{"schemaVersion":"cwiki-fiche-2.0","identifiers":{"inchiKey":"FAMPSKZZVDUYOS-HRGUGZIWSA-N","prefName":"Humulene","symbol":"Humulene","iupacName":"(1E,4E,8E)-2,6,6,9-tétraméthylcycloundéca-1,4,8-triène","aliases":["α-humulène","alpha-humulène","α-caryophyllène","alpha-caryophyllène","3,7,10-humulatriène"],"cas":"6753-98-6","pubchemCid":"5281520","chebiId":"CHEBI:5768","smiles":"C/C/1=C\\CC(/C=C/C/C(=C/CC1)/C)(C)C","molecularFormula":"C15H24","molecularWeight":204.35,"xrefs":{"pubchem":"https://pubchem.ncbi.nlm.nih.gov/compound/5281520","chebi":"https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:CHEBI:5768"}},"classification":{"family":"terpene","familyLabel":"Terpene","origin":"plant","originLabel":"Plante","subgroup":"sesquiterpene","subgroupLabel":"Sesquiterpene","originCode":"E","originCodeLabel":"Enzymatic biosynthesis in the plant","originDebated":false,"chemicalClass":"Sesquiterpène monocyclique à squelette humulane, isomère à cycle ouvert du β-caryophyllène","sideChain":null,"form":null,"parent":null,"pharmacologicalClass":null,"naturalTrace":null,"structuralClassFr":null},"originSynthesis":{"heading":"Biosynthetic pathway","summaryFr":"A sesquiterpene formed from farnesyl pyrophosphate by terpene synthases. In the trichomes of the hemp variety « Finola », the enzyme CsTPS9FN makes both β-caryophyllene and α-humulene, in a ratio of about 2.5 to 1, close to the ratio of 2.4 to 1 measured in the plant's flowers (Booth 2017). In the ginger Zingiber zerumbet, a dedicated α-humulene synthase, ZSS1, has been cloned (Yu 2008). Cannabinoids, by contrast, are built from geranyl pyrophosphate, the precursor of monoterpenes (Booth 2017).","originNote":"A sesquiterpene formed by many plants. It owes its name to hops (Humulus lupulus), in which it was first identified (Dalavaye 2024) and whose essential oil it is a major constituent of: 38.0% of the volatile profile of the oil of the Chinook cultivar (Ovidi 2022). Hemp makes it itself through the terpene synthase CsTPS9FN of its trichomes (Booth 2017). It is also the main active constituent isolated from the essential oil of Cordia verbenacea, a plant of the Boraginaceae (Chaves 2008).","discovered":""},"pharmacology":{"summaryFr":"α-Humulene, formerly called α-caryophyllene, is a terpene and not a cannabinoid: this fifteen-carbon sesquiterpene is the ring-opened isomer of β-caryophyllene (Gertsch 2008). The difference matters. Where β-caryophyllene binds the human CB2 receptor (Ki = 155 nM), α-humulene does not displace the radioligand from that receptor (Ki > 20 µM; Gertsch 2008). At CB1 the picture is contradictory: LaVigne et al. (2021) describe a low-potency activation of human CB1 in cell culture, at high concentrations, and tetrad-like effects in mice at 200 mg/kg given intraperitoneally, partly blocked by rimonabant; Carey et al. (2024) found in rats, up to 320 mg/kg given subcutaneously, neither a THC-like effect in drug discrimination nor tetrad effects. The studies often cited for the lack of terpene activity at cannabinoid receptors (Santiago 2019, Finlay 2020) did not test it. In rodents, α-humulene isolated from Cordia verbenacea reduced carrageenan-induced paw oedema and the production of TNF-α and IL-1β (Fernandes 2007), notably at 50 mg/kg orally in mice (Passos 2007), and in ovalbumin-sensitised mice it reduced the recruitment of eosinophils into the airways (Rogerio 2009). In mice, its oral bioavailability is 18% (Chaves 2008). No clinical trial in humans has been found (Dalavaye 2024). A major constituent of hop essential oil, which gave it its name, it accounts on average for 19% of the sesquiterpenes in the flowers of the hemp « Finola » (Booth 2017).","receptorSummaryFr":"It is not a CB2 ligand: unlike its isomer β-caryophyllene, α-humulene does not displace [3H]CP55,940 from the human CB2 receptor (Ki > 20 µM; Gertsch 2008). At CB1 the data diverge. In CHO cells expressing human CB1, LaVigne et al. (2021) describe a low-potency activation: rimonabant-sensitive ERK phosphorylation at 500 µM, partial inhibition of cAMP at high micromolar concentrations, no β-arrestin 2 recruitment and a partial displacement of the radioligand that could not be fitted to a curve; in mice, 200 mg/kg given intraperitoneally produced tetrad-like effects, including an antinociception blocked by rimonabant and a catalepsy abolished by istradefylline, an adenosine A2A receptor antagonist. In rats, 32 to 320 mg/kg given subcutaneously produced neither a THC-like discriminative effect nor tetrad effects (Carey 2024). The two studies that found no activity of cannabis terpenes at CB1 and CB2 (Santiago 2019, Finlay 2020) did not test α-humulene. In vitro, it inhibits CYP3A activity in rat and human liver microsomes (Nguyen 2017).","binding":[{"target":"CB2","efficacy":"unknown","measure":null,"valueNm":null,"species":"human","assay":"[3H]CP55,940 displacement, human CB2","source":{"label":"Gertsch et al. 2008, PNAS: β-caryophyllene, a dietary cannabinoid","pmid":"18574142","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC2449371/"},"strength":null,"reported":"No displacement of the radioligand from human CB2 (Ki > 20 µM), unlike β-caryophyllene (Ki = 155 nM) in the same assay (Gertsch 2008)","confidence":"low"},{"target":"CB2","efficacy":"unknown","measure":null,"valueNm":null,"species":"human","assay":"ERK phosphorylation, CHO cells expressing human CB2","source":{"label":"LaVigne et al. 2021, Sci Rep: cannabimimetic cannabis terpenes","pmid":"33859287","doi":"10.1038/s41598-021-87740-8","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8050080/"},"strength":null,"reported":"ERK phosphorylation in cells expressing CB2, but α-humulene also activates ERK, without sensitivity to rimonabant, in CHO cells lacking a cannabinoid receptor: attribution to CB2 is not established (LaVigne 2021)","confidence":"low"},{"target":"CB1","efficacy":"full_agonist","measure":null,"valueNm":null,"species":"human","assay":"CHO cells expressing human CB1: ERK phosphorylation, cAMP inhibition, β-arrestin 2 recruitment, [3H]CP55,940 binding","source":{"label":"LaVigne et al. 2021, Sci Rep: cannabimimetic cannabis terpenes","pmid":"33859287","doi":"10.1038/s41598-021-87740-8","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8050080/"},"strength":null,"reported":"Low-potency activation, visible only at high concentrations (500 µM for ERK, effect blocked by rimonabant); partial cAMP inhibition, no β-arrestin 2 recruitment, partial radioligand displacement with no fittable curve. The authors do not rule out an indirect effect, via the membrane or via 2-AG (LaVigne 2021)","confidence":"low"},{"target":"CB1","efficacy":"unknown","measure":null,"valueNm":null,"species":"rat","assay":"in vivo: THC discrimination (3.2 mg/kg i.p.) and tetrad, α-humulene 32 to 320 mg/kg s.c., male Sprague-Dawley rats","source":{"label":"Carey, Ghodrati & France 2024, Behav Pharmacol: discriminative effects of cannabis terpenes in rats","pmid":"38660819","doi":"10.1097/FBP.0000000000000772","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11095836/"},"strength":null,"reported":"Neither a THC-like discriminative effect nor a tetrad effect (catalepsy, rotarod, tail-withdrawal latency, temperature); at 32 mg/kg, the THC ED50 shifted from 0.61 to 1.52 mg/kg. Authors' conclusion: no effect consistent with brain CB1 agonism (Carey 2024)","confidence":"low"},{"target":"CYP3A","efficacy":"inhibitor","measure":null,"valueNm":null,"species":"rat, human","assay":"rat and human liver microsomes","source":{"label":"Nguyen et al. 2017, Chem Biol Interact: inhibition of hepatic CYP3A","pmid":"29074051","doi":"10.1016/j.cbi.2017.10.021","url":"https://pubmed.ncbi.nlm.nih.gov/29074051/"},"strength":null,"reported":"Significant, non-competitive inhibition of CYP3A activity; caryophyllene oxide is the most potent inhibitor of the three sesquiterpenes tested (Nguyen 2017)","confidence":"low"}],"references":[{"label":"Gertsch et al. 2008, PNAS: α-humulene does not displace the radioligand from human CB2 (Ki > 20 µM)","pmid":"18574142","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC2449371/"},{"label":"LaVigne et al. 2021, Sci Rep: cannabimimetic cannabis terpenes, CB1 activation","pmid":"33859287","doi":"10.1038/s41598-021-87740-8","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8050080/"},{"label":"Carey, Ghodrati & France 2024, Behav Pharmacol: THC discrimination and tetrad in rats","pmid":"38660819","doi":"10.1097/FBP.0000000000000772","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11095836/"},{"label":"Booth et al. 2017, PLoS One: terpene synthases of Cannabis sativa (CsTPS9FN)","pmid":"28355238","doi":"10.1371/journal.pone.0173911","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC5371325/"},{"label":"Chaves et al. 2008, Planta Med: pharmacokinetics and tissue distribution of α-humulene in mice","pmid":"18951339","doi":"10.1055/s-0028-1088307","url":"https://pubmed.ncbi.nlm.nih.gov/18951339/"},{"label":"Fernandes et al. 2007, Eur J Pharmacol: anti-inflammatory effects of α-humulene and trans-caryophyllene from Cordia verbenacea","pmid":"17559833","doi":"10.1016/j.ejphar.2007.04.059","url":"https://pubmed.ncbi.nlm.nih.gov/17559833/"},{"label":"Passos et al. 2007, J Ethnopharmacol: Cordia verbenacea essential oil and its active compounds","pmid":"17084568","doi":"10.1016/j.jep.2006.09.032","url":"https://pubmed.ncbi.nlm.nih.gov/17084568/"},{"label":"Rogerio et al. 2009, Br J Pharmacol: α-humulene and allergic airway inflammation","pmid":"19438512","doi":"10.1111/j.1476-5381.2009.00177.x","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC2785529/"},{"label":"Santiago et al. 2019, Cannabis Cannabinoid Res: absence of entourage, six terpenes at CB1 and CB2 (α-humulene not tested)","pmid":"31559333","doi":"10.1089/can.2019.0016","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC6757242/"},{"label":"Finlay et al. 2020, Front Pharmacol: cannabis terpenoids and cannabinoid receptors (α-humulene not tested)","pmid":"32269529","doi":"10.3389/fphar.2020.00359","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7109307/"},{"label":"Nguyen et al. 2017, Chem Biol Interact: β-caryophyllene, caryophyllene oxide and α-humulene on drug-metabolising enzymes","pmid":"29074051","doi":"10.1016/j.cbi.2017.10.021","url":"https://pubmed.ncbi.nlm.nih.gov/29074051/"},{"label":"Dalavaye et al. 2024, Planta Med: scoping review of the clinical translation of α-humulene","pmid":"38626911","doi":"10.1055/a-2307-8183","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11254484/"},{"label":"Ovidi et al. 2022, Pharmaceuticals: essential oils of Kompolti hemp and Chinook hops (HS-GC-MS)","pmid":"36015124","doi":"10.3390/ph15080976","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC9413834/"},{"label":"Ibrahim et al. 2023, Cannabis Cannabinoid Res: GC-FID quantification of ten cannabis terpenes","pmid":"36322895","doi":"10.1089/can.2022.0188","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10589468/"},{"label":"Staton Laws & Smid 2024, Curr Res Toxicol: toxicity of sesquiterpenes to PC12 cells","pmid":"38193034","doi":"10.1016/j.crtox.2023.100144","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10772400/"},{"label":"Borges et al. 2026, Chem Biodivers: acute toxicity of α-humulene in adult zebrafish","pmid":"42503214","doi":"10.1002/cbdv.71534","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13401976/"},{"label":"Yu et al. 2008, Planta: α-humulene synthase ZSS1 from Zingiber zerumbet","pmid":"18273640","doi":"10.1007/s00425-008-0700-x","url":"https://pubmed.ncbi.nlm.nih.gov/18273640/"},{"label":"Yu et al. 2011, Cell Mol Life Sci: CYP71BA1 converts α-humulene to 8-hydroxy-α-humulene","pmid":"20730551","doi":"10.1007/s00018-010-0506-4","url":"https://pubmed.ncbi.nlm.nih.gov/20730551/"},{"label":"Chapman 1895, J Chem Soc Trans 67:780: « Some derivatives of humulene »","pmid":null,"doi":"10.1039/CT8956700780","url":"https://doi.org/10.1039/CT8956700780"},{"label":"ECHA CHEM: Humulene, EC No 229-816-7 (no Annex VI CLP index number)","pmid":null,"doi":null,"url":"https://chem.echa.europa.eu/api-substance/v1/substance/100.027.106"},{"label":"PubChem CID 5281520: identifiers and summary of ECHA C&L notifications","pmid":null,"doi":null,"url":"https://pubchem.ncbi.nlm.nih.gov/compound/5281520"}]},"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":"Absent from the schedules of the United Nations conventions of 1961 (INCB Yellow List, 65th edition, July 2026) and 1971 (Green List, 36th edition, 2025). In the European Union, it does not appear in the Union list of flavouring substances adopted by Implementing Regulation (EU) No 872/2012, where its isomer β-caryophyllene carries the number FL 01.007, and it has no harmonised classification under the CLP Regulation (ECHA, EC No 229-816-7).","reference":null,"url":null,"effectiveDate":null,"lastVerified":"2026-10-20","supersededBy":null},{"jurisdiction":"fr","jurisdictionLabel":"France","label":"Not classified as a narcotic in France: a terpene with no cannabinoid skeleton, α-humulene is named neither in the order of 22 February 1990 listing narcotic substances nor in the ANSM consolidated list (update of 26/06/2026, checked on 27/10/2026).","reference":null,"url":null,"effectiveDate":null,"lastVerified":"2026-10-20","supersededBy":null}],"sourcesFr":"EUR-Lex, UNODC, CND, ANSM, IUPHAR/BPS, ChEBI, EUDA."},"references":[{"label":"Gertsch et al. 2008, PNAS: α-humulene does not displace the radioligand from human CB2 (Ki > 20 µM)","pmid":"18574142","doi":null,"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC2449371/"},{"label":"LaVigne et al. 2021, Sci Rep: cannabimimetic cannabis terpenes, CB1 activation","pmid":"33859287","doi":"10.1038/s41598-021-87740-8","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8050080/"},{"label":"Carey, Ghodrati & France 2024, Behav Pharmacol: THC discrimination and tetrad in rats","pmid":"38660819","doi":"10.1097/FBP.0000000000000772","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11095836/"},{"label":"Booth et al. 2017, PLoS One: terpene synthases of Cannabis sativa (CsTPS9FN)","pmid":"28355238","doi":"10.1371/journal.pone.0173911","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC5371325/"},{"label":"Chaves et al. 2008, Planta Med: pharmacokinetics and tissue distribution of α-humulene in mice","pmid":"18951339","doi":"10.1055/s-0028-1088307","url":"https://pubmed.ncbi.nlm.nih.gov/18951339/"},{"label":"Fernandes et al. 2007, Eur J Pharmacol: anti-inflammatory effects of α-humulene and trans-caryophyllene from Cordia verbenacea","pmid":"17559833","doi":"10.1016/j.ejphar.2007.04.059","url":"https://pubmed.ncbi.nlm.nih.gov/17559833/"},{"label":"Passos et al. 2007, J Ethnopharmacol: Cordia verbenacea essential oil and its active compounds","pmid":"17084568","doi":"10.1016/j.jep.2006.09.032","url":"https://pubmed.ncbi.nlm.nih.gov/17084568/"},{"label":"Rogerio et al. 2009, Br J Pharmacol: α-humulene and allergic airway inflammation","pmid":"19438512","doi":"10.1111/j.1476-5381.2009.00177.x","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC2785529/"},{"label":"Santiago et al. 2019, Cannabis Cannabinoid Res: absence of entourage, six terpenes at CB1 and CB2 (α-humulene not tested)","pmid":"31559333","doi":"10.1089/can.2019.0016","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC6757242/"},{"label":"Finlay et al. 2020, Front Pharmacol: cannabis terpenoids and cannabinoid receptors (α-humulene not tested)","pmid":"32269529","doi":"10.3389/fphar.2020.00359","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7109307/"},{"label":"Nguyen et al. 2017, Chem Biol Interact: β-caryophyllene, caryophyllene oxide and α-humulene on drug-metabolising enzymes","pmid":"29074051","doi":"10.1016/j.cbi.2017.10.021","url":"https://pubmed.ncbi.nlm.nih.gov/29074051/"},{"label":"Dalavaye et al. 2024, Planta Med: scoping review of the clinical translation of α-humulene","pmid":"38626911","doi":"10.1055/a-2307-8183","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11254484/"},{"label":"Ovidi et al. 2022, Pharmaceuticals: essential oils of Kompolti hemp and Chinook hops (HS-GC-MS)","pmid":"36015124","doi":"10.3390/ph15080976","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC9413834/"},{"label":"Ibrahim et al. 2023, Cannabis Cannabinoid Res: GC-FID quantification of ten cannabis terpenes","pmid":"36322895","doi":"10.1089/can.2022.0188","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10589468/"},{"label":"Staton Laws & Smid 2024, Curr Res Toxicol: toxicity of sesquiterpenes to PC12 cells","pmid":"38193034","doi":"10.1016/j.crtox.2023.100144","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10772400/"},{"label":"Borges et al. 2026, Chem Biodivers: acute toxicity of α-humulene in adult zebrafish","pmid":"42503214","doi":"10.1002/cbdv.71534","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13401976/"},{"label":"Yu et al. 2008, Planta: α-humulene synthase ZSS1 from Zingiber zerumbet","pmid":"18273640","doi":"10.1007/s00425-008-0700-x","url":"https://pubmed.ncbi.nlm.nih.gov/18273640/"},{"label":"Yu et al. 2011, Cell Mol Life Sci: CYP71BA1 converts α-humulene to 8-hydroxy-α-humulene","pmid":"20730551","doi":"10.1007/s00018-010-0506-4","url":"https://pubmed.ncbi.nlm.nih.gov/20730551/"},{"label":"Chapman 1895, J Chem Soc Trans 67:780: « Some derivatives of humulene »","pmid":null,"doi":"10.1039/CT8956700780","url":"https://doi.org/10.1039/CT8956700780"},{"label":"ECHA CHEM: Humulene, EC No 229-816-7 (no Annex VI CLP index number)","pmid":null,"doi":null,"url":"https://chem.echa.europa.eu/api-substance/v1/substance/100.027.106"},{"label":"PubChem CID 5281520: identifiers and summary of ECHA C&L notifications","pmid":null,"doi":null,"url":"https://pubchem.ncbi.nlm.nih.gov/compound/5281520"}],"meta":{"slug":"humulene","url":"https://en.phytogrammes.com/wiki/humulene","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."}}