IngredientsAlpha acids are prenylated acylphloroglucinol derivatives found in the resinous lupulin glands of the hop plant (Humulus lupulus), serving as the primary source of bitterness, flavor, and antimicrobial preservation in beer through their isomerization during the brewing process. Hops (Humulus lupulus) are flowering plants belonging to the Cannabaceae family, primarily known for their use in brewing beer, where the female flowers (cones) of the hop plant are added to provide bitterness, flavor, and aroma. The plant is a perennial herbaceous liana native to Eurasia, Europe, and the United States. The female plants produce strobiles, which are cone-like reproductive structures.
Alpha acids (α-acids) are a class of chemical compounds primarily of importance to the production of beer. They are found in the resin glands of the flowers of the hop plant and are the source of hop bitterness. The alpha acid "rating" on commercial hops products is standardized: the alpha acid "rating" on hops indicates the amount of alpha acid as a percentage of total weight of the hop.
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). Humulone is a prevalent member of the class of compounds known as alpha acids, which collectively give hopped beer its characteristic bitter flavor. 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.
With the molecular formula C₂₁H₃₀O₅ and a molar mass of 362.46 g/mol, humulone is an optically active compound, specifically the R-(−)-enantiomer, characterized by a melting point of 64.5°C and a pKa of 5.0. Humulone exhibits low solubility in water, approximately 6 mg/L at 25 °C and neutral pH, but is highly soluble in ethanol and alkaline solutions due to its ability to form salts.
The nomenclature "alpha acid" is a classification term rather than a direct structural descriptor. The term "alpha" refers to a class of compounds in hops that include humulone, adhumulone, and cohumulone. The alpha acids were likely named as such to distinguish them from beta acids (like lupulone) and other hop components. The exact origin of the "alpha" nomenclature in brewing is not entirely clear, but it has become a standard term in the industry to refer to these bitter-contributing compounds.
Common alpha acids include humulone, adhumulone, cohumulone, posthumulone, and prehumulone. Humulone serves as the primary α-acid in hops, with homologs such as cohumulone differing by the substitution of the isovaleryl side chain with a shorter propanoyl group (ethyl-substituted), while adhumulone features a 2-methylbutanoyl chain; these variations account for the diversity in hop bitter acid profiles.
Adhumulone levels in hops are typically constant at 15% of the total alpha acid content across all varieties, whereas cohumulone and humulone levels vary (20%–50%) depending on variety. Pre- and posthumulone are minor constituents.
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. Although humulones in themselves are not particularly bitter and are poorly soluble, they are converted into the bitter-tasting and more soluble isohumulones by an isomerization reaction that occurs during the process of boiling wort in the brew.
The rate of isomerization of alpha acids to iso-alpha acids (the compounds contributing bitter taste to beer) was determined across a range of temperatures (90–130°C) to characterize the rate at which iso-alpha acids are formed during kettle boiling. These "alpha acids" survive the boiling process, although numerous oxidized derivatives are produced. The iso-alpha acids are significantly more soluble than humulone at the pH levels typically present in the brewing process.
Beyond the iso-alpha acids (IAA) formed during brewing, several chemically reduced derivatives have been developed for research and supplemental use: rho iso-alpha-acids (RIAA) can be produced via sodium borohydride reduction of the C6 carbonyl of the iso-alpha-acids which are produced from the isomerization of humulone. Tetrahydro-iso-alpha acids (THIAA or "Tetra") represent another derivative class. Tetrahydro-iso-alpha acids commonly called THIAA or Tetra are modified hop acids extracted from hop (Humulus lupulus L.) which are frequently used in brewing industry mainly in order to provide beer bitterness and foam stability.
Humulus lupulus strobiles have a long traditional medicinal use in Europe, in the form of herbal tea, infusions, powdered herbal substance, or alcoholic extracts for the relief of insomnia, excitability, and specifically for restlessness associated with nervous tension, headache, and/or indigestion. The dried strobiles, extracts, and tinctures are used medicinally, and hops are also available in many other forms including beverages, tablets, capsules, creams, and gels. In the supplement industry, alpha acid-enriched fractions and isomerized hop extracts (standardized for iso-alpha acid content, expressed as a percentage) are the most common forms used in clinical investigations.
Humulus lupulus L., commonly known as hops, has been employed as a medicinal plant, with a history of use dating back to Roman times. Before the use in the brewing industry, hops were traditionally applied for medicinal purposes, mainly for the treatment of sleeping disorders, for activation of gastric functions and as stomachic, antibacterial, and antifungal remedies.
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 (Fluckiger and Hanbury, 1879; Maisch, 1892; Schleif and Galludet, 1907; Greenish, 1909; Culbreth, 1927; Gathercoal and Wirth, 1936) as well as in modern textbooks of Phytotherapy.
Beyond its role in brewing, hop has long been employed in traditional medicine to relieve a variety of ailments, especially insomnia, excitability, and restlessness associated with nervous tension. Additionally, hop has been used to manage headaches and digestive complaints, making it a multifaceted remedy in folk medicine. The German Commission E approved use of hops for mood disturbances such as restlessness and anxiety as well as sleep disturbances.
Hops have long been used as a sedative and sleeping aid in drinks. In addition, soft pillows filled with hops have been popular. Originally, they were heated and lasted for about three days before being replaced. This "hop pillow" preparation was particularly widespread in European folk medicine.
By the end of the 1800s, hops were commonly used in mainstream medicine in the United States to treat insomnia and as a bitter to aid digestive upset. In the early 1900s, eclectic physicians in the United States are reported to have used hops as a hypnotic specifically for insomnia because of worry or nerve weakness. In North America, several Native American tribes independently discovered the medicinal properties of Humulus for indigestion, as a sedative and sleep aid, and to relieve toothache.
Buds or hops of Humulus lupulus are used in Iranian ethnomedicine as a sedative. Other ethnobotanical examples include treatments against leprosy, toothache, fever, gastric problems, and anxiety, and use as preservative, deodorant, and cattle fodder.
Traditional digestion-related uses were prominent. Soothing the stomach and promoting healthy digestion have been among the strongest historical uses of this herb. Hops tea was also recommended by herbalists as a mild sedative and remedy for insomnia, particularly for those with insomnia resulting from an upset stomach. A pillow filled with hops was sometimes used to encourage sleep.
Hop-derived chalcones (xanthohumol), prenylflavonoids (isoxanthohumol, 8-prenylnaringenin), and (iso-) α- and β-bitter acids ((iso-)humulone and (iso-)lupulone) are among the bioactive compounds accounting for various modes of action in the prevention or potential treatment of many (lifestyle) diseases. Among these, the alpha acids and their isomerized and reduced derivatives have attracted the most systematic pharmacological attention.
It was found that the sedating activity of Humulus could be attributed to the bitter alpha and beta acids and its essential oil. The most active of three groups of constituents were the alpha acids; however, the beta acids and the essential oil clearly contributed to the sedating activity of lipophilic H. lupulus extracts.
The iso-alpha acids — primarily isohumulone, isocohumulone, and isoadhumulone — are the biologically most extensively investigated derivatives. The most common iso-α-acids are cis- and trans-isohumulone. The main bittering component in beer, hop iso-α-acids, have been characterised as weak acids, which act as ionophores impairing microbial cells' function under acidic conditions as present in beer.
Isomerised bitter acids (isoadhumulone, isocohumulone, and isohumulone) from hops, used in the brewing process of beer, are known to inhibit members of the aldo-keto-reductase superfamily. Aldo-keto-reductase 1B10 (AKR1B10) is upregulated in various types of cancer and has been reported to promote carcinogenesis. Inhibition of AKR1B10 appears to be an attractive means to specifically treat RAS-dependent malignancies.
Further chemical reduction of iso-alpha acids gives rise to the rho iso-alpha acids (RIAA) and tetrahydro iso-alpha acids (THIAA), both of which have been investigated specifically for anti-inflammatory and metabolic applications. These derivatives retain the core ring structure but with modified carbonyl or side-chain functionality, which alters their biological activity profile relative to the parent alpha acids and iso-alpha acids.
All three studied classes of hop bitter acids (alpha acids, beta acids, and iso-alpha acids) blocked the tumor necrosis factor alpha (TNF)-induced production of the cytokine IL-6, and inhibited the transactivation of the pro-inflammatory transcription factors nuclear factor kappa B (NF-κB), activator protein-1 (AP-1), and cAMP-response element-binding protein (CREB). In this respect, the six-membered ring compounds (alpha acids and beta acids) showed equal potency, whereas the five-membered ring iso-alpha acids were effective only when used at higher concentrations.
It has been previously demonstrated that tetrahydro iso-alpha acid compounds inhibit LPS-stimulated PGE2, TNF-α, IL-6, nitric oxide and COX-2 abundance, as well as the NF-κB pathway. RIAA selectively inhibited the NF-κB pathway while having no effect on ERK1/2, p38, and JNK phosphorylation in LPS-stimulated RAW 264.7 cells. RIAA also inhibited GSK-3α/β kinase activity and GSK-3β-dependent phosphorylation of β-catenin in RAW 264.7 cells.
It was recently reported that isohumulones activated peroxisome proliferator-activated receptors (PPARs) α and γ in vitro and modulated glucose and lipid metabolism in vivo. It has been proposed that hops iso-alpha acids increase liver fatty acid oxidation and normalize adipocyte hypertrophy via the co-activation of PPARα and PPARγ.
In C57BL/6N male mice, isomerized hop extract (IHE) primarily containing isohumulones increased liver weight and reduced plasma triglyceride and free fatty acid levels. Microarray analysis showed that IHE dose-dependently upregulated the expression of hepatic genes involved in microsomal ω-oxidation and peroxisomal and mitochondrial β-oxidation. These effects were common in both genders and very similar to those found with the PPARα agonist, fenofibrate. Moreover, these effects were not found in PPARα-deficient mice.
Humulone is under basic research with in vitro studies to determine if it has biological properties, such as possible GABAA receptor activity or antibacterial effects. Extracts of the bitter alpha-acids present in H. lupulus have been shown to decrease nocturnal activity, acting as a sleep aid, in certain concentrations.
When addressing the molecular mechanisms underlying the antibacterial effects of hop, researchers hypothesized that the bacterial cell membrane was the main target of the biologically active ingredients. Lupulone and humulone were shown to interfere with the phosphoenolpyruvate (PEP) system of Gram-positive bacteria. In the context of beer preservation, the hop iso-α-acids have been characterised as weak acids, which act as ionophores impairing microbial cells' function under acidic conditions.
Because hop extracts are used as flavoring agents for their bitter properties, it has been hypothesized that bitter taste receptors (Tas2rs) could be mediating their beneficial effects in metabolic disease. Studies have shown that exposure of cultured enteroendocrine cells to bitter tastants can stimulate release of hormones, including glucagon-like peptide 1 (GLP-1). These findings have led to the suggestion that activation of Tas2rs may be of benefit in diabetes. Alpha acids, in particular cohumulone, are among the most potent activators of Tas2R signalling in intestinal enteroendocrine cells.
Isomerised bitter acids (isoadhumulone, isocohumulone and isohumulone) from hops are known to inhibit members of the aldo-keto-reductase superfamily. Aldo-keto-reductase 1B10 (AKR1B10) is upregulated in various types of cancer and has been reported to promote carcinogenesis. Inhibition of AKR1B10 appears to be an attractive means to specifically treat RAS-dependent malignancies.
Iso-α-acids have been found to activate peroxisome-proliferator-activated receptor-γ (PPAR-γ), a known therapeutic target in Alzheimer's disease (AD), highlighting a possible role of these compounds on the pathogenesis of AD.
This is arguably the area with the most systematic accumulation of evidence spanning cell studies, animal models, and human trials.
Preclinical evidence: Diabetic KK-Ay mice treated with isohumulones (isohumulone and isocohumulone) showed reduced plasma glucose, triglyceride, and free fatty acid levels (65.3, 62.6, and 73.1%, respectively, for isohumulone); similar reductions were found following treatment with the thiazolidinedione drug, pioglitazone. Isohumulone treatment did not result in significant body weight gain, although pioglitazone treatment did increase body weight (10.6% increase versus control group). C57BL/6N mice fed a high-fat diet and treated with isohumulones showed improved glucose tolerance and reduced insulin resistance. Furthermore, these animals showed increased liver fatty acid oxidation and a decrease in size and an increase in apoptosis of their hypertrophic adipocytes.
The absence of insulin resistance in HFD-META060 (tetrahydro iso-alpha acid) mice compared to high-fat diet mice that developed marked insulin resistance strongly suggests that tetrahydro iso-alpha acids exert beneficial effects on plasma glucose, inflammation, and insulin resistance independently of body weight loss or lower body fat accumulation.
Human clinical evidence: A double-blind, placebo-controlled pilot study for studying the effect of isohumulones on diabetes suggested that isohumulones significantly decreased blood glucose and hemoglobin A1c levels after 8 weeks (by 10.1 and 6.4%, respectively, versus week 0).
In a follow-up study with 94 subjects, ingestion of isohumulones (isomerized hop extract) had beneficial effects in diabetes and obesity. Volunteers with prediabetes received either placebo, 16 mg, 32 mg, or 48 mg of isohumulones for 12 weeks. After treatment, fasting blood glucose was decreased in the 32 mg and 48 mg groups after 4 weeks but did not change in the placebo group. HbA1c was also significantly decreased after 4 weeks in the 16 mg group and after 8 weeks in the 32 mg and 48 mg groups.
The low number of clinical trials with low risk of bias is due to the lack of trials including a large number of subjects. The overall human evidence in this domain is therefore preliminary and promising but not yet definitive. Most trials are small and short-term.
Combining hop acids and selective agonists for GRα, PPARα, or PPARγ resulted in additive inhibition of NF-κB activity after TNF treatment, which may open up new avenues for combinatorial anti-inflammatory strategies with fewer side effects. Furthermore, systemic administration of hop bitter acids efficiently inhibited acute local inflammation in vivo.
Clinically, RIAA (1000 mg/day) produced a 54% reduction in WOMAC Global scores in a 6-week, open-label trial of human subjects exhibiting knee osteoarthritis. This result, while encouraging, comes from an open-label (unblinded) trial design, which is an important limitation when assessing efficacy.
The inhibitory effect of RIAA on inflammatory markers was assessed by measuring nitric oxide in LPS-stimulated macrophages, RANKL-mediated TRAP activity in transformed osteoclasts, and TNF-α/IL-1β-mediated MMP-13 expression in SW1353 cells. Mice with collagen-induced arthritis were fed RIAA for 2 weeks, and symptoms of joint swelling, arthritic index, and joint damage were assessed. The in vitro and animal data in this area are compelling, but robust randomized controlled human trials specifically targeting alpha acid fractions for inflammatory joint disease are limited.
The most active of three groups of constituents were the alpha acids; however, the beta acids and the essential oil clearly contributed to the sedating activity of lipophilic H. lupulus extracts. In experimental models, spontaneous locomotor activity was reduced, ketamine-induced sleeping time was increased, and body temperature was reduced. These actions indicate a sedating effect on the CNS; however, anxiolytic activity was not always observed.
A randomized, placebo-controlled, double-blind crossover study used two 4-week intervention periods (Humulus or placebo; two 0.2-g capsules once daily) separated by a 2-week interval period. Anthropometric measurements, assessments, and morning cortisol plasma levels were performed at the beginning and the end of the 4-week treatment periods. The authors found no changes in morning cortisol, but they did find significant decreases in anxiety, depression, and stress scores with Humulus compared with placebo.
Hops is frequently investigated in combination with valerian rather than as a standalone alpha acid intervention. The German Commission E and ESCOP monographs endorse use of hop strobiles — which contain alpha acids — for sleep disturbance, most commonly in combination preparations. The German Commission E Monographs advised to use the plant in the treatment of "discomforts during restlessness or anxiety and sleep disturbances." The evidence for isolated alpha acids in human sleep trials is much thinner than for whole-hop or hop-valerian preparations.
Cermak et al. (2017) tested the antimicrobial activity of purified hop constituents humulone, lupulone, and xanthohumol (XN) against anaerobic bacteria of indigenous human flora including Bacteroides fragilis, Clostridium perfringens, and Clostridium difficile. Results demonstrated that XN 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 XN, underlining a synergistic effect when used in combination with antibiotic drugs, not only on Gram-positive but also on Gram-negative bacteria. The reviewed studies revealed that lupulone and xanthohumol do in fact inhibit the growth of Gram-positive bacteria in vitro. Critically, all antimicrobial evidence to date for alpha acids specifically is in vitro or preclinical; no clinical human trials evaluating alpha acids for infectious disease treatment have been identified in the peer-reviewed literature.
Several in vivo/vitro studies and human interventional trials have demonstrated the beneficial effects of iso-α-acids on weight gain, lipid metabolism, glucose homeostasis, insulin sensitivities, and inflammation by acting on different targets. All these activities suggest a possible role of bitter hop acid in preventing metabolic syndrome and its related diseases.
Isohumulones have been shown to activate PPARα pathways that upregulate hepatic fatty acid oxidation genes in rodent models. Subjects with elevated LDL cholesterol and metabolic syndrome have been reported to benefit from supplementation with soy protein, phytosterols, hops rho iso-alpha acids, and Acacia nilotica proanthocyanidins. This study used a combination product, making it difficult to attribute lipid-lowering effects specifically to the alpha acid fraction.
Secondary plant compounds derived from hops such as xanthohumol or iso-α-acids may have beneficial effects on the development of liver diseases of various etiologies. In the specific mouse study examining alcohol-induced liver damage, female C57Bl/6J mice pretreated for 4 days with an iso-α-acid-rich extract (~30% iso-α-acids from hops, 0.75 mg/kg body weight), were fed one bolus of ethanol or an iso-caloric maltodextrin solution. Iso-α-acids markedly attenuated the development of acute alcohol-induced damage in mice. This constitutes animal-only evidence; no controlled human trial on alpha acids and liver disease has been verified in the peer-reviewed literature.
In recent years hop has been subject to research on numerous medical applications particularly due to its inhibitory effects on bone resorption. Hop rho iso-alpha acids, berberine, vitamin D3, and vitamin K1 were reported to favorably impact biomarkers of bone turnover in postmenopausal women in a 14-week trial. This, again, was a combination product study; isolating the specific contribution of alpha acids to bone-turnover effects is not possible from this design.
Hop has been subject to research on disease-alleviating effects in neurobiological diseases such as Alzheimer's disease. Iso-α-acids have been found to activate PPAR-γ, a known therapeutic target in Alzheimer's disease, highlighting a possible role of these compounds on the pathogenesis of AD. This area remains at the preclinical and mechanistic stage; there are no published human clinical trials specifically testing alpha acids for Alzheimer's disease.
AKR1B10 is upregulated in various types of cancer and has been reported to promote carcinogenesis. Inhibition of AKR1B10 appears to be an attractive means to specifically treat RAS-dependent malignancies. The humulone analogues n-humulone, adhumulone, and cohumulone were found to selectively inhibit AKR1B10 in in vitro assays. All cancer-related evidence for alpha acids from hops remains preclinical (cell line and animal studies); no clinical oncology trials have been identified.
Administration of hop-derived extracts has been shown to reduce body weight and fat mass and improve glucose homeostasis in rodent models. A clinical trial published in the American Journal of Clinical Nutrition studied whether an extract of hops modulates gut peptide hormone secretion and energy intake in healthy-weight men, using a randomized crossover design. The findings indicated that intraduodenal hop extract administration affected upper gut motility and hormone secretion, with preliminary signals of reduced energy intake, though evidence remains early-stage.
The following dosages are cited directly as reported in the identified sources. They do not represent recommendations and should be understood strictly as research parameters.
As a historical food constituent, hops has "generally recognized as safe" (GRAS) status by the FDA; however, use of medicinal quantities of hops may pose more risk than common levels of exposure in food use.
Toxicity was assessed in a 21-day oral, mouse subchronic toxicity study where no dose-dependent histopathological effects were noted. A subchronic toxicity study of the hops alpha-acids was conducted in dogs; while high doses induced vomiting, the animals generally tolerated the compound. The LD50 for orally administered hop extract or lupulones in mice is approximately 500 to 3,500 mg/kg.
Dogs appear to be somewhat sensitive to hops compounds. A malignant hyperthermic reaction was observed in 5 dogs who consumed boiled hops residues used in home brewing.
Drug interaction potential was evaluated against six major CYPs; of relevance, RIAA inhibited CYP2C9. CYP2C9 is involved in the metabolism of numerous drugs including warfarin, certain NSAIDs, and several antidiabetic agents. This finding is pharmacologically significant and warrants attention in research settings.
Cardiovascular safety was addressed by PGI-M measurements where RIAA (1000 mg) did not reduce PGI-M or affect the urinary PGI-M/TXB2 ratio. This suggests that, unlike conventional NSAIDs, RIAA at this dose did not appear to suppress prostacyclin-mediated cardiovascular protection in the studied subjects.
Gastrointestinal safety was assessed using the fecal calprotectin biomarker in a 14-day human clinical study; RIAA (900 mg/day) produced no change compared to naproxen (1000 mg/day), which increased fecal calprotectin 200%. Fecal calprotectin is a marker of intestinal inflammation; this finding suggests a more favorable GI safety profile for RIAA relative to naproxen in the short term.
Risks bias assessment, based on a checklist adapted from the Cochrane Handbook for Systematic Reviews of Interventions, identified that the low number of clinical trials with low risk of bias is due to the lack of trials including a large number of subjects. Several in vivo/vitro studies and human interventional trials have demonstrated the beneficial effects of these molecules on weight gain, lipid metabolism, glucose homeostasis, insulin sensitivities, and inflammation by acting on different targets. All these activities suggest a possible role of bitter hop acid in preventing metabolic syndrome and its related diseases. However, most human trials are small, short in duration, and sometimes unblinded. Many significant findings come from animal models or in vitro systems, and their translation to human therapeutic use requires further confirmation through adequately powered randomized controlled trials.
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