The plant of Humulus lupulus L. is well-known throughout the world as the raw material in the brewing industry. The female inflorescences (hop cones or “hops”), rich in polyphenolic compounds and acyl phloroglucides are widely used to preserve beer and to give it a characteristic aroma and flavour. In addition hop cones have long been used for medicinal purposes. In particular, hop preparations were mainly recommended for the treatment of sleeping disorders, as a mild sedative, and for the activation of gastric function as bitter stomachic.
Starting from the second half of the 20th century, several phytochemical studies were performed to investigate the composition of hop cones and other parts of the plant, leading to the isolation and identification of pharmacologically relevant compounds such as flavanones, chalcones, phloroglucinol derivatives. During the past decade, many pharmacological investigations in vitro and in vivo tried to produce scientific evidence of the reported traditional uses.
Humulus lupulus was first mentioned by the naturalist Pliny the Elder (23–79 A.D.) who described the use of the young shoots as a vegetable by the Romans (1). It has been mainly recommended as a mild sedative useful to treat sleeplessness and nervousness (2). Traditionally hops were used to treat excitability and restlessness associated to tension headache; to improve appetite and digestion; to relieve toothache, earache and neuralgia (1,3). In addition hops have been reputed to exert diuretic, antispasmodic and anaphrodisiac effects (2,4). Native American tribes used hops as a sedative, antirheumatic, analgesic and as a urinary aid for “gravel” and inflammation (2,5,6). Also they used heated hops as a poultice in the treatment of pneumonia (8) and a decoction of hops was recommended for intestinal pain and fevers in Dakota (6). In India, the Ayurvedic Pharmacopoeia recommends hops to treat restlessness associated with nervous tension, headache and indigestion (7). In traditional Chinese medicine hops are used to treat insomnia, restlessness, dyspepsia and lack of appetite.
The Committee on Herbal Medicinal Products (HMPC) of the European Medicines Agency (8) report the traditional use of Humulus lupulus for relief of mild symptoms of mental stress and insomnia. The German Commission E and European Scientific Cooperative on Phytotherapy (9) approved hops as a treatment for excitability, mood disturbances (restlessness, anxiety) and sleep disturbances.
Sedative activity
The traditional use of hops as a mild sedative stems from the observation of sleepiness and fatigue in the hop-pickers, apparently due to the transfer of hop resin from their hands to their mouths (10). The German Commission E approved hops for the treatment of “mood disturbances, such as restlessness and anxiety, sleep disturbances” (2). The first investigation carried out in rodents was published by Hansel and Wagener (11).
The tranquilizing property of different extracts of Humulus lupulus, intraperitoneally was investigated by Bravo et al. (12). The authors observed a reduction in spontaneous motor activity. The neuropharmacological effect of an undefined hop extract was evaluated by Lee et al. (13): hypothermic, analgesic and anticonvulsant activities were observed. In addition sedative and hypnotic properties were ascribed to the hop extract following the observation of a dose-dependent reduction in spontaneous locomotor activity and a dose-dependent increase in pentobarbital-induced sleeping time.
Hansel et al. (14,15) attributed the sedative effect of hops to 2-methyl-3-butene-2-ol. In later investigations into the neuropharmacological activity of Humulus lupulus a CO2 hop extract (16,17) exerted a pentobarbital sleep-enhancing effect in a dose-dependent manner and also suggested an antidepressant-like activity.
Hypnotic components
A further study describing the sedative property of Humulus lupulus has been recently published by Schiller et al. (18). A recent study showed that myrcenol, which is produced during boiling hops, was able to prolong pentobarbital induced sleeping time in a preclinical model and to potentiate GABAa receptor response in vitro (19). Myrcenol could represent a positive modulator of GABAa receptor response as a component of beer.
In spite of these recent studies, the identity of the active sedative principle/s of hops as well the mechanism/s of action is still questionable A study aimed to clarify the interaction of sedative herbs with selected central nervous system receptors demonstrated the capacity of a hop dried extract to bind serotoninergic 5-HT6 receptors as well as melatoninergic ML1 receptors (20). The involvement of 5-HT receptors in depression and sleep disturbances has been demonstrated (21) and the role of melatonin in the regulation of circadian rhythm is well-known (22).
A number of clinical investigations on the efficacy of hops in sleep disturbances have been performed using preparations containing a combination of hops and other sedative herbs, particularly valerian. A randomized, double-blind, controlled trial in patients suffering from sleep disorders showed equivalent efficacy and tolerability between a hop–valerian preparation and a benzodiazepine drug (23). Sleep quality was determined by psychometric tests, psychopathologic scales and sleep questionnaires. This study pointed out that the hop–valerian treatment for 2 weeks did not elicit the withdrawal symptoms, normally occurring with the benzodiazepine therapy.
The pharmacodynamic effects of a commercially available mixture of valerian and hops were studied in young adult patients using quantitative topographical electroencephalography (24). A clear effect at the central nervous system level was observed 4 h after the intake of the mixture.
A multicentre, randomized and placebo-controlled study was performed in 184 patients with mild insomnia, nightly administered for 28 days with a combination of standardized extracts of hops and valerian (25). Sleep parameters were measured by daily diaries and polysomnographic assays. The combination hops and valerian showed a modest hypnotic effect, improving sleep without producing significant residual effects and rebound insomnia.
The lack of residual sedative effects was previously stressed by Gerhard et al. (26) in healthy volunteers, receiving a hop–valerian combination or flunitrazepam, used as reference drug. The objective measurement of cognitive psychomotor performance and the subjective questionnaries on well-being led to emphasize the impairment of vigilance in the morning after the ingestion of the benzodiazepine drug, while more alertness and activity were observed in patients treated with the herbal remedy. A herbal preparation, containing lavender oil, lemon balm and oat extracts besides hops, exhibited a relaxing effect, documented by electroencephalographic analysis, in healthy volunteers (27).
References
1. Grieve, M., 1971. A Modern Herbal. Dover Publications, Inc., New York.
2. Blumenthal, M., 1998. The Complete German Commission E Monograph: Therapeutic Guide to Herbal Medicines. American Botanical Council, Austin,TX, p. 147.
3. Barnes, J., Anderson, L., Phillipson, J. (Eds.), 2002. Herbal Medicines: A Guide for Health Care Professionals. Pharmaceutical Press, London.
4. Weiss, R.F., 1988. Herbal Medicine. Ab Arcanum, Gothenburg, Sweden, pp. 285–286.
5. Hamel, P.B., Chiltoskey, M.U., 1975. Cherokee Plants and Their Uses. A 400-years History. Herald Publishing Co., Sylva, NC.
6. Bown, D., 2001. The Herb Society of America New Encyclopedia of Herbs and Their Uses. Dorling Kindersley Ltd., London.
7. Karnick, C.R., 1994. Pharmacopoeial Standards of Herbal Plants, vol.12. Sri Satguru Publications, Delhi, vol. 1, pp. 183–184, vol. 2, p. 67.
8. EMEA 2007 http://www.emea.europa.eu/pdfs/human/hmpc/humulus lupulus/flos/51361706en.pdf.
9. European Scientific Cooperative on Phytotherapy, 2003. ESCOP Monographs: “Lupuli flos”. The Scientific Foundation for Herbal Medicinal Products, 2nd ed. Thieme Verlag, New York
10. Tyler, V.E., 1987. The New Honest Herbal. A Sensible Guide to Herbs and Related Remedies, 2nd ed. Stickley Co., Philadelphia, pp. 125–126.
11. Hansel, R., Wagener, H.H., 1967. Attempts to identify sedative-hypnotic active substances in hops. Arzeneimittel-Forshung/Drug Research 17, 79–81.
12. Bravo, L., Cabo, J., Fraile, A., Jimenez, J., Villar, A., 1974. Estudio farmacodinamico del lupulo (Humulus lupulus L.). Accion tranquilizante. Bollettino Chimico Farmaceutico 113, 310–315.
13. Lee, K.M., Jung, J.S., Song, D.K., Kr¨auter, M., Kim, Y.H., 1993. Effects of Humulus lupulus extract on the central nervous system in mice. Planta Medica 59, A691.
14. Hansel, R., Wohlfart, R., Coper, H., 1980. Sedative-hypnotic compounds in the exhalation of hops, II. Zeitschrift Fur Naturforschung 35, 1096–1097.
15. Hansel, R., Wohlfart, R., Schmidt, H., 1982. The sedativ-hypnotic principle of hops. 3. Communication: contents of 2-methyl-3-butene-2-ol in hops and hop preparations. Planta Medica 45, 224–228.
16. Zanoli, P., Rivasi, M., Zavatti, M., Brusiani, F., Baraldi, M., 2005. New insight in the neuropharmacological activity of Humulus lupulus L. Journal of Ethnopharmacology 102, 102–106.
17. Zanoli, P., Zavatti, M., Rivasi, M., Brusiani, F., Losi, G., Puia, G., Avallone, R., Baraldi, M., 2007. Evidence that the _-acids fraction of hops reduces central GABAergic neurotransmission. Journal of Ethnopharmacology 109, 87–92.
18. Schiller, H., Forster, A., Vonhoff, C., Hegger, M., Biller, A., Winterhoff, H., 2006. Sedating effects of Humulus lupulus L. extracts. Phytomedicine 13, 535–541.
19. Aoshima, H., Takeda, K., Okita, Y., Hossain, S.J., Koda, H., Kiso, Y., 2006. Effects of beer and hop on ionotropic _-aminobutyric acid receptors. Journal of Agricultural and Food Chemistry 54, 2514–2519.
20. Abourashed, E.A., Koetter, U., Brattstr¨om, A., 2004. In vitro binding experiments with a Valerian, hops and their fixed combination extract (Ze91019 to selected central nervous system receptors. Phytomedicine 11, 633– 638.
21. Pickering, D.S., Niles, L.P., 1990. Pharmacological characterization of melatonin binding sites in Syrian hamster hypothalamus. European Journal of Pharmacology 175, 71–77.
22. Butterweck, V., Brattstroem, A., Grundmann, O., Koetter, U., 2007. Hypothermic effects of hops are antagonized with the competitive malatonin receptor antagonist luzindole in mice. Journal of Pharmacy and Pharmacology 59, 549–552.
23. Schmitz, M., Jackel, M., 1998. Comparative study for assessing quality of life of patients with exogenous sleep disorders (temporary sleep onset and sleep disorders) treated with a hops–valerian preparation and a benzodiazepine drug. Wiener Medizinische Wochenschrift 148, 291–298.
24. Vonderheid-Guth, B., Todorova, A., Brattstrom, A., Dimpfel,W., 2000. Pharmacodynamic effects of valerian and hops extract combination (Ze 91019) on the quantitative-topographical EEG in healthy volunteers. European Journal of Medical Research 5, 139–144.
25. Morin, C.M., Koetter, U., Bastien, C., Ware, J.C., Wooten, V., 2005. Valerian–hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial. Sleep 28, 1465–1471.
26. Gerhard, U., Linnenbrink, N., Georghiadou, C., Hobi, V., 1996. Vigilance decreasing effects of 2 plant-derived sedatives. Schweizerische Rundschau fur Medizin Praxis 85, 473–481.
27. Dimpfel,W., Pischel, I., Lehnfeld, R., 2004. Effects of lozenge containing lavender oil, extracts from hops, lemon balm and oat on electrical brain activity of volunteers. European Journal of Medical Research 9, 423–431.
