Herbal Remedies for Anxiety and Insomnia: Kava and Valerian
David Mischoulon
Insomnia and anxiety are highly prevalent, affecting up to one third of the population (1). Despite the various anxiolytic and hypnotic medications on the market, such as Buspirone, zolpidem, benzodiazepines, and antidepressants, many individuals do not find them satisfactory. Some people do not respond well to these medications, or experience too much daytime sedation for regular use. Due to concerns about the risk of abuse, dependence, and withdrawal with benzodiazepine use, many clinicians are reluctant to prescribe them to individuals with history of substance abuse. Even the newer anxiolytic-hypnotics that are safer from a dependence standpoint may prove too strong and sedating for some. Consequently, many people seek out natural treatments, such as kava and valerian. This chapter focuses primarily on these two remedies, which represent the more thoroughly studied herbal anxiolytics.
KAVA (PIPER METHYSTICUM FORST)
Medicinal use of the kava (or kava-kava) shrub originated in the Pacific Islands, where it is prepared from the rhizome of the plant, to be consumed as a ceremonial tribal drink (2). Polynesians have said that with kava, you “can’t hate.” The kava preparation is thought to have a calming effect, but without altering consciousness (3). In Polynesian tribes, kava was traditionally prepared by virgins who chewed kava roots, placed the mash in a pot, and allowed it to ferment into a tea-like drink. Kava became increasingly popular in the United States during the late 1990s for stress reduction, often used by harried individuals who needed to unwind after a hard day’s work. Unfortunately, kava has recently met with some concerns over toxicity risk, and this has significantly impacted on its popularity and availability worldwide.
Clinical Trials
There are more than a dozen published studies examining the efficacy of kava, almost all the studies are double-blind, placebo-controlled, randomized clinical trials (RCTs) (Table 8.1). These studies include mostly comparisons of kava monotherapy against placebo for anxiety symptoms of different types (4, 5, 6, 7, 8, 9, 10, 11), and at least two comparisons between kava and other active therapies (12,13).
The above studies had sample sizes ranging from 20 to 141, and averaged between 60 and 70 subjects. Study durations were generally between 4 and 8 weeks, although some studies ran as long as 3 to 6 months. Collectively, symptoms and disorders treated in these studies included generalized anxiety, tension, agitation, agoraphobia, specific phobia, generalized anxiety disorder (GAD), adjustment disorder, and insomnia. Kava doses were usually in the range of 150 to 400 mg per day, and most studies reported efficacy and good tolerability for these doses compared to placebo. A dose-finding study (9) in which 141 subjects were randomized to 150 to 300 mg per day of kava or placebo demonstrated a significant advantage for kava in many categories, but improvement was more robust with higher doses of kava (300 mg per day), suggesting a dose-response pattern.
TABLE 8.1 Selected Clinical Trials of Kava Therapy | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Two studies have compared kava against standard anxiolytics and antidepressants. Boerner et al. (12) randomized 129 subjects in a three-way manner, to kava 400 mg per day, Buspirone 10 mg per day, or opipramol 100 mg per day for 8 weeks. Response rates, defined as 50% or greater reduction of the Hamilton Anxiety (HAMA) scale, were 75% in each treatment group, with a 60% remission rate overall. Connor et al. (13) reported on three trials with a total of 64 subjects with GAD, treated with kava, venlafaxine, or placebo. The investigators reported no significant differences in efficacy between the three interventions.
Kava has also been studied for perimenopausal symptoms. De Leo et al. (14) treated women with menopausal anxiety by using a regimen of hormone replacement therapy (with or without progestogens), to which they add either kava or placebo for 6 months. Though all treatment groups improved, those receiving kava had the best results overall. Cagnacci et al. (15) treated 68 perimenopausal women for 3 months with a regimen of calcium alone versus calcium plus daily doses of kava (100 mg or 200 mg). Again, the addition of kava produced significant improvement of mood and anxiety.
Mechanisms of Action
Kava’s effect is thought to be related to kavapyrones, which function as central muscle relaxants (16,17) and anticonvulsants (18). Kavapyrones have half-lives ranging from 90 minutes to several hours, and their bioavailability varies depending on the type of preparation. Kavapyrones reduce the excitability of the limbic system similar to benzodiazepines, but without physical or psychologic tolerance or dependency (19,20) or cognitive difficulties (21). Kava has been shown to have an effect on reflex vagal control of heart rate in GAD (22). An analgesic effect in mice has also been demonstrated (23).
Kavapyrones may interact with gamma-aminobutyric acid type A (GABA-A) receptors (24, 25, 26). Three kavapyrones, (+)-methysticin, (+)-kavain, and the synthetic racemate (±)-kavain, inhibit the uptake of tritiated norepinephrine, but not the uptake of tritiated serotonin, in the cerebral cortex and hippocampus of rats (27). Kawain and dihydromethysticin may enhance the effects of the anxiolytic serotonin-1A agonist ipsapirone, and activation of NMDA receptors and/or voltage-dependent calcium channels may be involved in kava’s mechanism of action (28). Other components such as methysticin and dihydromethysticin may have a neuroprotective role (29). Finally, the inhibition of monoamine oxidase B may also be involved in kava’s anxiolytic effect (30). All of these mechanisms may contribute to kava’s overall psychotropic effect. Given its apparent low potential for abuse, kava has often been recommended for individuals with low degrees of anxiety, or who have abuse or tolerability problems with standard agents (31).
Dosing
The literature reviewed in this chapter has reported efficacy for kava at doses ranging from 70 to 400 mg per day, with an average dose of about 200 to 250 mg per day. There is no consensus on an optimal daily dose (2), and it is important to note that these doses do not necessarily reflect the amount of active ingredients. Kava is available in many different types of preparations, including tablets, tinctures, and “tea bags.” Extraction and standardization procedures may differ widely between manufacturers, resulting in preparations with different proportions of components. This makes it difficult to estimate the amount of active ingredient consumed per dose, and may impact on observed efficacy as well as bioavailability.
Adverse Effects and Toxicity
The most common side effects of kava include gastrointestinal upset, allergic skin reactions, headaches, and dizziness (2,32). There are reports of adverse interactions between kava and benzodiazepines (33,34) and mixed findings regarding adverse interactions between kava and alcohol (35, 36, 37).
More serious toxic reactions have been reported with high doses (300 to 400 g per week) or prolonged use of kava. A survey of Aboriginal kava users (38) revealed a high rate of complaints of poor health and a “puffy” face, a scaly rash, and increased patellar reflexes. Other characteristics of heavy kava users include subnormal weight, abnormal liver function tests, hematuria, poorly acidified urine, and abnormal blood indices. Shortness of breath in kava users was also associated with tall P waves on a resting electrocardiogram, suggesting pulmonary hypertension.
Other documented adverse effects of kava include Parkinsonism (39), changes in mental status (40), blepharospasm and saccade (41), as well as ataxia, skin rash, hair loss, redness of the eyes, impaired visual accommodation, respiratory problems, loss of appetite, and seizures (2,41, 42, 43). Another unique side effect is the yellowing of the skin called kava dermopathy, which is thought to be secondary to kava-related interference with cholesterol metabolism (44).
Most kava-related toxic effects are reversible if the use of kava is discontinued immediately. However, a 2004 report (45) described at least 78 cases of severe kava-related liver toxicity; these include 36 cases of hepatitis and cirrhosis, 11 cases of liver failure requiring transplant, and 4 deaths. In many instances, a direct relationship between kava and liver disease was difficult to ascertain. Only 4 cases involved kava monotherapy, and 23 cases involved concomitant ingestion of other potentially hepatotoxic drugs. Also, almost 80% of the patients took kava for prolonged time periods (3 months to 2 years) and/or in “overdoses” (>480 mg per day), with some doses at least 100 times higher than usual. A recent study of 62 Tongan and non-Tongan healthy adults in Hawaii, of which half were kava drinkers, found that among the kava drinkers there was a significant elevation in gamma-glutamyl transferase (GGT) and a nonsignificant elevation in alkaline phosphatase (ALP) (46).
Proposed toxic mechanisms of kava include inhibition of cytochrome P450 types 2C9, 2C19, 2D6, 3A4, 2E1, 1A2, and 4A9/11, a genetic deficiency of 2D6, inhibition of P-glycoprotein, reduced glutathione, cyclooxygenase inhibition (45), and mitochondrial toxicity (47). It should be noted, however, that some recent animal studies have not supported toxicity (48,49). Sudden emergence of toxicity in humans probably reflects increasing use without physician supervision.
As a result of these toxicity cases, kava products have been withdrawn in Switzerland, France, Germany, and the United Kingdom (45). The U.S. Food and Drug Administration has issued a consumer advisory and is further investigating kava’s safety, and several retailers have voluntarily withdrawn kava from the market (50).
Recommendations for Safe Use of Kava
In view of the growing evidence for toxicity, kava should be avoided in individuals with a history of liver disease, alcohol use, and in those who are taking concurrent medications with potential liver toxicity. Anyone who uses kava should do so under physician supervision, which should include regular monitoring of liver function tests, particularly alanine aminotransferase (ALT), GGT, and ALP. If any abnormalities found, then kava should be discontinued immediately and liver enzymes should be retested in about 2 weeks, by which time they should return to normal (51).
Duration of use of kava is not recommended to exceed 3 months (2). There are no studies addressing the question of safety in pregnancy, and for this reason, kava is not recommended for use in pregnant women.
Conclusions
The studies reviewed in this chapter suggest that kava may be more effective than placebo for mild anxiety states and disorders, and for insomnia, but not for severe anxiety. Kava has also been shown to improve cognitive function and positive affect in anxious subjects (52). However, most of these studies are limited by small samples, short duration of treatment, and a lack of rigorous diagnostic criteria. In many instances, the study samples were not “psychiatric” populations per se, but healthy individuals with mild and diverse anxiety symptoms and states. Some studies have examined subjects with more formal but varied anxiety diagnoses, which present the problem of comparing “apples and oranges.” There is a dearth of comparisons between kava and standard anxiolytics. No published studies have yet tested kava’s efficacy for panic disorder, or examined kava in combination with registered anxiolytics. A recent effect-size analysis (53) examined various treatments for GAD, and found the poorest results for complementary and alternative applications, including kava and homeopathy, which appeared to perform even worse than placebo. A meta-analysis (54) of six placebo-controlled, randomized trials with the kava extract WS1490 found an odds ratio of 3.3 (95% confidence interval [CI] = 2.09 to 5.22) for success in patients with nonpsychotic anxiety disorders, and a mean improvement in the HAMA scale (5.94 points; 95% CI = −0.86 to 12.8) compared to placebo, with perhaps a greater effect in females and younger patients.
In general, kava may be best suited for individuals with low degrees of anxiety and/or those who have abuse or tolerability problems with standard agents. More rigorous studies on safety and efficacy are needed, especially comparisons between kava and conventional anxiolytics. Likewise, the toxicities associated with kava need to be better characterized, especially from a risk-benefit standpoint. Given what is known about kava’s mechanisms of action, it is possible that future studies may reveal a risk of tolerance or dependency. With this in mind, as well as its other potential toxicities, kava should be prescribed and used with great caution, and preferably not as a first line of treatment for anxiety.
VALERIAN (VALERIANA OFFICINALIS)
The root of V. officinalis has been used as a sedative and mild hypnotic for more than 1,000 years (55,56). Valerian gets its name from the Latin word valere, which means “in good health.” It is called baldrian in German. The plant is a perennial that grows in temperate and warm climates (57). V. officinalis is grown primarily in Western Europe and is very popular around the world, especially among the Hispanic population (58), which historically favors natural remedies (59).
Clinical Trials
At least 37 clinical trials, of which 29 are placebo controlled, have been performed examining the efficacy and safety of different types of valerian preparations (60). The components of the valerian preparations used are not clearly specified in some reports (2). Some of the studies reviewed in this chapter were performed on healthy subjects and others on symptomatic individuals. Most were double-blind RCTs, with sample sizes ranging from as little as a half-a-dozen subjects to more than 900, and averaged about 100 subjects per study. Treatment periods ranged from as short as 1 night, to as long as 6 weeks, and doses and dosing schedules were very diverse (see Table 8.2 for summary of selected trials).
One of the more notable studies comparing valerian against placebo includes the placebo-controlled trial with symptomatic patients by Leathwood and Chauffard (61). Subjects who received valerian 450 mg per night had a decreased sleep latency compared to placebo. Doses of 900 mg had no statistically significant advantage over 450 mg. The authors concluded that symptomatic individuals appeared to require a longer period to respond to valerian. Vorbach et al. (62) carried out a placebo-controlled, double-blind study in 121 patients with significant sleep disturbance. Although initially there was little difference between valerian and placebo, the valerian-treated group had a significantly better overall response after 4 weeks.
Related posts:
Complementary and Alternative Medicine in Society: An Introduction
Evaluating the Data: Limitations of Research and Quality Assurance Issues Regarding Natural Remedies
Inositol in the Treatment of Psychiatric Disorders
Therapeutic Potential of Melatonin in Sleep and Circadian Disorders
Acupuncture for the Treatment of Psychiatric Disorders
Homeopathy and Its Applications in Psychiatry
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