Alpha-humulene

Other Names

(1E,4E,8E)-2,6,6,9-Tetramethyl-1,4,8-cycloundecatriene(1E,4E,8E)-2,6,6,9-Tetramethylcycloundeca-1,4,8-triene(1E,4E,8E)-humula-1(11),4,8-triene(E)-α-Caryophyllene1,4,8-Cycloundecatriene, 2,6,6,9-tetramethyl-, (1E,4E,8E)-1,4,8-Cycloundecatriene, 2,6,6,9-tetramethyl-, (E,E,E)-2,6,6,9-Tetramethyl-1,4,8-cycloundecatriene-, (1E,4E,8E)-3,7,10-Humulatrienealpha-CaryophylleneCycloundeca-1,4,8-triene, 2,6,6,9-tetramethyl-, (E,E,E)-Humulenetrans,trans,trans-2,6,6,9-Tetramethyl-1,4,8-cycloundecatrieneα-Caryophylleneα-Humulenα-Humuleneα-Humulene (α-caryophyllene)α-Humulenenα-Humullene

Synopsis

Alpha-Humulene: A Comprehensive Reference

1. Identity and Chemical Profile

Names and Classification

Alpha-humulene (also known as α-humulene) is a naturally occurring monocyclic sesquiterpene with the molecular formula C₁₅H₂₄. Its structure contains an 11-membered ring and consists of three isoprene units bearing three non-conjugated carbon–carbon double bonds, two of them triply substituted and one doubly substituted. Its CAS number is 6753-98-6, and it carries the synonyms α-caryophyllene and (±)-α-humulene. It is also named chemically as "2,6,6,9-Tetramethyl-1,4,8-cycloundecatriene" or "3,7,10-Humulatriene."

Alpha-humulene is an isomer of beta-caryophyllene, sharing the same chemical formula but a different molecular structure that drives distinct aroma and bioactivity. Like other sesquiterpenoids, it is derived from farnesyl diphosphate (FPP), and its formation is catalyzed by sesquiterpene synthase enzymes.

Discovery and Naming

Alpha-humulene was first identified in the essential oils of Humulus lupulus (hops), from which it derives its name. The name is derived from the hops plant, Humulus lupulus, which is commonly found in the cone flower of hops; the hops plant belongs to the hemp family (Cannabaceae) and is related to cannabis.

Natural Sources and Botanical Occurrence

Alpha-humulene has been found in many aromatic plants on all continents, often together with its isomer beta-caryophyllene. Proven α-humulene emitters into the atmosphere include pine trees, orange orchards, marsh elders, tobacco, and sunflower fields.

α-Humulene is contained in the essential oils of aromatic plants such as Salvia officinalis (common sage), Lindera aggregata (Japanese spicebush), ginseng species, comprising up to 29.9% of the essential oils of Mentha spicata, the ginger family (Zingiberaceae), 10% of the leaf oil of Litsea mushaensis (a Chinese laurel tree), and approximately 4% of the leaf extract of Cordia verbenacea (erva baleeira), a bush in coastal tropical South America.

α-Humulene, a natural monocyclic sesquiterpenoid, is also originally produced from Humulus lupulus and Zingiber zerumbet. It is also a key aromatic compound in agarwood originating from Aquilaria malaccensis. In addition to hops, humulene is found in sage, cloves, ginseng, coriander, and balsam fir.

Sensory Profile and Common Forms

The aroma of humulene is earthy, woody, and herbal, and it is known for giving beer its "hoppy" smell. Through gas chromatography–mass spectrometry analysis, the hydrolysis products of humulene epoxide II specifically produce a "hoppy" aroma in beer.

Alpha-humulene is encountered as a natural ingredient in several forms: it is obtainable from one or more essential oils or from one or more plant parts. In a commercially developed product context, the herbal medicine Acheflan®, the first fully developed herbal medicine in Brazil, contains the essential oil of Cordia verbenacea DC at 0.5% in both cream and aerosol form, indicated for topical treatment of muscle aches and tendinitis. The two principal components of the essential oil responsible for anti-inflammatory activity are α-humulene and (−)-trans-caryophyllene.

2. Traditional and Historical Use

The therapeutic uses of essential oils containing the humulene terpene, such as sage oil, trace back to the remedies of ancient Chinese apothecaries. Even today, Chinese ginseng, which contains humulene, is used for many purposes, notably as an energy booster, a natural antibiotic, and an appetite suppressant.

The aerial parts of Cordia verbenacea are used in folk medicine for their anti-rheumatic, anti-inflammatory, analgesic, and healing properties in the form of alcoholic extracts, decoctions, and infusions. Several compounds are found in the aerial parts of C. verbenacea including tannins, flavonoids, and essential oils; the main components of the essential oil are α-pinene, β-phelandrene, citronelol acetate, β-elemene, trans-caryophyllene, β-gurjunene, α-humulene, aloaromadendrene, bicyclogermacrene, δ-cadinene, spatulenol, and epoxycaryophyllene.

Some of the plants used in Traditional Chinese Medicine and herbal medicine contain humulene, which has various therapeutic uses. In European herbalism, hops were brewed not only for flavoring beer but also for their calming and digestive properties; folk remedies involved using hop infusions and poultices to soothe inflammation, support restful sleep, and promote overall wellness.

It is important to note that while the plants containing alpha-humulene have verified traditional-use histories in multiple cultures, the specific attribution of bioactivity to the isolated α-humulene molecule is a modern scientific endeavor. Traditional preparations were whole-plant extracts, tinctures, decoctions, or distilled oils — not isolated sesquiterpene fractions.

3. Chemical Constituents, Biosynthesis, and Mechanisms of Action

Biosynthesis

Sesquiterpenes, including α-humulene, are formed by 15 carbons and 3 isoprene units. Humulene and caryophyllene are representative sesquiterpenes derived from an initial macrocyclic intermediate formed by a C1–C11 ring closure. These sesquiterpenes are distinguished by being directly derived from the all-trans farnesyl pyrophosphate (FPP) substrate and do not require isomerization to the cisoid conformation or nerolidyl diphosphate intermediate.

Atmospheric Reactivity

α-Humulene is a biogenic volatile organic compound emitted by numerous plants, with a relatively high potential for secondary organic aerosol formation in the atmosphere. It quickly reacts with ozone in sunlight (photooxidation) to form oxygenated products, and has a very high reaction rate coefficient (1.17×10⁻¹⁴ cm³ molecule⁻¹ s⁻¹) compared to most monoterpenes.

Anti-inflammatory Mechanisms

The anti-inflammatory action of α-humulene is one of the most thoroughly characterized aspects of its pharmacology, operating through several overlapping molecular pathways:

NF-κB and AP-1 Inhibition: NF-κB and activator protein 1 (AP-1) signaling play major roles in the initiation of inflammation in human cells through their transcriptional activities. Administration of α-humulene to inflamed lung tissue of female BALB/c mice decreased NF-κB activation and activator protein 1.
Cytokine Suppression: In human THP-1-derived macrophages, the pro-inflammatory cytokines IL-6, TNF-α, and IL-1β were measured by ELISA; a dose-dependent effect of α-humulene on IL-6 release was observed at concentrations from 0.5 to 100 µM, with a maximum IL-6 inhibition of 60% compared to the LPS reference value at 100 µM.
Prostaglandin and COX-2 Suppression: Both α-humulene and (−)-trans-caryophyllene reduced the production of prostaglandin E₂ (PGE₂), as well as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression induced by intraplantar carrageenan injection in rats.
Histamine and Mast Cell Modulation: A decrease in IL-6 mRNA expression levels and histamine levels, via control of intracellular calcium and cyclic adenosine monophosphate (cAMP) levels, in PMA-stimulated human mast cells (HMC-1) was observed upon addition of α-humulene.

Anticancer Mechanisms

ROS Production and Glutathione Depletion: Studies evaluating balsam fir oil and isolated α-humulene on cellular glutathione (GSH) content and reactive oxygen species (ROS) production found that both induced a dose- and time-dependent decrease in cellular GSH content and an increase in ROS production, suggesting that GSH depletion and ROS production may be implicated in the cytotoxicity of α-humulene.
Synergy with β-Caryophyllene: The potentiating effect of β-caryophyllene on the anticancer activity of α-humulene, isocaryophyllene, and paclitaxel against MCF-7, DLD-1, and L-929 human tumor cell lines was evaluated; a non-cytotoxic concentration of β-caryophyllene significantly increased the anticancer activity of α-humulene on MCF-7 cells — α-humulene alone (32 µg/mL) inhibited cell growth by about 50%, compared with 75% when combined with 10 µg/mL β-caryophyllene.

Gastroprotective Mechanisms

In rat models, α-humulene significantly inhibited gastric lesions in HCl/ethanol-induced acute gastritis and decreased gastric acid secretion in pyloric ligation-induced gastric ulcers. It reduced ROS and malondialdehyde through upregulation of prostaglandin E₂ and superoxide dismutase (SOD), and in HMC-1 cells decreased intracellular calcium and increased intracellular cAMP levels, resulting in low histamine levels.

Mucosal Protective Mechanisms

α-Humulene also reduced expression levels of cytokine genes such as IL-1β, IL-6, and TNF by downregulating NF-κB nuclear translocation, and upregulated expression of mucin 5AC (Muc5ac), Muc6, trefoil factor 1 (Tff1), trefoil factor 2 (Tff2), and polymeric immunoglobulin receptor (pigr) — all of which are factors involved in protecting the gastric mucosal lining.

4. Scientific Evidence by Area of Use

4.1 Anti-Inflammatory Activity

Anti-inflammatory activity is the most extensively studied property of α-humulene in the peer-reviewed literature. All available evidence is from preclinical (animal and cell) studies; no human clinical trials isolating α-humulene as an intervention have been published.

Key preclinical study (2007, European Journal of Pharmacology): Oral treatment with both α-humulene and (−)-trans-caryophyllene displayed marked inhibitory effects in different inflammatory experimental models in mice and rats. α-Humulene and (−)-trans-caryophyllene were effective in reducing platelet activating factor-, bradykinin-, and ovalbumin-induced mouse paw oedema, while only α-humulene was able to diminish oedema formation caused by histamine injection. Both compounds had important inhibitory effects on carrageenan-induced paw oedema. Systemic treatment with α-humulene largely prevented both TNF-α and IL-1β generation in carrageenan-injected rats, whereas (−)-trans-caryophyllene diminished only TNF-α release. The anti-inflammatory effects of α-humulene and (−)-trans-caryophyllene were comparable to those observed in dexamethasone-treated animals, and these findings indicate that both compounds might represent important tools for the management and/or treatment of inflammatory diseases.

Key preclinical study (2009, British Journal of Pharmacology): The key result was that α-humulene was effective in preventing eosinophil recruitment to the bronchoalveolar lavage fluid (BALF) and lung, similar to that reported for corticosteroids. Interestingly, animals treated with dexamethasone for 22 days clearly demonstrated weight loss, while animals treated with α-humulene gained weight similarly to control animals, suggesting a minor collateral effect profile. The inhibition of eosinophil recruitment was related to reduction of relevant asthma-related mediators, namely IL-5, CCL11, and LTB4; these effects were associated with diminished P-selectin expression and inhibition of NF-κB and AP-1 pathways. Trans-caryophyllene failed to exhibit either preventive or therapeutic anti-inflammatory properties in this model. α-Humulene, given either orally or by aerosol, exhibited marked anti-inflammatory properties in the murine model of airways allergic inflammation, mediated via reduction of inflammatory mediators, adhesion molecule expression, and transcription factor activation.

Key in-vitro study (2024, Cell Biochemistry and Biophysics / PMC): A possible anti-inflammatory effect of the sesquiterpene α-humulene on lipopolysaccharide (LPS) induction was tested using human THP-1-derived macrophages, with measurement of IL-6, TNF-α, and IL-1β cytokine release by ELISA. A dose-dependent effect on IL-6 release was observed at 0.5 and 100 µM α-humulene, with maximum IL-6 inhibition of 60% at 100 µM compared to the LPS reference value.

The sesquiterpenes β-caryophyllene and α-humulene have been described as having pronounced anti-inflammatory properties comparable to dexamethasone, through regulation of inflammatory protein expression. The overall evidence strength for anti-inflammatory activity is moderate in preclinical models, with consistent findings across multiple rodent and cell-based systems, but the absence of human clinical trials significantly limits the ability to draw conclusions about efficacy in humans.

4.2 Anticancer / Antitumor Activity

All evidence is from in-vitro and animal studies. No human clinical trial data on α-humulene as an anticancer agent are available.

Key preclinical study (2003, Planta Medica — Legault et al.): The antitumor activity of the essential oil of Abies balsamea (balsam fir oil) was evaluated against several solid tumor cell lines including MCF-7, PC-3, A-549, DLD-1, M4BEU, and CT-26; balsam fir oil was found active against all solid tumor cell lines tested, with GI₅₀ values ranging between 0.76 and 1.7 mg/mL. All constituents tested were inactive (>250 µM) except for α-humulene (GI₅₀ = 55–73 µM), which thus appears responsible for the cytotoxicity of the oil.

Synergy study (2007, Journal of Pharmacy and Pharmacology — Legault & Pichette): A non-cytotoxic concentration of β-caryophyllene significantly increased the anticancer activity of α-humulene on MCF-7 cells: α-humulene alone (32 µg/mL) inhibited cell growth by about 50%, compared with 75% when combined with 10 µg/mL β-caryophyllene.

The evidence for anticancer activity is preliminary and exclusively preclinical. Findings from cell-line and animal models are not equivalent to demonstrated efficacy in humans and must be interpreted with considerable caution.

4.3 Antibacterial and Antimicrobial Activity

Key preclinical study (2006, Phytotherapy Research — Pichette et al.): The antibacterial activity of the essential oil of Abies balsamea (balsam fir) was evaluated against Escherichia coli and Staphylococcus aureus; the oil was inactive against E. coli (>100 µg/mL) but active against S. aureus, with an MIC of 56 µg/mL. Three constituents were active against S. aureus: α-pinene, β-caryophyllene (MIC 5.1 µg/mL), and α-humulene (MIC 2.6 µg/mL).

A published study also reported antibacterial and antibiofilm effects of α-humulene against Bacteroides fragilis (Canadian Journal of Microbiology, 2020). Evidence for antimicrobial activity is preliminary and limited to laboratory models, with no human clinical data available.

4.4 Gastroprotection and Gastric Mucosal Integrity

Key preclinical study (2021, Antioxidants / PMC — Yeo et al.): A study designed to determine whether α-humulene has a protective role against gastric injury used both a rat model of HCl/ethanol-induced gastritis and human mast cells (HMC-1). α-Humulene significantly inhibited gastric lesions in HCl/ethanol-induced acute gastritis and decreased gastric acid secretion in pyloric ligation-induced gastric ulcers. It also reduced ROS and malondialdehyde through upregulation of prostaglandin E₂ and superoxide dismutase. In HMC-1 cells, α-humulene decreased intracellular calcium and increased intracellular cAMP, resulting in low histamine levels, and reduced the expression of cytokine genes IL-1β, IL-6, and TNF by downregulating NF-κB nuclear translocation. The authors concluded that α-humulene may attenuate HCl/ethanol-induced gastritis by inhibiting histamine release and NF-κB activation and stimulating antioxidants and mucosal protective factors, suggesting it is a potential drug candidate for stress-induced or alcoholic gastritis.

Evidence strength: preliminary, preclinical only. No human studies available.

4.5 Insect Repellent Properties

In 2015, researchers in Brazil identified α-humulene as an active contributor to the insect repellent properties of Commiphora leptophloeos leaf oil, specifically against the yellow fever mosquito, Aedes aegypti. This finding is a single in-vitro/laboratory characterization and its applicability as a human-applied repellent has not been clinically tested.

4.6 Appetite Suppression

α-Humulene is frequently described in the literature as a potential appetite suppressant, particularly in the context of cannabis terpene profiles. However, the primary peer-reviewed evidence underlying this claim relates to the regulation of interleukin-8 (IL-8) secretion in intestinal epithelial cells. A study cited in the published literature (Satsu et al., 2004, BioFactors) reported on the regulation of IL-8 secretion in human intestinal epithelial Caco-2 cells by α-humulene. Direct human clinical evidence for appetite suppression by isolated α-humulene is absent from the reviewed literature.

4.7 Broader Pharmacological Activities (Systematic Review)

A systematic review (SR) conducted in accordance with PRISMA guidelines, using PubMed, Scopus, and Web of Science databases, included original articles from preclinical and clinical studies investigating the pharmacological activities and toxicological effects of α-humulene and its isomers written in English, Portuguese, and Spanish; the initial search resulted in 5,165 articles, of which 46 were selected for final analysis. After grouping into categories, 41% of the investigated articles reported that α-humulene and its isomers had antitumor activity, followed by anti-inflammatory and antimicrobial activities (20% each), other pharmacological activities (15%), and potential toxic effects (2%).

5. Body Systems and Health Areas of Association

Immune System / Inflammatory Pathways: Inhibition of NF-κB, AP-1, COX-2, iNOS; suppression of TNF-α, IL-1β, IL-6, IL-5, prostaglandin E₂; inhibition of eosinophil recruitment; modulation of mast cell histamine.
Respiratory System: α-Humulene, given either orally or by aerosol, exhibited marked anti-inflammatory properties in a murine model of airways allergic inflammation, mediated via reduction of inflammatory mediators, adhesion molecule expression, and transcription factors activation.
Gastrointestinal System: Gastroprotection via mucosal integrity (upregulation of mucins and trefoil factors), reduction in gastric acid secretion, and antioxidant activity in gastric tissue.
Oncology (Preclinical): Cytotoxicity against multiple solid tumor cell lines in vitro via ROS production and glutathione depletion; synergistic anti-proliferative effects with β-caryophyllene and paclitaxel.
Microbiology: In-vitro antibacterial activity against S. aureus and B. fragilis.
Musculoskeletal / Pain: Topically, within the product Acheflan®, the essential oil of C. verbenacea (containing α-humulene) is indicated for muscle aches and tendinitis.
Vector Control (Experimental): Insect repellent activity against Aedes aegypti in laboratory studies.

6. Pharmacokinetics

Pharmacokinetics have been characterized in mouse studies. A quantitative study assessed the plasma and tissue levels, tissue distribution, and skin (ear) absorption of α-humulene — identified as the main active constituent isolated from Cordia verbenacea — after oral, intravenous, and topical administration in mice, concluding that α-humulene exhibited a rapid onset and relatively good absorption following oral and topical administration.

The peak α-humulene concentration was achieved 15 minutes following oral administration at a dose of 150 mg/kg. The α-humulene plasma concentration then gradually decreased, becoming almost undetectable at 2 hours after intravenous administration and 12 hours after oral administration. When the essential oil of C. verbenacea was given orally at 1 g/kg, peak plasma concentration was observed after 30 minutes, detectable only up to 2 hours. Oral bioavailability of α-humulene was found to be 18%. The half-lives were very short — 16.8 minutes after oral administration and 1.8 minutes after intravenous administration — while elimination half-lives were longer: 118.2 minutes (oral) and 55 minutes (intravenous).

A high amount of the compound was found in the liver following oral administration (at 0.5 hours), followed by the kidneys, heart, lungs, spleen, and brain. These pharmacokinetic findings further contribute to explaining the topical and systemic anti-inflammatory and antinociceptive properties previously reported for the essential oil and for α-humulene obtained from Cordia verbenacea, and also provide support for clinical studies conducted with the phytomedicine Acheflan®.

Computational pharmacokinetic studies have indicated that α-humulene, along with other sesquiterpenes including caryophyllene, may not readily cross the blood-brain barrier due to their heavy molecular weight.

7. Dosage Forms and Reported Dosages

There are no established standardized dosages for isolated α-humulene as a dietary supplement in humans. The following dosages were reported only in preclinical (mouse/rat) studies:

Oral dose of 150 mg/kg in mice, yielding peak plasma concentration at 15 minutes (Chaves et al., Planta Medica, 2008).
Oral dose of 1 g/kg of C. verbenacea essential oil in mice, with peak α-humulene plasma concentration observed at 30 minutes (Chaves et al., 2008).
Concentrations of 0.5 to 100 µM α-humulene were tested in LPS-induced human macrophage (THP-1) cell cultures, showing dose-dependent IL-6 inhibition (2024 PMC study).
In cell studies with human tumor lines (MCF-7), α-humulene at 32 µg/mL inhibited cell growth by approximately 50%, with combined effects at 10 µg/mL β-caryophyllene increasing inhibition to 75% (Legault & Pichette, 2007).
In antibacterial testing against S. aureus, α-humulene demonstrated activity at an MIC of 2.6 µg/mL (Pichette et al., 2006).

The commercial product Acheflan® contains the essential oil of Cordia verbenacea DC at 0.5% in both cream and aerosol forms. The overall body of evidence does not support specific dosage recommendations for α-humulene as an isolated human dietary supplement.

8. Safety Considerations

Formal safety and toxicology data specifically for isolated α-humulene in humans are limited. The available preclinical data are summarized below.

Preclinical Safety Signal

Of 46 studies included in the published systematic review of α-humulene and its isomers, 2% reported potential toxic effects. This represents a small but non-zero reported toxicity signal in preclinical research.

Pharmacokinetic studies of α-humulene using oral and intravenous doses of up to 1,000 mg/kg in mice demonstrated that peak plasma concentrations can reach from 2–20 µg/mL without adverse effects in the short term. This is a very high dose on a per-weight basis in a mouse model and cannot be directly extrapolated to safe human doses.

Comparison with Corticosteroid Controls

Animals treated with dexamethasone for 22 days (preventive protocol) clearly demonstrated weight loss, while animals treated with α-humulene or trans-caryophyllene gained weight similarly to control animals, suggesting a minor collateral effect profile relative to corticosteroid comparators in that model. This finding, while favorable, remains preclinical.

Blood-Brain Barrier and CNS Considerations

Computational studies suggest α-humulene may not be a blood-brain barrier permeant due to its molecular weight. Other smaller compounds that can easily cross the blood-brain barrier could potentially serve as CNS antioxidants and drug candidates for neurodegenerative diseases.

Topical Product Safety

In vitro release and permeation studies of the commercial Acheflan® products found that the commercial formulations have a low release profile that appears to restrict permeation of the oil components, in contrast to the pure essential oil, which presented a good capacity to permeate through skin. This suggests the commercial 0.5% cream and aerosol formulations may have limited dermal penetration of active components under normal use conditions.

Absence of Human Clinical Data

No published randomized controlled trials, prospective cohort studies, or other formal human clinical studies specifically evaluating the safety, tolerability, or efficacy of isolated α-humulene as a dietary supplement or therapeutic agent have been identified in the peer-reviewed literature to date. The entirety of the mechanistic and efficacy evidence base is preclinical (cell culture and rodent models), and generalizability to human biology requires direct clinical investigation.

References

Health Conditions

Health conditions that Alpha-humulene may help support.

No conditions available.

Body Systems

Body systems that Alpha-humulene may help support.

No body systems available.