effect is not associated with the opioid system.

3.6 Neuroprotective Mechanisms

The results of research indicate S-(+)-carvone's activity towards free radical scavenging, acetylcholinesterase (AChE) inhibition, and metal-ion reduction/chelation. In silico studies based on AChE structure revealed that carvone interacts with amino acid residues creating the enzyme's active site. Studies performed on rat models showed that the administration of S-(+)-carvone (10 and 20 mg/kg body weight) in cerebral ischemia-reperfusion induced attenuated neuronal injury, developed antioxidant activity, and decreased glutathione (GSH), acetylcholinesterase, and malondialdehyde (MDA) levels.

3.7 Enantiomer-Specific Activity Differences

The enantiomers have a dominant impact not only on the smell of carvone but also on the activity of the monoterpene. Notably, anticonvulsant activity was observed in the case of S-(+)-carvone, while R-(−)-carvone did not exhibit this property. These enantiomer-specific differences in pharmacology mean that the botanical source (and thus the predominant enantiomer) can be a meaningful variable in evaluating biological effects.

4. Scientific Evidence by Area of Use

4.1 Overview of the Evidence Base

A systematic review searched the PubMed, Web of Science, and Scopus databases (searches conducted through July 2021). Two independent reviewers performed article selection, extracted relevant data, and assessed methodological quality using Syrcle's risk of bias tool. Ninety-one articles were selected that described 10 pharmacological activities of carvone, including antimicrobial, antispasmodic, anti-inflammatory, antioxidant, antinociceptive, and anticonvulsant activities, among others. The evaluation of methodological quality presented an uncertain risk of bias for most studies. In light of that, carvone stands out as a viable and promising alternative in the treatment of several pathological conditions. However, carrying out studies to evaluate possible mechanisms of action and the safety of this monoterpene is recommended.

Important caveat: These studies were carried out in vitro and in vivo (animal models) and involve a great deal of knowledge on mechanisms of action. However, other investigations regarding carvone's precise mechanisms of action as well as its acute and chronic toxicities are needed to validate its applications. The overwhelming majority of evidence to date is preclinical. Robust, registered human clinical trials specifically on isolated carvone are essentially absent from the published literature.

4.2 Digestive Health and Gastrointestinal Function

Traditional basis and preclinical evidence: Caraway oil, mainly D-carvone and L-limonene, inhibits intestinal fermentation processes by its antimicrobial effects and inhibits the formation of foam in the stomach and intestinal juice.

Clinical evidence (combination products): There are four clinical trials on the oral use of a proprietary combination of peppermint oil and caraway oil in the form of an enteric-coated capsule, which reported that the combination was well tolerated by the patients and that 4 weeks of treatment by this preparation decreased the IBS symptom severity score and improved the quality of life of patients with functional dyspepsia-concomitant IBS.

The important role of caraway oil in the management of functional dyspepsia has been confirmed in many clinical studies, but caraway oil is always used in combination with peppermint oil or menthol in enteric-coated pills. The topical use of caraway oil around the abdomen has relieved IBS symptoms in patients.

Evidence strength: Moderate for combination caraway-peppermint oil products in functional dyspepsia and IBS, consistent across several small-to-moderate clinical trials. There are no human clinical trials on caraway as a single entity. Evidence for isolated carvone as a standalone gastrointestinal agent in humans is therefore absent; what exists is attributed to multi-component essential oil combinations.

4.3 Antimicrobial Activity

Antibacterial: Carvone can be used as an antibacterial agent against many strains of bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Its antibacterial effects are often related to its capacity to penetrate into bacterial cells, inducing an increase in cell permeability and a decrease in cell membrane integrity. It also exhibits an antibiofilm effect against S. aureus.

Antifungal: The use of carvone as an antifungal has been investigated against various fungal strains (Candida spp.), mycotoxigenic fungi (Fusarium spp., Aspergillus spp., and Penicillium spp.), and dermatophytes (Trichophyton spp., Epidermophyton floccosum, and Microsporum spp.). Spearmint essential oil containing 62.9% carvone showed a superior effect against Cryptococcus neoformans and the dermatophytes Trichophyton rubrum and Trichophyton verrucosum (0.32 μL/mL) and also inhibited germ tube formation in Candida albicans up to 80% at concentrations eight times lower than the MIC.

Evidence strength: Preclinical (in vitro) only. Minimum inhibitory concentrations have been established against multiple pathogens in laboratory conditions, but these findings have not been translated to clinical trials in humans. Evidence is preliminary.

4.4 Anti-inflammatory Activity

(R)-(-)-carvone significantly inhibited resynthesis of the inhibitor of NF-κB (IκB)-α induced by LPS, though it did not interfere with the canonical NF-κB activation pathway, suggesting that it may interfere with its transcriptional activity. (R)-(-)-carvone also showed a tendency to decrease the levels of acetylated NF-κB/p65 in the nucleus, without affecting the activity and protein levels of Sirtuin-1.

Evidence strength: In vitro and animal model data only. Promising mechanistic findings from cell culture and rodent studies, but no human clinical trials on carvone's anti-inflammatory effects have been identified in the peer-reviewed literature. Evidence is preliminary.

4.5 Anticancer Activity

Carvone has demonstrated anticancer properties by inducing apoptosis, causing cell cycle arrest, and inhibiting tumor invasion in cancer cell lines such as MCF-7 (breast cancer), A-549 (lung cancer), and KMS-5 (myeloma). D-carvone has been shown to induce apoptosis and regulate the JAK2/STAT3 cascade. Carvone also exhibited anticancer activity against myeloma and melanoma cells and breast cancer cells.

This compound has exhibited remarkable biological effects in vitro and in vivo and therefore may be a key candidate in drug development. Its anticancer and anti-inflammatory activities are promising with different mechanisms of action, allowing it to be considered as a potential agent for new anti-inflammatory and anticancer drugs. However, the pharmacodynamic actions were not well understood and further investigations should be carried out to elucidate its mechanisms.

Evidence strength: In vitro (cell line) and animal data only. All anticancer findings to date are from cell culture experiments. No human clinical trials in oncology have been reported. Evidence is very preliminary and cannot be extrapolated to clinical efficacy.

4.6 Anticonvulsant Activity

Studies examined the effects of carvone against seizures induced by pilocarpine, pentylenetetrazole, and picrotoxin in mice. After acute treatment at repeated oral doses (25 mg/kg, 50 mg/kg, and 75 mg/kg) for 14 days, positive anticonvulsant effects in the epilepsy models were recorded. Furthermore, it was shown that carvone could act on an allosteric site of GABA-A receptors, different from the site of action of benzodiazepines.

Evidence strength: Animal model data only. Mechanistically interesting GABA-A modulation has been proposed, but no human evidence exists. Evidence is preliminary.

4.7 Anxiolytic Activity

Research showed the anxiolytic effects of (R)-(−)-carvone extracted from Lippia alba essential oil, which is widely used in Central and South America as a tranquilizer. Data from this research suggests that L. alba may exert anxiolytic-like effects on a specific subset of defensive behaviors that have been implicated in generalized anxiety disorder, and suggest that carvone is one of the key constituents responsible.

Evidence strength: Animal (rodent) model data only. Evidence is preliminary and derived from studies on the essential oil matrix, not isolated carvone in humans.

4.8 Neuroprotective and Anti-neurodegenerative Activity

A 2024 study aimed to evaluate the potential anti-neurodegenerative activity of S-(+)-carvone, including in vitro experiments (butyrylcholinesterase inhibitory, neuro- and hepatotoxicity as well as neuro- and hepatoprotective activity), in vivo (memory acquisition, locomotor activity), and ex vivo (determination of S-(+)-carvone's level in tissues collected from mice). Results revealed the multidirectional character of S-(+)-carvone. It was shown that S-(+)-carvone is capable of butyrylcholinesterase inhibition (40% for 0.025 mg applied onto the plate), and neuroprotection and hepatoprotection at selective concentrations against reactive oxygen species generation and lipid peroxidation, along with a non-hepatotoxic character. Additionally, multiple-dose administration of the monoterpene at a dose of 100 mg/kg had a positive influence on memory acquisition.

Evidence strength: In vitro and rodent model data. The butyrylcholinesterase inhibition finding is mechanistically relevant to Alzheimer's disease research, but all evidence is preclinical. No human trials exist.

4.9 Antioxidant Activity

Pharmacological investigations have shown that carvone exhibits antioxidant activities, among its other multiple pharmacological properties. Results indicate carvone's activity towards free radical scavenging, acetylcholinesterase (AChE) inhibition, and metal-ion reduction/chelation.

Evidence strength: In vitro evidence for free radical scavenging is established, and animal model evidence supports systemic antioxidant effects. No specific human clinical trials for carvone's antioxidant properties have been published.

4.10 Antidiabetic Activity

The antidiabetic effects of carvone involve action on cellular and molecular targets such as inducing apoptosis, autophagy, and senescence. Monoterpenoids such as carvone have been documented to have antidiabetic and antihyperlipidemic effects in preclinical studies.

Evidence strength: Preclinical (in vitro and animal) only. No human clinical trial evidence for antidiabetic properties of carvone has been identified.

4.11 Insect Repellent Activity

R-(−)-Carvone has been approved by the U.S. Environmental Protection Agency for use as a mosquito repellent. This represents one of the few regulatory-level endorsements of a specific biological activity for carvone, though it relates to an agrochemical/pest-control context rather than a dietary supplement indication.

5. Body Systems and Health Areas

• Gastrointestinal system: Antispasmodic activity has been identified, with combination studies in functional dyspepsia and IBS. Traditional and some clinical data support carminative and antispasmodic effects when consumed as caraway or combination essential oil preparations.
• Immune/anti-infective: Antibacterial, antifungal, antiparasitic, and antineuraminidase (anti-influenza) activities have been reported in vitro.
• Central nervous system: Carvone has effects on the nervous system, including reported anticonvulsant, antinociceptive, anxiolytic, and neuroprotective activities in animal models.
• Hepatic system: Carvone has effects on hepatic metabolism. Neuroprotective studies have also noted hepatoprotective activity at selective concentrations in preclinical settings.
• Oncological research: Anticancer activity has been observed in multiple cancer cell lines (breast, lung, myeloma, melanoma) through induction of apoptosis and cell cycle arrest; all evidence is in vitro.
• Metabolic/endocrine: Preliminary antidiabetic and antihypertensive properties have been identified in preclinical studies.
• Agricultural and food preservation: Several applications of carvone including use as a potato sprouting inhibitor and antimicrobial agent have been established.

6. Pharmacokinetics and Dosage Forms

6.1 Absorption and Pharmacokinetics

In order to confirm bioequivalence of an enteric-coated formulation containing peppermint oil and caraway oil (Enteroplant) and an immediate release formulation of both oils, the pharmacokinetics of menthol and carvone after oral administration of the two formulations were studied in a randomized, two-period cross-over study in 16 healthy male volunteers. Subjects received 180 mg peppermint oil and 100 mg caraway oil, once as 2 enteric-coated capsules (containing 90 mg peppermint oil and 50 mg caraway oil each) and once in the form of 5 immediate release capsules. The 90% confidence interval of the AUC for carvone was 79% to 119% and therefore slightly outside the acceptable range for bioequivalence of 80% to 125%. However, this was considered not clinically relevant, in particular since the dosage of the enteric-coated capsule lies at the upper limit of the model text and positive clinical studies, also on the therapeutic equivalence of the two formulations, are available.

A study determined whether an enantioselective difference in the metabolism of topically applied R-(−)- and S-(+)-carvone could be observed in man. R-(−)- and S-(+)-carvone were found to be stereoselectively biotransformed by human liver microsomes to 4R,6S-(−)- and 4S,6S-(+)-carveol, respectively, and 4R,6S-(−)-carveol is further glucuronidated. Following separate topical applications at a dose of 300 mg, R-(−)- and S-(+)-carvone were rapidly absorbed, resulting in significantly higher C_max levels for S-(+)-carvone (88.0 vs 23.9 ng mL⁻¹) and longer distribution half-lives. These data indicate that stereoselectivity in phase-I and phase-II metabolism has significant effects on the pharmacokinetics of the two enantiomers. This might serve to explain the increased blood levels of S-(+)-carvone.

6.2 Dosages Reported in Studies

The following dosages appear in the published research literature. They are reported descriptively as found in sources and do not constitute recommendations:

• In the enteric-coated pharmacokinetic study, subjects received 100 mg caraway oil (containing 50–65% d-carvone) as 2 enteric-coated capsules (50 mg each), taken with 250 mL water after a 10-hour fast.
• In mouse anticonvulsant studies, repeated oral doses of 25 mg/kg, 50 mg/kg, and 75 mg/kg for 14 days were used.
• In analgesic studies, mice treated with 100 and 200 mg/kg of R-(−)-carvone showed a significant decrease in the number of writhes.
• In neuroprotection rat models, S-(+)-carvone was administered at doses of 10 and 20 mg/kg body weight.
• In the 2024 neurodegenerative study, multiple-dose administration of S-(+)-carvone at a dose of 100 mg/kg had a positive influence on memory acquisition in mice.
• In a human topical absorption study, R-(−)- and S-(+)-carvone were applied at a dose of 300 mg.
• Carvone has a high annual consumption (almost 90 tonnes), with reported uses in many products (food, beverages, and oral hygiene products) in a usual range of 30–200 ppm.

No standardized or consensus therapeutic dose for carvone as a dietary supplement in humans has been established in the peer-reviewed literature.

7. Regulatory Status

The re-evaluation of natural flavor complexes (NFCs) by the FEMA Expert Panel was conducted based on a constituent-based procedure that evaluates the safety of NFCs dominated by alicyclic ketones such as menthone and carvone, secondary alcohols such as menthol and carveol, and related compounds. The FEMA Expert Panel affirmed the GRAS status of Spearmint Oil (FEMA 3032), Spearmint Extract (FEMA 3031), Caraway Oil (FEMA 2238), and Dill Oil (FEMA 2383).

In the United States, spearmint is generally recognized as safe (GRAS). Spearmint oil is listed under 21 CFR §182.20 as a natural flavoring substance. Caraway seed is defined by the FDA as the dried fruit of Carum carvi L., and the principal active ingredient of its volatile oil is d-carvone.

Carvone occurs naturally as dextrorotatory (d-) and levorotatory (l-) enantiomers in several food items; these may also be used as a pesticide, food flavoring, feed flavoring, in feed additives, in personal care products, and as (veterinary) medicine. In order to improve coherence regarding the risk assessment of carvone in the different food and feed sector areas, EFSA asked its Scientific Committee to establish a single ADI (Acceptable Daily Intake) for carvone, estimate the overall exposure of European consumers, and quantify the contribution for each source of exposure. Having reviewed the available information, the Scientific Committee decided to address d-carvone and l-carvone separately and limit its assessment to the oral intake of d- and l-carvone.

8. Safety Considerations and Interactions

8.1 General Toxicological Profile

L-carvone was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, and skin sensitization. Data show that l-carvone is not genotoxic and provided a No Expected Sensitization Induction Level (NESIL) of 2600 μg/cm² for the skin sensitization endpoint. Data on l-carvone provided a calculated Margin of Exposure (MOE) greater than 100 for the repeated dose toxicity and reproductive toxicity endpoints. The phototoxicity/photoallergenicity endpoint was completed based on data and UV/Vis spectra; l-carvone is not phototoxic or photoallergenic.

The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class II material (0.47 mg/day); the exposure to l-carvone is below the TTC. L-carvone was found not to be persistent, bioaccumulative, and toxic (PBT) per international fragrance standards.

8.2 Skin Sensitization

Regarding user safety, carvone-containing oils should be considered as irritants to skin and eyes and as dermal and respiratory sensitizers. Exposure of users by any route is considered a risk. Carvone (l-carvone) is a mint-tasting flavour additive to which most people are exposed and which can cause allergic contact reactions.

Direct contact with foods or products containing carvone may cause symptoms including burning, irritation, and redness. Direct contact may occur on the skin, lips, or mouth. Although it is rare, ingestion of foods that contain carvone could cause generalized symptoms such as itching or redness of the skin.

8.3 Hepatotoxicity Concerns

An important point when considering carvone as an active substance and its potential therapeutic use is the need to check its neurotoxicity and hepatotoxicity. The 2024 anti-neurodegenerative study demonstrated neuroprotection and hepatoprotection at selective concentrations against reactive oxygen species generation and lipid peroxidation, along with a non-hepatotoxic character of S-(+)-carvone at the doses tested. However, this was an in vitro and animal study finding; comprehensive human hepatotoxicity data remain limited.

8.4 Need for Further Safety Characterization

With its multiple mechanisms, carvone can be considered among natural compounds to develop therapeutic drugs. However, other investigations regarding its precise mechanisms of action as well as its acute and chronic toxicities are needed to validate its applications. The systematic review of pharmacological activities similarly concluded that carrying out studies to evaluate possible mechanisms of action and the safety of this monoterpene is recommended.

8.5 Gastroesophageal Reflux Interaction

Enteric coating of peppermint oil/caraway oil capsules avoids subjective discomfort to the patient caused by gastroesophageal reflux. Non-enteric-coated preparations containing caraway oil (and by extension carvone) may therefore exacerbate gastroesophageal reflux in susceptible individuals, which accounts for the clinical preference for enteric-coated formulations in studies on gastrointestinal indications.

8.6 Enantiomer-Specific Safety Considerations

EFSA's Scientific Committee decided to address d-carvone and l-carvone separately when assessing safety, recognizing that the two enantiomers may have different toxicological profiles. Given that most human dietary exposure is to R-(l)-carvone from spearmint-flavored products, and that existing toxicology studies have often focused on S-(d)-carvone from caraway, this enantiomeric gap represents an acknowledged limitation in the safety data.

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