Objective
To provide an update on the efficacy and safety of herbal products used for anxiety, depression, fibromyalgia and insomnia. A search of PubMed was conducted to find literature only in humans with randomized controlled trial or meta-analysis study designs or reviews written in English.
Anxiety
Kava (Piper methysticum)
Kava has been used traditionally in South Pacific cultures as an anxiolytic and relaxant often in ceremonial settings. The mechanism of action for anxiolysis is still unclear but it is believed that kavalactones 1) modulate GABA activity via alteration of lipid membrane structure and sodium channel function; 2) dowregulates β-adrenergic acitivity; and 3) inhibit monoamine oxidase B inihibition.
In a recent review (8/2009), Sarris J. et al. (1) concluded Kava is effective in the treatment of generalized anxiety disorder (GAD) from the following findings: 1) Cochrane review in 2003 [included 11 random controlled trials (RCT) studying the effects of kava monopreparations (60-280mg/d) on GAD] showed that kava had significantly greater anxiolysis than placebo; 2) Meta-analysis of 6 RCTs by Pittler et al. (2003) showed a 5.0-point reduction (95% CI 1.1-8.8) over placebo on the Hamilton anxiety scale (HAM-A); 3) Meta-analysis of 6 RCTs by Witte et al. (2005) showed OR=3.3 (success rate) (95% CI 2.09-5.22) in reduction of HAM-A; 4) RCT by Boerner et al. (2003) comparing kava (400mg) vs. buspirone (10mg) vs. opipramol (100mg) showed equivalent efficacy between treatments on all outcome measures.
Currently kava is restricted from use in the United Kingdom, Canada, and the European Union because of its potential hepatotoxicity—at least 93 cases of hepatoxicity have been documented wherein kava may be implicated, but only 3 cases with kava as the cause. However, most of these cases were poorly reported and many involved concurrent ingestion of other drugs and alcohol, excessive daily dose or long-term administration, and may have involved inappropriate kava preparations that have higher concentration of alkaloids. Some studies showed elevations in γ-glutamyl-transferases (65% vs. 26%) and alkaline phosphatases (23% vs. 3%) in kava drinkers compared to controls, but there is no evidence of irreversible liver damage.
The World Health Organization (WHO) recently recommended research into the safety and efficacy of aqueous extracts of kava. In reply to this suggestion, Sarris J. et al. (2) showed in the Kava Anxiety Depression Spectrum Study (KADSS), which was a double-blind, placebo-controlled crossover trial, that aqueous extracts of kava (250 mg/d) significantly reduced HAM-A [kava group from baseline score showed -9.9 points (95% CI -12.7 to – 7.1) vs. placebo group showed -0.8 (95% CI -4.3 to 2.7); after crossover: kava group showed -10.3 points (95% CI – 14.7 to -5.8) vs. placebo group showed rise of +3.3 points (95% CI -0.2 to +6.8)] with no indication of hepatotoxicity during the 3-week study period—no changes in liver enzymes seen. This study had a small sample size of 41 but effect sizes reflected strong clinical outcome.
Overall, aqueous extracts of kava appears to be an effective treatment option for GAD, but further long-term safety studies would be needed to rule out hepatotoxicity.
Depression
St. John’s Wort (SJW) (Hypericum perforatum)
SJW is among the oldest medicinal herbs in Europe and is still used for its main indication of depression. The mechanism of action is still unclear but it is believed that the hundreds of compounds included in the SJW extracts (roughly 150 compounds already characterized) act in totality as a monoamine oxidase inhibitor; non- selective reuptake inhibitor of serotonin, norepinephrine, and dopamine; and downregulator of β-adrenergic receptors and upregulator of 5-HT2 receptors.
In a recent review (4/2009), Linde K. (4) concluded from a current version of Cochrane review of St.John’s wort extracts for major depression (included 29 double-blind, randomized trials in about 5,500 participants meeting the DSM-IV criteria for major depression or having depressive episodes according to ICD-10) that the extracts are more efficacious than placebo [relative risk (RR)=1.48 with 95% confidence interval (CI)=1.23-1.77] and similarly efficacious as standard antidepressants (RR=1.01, 95% CI=0.93-1.12) while having better tolerability in the acute treatment of major depressive episodes. However, substantial variation or heterogeneity was found in outcomes especially between placebo-controlled trials. Meta-regression analyses in the Cochrane review showed this heterogeneity may be due to: 1) variations in extract quality or dosage—daily dose range was 80-1700mg but mostly 500-1200mg; 2) quality or precision of studies; 3) difference in severity of depression—more severe depression yielded less improvement; and 4) location of study—studies conducted in German-speaking countries yielded much higher response rates.
On average the proportion of patients reporting side effects (i.e.,1) gastrointestinal symptoms, 2) increased sun sensitivities) and dropout rates due to adverse events were similar compared to placebo group. The Cochrane review also showed proportion of patients reporting side effects and dropout rates due to adverse events were lower compared to old antidepressants such as imipramine [side effects/dropouts: odds ratio (OR)=0.39; 95% CI=0.30- 0.50/OR=0.25; 95% CI=0.13-0.46] or SSRIs (side effects/dropouts: OR=0.70; 95% CI=0.49-1.00/ OR=0.53; 95% CI- 0.34-0.83).
The main concern about SJW is its cytochrome P450 3A4 (CYP3A4) inductive effects that potentially could reduce the effectiveness of myriad of medications metabolized by CYP3A4.
Overall, SJW is more effective than placebo and as effective as standard antidepressants in the treatment of depressive disorders, while have a better side effect profile. Consideration of concomitant medications metabolized by CYP3A4 enzymes should be taken when recommending SJW.
Fibromyalgia (FM)
Creatine Monohydrate
Abnormal cerebral blood flow and irregularities in hippocampal metabolites, such as creatine, has been reported in some patients with FM. Creatine contributes to brain energy homeostasis by being a temporal and spatial buffer for cytosolic and mitochondrial pools of adenosine triphosphate. It is speculated that oral creatine supplementation may exert beneficial effects on cerebral blood flow via its effects on brain energy metabolism.
One open-label study showed significant improvement with creatine monohydrate as an add-on treatment in the primary outcome of FM impact questionnaire (FIQ). (4) The FIQ scores were the following: baseline mean + SD=52.63 + 14.8; maximum mean + SD=40.29 + 12.72; end of follow-up mean + SD=54.39 + 21.69. A Wilcoxon signed rank test with one-tailed P-values comparing the means were: P=0.04 for trend over the 12-week study period; P=0.006 for baseline vs. maximum improvement; and P=0.03 for maximum improvement vs. end of follow-up.
The significantly positive results however, were offset by the poor study design. This study was a non- placebo-controlled trial with a small sample population (N=30) and high dropout rates (14 dropouts). Although high dropout rates are common in FM clinical trials, this study did not meet its own power criteria (24 patients required for one-tailed significance level of 5% and power of 80%) as a result of dropouts. No adverse effects were reported but poor compliance due to inability swallowing large tablets and keeping up with frequent dosing regiment [3g/d divided in 3 doses of creatine monohydrate (1000mg tablets, Sup Herb, Israel) for 3 weeks, then 5g/d divided in 3 doses thereafter for total of 8 weeks] was notable.
Overall this study showed promising preliminary results for the use of creatine monohydrate as an add on treatment to standard FM therapy, but is limited by its weak study design.
Melatonin
Lower levels of melatonin has been found in conditions related to FM, e.g. idiopathic pain syndrome but a recent report showed similar levels of 6-sulphatoxymelatonin (aMT-6S) in FM patients compared to age-matched normal controls. (5) Given melatonin’s sedative effects and improvement of mood and fatigue, Citera G. et. al. conducted an open-label, controlled pilot study on the effects of melatonin in patients with FM. The study included 21 patients (2 dropouts) that were control-matched and excluded from comorbidities and medications that alter urinary aMT-6S levels. The treatment group received 3mg/d of melatonin 30min before sleep for 4 weeks.
Results showed significant improvement in visual analogue scale (VAS), which monitored sleep, pain, fatigue, depression, and anxiety; median tender point count; and severity of pain at day 30. Self and physician assessment of VAS (scale of 0 to 10, where 10 is worst) compared from day 0 to day 30 were 7 to 4.7 and 7.6 to 5.7, respectively at P<0.05. Median tender point count and severity of pain (both on scale of 0 to 24, where 24 is worst) compared from day 0 to day 30 were 10 to 14 and 12 to 18, respectively at P<0.05. Lower levels of urinary aMT-6S were found in FM patients compared with normal controls but were not significant.
Overall this pilot study showed promising results, but is limited by its weak study design.
Insomnia
Melatonin
Melatonin is a hormone produced by the pineal gland that is believed to play a vital role in regulating the sleep-wake cycle—low during daytime and elevated during nighttime, coinciding with the sleep phase. Few studies showed decreased melatonin levels in some patients with insomnia.
In a recent review (2/2008), Gooneratne NS. (6) summarized that melatonin (dose range of 0.1-10mg) has a clear role in management of circadian sleep disorders (e.g., delayed sleep phase syndrome) but has clinically insignificant benefit for primary insomnia and no benefit for secondary insomnia based on a large meta-analysis (7). The meta-analysis showed melatonin significantly decreased sleep onset latency (SOL) in delay sleep phase syndrome (Weighted mean difference: -38.8 min.; 95% CI -50.3 to -27.3 min). The review also discussed the potential benefit of melatonin improving sleep on a subgroup of patients with low levels of melatonin or abnormal timing of melatonin cycle, but evidence with strong study designs is lacking.
The meta-analysis found the most commonly reported adverse effects of melatonin were nausea (1.5%), headache (7.8%), dizziness (4.0%), and drowsiness (20.33%), but these incidences were not significant compared to placebo.
Overall, melatonin is a safe treatment option for management of circadian sleep disorders, such as delayed sleep phase syndrome, but is not effective in primary or secondary insomnia. Melatonin may improve subgroup of patients with low melatonin levels or abnormal melatonin cycles, but further investigation is required.
Valerian
Valerian has been used for its sedative-hypnotic effects to improve sleep. The exact mechanism of action is unknown but it is believed that the valepotriates, sesquiterpenes, and amino acids (GABA and glutamine) found in the extracts act on GABA receptors, A1 adenosine receptors, or 5-HT-5a receptors.
In a recent review (2/2008), Gooneratne NS. (6) summarized the results of several randomized, placebo- controlled studies on the effect of valerian (400-900mg) on sleep. One study (18 patients with no sleep problems) using subject and objective (polysomnography and actigraphy, respectively) measures showed that subject measures improved while only small clinically insignificant improvements were seen in objective measures. Another actigraphy-based study showed statistically significant improvement in sleep latency (from 15.8 +/- 5.8 min to 9.0 +/- 3.9 min, P<0.01) in patients with insomnia, but at higher doses of 900mg led to morning drowsiness. Similar results were seen in a 2-week polysomnography-based research where reductions in sleep latency were observed, but no overall improvement in sleep efficiency. A study on older adults with sleep problems showed subjective improvement of 63% vs.43% in the placebo group (statistically not different from placebo). Another randomized, placebo-controlled study of older adults with insomnia measuring objective outcomes showed improvements over placebo in total sleep time and slow-wave sleep. However, the valerian group was biased with worse baseline sleep parameters. A later similar study showed no significant benefit over placebo. Comparisons to other benzodiazepines, such as oxazepam, showed that valerian was as effective in improving sleep, but the study was not placebo-controlled and measured outcomes were based on subjective self-reports.
In general, valerian has been found to be safe with minimal side effects. Some rare side effects include gastrointestinal upset, contact allergies, headache, restless sleep, and mydriasis. However, it is important to note the safety concerns with the inconsistent quality of valerian extracts—a recent report by ConsumerLab.com noted 4 of 17 valerian products had no detectable valerian content, 4 had half the amount listed, two had lead contamination, and one had cadmium contamination.
Overall, good quality valerian is safe and may show small subjective improvements in sleep. Further studies with objective measures are required.
References:
- Sarris J and Kavanagh DJ. Kava and St. John’s Wort: current evidence for use in mood and anxiety disorders. J Altern Complement Med. 2009 Aug;15(8):827-36.
- Sarris J and Kavanagh DJ. The Kava Anxiety Depression Spectrum Study (KADSS): a randomized, placebo- controlled crossover trial using an aqueous extract of Piper methysticum. Psychopharmacology 2009;205:399- 407.
- Linde K. St. John’s Wort-an overview. Forsch Komplementmed 2009; 16: 146-155.
- Leader A, Amital D, Rubinow A et. al. Ann N Y Acad Sci. 2009 Sep;1173:829-36.
- Citera G, Arias MA, Maldonado-Cocco JA, et. al. The effect of melatonin in patients with fibromyalgia: a pilot
study. Clin Rheumatol. 2000;19(1):9-13.
- Gooneratne NS. Complementary and alternative medicine for sleep disturbances in older adults. Clin Geriatr
Med. Feb 2008;24(1):121-38.
- Buscemi N, Vandermeer B, Pandya R, et al. Melatonin for treatment of sleep disorders. Evid Rep Technol Assess (Summ). Nov 2004;(108):1-7.