Anxiety, insomnia, restlessness, tension, and pain syndromes.
Mechanism of Action
The neurophysiological activities of Piper methysticum are attributed primarily to the lipophilic resinous compounds, known as kavalactones (also known as kava pyrones), found in the root. To date, 18 different kavalactones have been identified; however, approximately 96% of the total pharmacological activity can be attributed to the presence of six kavalactones: methysticin, dihydromethysticin, kavain/kawain, dihydrokavain/kawain, demethoxyyangonin, and yangonin.1, 2 Synergistic actions between kavalactones have been reported, and could partly be explained by the uptake of these compounds into brain tissue,3 with limbic structures suggested as the principal site of kavalactone activity.4 Other minor constituents include amino acids; minerals (aluminum, iron, magnesium, potassium, calcium and sodium); and three chalcones (flavokavins A, B and C).5
Several studies have documented a wide spectrum of pharmacological effects of P. methysticum, including anxiolytic,6 analgesic,7 muscle relaxant,8 and mild anaesthetic9 effects. Other documented actions include sedation, euphoria, and both anticonvulsant and neuroprotective activity. The central nervous system effects of P. methysticum appear to be due to the activity of the compounds present in the lipid-soluble fraction.10
Numerous in vivo and in vitro studies suggest possible mechanisms and specific kavalactones that may mediate the actions of P. methysticum. These include blockade of voltage-gated sodium ion channels11; reduced excitatory neurotransmitter release due to blockade of calcium ion channels12; affinity for CB₁ receptors within the endocannabinoid system13; enhanced ligand binding to gamma-aminobutyric acid A (GABAA) receptors14; reversible inhibition of monoamine oxidase B; reduced neuronal reuptake of noradrenaline (norepinephrine) and dopamine15; and suppression of the synthesis of the eicosanoid thromboxane A2, which antagonizes GABAA receptor function.16
The sedating and anxiolytic properties of P. methysticum appear to be potentiated by inhibition of GABA,17 with kavain and dihydrokavain possessing the most significant anxiolytic activity,18 without the loss of mental acuity.
Physiological effects of P. methysticum are comparable to those of benzodiazepines, even though only a weak binding of kavalactones to GABAA and benzodiazepine receptors has been detected.19
Kavalactones appear to activate GABAergic effects via modulation of GABA channels.5 Their lipophilic nature allows for them to remain in the lipid membrane and potentially influence a variety of cell surface receptors.17 This influence may include an ability to increase the number of GABA binding sites rather than to change an affinity to bind GABA directly.14,17
It is theorized that N-methyl-d-aspartate (NMDA) receptors may be also involved in the kavalactone mechanism of action, as their effect on the brain is different from that of benzodiazepines and tricyclic antidepressants.
The anticonvulsive properties are similar to those of local anesthetics, such as procaine,8 and analgesic effects appear to occur via non-opiate pathways.3 Kavain, dihydrokavain, methysticin, and dihydromethysticin have been found to possess significant analgesic effects in animal studies, and kavain appears to be the most effective in surface anesthesia, comparable to cocaine in its strength and duration of action.20
At high concentrations kavalactones have been found to bind to brain opioid receptors21; however, analgesia does not appear to involve the opioid system or be associated with changes in locomotor activity or motor coordination. Analgesic effects are not antagonized by naloxone.7 A purported minimum of 12 kavalactones appear to bind at the same receptor sites as anxiolytics and muscle relaxants, suggesting P. methysticum may have analgesic properties similar to morphine, even if it does not work at the specific mu receptor.22
Several isolated cases of psychotic and severe dystonic reactions following kava use suggest that kava also has psychoactive properties, but there is no conclusive evidence that kava interferes with normal cognitive processes.23 It has been suggested that the novel physiological activity of P. methysticum that distinguishes it from other sedating substances such as alcohol or benzodiazepines is its ability to inhibit reuptake of noradrenalin in the prefrontal cortex. This noradrenergic effect differentiates the central effects of P. methysticum, as the combination of GABA modulation and increased noradrenergic activation contribute to feelings of physical relaxation, with no deleterious effects on cognition. Reduced neuronal reuptake of noradrenalin may in fact facilitate the cognitive effects of P. methysticum, thereby enhancing attentional visual processing speeds.24
Indications for P. methysticum supported by clinical trials are anxiety and nervous conditions including tension, and restlessness. P. methysticum appears to have an anxiolytic effect and to increase remission rates in patients with anxiety disorders, and specifically in cases of anxiety related to menopause. Furthermore, it decreases anxiety without the loss of mental acuity. Extrapolations from pharmacological studies indicate that it may also be used to improve cognitive performance; in the treatment of insomnia; to assist in withdrawal from benzodiazepine drugs; and as an analgesic and local anesthetic. It has also been shown to have minimal negative effects, and possibly positive effects, on reaction time and cognitive processing.
Anxiety: Data from multiple clinical studies suggest that P. methysticum is a non-addictive, non-hypnotic anxiolytic, which is superior to placebo for the symptomatic treatment of anxiety (GAD).4,25 One hundred and one patients with anxiety who scored at least 19 out of 30 on the Hamilton Anxiety Scale (HAMA) were randomized to receive either P. methysticum or placebo over approximately 6 weeks. Participants were administered a P. methysticum extract equal to 70% kavalactones (or 70 mg) in a product known as WS 1490, or a placebo capsule three time a day. Total HAMA scores showed a statistically significant difference with WS 1490 starting at 8 weeks, which increased later into the treatment period at weeks 12, 16, 20, and 24. The authors concluded that both short- and long-term efficacy of WS 1490 was superior to placebo, and that its tolerance was also good, with rare adverse events that were distributed evenly in both groups.26
Another randomized, placebo-controlled double-blind study looked at the clinical efficacy and tolerance of this same standardized kava extract (WS 1490). Twenty nine participants with states of “anxiety, tension and excitedness” received either one capsule of WS 1490 or a placebo three times a day for 4 weeks. Therapeutic efficacy was assessed by the HAMA (main outcome variable), the Adjectives Check List and the Clinical Global Impression Scale after 1, 2, and 4 weeks of treatment. After 1 week of treatment, overall HAMA scores showed a significant reduction in the kava group compared with placebo, and differences between the two groups were found to increase throughout the 4 weeks across all secondary outcome variables. In addition, no adverse reactions were noted.27
In another study, 50 participants with anxiety were given either 50 mg of WS 1490 three times a day over 4 weeks or placebo. Total HAMA scores at baseline were similar in both groups. WS 1490 showed a therapeutically relevant reduction in anxiety scores of more than 4 points versus placebo, along with good tolerance, and no drug-related adverse events or post-study withdrawal symptoms. The authors concluded that 150 mg of WS 1490 administered each day can be considered a safe and effective treatment for non-psychotic anxiety syndromes.28
A double-blind, randomized, placebo-controlled, parallel-group trial of anxiety investigated the efficacy and tolerability of 150 mg/day of WS 1490 given daily for 4 weeks. One hundred and forty one adult male and female patients who had a total HAMA score exceeding 18 points were randomized to receive treatment with 50 mg of WS 1490 three times a day or placebo. The primary outcome measure for treatment efficacy was the average total score of the Anxiety Status Inventory (ASI), with other secondary measures being self-rating scales measuring situational anxiety and tension, subjective well-being and personality structure in terms of subscores for neuroticism, extraversion, control and dominance. Of the 141 patients recruited, 14 (9 in the treatment group and 5 in the placebo group) withdrew prematurely (n = 127); 73% of the patients treated with WS 1490 compared with 56% of patients in the placebo group exhibited ASI score decreases of more than 5 points from baseline. Significant advantages for WS 1490 were also evident in most secondary outcome self-rating scale. Treatment was well tolerated and did not affect liver function tests. One adverse event (tiredness) was attributed to the extract.29
A 3-month randomized prospective study investigated the efficacy of a P. methysticum extract (100 mg capsule containing 55% kavain) on the mood of 80 perimenopausal women, with perimenopause being defined as amenorrhea for 6/24 months, occurring around 47–53 years of age, associated with the occurrence of hot flashes, and having a follicle-stimulating hormone (FSH) value higher than 30 IU/L. Participants received 1 g per day of calcium and were randomized to receive either no other treatment (control), one 100 mg kava capsule, or two 100 mg kava capsules daily. Anxiety, depression, and climacteric symptoms were evaluated at baseline, and at 1 and 3 month marks throughout the study. No significant improvement in climacteric symptoms was observed with either treatment groups; however, anxiety declined at 1 and 3 months, and depression declined at 3 months. The authors concluded that in perimenopausal women administration of P. methysticum induces an improvement of mood, particularly in anxiety.30
The Kava Anxiety Depression Spectrum Study (KADSS) was a 3-week placebo-controlled, double-blind crossover trial that used an aqueous extract of P. methysticum. Sixty adults who self-reported at least 1 month of persistent worry or anxiety, and who scored greater than 10 on the Beck Anxiety Inventory (BAI). HAMA, Montgomery–Asberg Depression Rating Scale (MADRS) and BAI scores were assessed pre- and post-treatment. Participants were given 5 tablets per day (each standardized to 50 mg of kavalactones), providing a total of 250 mg kavalactones, or placebo. The aqueous extract reduced participants’ scores across all measurement. It was also found to be safe, with no serious adverse effects and no clinical hepatotoxicity. The authors concluded that aqueous P. methysticum preparation appears to reduce symptoms of anxiety and depression in participants with elevated levels of generalized anxiety, and raised no safety concerns at the dose and duration studied.31
In 2013, the same authors of the KADSS aimed to build on their work in a sample of adults with clinical diagnosis of generalized anxiety disorder (GAD) and no comorbid depression. A placebo-controlled trial was designed to assess an aqueous P. methysticum extract in the treatment of GAD. Fifty eight patients with generalized anxiety disorder were randomized to 120 mg kavalactones (titrated up to 240 mg/day) or placebo for 6 weeks. Reduction in anxiety was measured using the HAMA scale as the primary outcome. When compared with placebo, P. methysticum was associated with increased remission (26% vs. 7%), reduced anxiety symptoms, no significant differences in liver function tests, and only one adverse event (increased headaches) was attributable to the P. methysticum extract. F-Aminobutyric acid (GABA) and noradrenaline transporter polymorphisms were also analyzed as potential pharmacogenetic markers of response. Within the kava group, GABA transporter polymorphisms rs2601126 and rs2697153 were found to be associated with HAMA reduction. The authors concluded that standardized kava may be a moderately effective short-term option for the treatment of GAD, and furthermore, that specific GABA transporter polymorphisms may potentially modify anxiolytic responses to kava treatment.32
A randomized, double-blind, parallel-group study compared the efficacy of P. methysticum with two medications commonly used to treat anxiety in 129 patients with with GAD over 8 weeks. At baseline, participants were randomized to receive either one tablet containing 400 mg P. methysticum extract (standardized to 30% kavalactones, extraction solvent 96% ethanol in water) once a day, one tablet containing 5 mg buspirone hydrochloride twice a day, or one tablet containing 50 mg opipramol dihydrochloride twice a day. All participants were seen at weeks 2, 4 and 8, and after another week without treatment (week 9), a follow-up visit was carried out to assess early relapses and symptoms of withdrawal. Efficacy rating scales and adverse events were assessed at all visits. The authors concluded that P. methysticum was as effective as buspirone or opipramol for treating generalized anxiety disorder with about 75% response rates and 60% remission rates at 9 weeks.33
Another study assessed the efficacy and safety of P. methysticum in treating patients who had DSM-IV criteria for GAD with a minimum of 6 months’ duration. Thirty seven adults were randomly assigned to 4 weeks of treatment with P. methysticum (standardized to 70 mg kavalactones) or placebo. P. methysticum dose was initiated at 140 mg kavalactones per day for 1 week, and then increased to 280 mg kavalactones per day. Weekly HAMA Scale, Hospital Anxiety and Depression Scale (HADS), and Self Assessment of Resilience and Anxiety (SARA) assessments were performed. Safety evaluations which included liver function tests (assessed by treatment group, comparing changes in liver enzymes aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin), that were performed at screening and at the completion of treatment. Overall, P. methysticum was well tolerated and appeared safe with respect to liver function (hepatic enzymes showed no significant alteration in liver function); however, its therapeutic benefit was not considered to be readily apparent, although one quarter of patients treated with kava met the criteria for remission, and P. methysticum did appear superior to placebo on the SARA in low anxiety subjects (i.e., HAMA Scale score under 19). Although P. methysticum was not considered superior to placebo overall, the authors concluded it would be premature to rule it out as efficacious in GAD.34
A systematic review of six randomized controlled trials in Germany evaluated P. methysticum for its effect on nonpsychotic anxiety disorders in the form of the standardized extract WS 1490, where doses ranged from 150 to 300 mg/day, and trial duration ranged from 4 to 24 weeks. In 345 patients (70% female) significant improvements in HAMA scores were found, including a proportion of patients achieving remission of anxiety (as defined as ≥50% reduction in baseline HAMA score) with P. methysticum when compared with placebo.35 Similar results were found in a Cochrane review of 12 randomized controlled trials comparing kava vs. placebo in 700 patients with clinical anxiety.36
Insomnia: A crossover trial investigated 24 subjects (adult men and women) with stress-induced insomnia of varying duration and intensity. All of the participants initially received 120 mg of P. methysticum (LI-150) daily for 6 weeks. After a 2-week wash-out period, they were then given 600 mg of valerian (LI-156) for another 6 weeks. After a further 2-week wash-out period, a final 6 weeks of combined kava and valerian was administered. Assessments include visual analogue scales (VAS) to record severity of stress as perceived by the subject and their degree of sleep disturbance, as well as any reports of side effects throughout the treatment. Results showed a significant reduction in mean total stress scores during the 6 weeks of kava treatment, with little difference after valerian was introduced or with the combination treatment; 67% of participants reported no side effects with P. methysticum, and 53% reported no side effects while on the combination therapy. The most common side effect reported was vivid dreams while on combination therapy, and gastric discomfort and dizziness with P. methysticum alone. The authors concluded that both the impact and severity of patients’ stress resulting in insomnia were rapidly relieved by kava treatment.37
Cognitive Performance: In contrast to benzodiazepine-type anxiolytics that can impair cognitive performance, and negatively affect mood and sleep cycles, P. methysticum can instead facilitate cognitive functioning, improve overall mood, and stabilize emotional disposition. Moreover, it has been theorized that P. methysticum selectively acts on limbic structures, promoting anxiolysis without causing clinically relevant sedation.38
Kavalactones have demonstrated neuroprotective effects, supporting the recovery of neurological deficits after cerebral infarction in animal models, effects which have been attributed to calcium channel agonism, sodium channel blocking, inhibition of monoamine oxidase, and inhibition of noradrenaline uptake.39
A double-blinded, placebo-controlled EEG-brain-mapping study conducted in healthy human volunteers demonstrated that single doses of the kavalactone, kawain, at 200, 400, and 600 mg respectively caused a dose-dependent shift towards lower brain wave frequencies (i.e., delta, theta, and alpha waves), and indicated a more sedating effect in the higher dosing range. Changes were found to be most pronounced in the frontal regions of the brain, with the pharmacodynamic peak being reached within the first hour. Self-rating scales suggested brain wave activation after the 200 mg dose, with mild sedation after 600 mg. Psychometric performance improved after all doses, and there were no adverse reactions reported.40
A double-blind crossover study assessed the effects of oxazepam and P. methysticum on behavior and event-related potentials (ERPs) in a recognition memory task in 12 healthy participants. Participants were asked to identify within a list of visually presented words those that were being shown to them for the first time and those that were being repeated. When compared with oxazepam, P. methysticum showed a slightly increased recognition rate and a larger ERP difference (based on milliseconds post-stimulus) between repeated and new words compared with oxazepam, which was associated with a significantly worse recognition rate.41
A double-blind randomized placebo-controlled trial looked at the acute effects of P. methysticum on emotional reactivity and cognitive performance. The mood of 20 healthy subjects was assessed using the state-trait-cheerfulness-inventory, and cognitive performance was examined with the Sperling partial report and the Sternberg item recognition task, which were used as an index for visual attention and short-term memory processing. It was found that a single 300-mg dose of P. methysticum (standardized to 30% kavalactones) led to an increase in cheerfulness, and its mood-elevating effects were most prominent in trait cheerful subjects. Moreover, P. methysticum improved the accuracy and speed of performing a report and item recognition task, and authors indicated a beneficial effect on both visual attention and short-term memory retrieval. The authors concluded that unlike conventional benzodiazepine-type anxiolytics, which tend to impair cognitive performance and to increase the occurrence of negative affective states, beyond its anxiolytic effects P. methysticum can facilitate cognitive functioning and support a positive mood.42
Safety in Pregnancy and Breastfeeding
P. methysticum has not been studied in pregnancy or lactation, and thus its use is discouraged due to possible decreases in uterine tone, and the possibility of lactone transport into breast milk with unknown effects.43
Data from many studies and clinical trials suggest that adverse events from P. methysticum are, in general, rare, mild, and reversible. However, some published case reports indicate that serious adverse events are possible, and most commonly include dermatological reactions, neurological complications and, of greatest concern, liver damage. In recommended doses, over short periods of time (<1–2 months), P. methysticum may be regarded as safe and well-tolerated by most users.44
Liver: P. methysticum is reported to be potentially hepatotoxic, but results remain inconsistent in studies, and the pathogenesis of kava hepatotoxicity has not yet been sufficiently elucidated. Cases of severe liver toxicity associated with P. methysticum intake have been reported in Europe and the US; however, a direct causal relationship has been difficult to establish in the majority of cases, and there is insufficient evidence to implicate P. methysticum as the solely responsible agent.16
Heavy consumption of P. methysticum has been associated with increased concentrations of glutamyltransferase (GGT)45; however, thus far no studies have definitely supported toxicity of kavalactones.3 Clinical, pre-clinical, and toxicological studies have so far failed to show toxicity of P. methysticum preparations and their constituents, with the mechanism of possible hepatotoxicity proposed to be due to saturation of the cytochrome P450 detoxification pathway.46
P. methysticum has been used traditionally in the South Pacific Islands for centuries.47 The first cases of P. methysticum related hepatotoxicity in Western countries were described in 1998. P. methysticum products were subsequently withdrawn from Europe, US, and Australian markets. However, Food and Drug Administration (FDA) and Center for Disease Control and Prevention (CDC) warnings and European regulatory agency warnings have been largely diffused since 2002. The UK’s Medicines Control Agency and Committee on Safety of Medicines I 2002 compiled a total of 68 cases related to P. methysticum, of which its association to liver damage was judged to be “probable” in 14 cases, “possible” in 30, and “unassessable” in the remainder.48 As of 2002, The CDC reported 10 cases of fulminant hepatic failure requiring liver transplant associated with P. methysticum,49 and in 2003 a case of acute liver failure and death was associated with the use of a preparation containing P. methysticum and Passiflora incarnata.50 In data supplied by the Medicines Control Agency, out of 60 cases of P. methysticum toxicity reported, concomitant medication or a pre-existing liver complaint were present in all but two cases.46 From the incidence of case reports compared with the sales figures for P. methysticum extracts, it is estimated that the likelihood of hepatotoxicity is one case in 60–125 million people.51
Proposed causes for alleged kava-induced hepatotoxicity include low quality of cultivar, a lack of standardization, contamination (e.g., with toxic alkaloid pipermethystine found in leaf), inappropriate preparation (e.g., the use of organic solvents such as ethanol and acetone), metabolic or immune mediated idiosyncrasies (e.g., prior liver disease or genetic variability such as deficient CYP2D6 activity leading to slower drug metabolism), excessive doses, and concomitant use with alcohol.52,53,54
Of major concern are herb–drug interactions, since one review established that 64% of patients with verified P. methysticum hepatotoxicity used up to 20 different synthetic drugs and dietary supplements.55 Another evaluation of 26 patients with suspected P. methysticum hepatotoxicity revealed a probable causal relationship for P. methysticum alone in only a single case, concluding that in only a few unusually susceptible patients, P. methysticum hepatotoxicity represents a rare idiosyncratic reaction of the metabolic type, especially when therapeutic dosing recommendations are not followed.56
Side Effects: Adverse effects from ingestion of P. methysticum are not generally expected when used within the recommended dosage; however, an established side effect characteristic of heavy P. methysticum use includes pigmentation of the skin known as kava dermopathy (ichthyosiform eruption and yellowing). Kava dermopathy, occurs only with prolonged use of large amounts, and is reversible on reduced intake or cessation.58
There have been several isolated reports of dopamine antagonism, psychotic syndromes, severe choreoathetosism, and possible seizures following P. methysticum use; however, there is no conclusive evidence that it interferes with normal cognitive processes. In fact, data collected from among the heaviest reported kava drinkers in the world found no impairment in cognitive function or evidence of brain dysfunction in individuals who were currently heavy kava users.59 Nonetheless, P. methysticum should be used cautiously in elderly patients, especially those with Parkinson’s disease, or in patients with a history of medication-induced extrapyramidal effects due to potential additive effects.60,61
P. methysticum does not appear to have addictive effects, or to affect sexual function in patients with generalized anxiety disorder who received kava for 6 weeks (liver function tests also appear unaffected).62 In one comparison study, intoxicated kava drinkers who consumed 205 g of kava powder (approximately 140-times the recommended clinical dose) were compared with a control group. The intoxicated subjects showed ataxia, tremors, sedation, blepharospasm, and elevated liver enzymes (GGT and alkaline phosphatase), together with saccadic dysmetria, saccadic slowing, and reduced accuracy performing a visual search task. Other reported side effects include gastrointestinal upset, allergic rash, and mild headache.43
Interactions: Rare cases of interactions have occurred with pharmaceutical drugs that share one or more mechanisms of action with P. methysticum. Kavalactones are potent inhibitors of several CYP450 enzymes, suggesting a potential for causing pharmacokinetic interactions with drugs and other herbs that are metabolized by the same CYP450 enzymes.63 This potential to modulate the activity of drug-metabolizing enzymes may influence pharmacokinetic interactions for a variety of medications including antiplatelet agents, diuretics, other potentially hepatotoxic drugs, and anticancer drugs.64
Controlled trials suggest that P. methysticum extracts do not impair cognitive performance or potentiate the effects of central nervous system depressants; however, a synergistic effect is possible for substances acting on the central nervous system, especially those which cause sedation or lethargy. Medications and substances that may have additive effects when taken concomitantly include alcohol and barbiturates,7,65 anxiolytic medications (e.g., selective serotonin reuptake inhibitors and benzodiazepines,66,67), analgesics and opioids,68 dopaminergic antagonists (e.g., droperidol, haloperidol, risperidol, and metoclopramide), melatonin, and monoamine oxidase inhibitors.69
P. methysticum extracts are mainly standardized to their kavalactone content (often 30%), and dosed between 100 and 400 mg kavalactones per day for the treatment of insomnia and anxiety disorders. Whole dried rhizome has been used in doses between 1.5 and 3 g per day (kavalactone content of the root varies between 3% and 20%). The LD50 for kavalactones was established to be approximately 300-400 mg/kg daily.43,51
P. methysticum belongs to the pepper family. It has been used for centuries to decrease anxiety and fatigue, and to produce a sociable attitude, relieve pain, and help induce sleep. The effects of the kava may vary between individuals, with lower doses generally creating a mild feeling of sleepiness and relaxation of the body and the muscles, happiness, and numbness or tingling of the mouth, tongue and throat.
Historically the drinking of kava was considered sacred, and its use was limited to defined social classes such as priests and chiefs. Kava was prepared by cutting the root into small pieces, then chewed by several people and spat into a bowl, where it was mixed with coconut milk, strained through coconut fiber, and then blended with water.
Traditional aqueous extracts were used by many of the island cultures of the Pacific Ocean, including Fiji, Vanuatu, Hawaii, and Polynesia, mainly for ceremonial purposes. Ceremonial occasions included welcome ceremonies for visiting parties, family feasts, and important community activities, as well as informal kava drinking on a social basis. In Fiji, where kava is considered the national drink, it carries the symbolic function of bringing two groups of people together. Before receiving the drink, the tradition is to clap the hands once, then after finishing the drink, one has to clap three more times. Once the ceremonial drinking is complete, everyone gathered would be friends, and the rest of the celebrations can begin.
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