{"schemaVersion":"cwiki-fiche-2.0","identifiers":{"inchiKey":"XMGQYMWWDOXHJM-UHFFFAOYSA-N","prefName":"Limonene","symbol":"Limonene","iupacName":"1-méthyl-4-prop-1-én-2-ylcyclohexène","aliases":["limonène","d-limonène","l-limonène","(R)-(+)-limonène","(S)-(−)-limonène","dipentène","dl-limonène","p-mentha-1,8-diène"],"cas":"138-86-3","pubchemCid":"22311","chebiId":"CHEBI:15384","smiles":"CC1=CCC(CC1)C(=C)C","molecularFormula":"C10H16","molecularWeight":136.23,"xrefs":{"pubchem":"https://pubchem.ncbi.nlm.nih.gov/compound/22311","chebi":"https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:CHEBI:15384"}},"classification":{"family":"terpene","familyLabel":"Terpene","origin":"plant","originLabel":"Plante","subgroup":"monoterpene","subgroupLabel":"Monoterpene","originCode":"E","originCodeLabel":"Enzymatic biosynthesis in the plant","originDebated":false,"chemicalClass":"Monoterpène monocyclique (squelette p-menthane), sans le squelette des cannabinoïdes","sideChain":null,"form":null,"parent":null,"pharmacologicalClass":null,"naturalTrace":null,"structuralClassFr":null},"originSynthesis":{"heading":"Biosynthetic pathway","summaryFr":"A monoterpene formed from geranyl diphosphate (GPP), the ten-carbon precursor of monoterpenes, by a limonene synthase. In the trichomes of the 'Finola' hemp variety, the terpene synthase CsTPS1FN converts GPP mainly into (−)-limonene, with small amounts of α-pinene, camphene, β-pinene and myrcene; other hemp terpene synthases, such as CsTPS5FN, form it as a secondary product, and only the transcript level of CsTPS1FN correlates significantly with the (−)-limonene content (Booth 2017). GPP is also a building block of cannabinoid biosynthesis (Booth 2017): limonene and the hemp cannabinoids share a precursor, not a pathway.","originNote":"A monoterpene very widespread in the plant kingdom, and not a cannabinoid. Citrus peel oil is described as consisting of (R)-(+)-limonene, or d-limonene (Matura 2002), and the International Agency for Research on Cancer describes it as occurring naturally in citrus and in a variety of other plants (IARC 1999). Hemp makes it itself, in the other form: in the inflorescences of 22 plants of the 'Finola' variety, (−)-limonene made up on average 12 ± 10% of the monoterpenes (Booth 2017).","discovered":""},"pharmacology":{"summaryFr":"Limonene is a monoterpene, not a cannabinoid: it is a hydrocarbon with no oxygen atom, and published assays find no activity at the cannabinoid receptors. Its molecule carries one stereocentre, giving two enantiomers: (R)-(+)-limonene, or d-limonene, of which citrus peel oil is described as consisting (Matura 2002), and (S)-(−)-limonene, or l-limonene, which the terpene synthase CsTPS1FN of 'Finola' hemp forms, and which made up on average 12 ± 10% of the monoterpenes of 22 plants (Booth 2017). At the human CB1 and CB2 receptors, (R)-(+)-limonene up to 100 µM had no effect of its own and did not change the action of Δ9-THC in AtT20 cells (Santiago 2019), and limonene at 10 µM neither displaced the radioligand nor changed cAMP in HEK cells (Finlay 2020); the study by LaVigne (2021), which supports an 'entourage effect' of other terpenes, did not include it. In vitro, it behaves as an agonist of the adenosine A2A receptor (Park 2011). In humans, it has been given orally to seven healthy volunteers at 100 mg/kg (Crowell 1994) and to cancer patients in a phase I trial, whose maximum tolerated dose was 8 g/m² per day (Vigushin 1998); it circulates mainly as perillic acid, dihydroperillic acid and limonene-1,2-diol. The kidney tumours that d-limonene induces in male rats go through α2u-globulin, a protein specific to the male rat, a mechanism IARC judges not relevant to humans (Group 3, 1999); oxidised by air, however, limonene forms contact allergens (Karlberg 1994), to which 2.6% of 2 411 dermatitis patients reacted (Matura 2006).","receptorSummaryFr":"Limonene is a terpene, not a cannabinoid: two teams measured no activity at the human CB1 and CB2 receptors. (R)-(+)-limonene, from 1 nM to 100 µM, did not change the membrane potential of AtT20 cells expressing either receptor, nor the response to CP55,940 or Δ9-THC (Santiago 2019); at 10 µM, limonene did not displace [3H]CP55,940 from membranes of HEK cells expressing these receptors and had no effect on cAMP, alone or combined with Δ9-THC, cannabidiol or 2-AG (Finlay 2020). The study by LaVigne and colleagues (2021), which describes CB1 activation by other terpenes, did not test limonene. At 10 µM, (R)-(+)-limonene does not activate the human TRPA1 and TRPV1 channels either (Heblinski 2020). It does, however, bind the human adenosine A2A receptor expressed in CHO cells, where it raises cAMP and activates protein kinase A: it is an A2A agonist in vitro (Park 2011). In mice, its anxiolytic-like effect was blocked by an A2A receptor antagonist (Song 2021).","binding":[{"target":"CB1","efficacy":"unknown","measure":null,"valueNm":null,"species":"human","assay":"membrane potential (FLIPR), AtT20 cells expressing human CB1; (R)-(+)-limonene from 1 nM to 100 µM","source":{"label":"Santiago et al. 2019, Cannabis Cannabinoid Res: no entourage effect at CB1 and CB2","pmid":"31559333","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC6757242/"},"strength":null,"reported":"No effect of its own; no change in the response to CP55,940 (1 µM) or in that to Δ9-THC in the presence of limonene at 10 µM","confidence":"low"},{"target":"CB2","efficacy":"unknown","measure":null,"valueNm":null,"species":"human","assay":"membrane potential (FLIPR), AtT20 cells expressing human CB2; (R)-(+)-limonene from 1 nM to 100 µM","source":{"label":"Santiago et al. 2019, Cannabis Cannabinoid Res: no entourage effect at CB1 and CB2","pmid":"31559333","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC6757242/"},"strength":null,"reported":"No effect of its own; no change in the response to CP55,940 (1 µM) or in that to Δ9-THC in the presence of limonene at 10 µM","confidence":"low"},{"target":"CB1","efficacy":"unknown","measure":null,"valueNm":null,"species":"human","assay":"[3H]CP55,940 displacement, HEK membranes expressing human CB1, and cAMP inhibition (CAMYEL BRET); limonene at 10 µM","source":{"label":"Finlay et al. 2020, Front Pharmacol: cannabis terpenes do not act at cannabinoid receptors","pmid":"32269529","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7109307/"},"strength":null,"reported":"No change in binding or in cAMP, alone or combined with Δ9-THC, cannabidiol or 2-AG","confidence":"low"},{"target":"CB2","efficacy":"unknown","measure":null,"valueNm":null,"species":"human","assay":"[3H]CP55,940 displacement, HEK membranes expressing human CB2, and cAMP inhibition (CAMYEL BRET); limonene at 10 µM","source":{"label":"Finlay et al. 2020, Front Pharmacol: cannabis terpenes do not act at cannabinoid receptors","pmid":"32269529","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7109307/"},"strength":null,"reported":"No change in binding or in cAMP, alone or combined with Δ9-THC, cannabidiol or 2-AG","confidence":"low"},{"target":"TRPV1","efficacy":"unknown","measure":null,"valueNm":null,"species":"human","assay":"intracellular calcium (Calcium 5), HEK Flp-In T-Rex cells expressing human TRPV1; (R)-(+)-limonene at 10 µM","source":{"label":"Heblinski et al. 2020, Cannabis Cannabinoid Res: cannabis terpenoids, TRPA1 and TRPV1","pmid":"33376801","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7759271/"},"strength":null,"reported":"No activation; no change in the response to capsaicin or to anandamide","confidence":"low"},{"target":"TRPA1","efficacy":"unknown","measure":null,"valueNm":null,"species":"human","assay":"intracellular calcium (Calcium 5), HEK Flp-In T-Rex cells expressing human TRPA1; (R)-(+)-limonene at 10 µM","source":{"label":"Heblinski et al. 2020, Cannabis Cannabinoid Res: cannabis terpenoids, TRPA1 and TRPV1","pmid":"33376801","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7759271/"},"strength":null,"reported":"No activation; no significant change in the responses to the agonists tested","confidence":"low"},{"target":"A2A","efficacy":"full_agonist","measure":null,"valueNm":null,"species":"human","assay":"radioligand binding (selective affinity for A2A); CHO cells expressing the human A2A receptor: rise in cAMP, protein kinase A activation, CREB phosphorylation and rise in cytosolic calcium","source":{"label":"Park et al. 2011, Biochem Biophys Res Commun: limonene, an agonist ligand of adenosine A2A receptors","pmid":"21134357","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/21134357/"},"strength":null,"reported":null,"confidence":"low"}],"references":[{"label":"Santiago et al. 2019, Cannabis Cannabinoid Res: cannabis terpenoids do not modulate Δ9-THC at CB1 and CB2 receptors","pmid":"31559333","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC6757242/"},{"label":"Finlay et al. 2020, Front Pharmacol: cannabis terpenoids do not act at cannabinoid receptors","pmid":"32269529","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7109307/"},{"label":"Heblinski et al. 2020, Cannabis Cannabinoid Res: cannabis terpenoids, TRPA1 and TRPV1 channels","pmid":"33376801","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7759271/"},{"label":"LaVigne et al. 2021, Sci Rep: cannabimimetic Cannabis sativa terpenes (limonene not tested)","pmid":"33859287","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8050080/"},{"label":"Booth, Page & Bohlmann 2017, PLoS One: terpene synthases of Cannabis sativa","pmid":"28355238","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC5371325/"},{"label":"Park et al. 2011, Biochem Biophys Res Commun: limonene, an agonist ligand of adenosine A2A receptors","pmid":"21134357","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/21134357/"},{"label":"Song et al. 2021, Phytomedicine: limonene, the A2A receptor and anxiety-like behaviour in mice","pmid":"33548867","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/33548867/"},{"label":"Crowell et al. 1994, Cancer Chemother Pharmacol: human metabolism of d-limonene","pmid":"7987974","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/7987974/"},{"label":"Vigushin et al. 1998, Cancer Chemother Pharmacol: phase I trial and pharmacokinetics of d-limonene","pmid":"9654110","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/9654110/"},{"label":"Falk-Filipsson et al. 1993, J Toxicol Environ Health: human exposure to d-limonene by inhalation","pmid":"8421324","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/8421324/"},{"label":"Miyazawa, Shindo & Shimada 2002, Drug Metab Dispos: metabolism of (+)- and (−)-limonenes by CYP2C9 and CYP2C19","pmid":"11950794","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/11950794/"},{"label":"Karlberg et al. 1992, Contact Dermatitis: air oxidation of d-limonene creates potent allergens","pmid":"1395597","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/1395597/"},{"label":"Karlberg et al. 1994, Arch Dermatol Res: hydroperoxides of oxidised d-limonene, potent contact allergens","pmid":"8154930","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/8154930/"},{"label":"Matura et al. 2002, J Am Acad Dermatol: oxidised citrus oil (R-limonene), a frequent skin sensitiser in Europe","pmid":"12399762","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/12399762/"},{"label":"Matura et al. 2006, Contact Dermatitis: oxidised S-(−)-limonene, like R-(+), a frequent cause of contact allergy","pmid":"17026692","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/17026692/"},{"label":"IARC 1999, Monographs volume 73: d-limonene, summary and evaluation (Group 3)","pmid":null,"doi":null,"url":"https://inchem.org/documents/iarc/vol73/73-11.html"},{"label":"NTP TR-347: toxicology and carcinogenesis of d-limonene in F344/N rats and B6C3F1 mice (gavage)","pmid":null,"doi":null,"url":"https://ntp.niehs.nih.gov/publications/reports/tr/300s/tr347"},{"label":"Implementing Regulation (EU) No 872/2012 of 1 October 2012: Union list of flavouring substances","pmid":null,"doi":null,"url":"https://eur-lex.europa.eu/legal-content/FR/TXT/?uri=CELEX:32012R0872"},{"label":"Regulation (EU) 2023/1545 of 26 July 2023: labelling of fragrance allergens in cosmetics","pmid":null,"doi":null,"url":"https://eur-lex.europa.eu/legal-content/FR/TXT/?uri=CELEX:32023R1545"},{"label":"Regulation (EC) No 1272/2008 (CLP), consolidated version of 1 July 2026, Annex VI","pmid":null,"doi":null,"url":"https://eur-lex.europa.eu/legal-content/FR/TXT/?uri=CELEX:02008R1272-20260701"},{"label":"Delegated Regulation (EU) 2021/849 of 11 March 2021: harmonised classification of d-limonene","pmid":null,"doi":null,"url":"https://eur-lex.europa.eu/legal-content/FR/TXT/?uri=CELEX:32021R0849"},{"label":"21 CFR 182.60: synthetic flavouring substances recognised as safe (United States)","pmid":null,"doi":null,"url":"https://www.ecfr.gov/current/title-21/section-182.60"},{"label":"ANSM, consolidated list of substances classified as narcotics, updated 26/06/2026","pmid":null,"doi":null,"url":"https://ansm.sante.fr/uploads/2026/06/26/20260626-stupefiants-version-consolidee.pdf"},{"label":"INCB, Green List, 36th edition (2025): psychotropic substances under international control","pmid":null,"doi":null,"url":"https://www.incb.org/incb/uploads/documents/Psychotropics/forms/greenlist/2026/2510307E.pdf"},{"label":"INCB, Yellow List, 65th edition (July 2026): narcotic drugs under international control","pmid":null,"doi":null,"url":"https://www.incb.org/incb/uploads/documents/Narcotic-Drugs/Yellow_List/65th_Edition/YL_65th_EN_unedited.pdf"}]},"pharmacokinetics":null,"metabolism":null,"detection":null,"subjectiveEffects":{"state":"uncharacterised","method":"https://en.phytogrammes.com/wiki/a-propos#methode-effets","axes":[],"doseRanges":null,"humanDataCharacterised":true},"indications":{"approvedMedicines":[]},"harmProfile":{"unstudiedBanner":false,"bannerTextFr":null,"toxicologyFr":null},"legal":{"scheduleStatus":"unscheduled","scheduleLabel":"Unscheduled","frScheduleStatus":"unscheduled","tiers":[{"jurisdiction":"international","jurisdictionLabel":"International","label":null,"reference":null,"url":null,"effectiveDate":null,"lastVerified":"2026-10-20","supersededBy":null},{"jurisdiction":"eu","jurisdictionLabel":"Union européenne","label":"No schedule of the 1961 and 1971 United Nations conventions covers limonene (INCB Yellow List, 65th edition, July 2026; Green List, 36th edition, 2025). In the Union, it is on the list of authorised flavouring substances (Implementing Regulation (EU) No 872/2012: FL 01.001 limonene, FL 01.045 d-limonene, FL 01.046 l-limonene). In cosmetics, entry 88 of Annex III to Regulation (EC) No 1223/2009, as worded by Regulation (EU) 2023/1545, requires it to be named in the ingredient list above 0.001% in leave-on products and 0.01% in rinse-off products, with a peroxide value below 20 millimoles per litre. Its harmonised CLP classification includes skin sensitisation (category 1B for d-limonene, category 1 for racemic limonene and l-limonene) and, for d-limonene, the aspiration hazard (Asp. Tox. 1). In the United States, limonene (d-, l- and dl-) is listed among the synthetic flavouring substances generally recognised as safe (21 CFR 182.60).","reference":null,"url":null,"effectiveDate":null,"lastVerified":"2026-10-20","supersededBy":null},{"jurisdiction":"fr","jurisdictionLabel":"France","label":"Not classified as a narcotic in France: limonene does not appear on the consolidated list of substances classified as narcotics published by the ANSM (updated 26/06/2026), which compiles the order of 22 February 1990 and the decisions of the Agency's director general. Its uses as a food flavouring and as a fragrance ingredient in cosmetics fall under European Union law.","reference":null,"url":null,"effectiveDate":null,"lastVerified":"2026-10-20","supersededBy":null}],"sourcesFr":"EUR-Lex, UNODC, CND, ANSM, IUPHAR/BPS, ChEBI, EUDA."},"references":[{"label":"Santiago et al. 2019, Cannabis Cannabinoid Res: cannabis terpenoids do not modulate Δ9-THC at CB1 and CB2 receptors","pmid":"31559333","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC6757242/"},{"label":"Finlay et al. 2020, Front Pharmacol: cannabis terpenoids do not act at cannabinoid receptors","pmid":"32269529","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7109307/"},{"label":"Heblinski et al. 2020, Cannabis Cannabinoid Res: cannabis terpenoids, TRPA1 and TRPV1 channels","pmid":"33376801","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7759271/"},{"label":"LaVigne et al. 2021, Sci Rep: cannabimimetic Cannabis sativa terpenes (limonene not tested)","pmid":"33859287","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8050080/"},{"label":"Booth, Page & Bohlmann 2017, PLoS One: terpene synthases of Cannabis sativa","pmid":"28355238","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC5371325/"},{"label":"Park et al. 2011, Biochem Biophys Res Commun: limonene, an agonist ligand of adenosine A2A receptors","pmid":"21134357","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/21134357/"},{"label":"Song et al. 2021, Phytomedicine: limonene, the A2A receptor and anxiety-like behaviour in mice","pmid":"33548867","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/33548867/"},{"label":"Crowell et al. 1994, Cancer Chemother Pharmacol: human metabolism of d-limonene","pmid":"7987974","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/7987974/"},{"label":"Vigushin et al. 1998, Cancer Chemother Pharmacol: phase I trial and pharmacokinetics of d-limonene","pmid":"9654110","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/9654110/"},{"label":"Falk-Filipsson et al. 1993, J Toxicol Environ Health: human exposure to d-limonene by inhalation","pmid":"8421324","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/8421324/"},{"label":"Miyazawa, Shindo & Shimada 2002, Drug Metab Dispos: metabolism of (+)- and (−)-limonenes by CYP2C9 and CYP2C19","pmid":"11950794","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/11950794/"},{"label":"Karlberg et al. 1992, Contact Dermatitis: air oxidation of d-limonene creates potent allergens","pmid":"1395597","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/1395597/"},{"label":"Karlberg et al. 1994, Arch Dermatol Res: hydroperoxides of oxidised d-limonene, potent contact allergens","pmid":"8154930","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/8154930/"},{"label":"Matura et al. 2002, J Am Acad Dermatol: oxidised citrus oil (R-limonene), a frequent skin sensitiser in Europe","pmid":"12399762","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/12399762/"},{"label":"Matura et al. 2006, Contact Dermatitis: oxidised S-(−)-limonene, like R-(+), a frequent cause of contact allergy","pmid":"17026692","doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/17026692/"},{"label":"IARC 1999, Monographs volume 73: d-limonene, summary and evaluation (Group 3)","pmid":null,"doi":null,"url":"https://inchem.org/documents/iarc/vol73/73-11.html"},{"label":"NTP TR-347: toxicology and carcinogenesis of d-limonene in F344/N rats and B6C3F1 mice (gavage)","pmid":null,"doi":null,"url":"https://ntp.niehs.nih.gov/publications/reports/tr/300s/tr347"},{"label":"Implementing Regulation (EU) No 872/2012 of 1 October 2012: Union list of flavouring substances","pmid":null,"doi":null,"url":"https://eur-lex.europa.eu/legal-content/FR/TXT/?uri=CELEX:32012R0872"},{"label":"Regulation (EU) 2023/1545 of 26 July 2023: labelling of fragrance allergens in cosmetics","pmid":null,"doi":null,"url":"https://eur-lex.europa.eu/legal-content/FR/TXT/?uri=CELEX:32023R1545"},{"label":"Regulation (EC) No 1272/2008 (CLP), consolidated version of 1 July 2026, Annex VI","pmid":null,"doi":null,"url":"https://eur-lex.europa.eu/legal-content/FR/TXT/?uri=CELEX:02008R1272-20260701"},{"label":"Delegated Regulation (EU) 2021/849 of 11 March 2021: harmonised classification of d-limonene","pmid":null,"doi":null,"url":"https://eur-lex.europa.eu/legal-content/FR/TXT/?uri=CELEX:32021R0849"},{"label":"21 CFR 182.60: synthetic flavouring substances recognised as safe (United States)","pmid":null,"doi":null,"url":"https://www.ecfr.gov/current/title-21/section-182.60"},{"label":"ANSM, consolidated list of substances classified as narcotics, updated 26/06/2026","pmid":null,"doi":null,"url":"https://ansm.sante.fr/uploads/2026/06/26/20260626-stupefiants-version-consolidee.pdf"},{"label":"INCB, Green List, 36th edition (2025): psychotropic substances under international control","pmid":null,"doi":null,"url":"https://www.incb.org/incb/uploads/documents/Psychotropics/forms/greenlist/2026/2510307E.pdf"},{"label":"INCB, Yellow List, 65th edition (July 2026): narcotic drugs under international control","pmid":null,"doi":null,"url":"https://www.incb.org/incb/uploads/documents/Narcotic-Drugs/Yellow_List/65th_Edition/YL_65th_EN_unedited.pdf"}],"meta":{"slug":"limonene","url":"https://en.phytogrammes.com/wiki/limonene","lastVerified":"2026-10-20","dataUpdatedAt":"2026-10-27","confidence":"high","dataCompletenessPct":80,"audit":null,"wikipedia":null,"disclaimerFr":"Contenu éditorial informatif, sans valeur d'avis médical ni juridique. Sources primaires citées par fiche. Réservé aux adultes."}}