Hops (Humulus lupulus): An Overview of Clinical Applications
Abstract
Hops (Humulus lupulus) has been used for millennia in the brewing of beer, imparting flavour and aroma to the beverage, as well as improving shelf life. Interest in hops as a medicine, however, did not gain momentum until the early 1800s. Modern investigation has revealed an array of constituents of interest, having impact across a broad number of important clinical indications. The prenylflavanoid xanthohumulol is a noted antioxidant and is receiving extensive preclinical interest as an anti-tumour agent. This molecule is capable of undergoing transformation by gut microbes giving rise to 8-prenylnaringenin, a powerful phytoestrogen heralded as delivering hops’ impact to symptoms of menopause. The bitter acids of hops are principally credited with delivering effects related to sedation. The paper introduces clinicians to a versatile medicine, showcasing human level evidence of hops across an array of clinical indications that includes sleep, menopause, weight loss, cognition, mental health, allergy, and overactive bladder.
Introduction
Hops (Humulus lupulus) has been used for millennia in the brewing of beer, imparting flavour and aroma to the beverage, as well as improving shelf life. It is a climbing vine belonging to the Cannabaceae family. It is believed to be native to Eurasia, yet has been grown as various cultivars globally for centuries. Hops is perennial, growing aggressively from the end of April until the beginning of July, reaching heights of seven to eight meters under favourable conditions. Only female hops plants are commercially cultivated, as presence of male hops will turn the prized flowers of the female plants into valueless nuts (American Botanical Counsel 2022).
While the use of hops to improve flavour and shelf life of beer has been around for millennia, there was very little historical interest in medicinal applications of the plant. Paracelsus (1493-1541) seems to be the first scholar to mention hops as a medicine, citing its use as a digestive aid. Use of hops flowers as a bitter and a calming agent was first noted by Hecker in 1814 (American Botanical Counsel 2022).
The past several decades have seen a keen interest in a wide array of potential clinical applications of hops, and a large number of hops constituents have received considerable attention. Estrogenic principles of hops, notably 8-prenylnaringenin (8-PN) (and to a lesser extent 6-PN) have been extensively reviewed. 8-PN is widely considered the most potent phytoestrogen in the plant world (Calvo-Castro et al 2018, Chadwick et al 2006, Stulikova et al 2018). Prenylflavanoids, notably xanthohumulol, also receive keen research interest as both an antioxidant compound (Zugravu et al 2022) and potential antitumour agent (Girisa et al 2021, Jiang et al 2018, Zugravu et al 2022). Of tremendous interest is the ability of gut microbes to convert xanthohumulol to 8-PN (Possemiers et al 2006). Alpha and beta acids are antioxidants and are largely recognized for the sedating effects of hops (Ayabe et al 2020, Benkherouf et al 2020, Min et al 2021).
Many of the bitter constituents of hops degrade fairly rapidly, and as such hops is typically stored under refrigeration. Fifty to 70% of hops’ bitter acids will degrade after only six months of storage (American Botanical Counsel 2022). An interesting observation among the various human trials of hops is that both fresh and matured, or oxidized, preparations are employed. Summaries of human trials below highlight whether the preparation is fresh or matured, when possible. It may be appropriate for a clinician to seek out both a fresh and matured version of the substance, depending which indication is principally sought from the intervention.
The objective of this review is to showcase human level evidence of clinical application of hops. Areas covered include sleep, menopause, weight loss, cognition, mental health, allergy, and overactive bladder.
Hops: Human Trials
A summary of human intervention trials utilizing hops can be found in Table 1. Of the 19 human trials presented, it should be noted that eight deliver hops in combination with other medicines. However, most of these trials (all but two) fall under the realm of hops as an agent to benefit sleep. Across all other indications, hops was principally used as a stand-alone ingredient.
Of the seven human trials reviewed for sleep, all but one (Franco et al 2012) examined hops in combination with other medicines. Most commonly, hops was combined with valerian. The one trial of hops as a stand-alone administered dealcoholized beer to female nurses working nightshift. While small, the trial was well controlled and showed significant positive impact using actigraphy as the principal endpoint measure (see Table 1) (Franco et al 2012). Another trial of note examining sleep compared valerian + hops to zolpidem showing improvement across both groups with no differences between groups (Maroo et al 2013). It is exciting to observe the gentle combination of valerian and hops achieving equivalent clinical outcome to a so called “Z-drug”.
Four trials are presented evaluating hops for the treatment of menopausal symptoms, three of which use hops as a stand-alone ingredient (Aghamiri et al 2016, Erkkola et al 2010, Heyerick et al 2006), while the fourth combines hops with soy (Kim et al 2021). The trials suffer from large positive placebo effects, yet some findings of significance are found favouring hops (see Table 1).
A very interesting pair of trials examines hops for weight loss and appetite suppression. Both trials use mature, or oxidized hops extracts, suggesting fresh versus mature preparations may be useful for different clinical applications. An RCT with 200 participants demonstrated reduced visceral fat and total fat area with CT used to confirm findings (Morimoto-Kobayashi et al 2016, Suzuki et al 2018). The second study found a significant impact on subjective reporting of hunger from participants following single administration of mature hops extract prior to a 24-hour fast (Walker et al 2019). See Table 1.
Two separate studies by the same research team demonstrated an important benefit of hops administration for various markers of cognition among healthy adults (Fukuda et al 2020A) and among adults with perceived subjective cognitive decline (Fukuda 2020B). Both studies used mature hops extracts. Two studies of hops are presented showing hops extract delivering significant benefit for mood, anxiety, and stress (Kyrou et al 2017, Ohara et al 2018). Also of interest is a trial showing impressive impact of a hops-containing beverage on allergic responses among individuals suffering from Japanese cedar pollinosis (Segawa et al 2007). Lastly, a large, well-controlled trial found impressive impact from a combination product containing hops on symptoms of overactive bladder, a condition notoriously difficult to treat (Gauruder-Burmester et al 2019). See Table 1.
Discussion
For a little over 15 years human trials have been evaluating hops for an array of clinical indications. Preclinical inquiry has demonstrated an unusually large number of molecules of interest, each with quite diverse targets in the human body. The most researched indication for hops, insomnia, typically evaluates hops in combination with other medicines, most commonly valerian. Quite reproducibly these combinations are proving successful in human study. The other areas of clinical inquiry are in need of further research, yet the available evidence certainly suggests use of hops for cognition, mental health, weight loss, and allergy is not without merit. Overactive bladder is notoriously difficult to treat, and the fact that a combination of natural medicines proved successful is encouraging. The combination included Uromedic pumpkin seed oil, Rhus aromatica bark extract, and Humulus lupulus cone extract. Reproduction of the study by Gauruder-Burmester and colleagues (2019) would be very welcomed.
None of the studies reviewed reported safety concerns of significance. An evaluation of herb-drug interaction administered a standardized hops extract to 16 peri- and postmenopausal women for two weeks, then challenged with a validated four-drug probe including tolbutamide, caffeine, dextromethorphan, and alprazolam. The paper found no significant impact of hops on several key P450 enzymes (CYP2C9, CYP1A2, CYP2D6, CYP3A4, and CYP3A5) (van Breemen et al 2020). Some animal evidence has demonstrated that hops can increase prolactin. A human trial gave a slow-cooked hops soup to men and women. The soup had no impact on prolactin in either group (Drugs and Lactation Database 2021).
Table 1. Human Intervention Trials of Hops
| Methods | Outcomes | Reference |
| Sleep | ||
| RCT in 101 participants with primary insomnia assigned to two capsules of olive oil (placebo) or two capsules of Cyclamax™ (260mg soya oil, 173mg Cade oil, 50mg Houblon (Humulus lupulus extract), and 6mg soya lecithin) two hours prior to bed for one month. Endpoint measures included LSEQ questionnaire, pre and post intervention actigraphic movement measurement, and urinary melatonin output. | Large positive impact to sleep quality, and modest improvement as measured by actigraphy, with no impact on urinary melatonin. However, the placebo group improved to a similar magnitude as the group receiving active treatment, and therefore there was no impact of the intervention relative to placebo. | Cornu et al 2010 |
| Female nurses (N=17) working nights or rotating shifts assigned to receive 333ml 0% alcohol beer with dinner for 14 days. Participants served as their own controls. Actigraphy pre and post intervention served as the primary endpoint measure. | Actigraphy demonstrated significant improvements for parameters of sleep latency and total activity during sleep, relative to baseline. | Franco et al 2012 |
| RCT in 91 participants with primary insomnia randomized to 10mg zolpidem or NSF-3™ (300mg valerian extract, 80mg passionflower extract, and 30mg hops extract) for two weeks. Assessments occurred at baseline, seven days, and upon study completion. ISI and ESSS served as main endpoint measures. | Both groups demonstrated significant improvement across many parameters of the ISI, notably total sleep time, sleep latency, number of nightly awakenings, and total ISI. ESSS was not significantly altered in either group. Differences between groups were not significant. Adverse events were reported 12 and 16 times with NSF-3™ and zolpidem, respectively, limited to concerns of drowsiness. | Maroo et al 2013 |
| RCT in 171 participants randomized to placebo or Lactium™ (75mg per tablet, delivering 4.5g equivalent Zizyphus, 500mg equivalent Humulus, 52.5mg elemental magnesium as oxide, and 8.23mg vitamin B6) for two weeks. Primary outcome measure was sleep quality as assessed using the PSQI. Secondary outcomes included assessment of mood and anxiety, cognition, and stress reactivity. | PSQI improved significantly in both groups, with no between-group differences. Likewise, mood, anxiety, and stress improved significantly in both groups, with no between-group differences. | Scholey et al 2017 |
| Patients (N=44) were administered 2ml of tincture (1:10 extract valerian + 1:12 extract hops in 61% ethanol) or placebo for two consecutive nights at a sleep clinic. Electrohypnography served as the principal endpoint measure. | The intervention significantly increased depth of sleep as well as total sleep time. | Dimpfel and Suter 2008 |
| Patients were administered 500mg of valerian extract, valerian + 120mg hops extract, or placebo. Principle outcome measure was sleep latency. | Valerian + hops, yet not valerian alone, significantly reduced sleep latency. | Koetter et al 2007 |
| Multicentre trial among 184 participants assigned to valerian-hops combination (187mg valerian extract + 41.9mg hops extract), or 25mg diphenhydramine or placebo for 28 days. Patient diaries, quality of life questionnaires, and polysomnography served as endpoint measures. | Individuals in the valerian-hops group, as well as the diphenhydramine group both experienced significant improvement in patient-rated insomnia score. Quality of life scores were also significantly improved in the valerian-hops group. However, other measures of patient satisfaction, sleep latency, and polysomnography all failed to show outcomes of statistical significance. | Morin et al 2005 |
| Menopause | ||
| RCT of dried hops (flowering part) at 500mg per day versus placebo to 120 women for 12 weeks. Greene scale and number of hot flashes served as main endpoint measures. | The Greene scale significantly improved and the number of hot flashes was significantly reduced among participants receiving hops. | Aghamiri et al 2016 |
| RCT of 67 menopausal women receiving placebo, or hops extract containing 100mcg or 250mcg of 8-prenylnaringenin. KI and patient questionnaire served as main endpoint measures. | All three groups achieved significant improvements in KI and subjective symptom reporting. The 100mcg per day dose performed superior to placebo at six weeks, yet not at 12 weeks. | Heyerick et al 2006 |
| A soy and hops extract combination versus placebo was administered to 78 women experiencing menopausal symptoms for 12 weeks. KI (baseline greater than 20) served as the principal endpoint measure. | KI decreased a mean 20.61 points in the treatment group versus 14.80 in the placebo group (p<0.05). The treatment group also reported significant improvement relative to placebo in fatigue, paresthesia, arthralgia and myalgia, palpitation and vaginal dryness. | Kim et al 2021 |
| A 16-week crossover trial in 36 women assigned to receive hops (75mg extract containing 100mg of 8-PN) or placebo for eight weeks. Subjects were then crossed over to receive the opposite treatment for the remaining eight weeks. KI and MRS served as principal endpoint measures. | At eight weeks, both hops and placebo significantly improved KI and MRS. After crossover, patients initially on hops now on placebo saw worsening of symptoms, whereas patients initially on placebo now on hops showed further improvements. By week 16, KI and MRS were significantly improved I the hops group relative to placebo group. | Erkkola et al 2010 |
| Weight Loss | ||
| RCT in 200 participants with BMI 25-30 randomized to placebo beverage or 350ml of test beverage containing mature hops extract providing 35mg of mature hop bitter acids for 12 weeks. CT of the abdomen served as the primary endpoint measure. | Significant reductions in visceral fat area were observed in the active group by week eight and remained significant at week 12. Total fat area was significantly reduced in the active group at week 12. | Morimoto-Kobayashi et al 2016 and Suzuki et al 2018 |
| Adult men (N=30) were participating in a 24 hour fast (6pm-6pm) one day per week for three weeks. Amarasate™, a bitter hops-based appetite suppressant was given at 500mg, 200mg, or placebo. Intervention was administered in divided doses 16 and 20 hours into each fast period. Visual analogue scales validated for subjective assessment of appetite served as the main endpoint measure. | Both doses of bitter hops extract produced significant reductions in hunger (>10%) relative to placebo. At no timepoint were outcomes different between the two doses of extract. | Walker et al 2019 |
| Cognition | ||
| MHBE 35mg per day versus placebo administered for 12 weeks to 60 healthy adults ages 45-64. A battery of neuropsychological questionnaires was conducted at six and 12 weeks. | MHBE significantly improved verbal fluency, subjective fatigue and anxiety. MHBE significantly reduced the Stroop test score. | Fukuda et al 2020A |
| Subjects (N=100) ages 45-69 with perceived subjective cognitive decline randomized to placebo or 35mg per day of MHBE for 12 weeks. A battery of eight validated scales were employed evaluating cognition, attention, stress and mood. Salivary assessment of B-endorphin, cortisol, chromogranin A and a-amylase was also performed. | SDMT and memory retrieval significantly improved in the group receiving MHBE. Salivary B-endorphin was significantly reduced in the group receiving MHBE. The authors conclude “MHBA improves cognitive function, attention, and mood state in older adults”. | Fukuda et al 2020B |
| Mental Health | ||
| Otherwise-healthy university students were screened using the DASS-21. Those with mild depression, anxiety and stress were enrolled. Crossover trial of four weeks each with a two-week washout. Hops dry extract at 400mg per day vs placebo. | DASS-21 significantly improved for mood, anxiety, and stress during treatment with hops versus placebo. | Kyrou et al 2017 |
| Thirty minutes prior to an intentionally administered stress test (TSST), subjects consumed a test beverage containing 950ng of B-Eudesmol (an oxygenated sesquiterpene shown to affect autonomic nerve activity in animal models) or placebo beverage. Salivary 3-methoxy-4-hydroxyphenylglycol (MHPG) following the TSST served as the main endpoint measure (MHPG is a major breakdown product of noradrenaline) | Following the TSST, participants consuming the test beverage had significantly lower levels of MHPG relative to participants consuming the placebo beverage. | Ohara et al 2018 |
| Allergy | ||
| A beverage containing 100mg of hops water extract was administered versus a placebo beverage daily for 12 weeks during Japanese cedar pollinosis season to 39 participants. Symptom diary, blood sampling, and physical exam served as endpoint measures. | Participants receiving the hops water extract reported significantly fewer symptoms and reduced medication use. Physical exam demonstrated the hops group to have less nasal swelling, nasal discharge, and improved nasal colour and characteristics of nasal discharge. Eosinophil infiltration into nasal discharge was absent from hops-treated participants yet present in participants receiving the placebo beverage. | Segawa et al 2007 |
| Overactive Bladder | ||
| Open trial of Granu Fink femina (combination of Uromedic pumpkin seed oil, Rhus aromatica bark extract, and Humulus lupulus cone extract) administered to 117 women experiencing overactive bladder for 12 weeks. Symptom diary and quality of life questionnaires served as endpoint measures. | After 12 weeks of treatment, daytime urinary frequency significantly improved in 77/99 participants. Nighttime urinary frequency improved in 70/100 participants. Frequency of leakages and used pads significantly decreased from 0.9 and 2.0, respectively, at baseline to 0.4 and 1.4 respectively after 12 weeks of treatment. | Gauruder-Burmester et al 2019 |
Abbreviations
8-PN = 8-prenylnaringenin
DASS-21 = Depression anxiety stress scale-21
ESSS = Epworth sleepiness scale score
ISI = Insomnia severity index
KI = Kupperman Index
LSEQ = Leeds questionnaire evaluation sleep
MHBE = Matured hops bitter extract
MRS = Menopause rating scale
PSQI = Pittsburgh sleep quality index
RCT = Randomized controlled trial
SDMT = Symbol digit modalities test
STAI = State-trait anxiety inventory
TSST = Trier social stress test
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