Humulones: A Comprehensive Reference
1. Identity and Chemical Nature
Botanical Source and Nomenclature
Humulone (α-lupulic acid), a vinylogous type of organic acid, is a bitter-tasting chemical compound found in the resin of mature hops (Humulus lupulus). The term humulones (often used in the plural) refers collectively to the class of α-acids found in hops, of which humulone (also designated n-humulone) is the principal member alongside cohumulone and adhumulone.
The hop (Humulus) is a small genus of flowering plants, native to the temperate Northern Hemisphere. The female flowers, commonly called hops, are used as flavouring and stabilizers during beer brewing. Hop (Humulus lupulus) is best known for its use in beer brewing owing to its bittering flavor and floral aroma. Today, the brewing industry uses as much as 98% of the produced hop crop worldwide.
Chemical Classification and Structure
Hop bitter acids are prenylated derivatives of phloroglucinol (1,3,5-trihydroxybenzene, C₆H₆O₃), occurring as soft, pale yellow oils or resins soluble in hydrocarbon solvents such as hexane (soft resins). Bitter acids are divided into two main chemical classes: α-acids (humulones) and β-acids (lupulones), which differ in the substituent in C6: in β-acids, the hydroxyl group present in α-acids is replaced by a prenyl group.
In terms of structure, humulone is a phloroglucinol derivative with three isoprenoid side-chains. Two side-chains are prenyl groups and one is an isovaleryl group. The acidity of the ring enol moieties that give rise to its designation as an acid lie in their vinylogous relationship with the ring and side chain carbonyl functional groups.
The three principal α-acid analogs that constitute the humulone class are:
- n-Humulone (humulone proper; CAS 26472-41-3; molecular formula C₂₁H₃₀O₅)
- Cohumulone — characterized by a smaller isobutyryl side chain
- Adhumulone — carries a methylbutyryl side chain
The α-acids, particularly humulone (35%–70% of total α-acids), cohumulone (20%–65%), and adhumulone (10%–15%) are regarded as the most important constituents in determining the quality of hops. Most hop varieties contain about 10% of adhumulone in their α-acids, but the proportion of cohumulone appears to be a varietal characteristic.
Isomerization to Iso-α-Acids (Isohumulones)
During the wort boiling process, at alkaline pH (8–10), humulones undergo isomerization, via an acyloin-type ring contraction, to produce the corresponding iso-α-acids (iso-humulone, iso-cohumulone, and iso-adhumulone); these compounds are more bitter and soluble than their precursors, are responsible for the bitterness of beer, and, for this reason, define the commercial value of the hops themselves. Isohumulones, which impart bitter flavor and an antibacterial property to beers, are generated from humulones (also known as alpha acids) in the hop plant (Humulus lupulus L.) during the brewing process.
There are three main isohumulones (n-humulone, cohumulone, and adhumulone) that account for more than 80% of the hops-derived matter in beer. Each isohumulone occurs as a mixture of cis and trans isomers that can be reduced into rho, tetrahydro, or hexahydro analogs. This level of chemical complexity has hampered efforts to uncover the mechanism of action of isohumulones in metabolic syndrome.
Distribution in the Plant and Cultivar Variation
The bitter taste of beer is largely due to the presence of isohumulones (also known as iso-alpha acids), which are generated from humulones (also known as alpha acids) that exist within lupulin glands in hop cones. Indigenous North American hops usually have greater alpha acid content than European hops. Bittering hops and North American hop samples contained significantly more alpha acids (humulone, cohumulone, and adhumulone), and had a higher alpha-to-beta ratio than the aroma and European hop samples.
More than 100,000 tons of hops is grown annually across the world, primarily for use in making beer. Depending on the cultivar, hops can have from 5 to 20% by weight of alpha-acids and beta-acids.
Common Forms and Preparations
Humulones are encountered in a variety of processed and supplement forms:
- Dried hop strobiles: Humulus lupulus strobiles have a long traditional medicinal use in Europe, in the form of herbal tea, infusions, powdered herbal substance or alcoholic extracts.
- Hop resin extracts: Lipophilic extracts are used for the preparation of bath oils, whereas hydroalcoholic liquid extracts are prepared for internal use as sedatives.
- Isomerized hop extracts: An aqueous type of isohumulone extract, such as ISOHOP CON2 (Botanix Ltd., UK), is superior in terms of purity, stability, and usability compared to the viscous kettle type. ISOHOP CON2 is a solution standardized to 30% w/w isohumulones, produced from a supercritical CO₂ hop extract and isomerized under alkaline conditions. The purity of the isohumulones is approximately 80%, and its isohumulone:isocohumulone:isoadhumulone ratio is 37:48:15.
- Storage stability: The stability of stored strobiles and ethanol extracts, as measured by humulones, lupulones, and xanthohumol content, is optimal at 70% ethanol concentration.
2. Traditional and Historical Use
European Tradition
The medicinal potential of hop (Humulus lupulus L.) is widely cited in ancient literature and is also allowed in several official pharmacopoeias for the treatment of a variety of ailments, mainly related to anxiety states. This is due to the plethora of phytoconstituents (e.g., bitter acids, polyphenols, prenyl flavonoids) present in the female inflorescences, commonly known as cones or strobili, endowed with anti-inflammatory, antioxidant, antimicrobial, and phytoestrogen activities.
Young shoots have been eaten as a vegetable in many parts of Europe from the times of Pliny (Pliny the Elder c. 24–79 CE). Between 1300 and 1600, there was a widespread use of hops as a remedy for fevers, spleen disorders, as a diuretic, and for liver purging.
The German Leonhart Fuchs (1501–1566) opened a new era in hops knowledge in his Historia stirpium (Research on Medicinal Plants), first published in Latin in 1542. He equated hops and a plant he called Bryon and provided names used in his time to identify it: Lupus salictarius in Latin, Lupulus in the pharmacies, and commonly Humulus. These names hint at a common usage, particularly the reference to pharmacies.
The use of hops as a mild sedative came from the observation of fatigue, tiredness, and sleepiness symptoms in the hop pickers, apparently due to resin absorption during harvesting or processing hops. The tranquilizing and sleep-enhancing properties of H. lupulus were cited in old manuals of pharmacology and pharmacognosy from 1879 onward, as well as in modern textbooks of phytotherapy. The German Commission E Monographs advised use of the plant in the treatment of "discomforts during restlessness or anxiety and sleep disturbances."
Indigenous North American Traditions
In North America, various indigenous tribes used hops as a remedy for various ailments. The Delaware, for example, used it for earache and toothache; the Cherokee used it against sleeping disorders; the Navajo against coughs and colds; and the Dakota used hop infusions as a cure for intestinal disorders and wound healing. In Native American traditional medicines, the Cherokee used Humulus lupulus (hops) as a sedative, anti-rheumatic, analgesic, gynecological aid for breast and womb problems, and kidney and urinary aid for "gravel" and inflamed kidneys.
Ayurvedic and Asian Traditions
Hops were also used in Ayurvedic medicine, a traditional medicine used in India since ancient times and still widespread in the subcontinent today. In Indian Ayurvedic medicine, Humulus lupulus (hops) has been recommended for restlessness associated with nervous tension, headache, and indigestion, and is reported to act as a sedative, hypnotic, and antibacterial.
Official Pharmacopoeial Recognition
The dried, generally whole female inflorescences of hops are described in the European Pharmacopoeia (2005). They are also described in an ESCOP monograph (2003) as having a therapeutic indication, and hops are well documented in a number of handbooks including the British Herbal Pharmacopoeia (1983). The German Commission E approved use of hops for mood disturbances such as restlessness and anxiety as well as sleep disturbances. In allopathic medicine, Humulus lupulus medications underwent strict evaluations of their clinical therapeutic use by the EMA, with the result that dry and liquid extracts (ethanolic or sweet wine extract), tincture, as well as the comminuted or powdered herbal substance are indicated in the category of traditional herbal medicinal products beneficial for "relief of mild symptoms of mental stress and to aid sleep."
3. Key Constituents and Active Compounds
Humulones do not act in isolation; the biological activity of hop preparations derives from the interplay of the α-acids (humulones), iso-α-acids (isohumulones), β-acids (lupulones), prenylflavonoids (xanthohumol, isoxanthohumol, 8-prenylnaringenin), hop essential oils (including α-humulene, myrcene, linalool), and polyphenols. The focus of this article is on the humulone class.
α-Acid (Humulone) Subclass
- n-Humulone: The quantitatively dominant α-acid, comprising 35–70% of total α-acids. Prenylated phloroglucinol core with isovaleryl and two prenyl side chains.
- Cohumulone: Isobutyryl side chain variant; 20–65% of α-acids; its proportion is a varietal marker.
- Adhumulone: Methylbutyryl side chain variant; approximately 10–15% of α-acids.
Iso-α-Acid (Isohumulone) Subclass
Structures of α-acids (n-humulone, cohumulone, and adhumulone) and iso-α-acids (isohumulone, isocohumulone, and isoadhumulone) are produced after thermal isomerization through wort boiling. Each iso-α-acid exists as cis and trans stereoisomers and can be further reduced chemically to yield rho-isohumulones (reduced iso-alpha-acids, RIAA) and tetrahydroisohumulones (THIAA), which are used both in brewing and in some supplement contexts.
Other Notable Hop Constituents
Hop (Humulus lupulus L.) is an important source of phenolic compounds. Polyphenols — mainly phenolic acids, prenylated chalcones, flavonoids, catechins, and proanthocyanidins — comprise about 14.4% of dried hop cones. Hops also contain essential oils, such as linalool, pinene, myrcene, and humulenes.
4. Established Mechanisms of Action
4.1 COX-2 Inhibition and Anti-Inflammatory Signaling
In the screening test for substances that inhibit bone resorption, humulone (HU) from beer hop extracts showed a strong inhibitory activity. The value of IC₅₀ (50% inhibition of bone resorption) was 5.9 nM in pit formation assay. To study the mechanism of action, researchers found that HU inhibited the transcription of the cyclooxygenase-2 (COX-2) gene of osteoblast MC3T3-E1 cells with an IC₅₀ of 30 nM.
Humulone, the alpha acid contained in hops, has been shown to suppress cyclooxygenase-2 induction at the level of transcription. Humulone could therefore be considered a COX-2 inhibitor. Furthermore, humulone suppressed the TNF-alpha–dependent cyclooxygenase-2 induction with an IC₅₀ of about 30 nM, a fairly low concentration.
4.2 NF-κB Pathway Inhibition
In vitro studies have shown that isohumulones and their reduced derivatives, such as RIAA and THIAA, can dose-dependently decrease the nuclear translocation and abundance of NF-κB in lipopolysaccharide (LPS)-stimulated macrophages. Humulone (HC) induces transcription of the NF-κB cytoplasmic inhibitor protein gene IκBα, which decreases the quantity of NF-κB by binding and deactivation in the cytoplasm and preventing NF-κB from entering the nucleus.
4.3 Nrf2/Keap-1 Pathway and Quinone Reductase Induction
The induction of quinone reductase (QR) activity by humulones and isohumulones may be explained by activation of the transcription factor Nrf2/Keap-1 pathway, similar to other natural products containing "Michael acceptor" functionality. Induction of QR is a recognized cancer chemopreventive mechanism associated with Phase II detoxification enzymes.
4.4 PPARα Activation and Lipid Metabolism
Isohumulones upregulate the expression of key genes in hepatic fatty acid oxidation, and they ameliorate blood and hepatic lipid profiles through activation of PPARα. Reviews have focused primarily on the effects of isohumulones on lipid metabolism through PPARα activation. Mice with established diet-induced obesity (DIO) treated with isohumulones showed enhanced glucose tolerance and insulin sensitivity. These benefits were ascribed to direct activation of peroxisome proliferator-activated receptors (PPARs) α and γ.
4.5 GABAA Receptor Positive Allosteric Modulation
Recent evidence revealed that humulone, a prenylated phloroglucinol derivative comprising 35–70% of hops alpha acids, may act as a positive modulator of GABAA receptors at low micromolar concentrations. This raises the question whether humulone plays a key role in hops' pharmacological activity and potentially interacts with other modulators such as ethanol. Researchers demonstrated for the first time that humulone potentiates GABA-induced currents in α1β3γ2 receptors. In radioligand binding to native GABAA receptors, the inclusion of ethanol enhanced humulone modulation of GABA-induced displacement in rat forebrain and cerebellum, producing a leftward shift in displacement curves.
The humulone fraction demonstrated potent modulatory activity in rat forebrain membranes at low micromolar levels (IC₅₀ = 3.2 ± 0.4 μM). Notably, this effect exhibited resistance to flumazenil antagonism, paired with modest selectivity for the classical benzodiazepine binding site.
4.6 AKR1B10 Enzyme Inhibition
The chemopreventive effect of α- and iso-α-acids on biological systems has been investigated in earlier studies. Apart from their antibiotic capacities and antiangiogenic and antidiabetic properties, α-acids have been reported to interfere with carcinogenesis. For example, in human hepatocarcinoma cells, α-acids significantly reduced phosphorylation of NF-κB as well as AP-1 and ERK1/2 activity, thus reducing migration and proliferation. Unisomerized α-acids (adhumulone, cohumulone, and n-humulone) were separated and tested for their inhibitory potential on AKR1A1, AKR1B1, and AKR1B10 — an aldo-keto reductase involved in carcinogenesis and the metabolism of retinoids and steroids.
4.7 Antimicrobial Mechanism
Alpha acids have a mild antibiotic/bacteriostatic effect against Gram-positive bacteria, and favour the exclusive activity of brewing yeast in the fermentation of beer. The fundamental mechanism underlying the antibacterial activity of hop α-acids has been described in classic microbiology literature: membrane leakage in Bacillus subtilis 168 is induced by the hop constituents lupulone, humulone, isohumulone, and humulinic acid.
5. Scientific Evidence by Area of Use
5.1 Sedation, Sleep, and Anxiety
Mechanism and Preclinical Evidence: Some Lupuli flos components, including those contained in non-alcoholic beer, are believed to act in the CNS by influencing GABA, adenosine, serotonin, and melatonin neurotransmission with an effective sedative action that both modulates the circadian rhythms and the sleep-wake cycle and is beneficial for the induction of sleep. Humulone is a positive allosteric modulator of GABAA receptors. Some components of hop resin (including the degradation product 2-methyl-3-buten-2-ol) increase GABA activity by modulating GABAA receptors.
In behavioral tests, humulone shortened sleep onset and increased the duration of sleep induced by pentobarbital and decreased spontaneous locomotion in open field at 20 mg/kg (i.p.). Despite the absence of humulone effects on ethanol-induced sleep onset, sleep duration was increased dose-dependently down to 10 mg/kg (i.p.).
Clinical/Human Evidence: The sedative activity of hop extracts has been confirmed in vivo and in humans by an open study of 225 volunteers. It should be noted that most dedicated clinical trials of hops for sedation have evaluated whole-hop or valerian-hops combinations rather than isolated humulones. The medicinal use of valerian root and hop strobile as a combination (Valerianae radix et Lupuli flos) is indicated in the category of well-established medicinal use for the "relief of sleep disorders," and in the category of traditional use for the "relief of mild symptoms of mental stress and to aid sleep."
Evidence Strength: Preclinical (in vitro and animal) evidence for humulone-specific GABAA modulation is mechanistically well characterized; clinical evidence for isolated humulones remains limited, with most support coming from studies on whole-extract hops or hops-valerian combinations.
5.2 Anti-Inflammatory Activity
Preclinical Evidence: The anti-inflammatory properties of hops extract have been traced to the bitter principle humulone. In one study, humulone inhibited arachidonic acid-induced inflammatory ear edema in mice, and also inhibited skin tumor formation following initiation with a chemical challenge.
Increased LPS-induced TNF-α and IL-6 cytokine release could be inhibited in a dose-dependent manner by the addition of humulone at 0.5 and 0.25 µM, respectively. Humulone (HC) was used as a pharmacologically established positive control, which initiates an anti-inflammatory effect by counteracting the LPS-induced activation of the NF-κB pathway. Humulone induces transcription of the NF-κB cytoplasmic inhibitor protein gene IκBα, which decreases the quantity of NF-κB by binding and deactivation in the cytoplasm.
Evidence Strength: Evidence is primarily preclinical (cell culture and animal models). No dedicated randomized controlled trials in humans have been published evaluating isolated humulones for inflammatory endpoints.
5.3 Metabolic Syndrome, Lipid Metabolism, and Glycemic Control
Preclinical Evidence: An initial study with mixtures of isohumulones showed that obese-diabetic KK-Aʸ mice treated with these compounds had reduced glycemia and decreased plasma triglycerides and free fatty acid levels. Similarly, mice with established diet-induced obesity treated with isohumulones showed enhanced glucose tolerance and insulin sensitivity. These benefits were ascribed to direct activation of peroxisome proliferator-activated receptors (PPARs) α and γ.
Several PPARα-independent functions are also described. These physiologic actions of isohumulones may be potentially therapeutic for the prevention of dyslipidemia in metabolic syndrome and alcoholic fatty liver disease.
Human Clinical Evidence: A small double-blind, placebo-controlled trial in people with diabetes showed that treatment for 8 weeks with isohumulones significantly reduced blood glucose and hemoglobin A1c levels. Subsequent studies have reported positive effects of isohumulones in reducing weight gain and fat mass, improving glucose homeostasis and insulin sensitivity, decreasing liver lipid accumulation, and reducing plasma triglycerides in multiple rodent models. Notably, a larger clinical trial in Japanese subjects with prediabetes showed that 12-week treatment with isohumulones significantly reduced body weight, body mass index, fat mass, fasting blood glucose, and hemoglobin A1c levels.
Evidence Strength: Promising, but limited. The human trials reported are small, conducted primarily in Japanese populations, and have not been replicated in large-scale multicenter RCTs. Preclinical support is robust across multiple animal models, but translation to humans requires further investigation.
5.4 Bone Health and Resorption Inhibition
Preclinical Evidence: Humulone, the major constituent of the mixture of α-acids, has been shown to inhibit bone resorption using an in vitro "pit formation assay" (formation of pits on dentine slices incubated with mouse bone cells). Xanthohumol and humulone have been identified as inhibitors of bone resorption at concentrations at or above 10⁻⁶ and 10⁻¹¹, respectively. Humulone showed high inhibitory activity with an IC₅₀ of 5.9×10⁻⁹ M.
Humulone (HU) enhanced the differentiation-inducing action of vitamin D to myelogenous leukemia cells in the concentration of 0.5–2.5 μM.
Evidence Strength: Preclinical only (in vitro pit formation assay and cell-based studies). No human clinical studies have evaluated humulones specifically for osteoporosis or bone resorption outcomes.
5.5 Antimicrobial Activity
Hops' alpha bitter acids possess mild antiseptic activity against Gram-positive bacteria while their beta acids are reported to be more potent antimicrobials, making hops particularly suitable as beer preservatives. Cermak et al. (2017) tested the antimicrobial activity of purified hop constituents humulone, lupulone, and xanthohumol against some anaerobic bacteria of indigenous human flora (Bacteroides fragilis, Clostridium perfringens, Clostridium difficile). Results demonstrated that xanthohumol exhibited the highest antimicrobial activity against all three microorganisms, followed by β-acids and α-acids.
Fahle et al. (2022) reviewed the antibacterial activities of humulone, lupulone, and xanthohumol, also underlining a synergistic effect when used in combination with antibiotic drugs, not only on Gram-positive but also on Gram-negative bacteria.
Evidence Strength: Well-established in vitro evidence; the selectivity of α-acids for Gram-positive organisms is of historical importance in brewing science. No clinical antimicrobial trials with isolated humulones have been reported.
5.6 Cancer Chemopreventive and Antiproliferative Activity
A meta-analysis provides valuable insights into the antiproliferative effects of hop compounds, particularly xanthohumol (XN), which demonstrated strong activity against cancer cell lines while sparing normal cells. Findings underscore the therapeutic potential of hop-derived phytochemicals, including bitter acids like humulone and lupulone, in cancer treatment. However, further research — including preclinical and clinical studies — is necessary to validate these effects.
Apart from their antibiotic capacities and antiangiogenic and antidiabetic properties, α-acids have been reported to interfere with carcinogenesis. In human hepatocarcinoma cells, α-acids significantly reduced phosphorylation of NF-κB as well as AP-1 and ERK1/2 activity, thus reducing migration and proliferation.
Humulone demonstrated a close relationship between COX enzymes and angiogenesis. It also inhibited angiogenesis in chick embryo chorioallantoic membrane (CAM), with an ED₅₀ of 1.5 μg/CAM.
Evidence Strength: Preclinical and in vitro only. Evidence is preliminary. No clinical trials of humulones for cancer prevention or treatment in humans have been published.
5.7 Gastrointestinal and Spasmolytic Effects
Hops extract poses a potent spasmolytic and antispasmodic action on acetylcholine-induced contraction in isolated rat's ileum, which may be mediated by cholinergic systems. Traditional use for indigestion and gastrointestinal complaints is also noted in the EMA assessment of hops strobiles.
Evidence Strength: Preclinical (isolated tissue preparation). Clinical evidence specific to humulones is absent.
6. Body Systems and Health Areas Associated with Humulones
- Central Nervous System: Sedation, sleep latency reduction, anxiolysis — via GABAA receptor positive allosteric modulation. Alpha bitter acids exhibit sedative and hypnotic effects with potential therapeutic applications in insomnia and attention deficit hyperactivity disorder (ADHD) through modulation of the GABAA receptors.
- Musculoskeletal / Bone: In vitro inhibition of osteoclast-mediated bone resorption; COX-2-dependent mechanism in osteoblast cells.
- Metabolic / Endocrine: Activation of PPARα and PPARγ with consequent improvement of lipid profiles and insulin sensitivity in animal models; preliminary positive human data for isohumulones in prediabetes.
- Immune / Inflammatory: Inhibition of NF-κB translocation, suppression of pro-inflammatory cytokines (TNF-α, IL-6), and COX-2 gene transcription.
- Antimicrobial: Bacteriostatic activity, primarily against Gram-positive organisms, via membrane disruption.
- Oncology (preclinical): Induction of Phase II detoxification enzymes (via Nrf2), inhibition of AKR1B10, anti-angiogenic effects, and antiproliferative activity in cell lines.
- Digestive System: Spasmolytic and antispasmodic effects on smooth muscle; traditional use for indigestion.
7. Dosage Forms and Dosages Reported in Studies
The following dosages and forms have been reported in the scientific literature cited in this article. These are presented as documented in source materials and do not represent recommendations.
- Dried hop strobiles (traditional oral use): Dried strobile: 1.5–2 g; extract combination with valerian: 60 mg.
- Isohumulone extract in human clinical trial (prediabetes): A clinical trial in Japanese subjects with prediabetes used 12-week treatment with isohumulones, resulting in significant reductions in body weight, BMI, fat mass, fasting blood glucose, and HbA1c. (Specific per-day dosage not extractable from this source.)
- Isohumulone in the small diabetic trial: An 8-week double-blind, placebo-controlled trial with isohumulones showed significant reduction in blood glucose and hemoglobin A1c levels. (Specific per-day dosage not independently stated in the cited source.)
- Humulone in rodent behavioral studies: Humulone shortened sleep onset and increased sleep duration at 20 mg/kg (i.p.) in mice. Sleep duration was increased dose-dependently down to 10 mg/kg (i.p.) in the ethanol-induced sleep model.
- Humulone in in vitro COX-2 studies: Humulone (0.1, 1, 10, 100, 1000, 10000 nM; for 12 h) with 10 ng/ml TNFα dose-dependently decreases the amount of released PGE₂ with an IC₅₀ of about 30 nM in MC3T3-E1 cells.
- Humulone in the GABAA binding assay: The humulone fraction demonstrated potent modulatory activity in rat forebrain membranes at low micromolar levels (IC₅₀ = 3.2 ± 0.4 μM).
- Isomerized hop extract (ISOHOP CON2): Standardized to 30% w/w isohumulones.
8. Safety Considerations and Interactions
General Tolerability
It is of importance that isohumulone is tolerated without complaints (noted in older pharmaceutical literature regarding anti-tuberculosis testing of isohumulone). Hops preparations have a long history of dietary and medicinal use without widespread reports of serious adverse events at normal doses.
CNS Depression and Drug Interactions
A low dose of humulone (10 mg/kg) increased ethanol- but not pentobarbital-induced sleep duration, also pointing out a non-competitive synergy of humulone with ethanol at GABAA receptors, which could be responsible for further increased alcohol intoxication with high-hopped beers.
Humulus lupulus components are believed to act in the CNS by influencing GABA, adenosine, serotonin, and melatonin neurotransmission with an effective sedative action. As a consequence, concurrent use of hops-containing preparations with other CNS depressants carries a pharmacodynamic interaction risk. For example, hops have been reported to increase the effects of barbiturates such as amobarbital by pharmacodynamic synergism, potentially enhancing CNS depression.
Estrogenic Activity and Hormonal Effects
Lupuli flos also contains several compounds with estrogenic activity, such as the prenylated flavonoid 6-prenylnaringenin. Prenylflavonoids (xanthohumol, isoxanthohumol, and 8-prenylnaringenin) are capable of modulating aromatase activity, decreasing estrogen synthesis. Although the primary estrogenic activity resides in the prenylflavonoid fraction rather than in humulones per se, whole-hop preparations containing humulones may also deliver these estrogenically active constituents.
Contact Dermatitis
A cream and an herbal sedative, both containing Humulus lupulus (hops) extract, were identified as causing dermatitis in at least one documented case report. During the subsequent hop cultivation period, physical proximity to hops also provoked relapses of the patient's dermatitis. Occupational sensitization among hop workers has been reported in the literature.
Herb-Drug Interaction Considerations
Interactions occur at both the pharmacokinetic and pharmacodynamic levels. Unlike conventional drug substances, herbal medicines are composed of a complex of biologically active compounds. Therefore, the potential occurrence of herb-drug interactions is even more probable than for drug-drug interactions. Given humulones' established potentiation of GABAA receptor activity and their co-occurrence in hop preparations with other neuroactive compounds, additive or synergistic interactions with sedative-hypnotics, anxiolytics, and alcohol are a documented concern.
Pharmacopoeia-Recognized Use and Regulatory Status
EMA evaluations classify Lupuli flos dry and liquid extracts, tincture, and powdered herbal substance in the category of traditional herbal medicinal products for the "relief of mild symptoms of mental stress and to aid sleep." The German Commission E approved use of hops for mood disturbances such as restlessness and anxiety as well as sleep disturbances. These approvals pertain to the standardized strobile preparations, not to isolated humulone fractions as standalone supplements.
Stability and Storage
Once harvested, Humulus lupulus (hops) strobiles deteriorate upon aging and exposure to atmosphere. The stability of stored strobiles and ethanol extracts, as measured by humulones, lupulones, and xanthohumol content, is optimal at 70% ethanol concentration. Oxidative degradation of α-acids is a significant quality-control concern in both raw material storage and finished product formulation.
References
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