Piper methysticum

Common Names: Kava Kava, Kava, Intoxicating Long Pepper

Clinical Names: Piper methysticum

Summary

botanical name: Piper methysticum

common names: Kava Kava, Kava.

overview of interactions:

• herb affecting drug toxicity: Alcohol

• herb affecting drug performance: Benzodiazepines

• herb affecting drug toxicity: Alprazolam (Xanax®)

• herb possibly affecting drug class toxicity: Major Anesthetics

• herb possibly affecting drug class toxicity: Monoamine Oxidase Inhibitors

AHPA Botanical Safety Rating: 2b, 2c, 2d

see also: Herb Groups Neuroendocrine: Sedatives



Clinical

botanical name: Piper methysticum

common name: Kava Kava, Kava, Intoxicating Long Pepper.

parts used: Rhizome and roots.

qualities: Bitter, pungent, dry.

affinities: Nerves, urogenital tract.

actions: Anxiolytic, analgesic, muscular relaxant, sedative, anticonvulsant, antifungal.

dosage:
• dried rhizome: 1.5 - 4 g. daily.
• tincture: (Dried 1:3) 4 - 12 ml. daily.
• standardized extract: (30% - 70% kavalactones) 100 mg 2-3 times daily (manufacturer's preparations vary.)
• safe therapeutic dose range of kavalactones is 100-300mg daily

therapy: Anxiety, neuromuscular tension including tension headaches, muscle spasm; mild insomnia, restlessness.

AHPA Botanical Safety Rating: 2b, 2c, 2d

toxicity:
• Long term use of large doses (in excess of 400 mg kava lactones daily) is associated with exfoliative dermopathy, reversible on cessation of consumption. This dermatitis is not uncommon among habitual aboriginal users but reports of dermopathy in the Western medical literature are lacking.

• Commission E recommends duration of use not to exceed three months without medical advice but offers no explanation. There is anecdotal ethnobotanical evidence that prolonged use of high doses of kava may lead to tolerance and dependence. Rodent studies failed to demonstrate tolerance.

• Accommodative disturbances such as enlargement of the pupils and disturbances of occulomotor equilibrium have been described after consumption of 500 ml. kava beverage prepared in the Fijian manner.
(Blumenthal M, et. al. 1998; Matthews JD, et al. 1988.)

contraindications:
• contraindicated in pregnancy possibly due to loss of uterine tone.
(De Smet PAGM, 1993; Singh, 1992.)
• contraindicated in nursing mothers due to possible passage of pyrones into milk.
(De Smet PAGM, 1993.)

constituents:
• Resin, containing alpha pyrones (Kavalactones):
Demethoxyyangonin,
Dihydrokavain,
Yangonin,
Kavain,
Dihydromethysticin,
Methysticin.
Kavalactone content varies between 3% and 20%. Cultivars show varying composition of different major kavalactones. Analysis of different chemotypes suggest that kava drinkers prefer a higher percentage of kavain and lower percentage of dihydrokavain and dihydromethysticum.
(Lebot V, et al. 1992.)

pharmacology:
• Sedative and hypnotic effects: Kavalactones increase GABA receptor density in specific areas of rodent brain (especially hippocampus and amygdala) suggesting GABA-a receptor mediation of the sedative effects of kava, although earlier studies did not find GABA or benzodiazepine receptor binding. German EEG studies have confirmed the limbic structures, especially the amygdylar complex, mediate the sedative effects of kava
(Holm E, et al. Arzneimittelforschung 1991 Jul;41(7):673-683.)

• Muscle relaxing and anticonvulsant effects: Kretschmar et al found that kava extracts have "anti-strychnine" activity in rodents, acting similarly to the drug mephensin. Aqueous extracts depress spontaneous motor activity in rats without altering forced motor activity responses, according to O'Hara et al, and reduce amphetamine induced hypermotility in mice, according to Furgiuele et al.
(Furgiele A, et al. J Pharm Sci 1965,54:247-252. Kretzschmar R. Specialia. 1970.15:283-284; O'Hara MJ, et al. J Pharm Sci 1965;54:1021-1025.)

• Local anesthetic and analgesic effects: Gleitz et al demonstrated that kava extracts are antinocioceptive in mice and directly relax muscles by fast and specific inhibition of voltage dependent Na+ channels. Kava is well known for causing muscular relaxation without CNS inhibition. However a depressant activity at cord level is suggested by the abolition of flexor reflex in cats according to research by Furgiuele.
(Furgiele A, et al. J Pharm Sci 1965,54:247-252; Gleitz J, et al. Planta Med 1997 Feb;63(1):27-30; Jamieson DD, Duffield PH.Clin. Exp. Pharmacol Physiol 1990;17:509-514.)

• Other Effects: Kava has fungistatic activity but not against Candida spp. Kava extracts are neuroprotective against ischemic damage in rodents
(Backhaus C, Krieglstein. Eur J Pharmacology.1992;215:265-269.)

clinical trials:
Several studies have confirmed anxiolytic activity of kava extracts to be greater than placebo and equivalent to oxazepam (benzodiazopene) in potency and nature of anxiolytic action. A clinical study comparing oxazepam with Kava on psychometric tests found that kava improved performance, and oxazepam worsened it.
(Munte TF, et al. Neuropsychobiology 1993;27(1):46-53.)



Interactions

herb affecting drug toxicity: Alcohol

• research: In rodents, hypnotic effect of alcohol and kava enhance each other. No negative multiplicative effects with alcohol were found in a placebo controlled human clinical trial, and in fact Kava countered the effects of alcohol.
(Herberg KW. Blutakohol. 1993;30:96-104.1993; Jamieson DD, Duffield PH. Clin. Exp. Pharmacol. Physiol.1990;17:509-514.)

herb affecting drug group performance: Benzodiazepines

• mechanism: Benzodiazepine activity may be enhanced due to sedative and muscle-relaxant effects of kava pyrones.

• research: Even though research has moved past presumptive notions that kava acted via the same manner as benzodiazepines, its mechanism of action has not yet been fully determined. According to current research, kava appears to have its primary effect on the limbic system, a part of the brain involved in regulating emotions, mood and wakefulness.
(Holm E, et al. Arzneim Forsch 1991;41:673-683.)

• herbal support: Kava is sometimes used by practitioners of natural medicine in cases where benzodiazepines might be prescribed or where a patient is attempting to wean themselves off of benzodiazepines. Individuals taking benzodiazepine class medications should not begin use of kava without first consulting their prescribing physician, preferably in collaboration with a healthcare professional trained in herbal medicine.

herb affecting drug toxicity: Alprazolam (Xanax®)

• report: According to a case published in Annals of Internal Medicine a man reportedly went into a state of lethargy and disorientation after taking kava in combination with Xanax® (alprazolam) and other drugs. A review of the Almeida case by Bergner detailed that the patient was also concurrently taking Cimetidine and Terazosin. Cimetidine is known to reduce hepatic clearance of alprazolam, and Terazosin is associated with "somnolence" as a side effect. This suggests at very least the original report to be an oversimplification of a possible four-way interaction rather than a simple Kava-Xanax® interaction.
(Almeida, JC, Grimsley, EW. Ann Intern Med 1996 Dec 1;125(11):940-941; Bergner P, Med Herbalism 1999, 11.1:16-17)

• herbal concern: Until more solid research appears, kava should not be combined with benzodiazepines without supervision by an appropriately trained healthcare professional.

herb possibly affecting drug class toxicity: Major Anesthetics

• reports: Murphy discussed cases of patients who had been taking herbs prior to surgery and how this had influenced the course of events, particularly the postponing of the procedure. She emphasized the importance of the perioperative team members asking patients about their use of herbal remedies during assessments of medication use. McLeskey et al found that 170 of 979 (17.4%) of presurgical patients were taking herbal products. Median age of herb users and non-users was 62 years. Of the patients taking these agents, 55% took only one product, 45% took multiple products. In decreasing order, the most commonly utilized herbs among this group were: gingko biloba (32.4%), garlic (26.5%), ginger (26.5%), ginseng and St. John's Wort (14%). Nutraceuticals most widely used were glucosamine (17%), chromium picolinate (17%) and chondroitin (12%). John B. Neeld, Jr, MD, President of the American Society of Anesthesiologists, and others have specifically cautioned against St. John's Wort (Hypericum perforatum) and kava-kava (Piper methysticum) as potentially prolonging the sedative effect of anesthesia due to a presumed MAOI-like action. While numerous anecdotal reports and hypotheses as to mechanisms of action have circulated, no clinical research, published case reports or substantive pharmacological analysis has confirmed these claims of adverse effects or interactions.
(Murphy JM. AORN J. 1999 Jan;69(1):173-5, 177-178, 180-183; McLeskey CH, et al. Annual Meeting of American Society of Anesthesiologists. October 1999; Voelker R. JAMA, 281(20).May 26, 1999.1882.)

• herbal concerns: Numerous authorities have suggested that patients stop taking herbal medications at least 2 to 3 weeks before surgery. Until more conclusive research is available, individuals are advised to report any usage of herbs to their treating physician well in advance of any planned surgery and to stop taking any such herbs for at least three weeks prior to surgery unless specifically agreed upon with and supervised by the physician coordinating the surgery.

herb possibly affecting drug class performance: Monoamine Oxidase Inhibitors

• mechanism: An in vitro study on rodent platelets demonstrated MAO-B inhibitory activity with kava extracts and isolated kava lactones. Currently this is not believed to be the principal mechanism of the sedative activity of kava and the data is not necessarily applicable to humans.
(Uebelhack R, Franke L, Schewe HJ. Pharmacopsychiatry 1998 Sep;31(5):187-192.)

• herbal concern: Until more conclusive evidence is available, prudence would suggest avoiding the use of kava while taking prescription medications.

Please read the disclaimer concerning the intent and limitations of the information provided here.
Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.


References

Almeida JC, Grimsley EW. Coma from the health food store: interaction between kava and alprazolam. Ann Intern Med. 1996 Dec 1;125(11):940-941.

Backhaus C, Krieglstein J. Extract of Kava (Piper methysticum) and its methysticin constituents protect brain tissue against ischemic damage in rodents. Eur J Pharmacology.1992 215:265-269.

Baum SS, Hill R, Rommelspacher H. Effect of kava extract and individual kavapyrones on neurotransmitter levels in the nucleus accumbens of rats. Prog Neuropsychopharmacol Biol Psychiatry. 1998 Oct;22(7):1105-1120.
Abstract: 1. Kavapyrones have well-known psychotropic properties. The most common actions of the extract are relaxation and euphoria, depending on the circumstances of ingestion, whereas higher doses cause sleepiness and skeletal muscle relaxation. Several other actions have been reported such as anticonvulsant properties, neuroprotection and analgesia. No interactions with neuroreceptors have yet been found that would explain the multiple actions. 2. To reveal neuronal functions affected by the kavapyrones the authors studied their actions on the mesolimbic reward system using in vivo microdialysis. 3. A small dose of kava extract (20 mg/kg body weight i.p.) caused changes in rat behaviour and concentrations of dopamine in the nucleus accumbens. Higher doses (120 mg/kg i.p.) increased the levels of dopamine. With respect to the individual compounds, D,L-kawain induced in low doses a decrease in dopamine levels and in higher amounts either an increase or no change in dopamine concentrations. Yangonin resulted in a decrease of dopamine levels to below the detection limit and desmethoxyyangonin in an increase of dopamine levels. Dihydrokawain, methysticin and dihydromethysticin did not produce any significant changes of dopamine levels. D,L-kawain caused a decrease in 5-HT concentrations. Some of the other kavapyrones affected 5-HT levels as well. 4. The results suggest that the relaxing and slightly euphoric actions may be caused by the activation of the mesolimbic dopaminergic neurones. Changes of the activity of 5-HT neurones could explain the sleep-inducing action.

Bergner P. A second Opinion on reported kava-alprazolam herb -drug interaction. Medical Herbalism 1999, 11(1) :16-17.

Blumenthal M, Busse WR, Goldberg A, et al, eds. The Complete Commission E Monographs: Therapeutic Guide to Herbal Medicines. Boston, MA: Integrative Medicine Communications, 1998, 156-157.

Bone K. Kava: A safe herbal treatment for anxiety. Br J Phytother 1994;3:145-153.

Bradley PR, ed. British Herbal Compendium, vol 1. Bournemouth, Dorset, UK: British Herbal Medicine Association, 1992.

Buckley JP, Furgiulel AR, O’Hara MJ. Pharmacology of kava. In: Ethnopharmacoligcal Search for Psychoactive Drugs, ed. DH Efron, B Holmstedt, NS Kline. New York: Raven Press, 1979, 141-151.

Buckley JP, Furgiuele AR, O'Hara MJ. Pharmacology of kava. 2. Psychopharmacol Bull. 1967 Dec;4(3):11-12.

Cass H, McNally T. Kava: Nature's Answer to Stress, Anxiety, and Insomnia. Rocklin, CA: Prima Publishing, 1998.
Cupp MJ. Herbal remedies: adverse effects and drug interactions. Am Fam Physician. 1999 Mar 1;59(5):1239-1245. (Review)

D'Arcy PF. Adverse reactions and interactions with herbal medicines, part 1, adverse reactions. Adverse Drug Reactions and Toxicological Review 10 (Winter 1991) 189-208.

Davies LP, Drew CA, Duffield P, Johnston GA, Jamieson DD. Kava pyrones and resin: studies on GABAA, GABAB and benzodiazepine binding sites in rodent brain. Pharmacol Toxicol. 1992 Aug;71(2):120-126.
Abstract: Kava, an intoxicating beverage prepared from the pepper plant Piper methysticum, is widely consumed by the indigenous peoples in the islands of the South Pacific. As the first of a series of studies on the neuropharmacological interactions of kava with CNS receptors we tested purified pyrones and kava resin for activity on GABA and benzodiazepine binding sites in rat and mouse brain membranes. Only weak activity was observed on GABAA binding sites in washed synaptosomal membranes prepared from rat brain and this was abolished by extraction of the membranes with Triton X-100, suggesting that lipid soluble components were involved. No effects were observed on GABAB binding sites in rat brain membranes in vitro. Kava resin and pyrones exerted some weak effects on benzodiazepine binding in vitro but this did not correlate with pharmacological activity. In addition, in ex vivo studies, no effects were observed on [3H]diazepam binding to brain membranes prepared from mice in which selected kava constituents were injected intraperitoneally, whereas similarly administered diazepam (5 mg/kg) inhibited [3H]diazepam binding by greater than 95%. Similar lack of activity was observed in in vivo binding studies; injection of kava resin failed to influence the CNS binding of the benzodiazepine-receptor ligand [3H]Ro15-1788 injected into mice prior to sacrifice. The pharmacological activities of kava resin and pyrones do not appear to be explained by any significant interaction with GABA or benzodiazepine binding sites.

Demott K. St. John’s wort tied to serotonin syndrome. Clinical Psychiatry News 1998;26:28.
McLeskey CH, Meyer TA, Baisden CE, Gloyna DF, Roberson CR. The incidence of herbal and selected nutraceutical use in surgical patients. Annual Meeting of American Society of Anesthesiologists (ASA) October 1999.
Abstract: An estimated 60 million American adults are reported to use herbal products. Consumers assume, because these products are natural, they are harmless. However, reports of allergic reactions, adverse effects and drug-herb interactions are surfacing. Following IRB approval, a questionnaire was given to 979 presurgical patients. Subjects were asked to indicate the amount and duration of products taken. Age and surgical procedure were noted. 170 surgical patients (17.4%) reported taking such products. Median age of herb users and non-users was 62 years. Of the patients taking these agents, 55% took only one product, 45% took multiple products. In decreasing order, the most commonly utilized herbs among this group were: gingko biloba (32.4%), garlic (26.5%), ginger (26.5%), ginseng and St. John's Wort (14%). Nutraceuticals most widely used were glucosamine (17%), chromium picolinate (17%) and chondroitin (12%). Over 40 herbs were listed as occasionally taken. Females represented 63% of herbal users and 54% of non-users (p=0.05). 19.3% of female patients took one or more of these products vs. 14.5% of male patients. Neurosurgical, gynecologic and orthopedic surgical patients' use of herbals was slightly higher than other surgical groups at 21%, 21% and 20%. Recently one-third of the American public has been identified as users of herbal products. Our lower incidence may result from reluctance of patients to admit taking such products or lack of understanding among patients regarding drug intake and contents of these products. Anesthesia providers, surgeons, and patients should be aware that these medications may not be harmless and are in increasing use. Adverse effects and drug-herbal interactions may suggest alterations in an anesthetic plan.

DeSmet PAGM, et al.(eds.) Adverse Effects of Herbal Drugs 2 . NY. Springer Verlag, 1993.

Duffield AM, Jamieson DD, Lidgard RO, Duffield PH, Bourne DJ. Identification of some human urinary metabolites of the intoxicating beverage kava. J Chromatogr. 1989 Jul 28;475:273-281.
Abstract: Methane chemical ionization (CI) gas chromatography-mass spectrometry (GC-MS) has been used to identify some of the human urinary metabolites of the kava lactones following ingestion of kava prepared by the traditional method of aqueous extraction of Piper methysticum. All seven major, and several minor, kava lactones were identified in human urine. Observed metabolic transformations include the reduction of the 3,4-double bond and/or demethylation of the 4-methoxyl group of the alpha-pyrone ring system. Demethylation of the 12-methoxy substituent in yangonin (or alternatively hydroxylation at C-12 of desmethoxyyangonin) was also recognised. This product was isolated by high-performance liquid chromatographic analysis of crude urine extracts and characterised by methane CI GC-MS. In contrast to the situation prevailing in the rat no dihydroxylated metabolites of the kava lactones, or products from ring opening of the 2-pyrone ring system, were identified in human urine. GC-MS analysis of urine can be readily utilised to determine whether donors have recently consumed kava.

Friese J, Gleitz J. Kavain, dihydrokavain, and dihydromethysticin non-competitively inhibit the specific binding of [3H]-batrachotoxinin-A 20-alpha-benzoate to receptor site 2 of voltage-gated Na+ channels. Planta Med. 1998 Jun;64(5):458-459.
Abstract: The mode of action of the kava pyrones, kavain, dihydrokavain and dihydromethysticin on the specific binding of [3H]-batrachotoxinin-A 20-alpha-benzoate to epitope 2 of voltage-dependent Na+ channels was investigated by performing saturation experiments in the presence and absence of these kava pyrones. The tested compounds significantly decreased the apparent total number of binding sites (Bmax) for [3H]-batrachotoxinin-A 20-alpha-benzoate (control: 0.5 pmol/mg protein, kava pyrones: 0.2-0.27 pmol/mg protein) with little change in the equilibrium constants (KD) for [3H]-batrachotoxin-A 20-alpha-benzoate (control: 28.2 nM, kava pyrones: 24-31 nM). The results indicate for the kava pyrones a non-competitive inhibition of the specific [3H]-batrachotoxinin-A 20-alpha-benzoate binding to receptor site 2 of voltage-gated Na+ channels.

Furgiele A, et al. Central activity of aqueous extracts of Piper methysticum (kava) J Pharm Sci 1965,54:247-252.

Gleitz J, Beile A, Wilkens P, Ameri A, Peters T. Antithrombotic action of the kava pyrone (+)-kavain prepared from Piper methysticum on human platelets. Planta Med 1997 Feb;63(1):27-30.
Abstract: (+)-Kavain, a 4-methoxy-alpha-pyrone prepared from Piper methysticum Forst. (Piperaceae), was investigated regarding its assumed antithrombotic action on human platelets which was deduced from its ability to suppress arachidonic acid (AA)-induced aggregation, exocytosis of ATP, and inhibition of cyclooxygenase (COX) and thromboxane synthase (TXS) activity, the latter two effects being estimated from the generation of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2), respectively. Exogenously applied AA (100 mumol/l) provoked a 90% aggregation of platelets, the release of 14 pmol ATP, and the formation of either 220 pg TXA2 or 43 pg PGE2, each parameter being related to 10(6) platelets. An application of (+)-kavain 5 min before AA, dose-dependently diminished aggregation, ATP-release, and the synthesis of TXA2 and PGE2 with IC50 values of 78, 115, 71, and 86 mumol/l, respectively. The similarity of the IC50 values suggest an inhibition of COX by (+)-kavain as primary target, thus suppressing the generation of TXA2 which induces aggregation of platelets and exocytosis of ATP by its binding on TXA2-receptors.

Gleitz J, Friese J, Beile A, Ameri A, Peters T. Anticonvulsive action of (+/-)-kavain estimated from its properties on stimulated synaptosomes and Na+ channel receptor sites. Eur J Pharmacol 1996 Nov 7;315(1):89-97.
Abstract: Kava pyrones are constituents of the intoxicating pepper (Piper methysticum Forst), which has been shown to be anticonvulsive. The question of how the excitability of neurons is affected was investigated by determining the interaction of (+/-)-kavain with epitopes (site 1, site 2) of voltage-dependent Na+ channels and the action of (+/-)-kavain on 4-aminopyridine-stimulated synaptosomes as model of repetitive firing neurons. [3H]Saxitoxin and [3H]batrachotoxin were used for radioligand-binding assays performed with synaptosomal membranes. Gultamate released from 4-aminopyridine-stimulated cerebrocortical synaptosomes and the cytosolic concentrations of Na+ and Ca2+ ([Na+]i, [Ca+]i) were detected fluorometrically by using an enzyme-linked assay, sodium-binding benzofuranisophthalate (SBFI) and Fura-2, respectively. (+/-)-Kavain failed to compete with [3H]saxitoxin up to 400 mumol/l but dose-dependently suppressed binding of [3H]batrachotoxin with an IC50 value of 88 mumol/l (Ki = 72 mumol/l) although displacement of [3H]batrachotoxin was restricted to 33% of control at 400 mumol/l (+/-)-kavain. In stimulated synaptosomes, 5 mmol/l 4-aminopyridine provoked an increase in [Na+]i and [Ca2+]i by 9 mmol/l Na+ and 235 nmol/l Ca2+. Comparable to the reduction in [3H]batrachotoxin binding, 400 mumol/l (+/-)-kavain suppressed the increase in [Na+]i and [Ca2+]i to 38 and 29% of control, respectively. Consistent with the increase in [Na+]i and [Ca2+]i, 5 mmol/l 4-aminopyridine provoked glutamate release (rate: 38 pmol/s*mg protein) which was dose-dependently diminished to 60% of control by 400 mumol/l (+/-)-kavain. KCl depolarization (40 mmol/l) provoked an increase in [Ca2+]i and glutamate release almost identical to the responses elicited by 4-aminopyridine but 400 mumol/l (+/-)-kavain suppressed only the rate of glutamate release by 9% of control. The data suggest an interaction of (+/-)-kavain with voltage-dependent Na+ and Ca2+ channels, thereby suppressing the 4-aminopyridine-induced increase in [Na+]i, [Ca2+]i and the release of endogenous glutamate.

Herberg KW. Driving ability after intake of kava special extract WS 1490. Z Allgemeinmed 1993;69;271-277.

Herberg KW. [Effect of Kava-Special Extract WS 1490 combined with ethyl alcohol on safety-relevant performance parameters]. Blutalkohol. 1993 Mar;30(2):96-105. [Article in German]
Abstract: The Kava-special extract WS 1490 (3 x 100 mg/d over 8 days) was tested in a placebo-controlled randomised double-blind study to establish whether it has any adverse effects on safety-related performance when administered together with ethyl alcohol (0.05% blood alcohol concentration). The study was carried out as a comparison of two independent groups each containing 10 male and 10 female healthy volunteers aged between 18 to 60 years (mean: 40.45 +/- 12.2 years). The batteries of performance tests consisted of seven procedures. It was conducted before treatment without alcohol as well as the 1st, 4th and 8th day of treatment together with alcohol. The results showed no negative multiplicative effects caused by the Kava-special extract WS 1490 together with alcohol. With the concentration test however there was a remarkable advantage of the WS 1490 group at the 4th day of treatment (p < 1%). The collection of well-being data as well as the description of adverse events proved WS 1490 to be well tolerated.

Holm E, Staedt U, Heep J, Kortsik C, Behne F, Kaske A, Mennicke I . [The action profile of D,L-kavain. Cerebral sites and sleep-wakefulness-rhythm in animals]. Arzneimittelforschung 1991 Jul;41(7):673-683. [Article in German]

Jamieson DD, Duffield PH. Positive interaction of ethanol and kava resin in mice. Clin. Exp. Pharmacol. Physiol.1990;17:509-514.

Jussofie A, Schmiz A, Hiemke C. Kavapyrome enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of the rat brain. Psychopharmacology Psychopharmacology (Berl). 1994 Dec;116(4):469-474.
Abstract: Regional differences in the modulation of [3H] muscimol binding to GABAA receptor complexes by kavapyrones, compounds of the rhizome of the plant Piper methysticum which possess sedative activity, were demonstrated using membrane fractions obtained from target brain centers of kavapyrone action: hippocampus (HIP), amygdala (AMY) and medulla oblongata (MED), and from brain centers outside the main kavapyrone effects as frontal cortex (FC) and cerebellum (CER). The kava extract enhanced the binding of [3H] muscimol in a concentration-dependent manner with maximal potentiation of 358% over control in HIP followed by AMY and MED (main target brain centers). Minimal stimulation was observed in CER followed by FC. In contrast, apart from CER, the potency of kavapyrones was similar in the brain areas investigated with EC50 values ranging between 200 and 300 microM kavapyrones. Scatchard analysis revealed that the observed effects of kavapyrones were due to an increase in the number of binding sites (Bmax), rather than to a change in affinity. At a kavapyrone concentration of 500 microM the order of enhancement in Bmax was HIP = AMY > MED > FC > CER. When kavapyrones are included together with pentobarbital or HPO the two classes of compounds produced a more than additive, i.e., synergetic effect on [3H] muscimol binding. Our findings suggest that one way kavapyrones might mediate sedative effects in vivo is through effects on GABAA receptor binding.

Kinder C, Cupp MJ. Kava: an herbal sedative. Nurse Pract. 1998 Jun;23(6):14, 156. (Review)

Kretzschmar R, Meyer HJ, Teschendorf HJ, Zollner B. [Antagonistic action of natural 5,6-hydrogenated Kava pyrones against strychnine poisoning and experimental local tetanus]. Arch Int Pharmacodyn Ther. 1969 Dec;182(2):251-68. [Article in German]

Kretzschmar R. Strychnine anatagonistic potency of pyrone compounds of the Kava root (Piper methysticum F. Specialia. 1970.15:283-284

Kinzler E, Kromer J, Lehmann E. [Effect of a special kava extract in patients with anxiety-, tension-, and excitation states of non-psychotic genesis. Double blind study with placebos over 4 weeks]. Arzneimittelforschung. 1991 Jun;41(6):584-8. [Article in German]
Abstract: Clinical Efficacy of a Kava Extract in Patients with Anxiety Syndrome/Double-blind placebo controlled study over 4 weeks. In a randomized, placebo-controlled double-blind study two groups each containing 29 patients with anxiety syndrome not caused by psychotic disorders were treated for a period of 4 weeks with kava extract WS 1490 (Laitan) 3 x 100 mg/day or a placebo preparation. Therapeutic efficacy was assessed by the Hamilton-Anxiety-Scale (main target variable), the Adjectives-List and the Clinical-Global-Impression-Scale (secondary target variables) after 1, 2 and 4 weeks of treatment. The HAMA overall score of anxiety symptomatology revealed a significant reduction in the drug receiving group already after one week of treatment. This difference between the two groups of patients increased in the course of the study. The results of the secondary target variables were in agreement with the HAMA-score and demonstrate the efficacy of WS 1490 in patients with anxiety disorders. No adverse experiences caused by the medication were noted during the 4 week administration of WS 1490.

Langosch JM, Normann C, Schirrmacher K, Berger M, Walden J. The influence of (+/-)-kavain on population spikes and long-term potentiation in guinea pig hippocampal slices. Comp Biochem Physiol A Mol Integr Physiol. 1998 Jul;120(3):545-549.
Abstract: Little is known about the mechanisms of action of kava pyrones which are the pharmacological active compounds of the plant Piper methysticum Forst. We investigated the effects of the synthetic kava pyrone (+/-)-kavain on long-term potentiation (LTP) in the CA1-region of guinea pig hippocampal slices. (+/-)-Kavain reduced the amplitudes of extracellular field potential changes evoked by electrical stimulation in a concentration dependent manner. These effects were reversible. In experiments with LTP no changes were found in the presence of (+/-)-kavain. In conclusion, our findings suggest (+/-)-kavain to be an effective drug in modulating excitatory signals in the hippocampus of guinea pigs. Additionally, no alterations on synaptic plasticity in hippocampal neurons for this kava pyrone can be presumed.

Lebot V, Merlin M, Lindstrom L. Kava: The Pacific Drug. New Haven: Yale University Press, 1992.

Lehmann EE, Kinzler J, Friedmann J. Efficacy of a special kava extract (Piper methysticum) in patients with states of anxiety, tension and excitedness of non-mental origin. A double-blind placebo-controlled study of four weeks treatment. Phytomedicine 1996;3:113-119.

Mack RB. A less than Pacific odyssey: the use of kava. N C Med J. 1999 Mar-Apr;60(2):91-93.

Matthews JD, et al. Effects of the heavy usage of kava on physical health : summary of a pilot survey in the aboriginal community. Med J. Aust. 1988.148:548-555.

McLeskey CH, Meyer TA, Baisden CE, Gloyna DF, Roberson CR. The incidence of herbal and selected nutraceutical use in surgical patients. Annual Meeting of American Society of Anesthesiologists (ASA) October 1999.
Abstract: An estimated 60 million American adults are reported to use herbal products. Consumers assume, because these products are natural, they are harmless. However, reports of allergic reactions, adverse effects and drug-herb interactions are surfacing. Following IRB approval, a questionnaire was given to 979 presurgical patients. Subjects were asked to indicate the amount and duration of products taken. Age and surgical procedure were noted. 170 surgical patients (17.4%) reported taking such products. Median age of herb users and non-users was 62 years. Of the patients taking these agents, 55% took only one product, 45% took multiple products. In decreasing order, the most commonly utilized herbs among this group were: gingko biloba (32.4%), garlic (26.5%), ginger (26.5%), ginseng and St. John's Wort (14%). Nutraceuticals most widely used were glucosamine (17%), chromium picolinate (17%) and chondroitin (12%). Over 40 herbs were listed as occasionally taken. Females represented 63% of herbal users and 54% of non-users (p=0.05). 19.3% of female patients took one or more of these products vs. 14.5% of male patients. Neurosurgical, gynecologic and orthopedic surgical patients' use of herbals was slightly higher than other surgical groups at 21%, 21% and 20%. Recently one-third of the American public has been identified as users of herbal products. Our lower incidence may result from reluctance of patients to admit taking such products or lack of understanding among patients regarding drug intake and contents of these products. Anesthesia providers, surgeons, and patients should be aware that these medications may not be harmless and are in increasing use. Adverse effects and drug-herbal interactions may suggest alterations in an anesthetic plan.

Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med. 1998 Nov 9;158(20):2200-2211. (Review)

Munte TF, Heinze HJ, Matzke M, Steitz J. Effects of oxazepam and an extract of kava roots (Piper methysticum) on event-related potentials in a word recognition task. Neuropsychobiology 1993;27(1):46-53.
Abstract: Twelve healthy volunteers were tested in a double-blind crossover study to assess the effects of oxazepam and an extract of kava roots (Piper methysticum) on behavior and event-related potentials (ERPs) in a recognition memory task. The subjects' task was to identify within a list of visually presented words those that were shown for the first time and those that were being repeated. The repeated words were associated with an increased positivity beginning approximately 250 ms poststimulus. Oxazepam led to a reduction of a negative component in the 250-500 ms range for both old and new words and to a reduction of the old/new difference in the ERP associated with a significantly worse recognition rate. Kava on the other hand showed a slightly increased recognition rate and a larger ERP difference between old and new words.

Murphy JM. Preoperative considerations with herbal medicines. AORN J.1999 Jan;69(1):173-5, 177-178, 180-183.

Nowakowska E, Ostrowicz A, Chodera A. [Kava-kava preparations--alternative anxiolytics]. Pol Merkuriusz Lek 1998 Mar;4(21):179-180a. [Article in Polish] (Review)

O'Hara MJ, Kinnard WJ, Buckley JP. Preliminary characterisation of Aqueous extracts of Piper methysticum (Kava, Kava kava). J Pharm Sci 1965 Jul;54(7):1021-1025.

Pepping J. Kava: Piper methysticum. Am J Health Syst Pharm. 1999 May 15;56(10):957-958, 960. (Review)

Schirrmacher K, Busselberg D, Langosch JM, Walden J, Winter U, Bingmann D. Effects of (+/-)-kavain on voltage-activated inward currents of dorsal root ganglion cells from neonatal rats. Eur Neuropsychopharmacol. 1999 Jan;9(1-2):171-176.

Singh YN. Kava: an overview. J Ethnopharm. 1992;37:13-45.

Singh YN, Blumenthal M. Kava medicinals. HerbalGram 1997;39: 33-56

Suss R, Lehmann P. [Hematogenous contact eczema cause by phytogenic drugs exemplified by kava root extract]. Hautarzt. 1996 Jun;47(6):459-461. [Article in German]
Abstract: The increasing promotion of herbal drugs may lead to allergic problems. A case of systemic contact-type dermatitis after oral administration of kava extract illustrates this special problem. The kava plant is a member of the black pepper family; an intoxicant beverage prepared from the roots of this plant is used ceremonially by many traditional societies of the Southern Pacific. The beverage induces relaxation, enhances a sense of sociability and promotes sleep. These effects are utilized in herbal drugs containing kava, which are sold for insomnia, nervousness and depression. The ichthyosiform kava dermopathy is a well-known side effect of excessive use of kava; in this case report we describe an acute allergic side-effect of kava extract.

Tinsley JA. The hazards of psychotropic herbs. Minn Med. 1999 May;82(5):29-31. (Review)

Uebelhack R, Franke L, Schewe HJ. Inhibition of platelet MAO-B by kava pyrone-enriched extract from Piper methysticum Forster (kava-kava).Pharmacopsychiatry 1998 Sep;31(5):187-192.
Abstract: Kava-kava, a psychoactive beverage, induces relaxation, improves social interaction, promotes sleep and plays an important role in the sociocultural life in the islands of the South Pacific. On the other hand, standardized extracts of kava-kava roots are used for the therapy of anxiety, tension and restlessness. Kava pyrones, the major constituents of kava kava, are generally considered to be responsible for the pharmacological activity in humans and animals. To obtain more information on the mechanisms by which kava-kava exerts psychotropic properties we investigated the in vitro effects of kava-kava extract and pure synthetic kava pyrones on human platelet MAO-B, in comparison to amitriptyline, imipramine and brofaromine. Kava-kava extract was found to be a reversible inhibitor of MAO-B in intact platelets (IC50 24 microM) and disrupted platelet homogenates (IC50 1.2 microM). Structural differences of kava pyrones resulted in a different potency of MAO-B inhibition. The order of potency was desmethoxyyangonin &gt; (+/-)-methysticin &gt; yangonin &gt; (+/-) dihydromethysticin &gt; (+/-)- dihydrokavain &gt; (+/-)-kavain. The two most potent kava pyrones, desmethoxyyangonin and (+/-)-methysticin displayed a competetive inhibition pattern with mean Ki 0.28 microM and 1.14 microM respectively. The inhibition of MAO-B by kava pyrone-enriched extracts might be an important mechanism for their psychotropic activity.

Volz HP, Kieser M. Kava-kava extract WS 1490 versus placebo in anxiety disorders. A randomized placebo-controlled 25-week outpatient trial. Pharmacopsychiatry 1997 Jan;30(1):1-5.
Abstract: 101 outpatients suffering from anxiety of non-psychotic origin (DSM-III-R criteria: agoraphobia, specific phobia, generalized anxiety disorder, and adjustment disorder with anxiety) were included in a 25-week multicenter randomized placebo-controlled double-blind trial with WS 1490, a special extract of kava-kava. In the main outcome criterion, the Hamilton Anxiety Scale (HAMA), there was a significant superiority of the test drug starting from week 8 on. WS 1490 was also found to be superior with respect to the secondary outcome variables. HAMA subscores somatic and psychic anxiety, Clinical Global Impression, Self-Report Symptom Inventory-90 Items revised, and Adjective Mood Scale. Adverse events were rare and distributed evenly in both groups. These results support WS 1490 as a treatment alternative to tricyclic antidepressants and benzodiazepines in anxiety disorders, with proven long-term efficacy and none of the tolerance problems associated with tricyclics and benzodiazepines.

Walden J, von Wegerer J, Winter U, Berger M, Grunze H. Effects of kawain and dihydromethysticin on field potential changes in the hippocampus. Prog Neuropsychopharmacol Biol Psychiatry 1997 May;21(4):697-706.
Abstract: 1. The kava-pyrones kawain and dihydromethysticin are constituents of Piper methysticum which exert anticonvulsant, analgesic and anxiolytic properties. 2. In the present study the effect of these kava-pyrones were tested on field potential changes (fp) induced by omission of the extracellular Mg2+, recorded from the area CA1 and CA3 of the hippocampal slice preparation of guinea pigs. These fp are generated by an activation of NMDA receptors and voltage dependent calcium channels. 3. Kawain and dihydromethysticin reduced reversibly the frequency of occurrence of fp in a concentration range from 5 to 40 mumol/l and 10 to 40 mumol/l, respectively. 4. Reduction of the fp frequency after addition of subthreshold concentrations of 5 mumol/l kawain and 10 mumol/l dihydromethysticin indicated additive actions of both drugs. 5. Since the serotonin-1A agonist ipsapirone also exerts anxiolytic effects, subthreshold concentrations of kawain or dihydromethysticin were combined with a subthreshold concentration of ipsapirone in another set of experiments. Combining kawain and ipsapirone or dihydromethysticin and ipsapirone caused a reduction of the rate of fp to 0.76 and 0.81 of the baseline value, respectively. 6. The findings suggest that (i) single constituents of Piper methysticum may have additive actions, (ii) that the two components kawain and dihydromethysticin may enhance the effects of the anxiolytic serotonin-1A agonist ipsapirone and (iii) that activation of NMDA receptors and/or voltage dependent calcium channels may be involved in the elementary mechanism of action of some kava-pyrones.

Warnecke G. Psychosomatic dysfunctions in the female climacteric. Clinical effectiveness and tolerance of kava extract WS 1490. Fortschr Med 1991 Feb 10;109(4):119-122 [Article in German]
Abstract: Within the framework of a randomized, placebo-controlled double-blind study, two groups each containing 20 patients with climacteric-related symptomatology were treated for a period of 8 weeks with kava WS 1490 extract 3 X 100 mg/day or a placebo preparation. The target variable - the HAMA overall score of anxiety symptomatology - revealed a significant difference in the drug-receiving group vis-a-vis the placebo group already after only 1 week of treatment. The course of such further parameters as depressive mood (DSI), subjective well-being (patient diary), severity of the disease (CGI), and the climacteric symptomatology (Kuppermann Index and Schneider scale) over the overall period of treatment demonstrate a high level of efficacy of kava extract WS 1490 in neurovegetative and psychosomatic dysfunctions in the climacteric, associated with very good tolerance of the preparation.