revisão de plantas e desordens psiquiátricas.pdf

HERBAL MEDICINES FOR PSYCHIATRIC DISORDERS 703

Copyright 2007 John Wiley & Sons, Ltd. Phytother. Res. 21, 703716 (2007)DOI: 10.1002/ptr

Copyright 2007 John Wiley & Sons, Ltd.

PHYTOTHERAPY RESEARCHPhytother. Res. 21, 703716 (2007)Published online 11 June 2007 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/ptr.2187

REVIEW ARTICLEHerbal Medicines in the Treatment ofPsychiatric Disorders: A Systematic Review

Jerome SarrisSchool of Medicine, Department of Psychiatry, University of Queensland, Brisbane, Australia

This paper reports a critical review of 27 herbal medicines and formulas in treating a broad range of psychiatricdisorders (in addition to anxiety and depression), including obsessive-compulsive, seasonal affective, bipolardepressive, psychotic, phobic and somatoform disorders. Ovid Medline, Pubmed and the Cochrane Librarywere searched for pharmacological and clinical evidence of herbal medicines with psychotropic activity. Aforward search of later citations was also conducted. Whilst substantial high-quality evidence exists for the useof kava and St Johns wort in the treatment of anxiety and depression respectively, currently there is insufcientrobust clinical evidence for the use of many other herbal medicines in psychiatric disorders. Phytotherapieswhich potentially have signicant use in psychiatry, and urgently require more research are Rhodiola rosea(roseroot) and Crocus sativus (saffron) for depression; Passiora incarnata (passionower), Scutellarialateriora (scullcap) and Zizyphus jujuba (sour date) for anxiety disorders; and Piper methysticum (kava) forphobic, panic and obsessive-compulsive disorders. While depression and anxiety are commonly researched,the efcacy of herbal medicines in other mental disorders requires attention. The review addresses currentissues in herbal psychotherapy: herbal safety, future areas of application, the relationship of herbal medicinewith pharmaceuticals and the potential prescriptive integration of phytomedicines with synthetic psycho-tropic medicines. Particular attention is given to clinical and safety issues with St Johns wort and kava.Copyright 2007 John Wiley & Sons, Ltd.

Keywords: herbal medicine; psychiatry; complementary medicine; medicinal plants; mood disorders; psychiatric disorders.

Received 11 March 2007Revised 23 March 2007

Accepted 28 March 2007

* Correspondence to: Jerome Sarris, School of Medicine, Department ofPsychiatry, University of Queensland, Brisbane, Australia.E-mail: [email protected]

INTRODUCTION

The role of herbal medicine (HM) in the treatmentof various psychological disorders has become wellestablished over the past decade, with phytotherapeuticpreparations such as St Johns wort (SJW) and kavapossessing respectable clinical evidence. Whilst therehave been several recent literature reviews on HM andpsychiatric disorders (primarily depression or anxiety;Beaubrun and Gray, 2000; Ernst, 2006; Larzelere andWiseman, 2002; Wong et al., 1998), to date no com-prehensive review of clinically trialled psychoactive HMsacross a broad range of psychiatric conditions has beenreported. A systematic literature search was conductedto identify relevant trials of HM in the treatment ofmajor psychiatric disorders (see Table 1 below for thelist of conditions reviewed). Developmental, cognitive/neurological, sleep, eating and substance-abuse dis-orders and menstrual dysphoria were excluded fromthe review.

METHODS

The electronic databases Ovid Medline, Pubmed andThe Cochrane Library were accessed late 2006early2007. Ovid Medline was searched using the search termHerb$ and the subheadings Plants, Medicinal, Drugs,Chinese Herbal, Plant Extracts, Phytotherapy, PlantPreparations in combination with the search termsDepress$, Major Depressive Disorder, Anxiety,Generalized Anxiety Disorder, Dysthym$, Seasonal

Table 1. Psychiatric conditions reviewed

Disorder

Mood disordersMajor depressive disorderDysthymic disorderAnxious depressionSeasonal affective disorderBipolar disorderAnxiety disordersGeneralized anxiety disorderPanic disorderSocial phobiaObsessive-compulsive disorderSomatoform disorderSchizophrenic and psychotic disorders


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Affective Disorder, Bipolar Disorder, Panic Dis-order, Phobi$, Obsessive Compulsive Disorder,Somatoform Disorder, Schizophrenic and PsychoticDisorder. Pubmed database was accessed, with MeSHbeing employed to search major psychiatric headingsDepressive Disorder, Depression, Dysthymic disor-der, Bipolar Disorder, Anxiety, Anxiety Disorders,Phobic disorders, Panic Disorder, Seasonal Affec-tive Disorder, Somatoform disorders, Psychotic Dis-orders, Schizophrenia, in combination with the MeSHterms, Medicine, Herbal, Plants, Medicinal, Plantextracts, Phytotherapy and Drugs, Chinese herbal.A forward search of the papers reviewed was sub-sequently performed using Web of Science cited refer-ence search.

A total of 27 HMs or formulas, with traditional ormodern psychotropic usage were individually reviewedin Pubmed and Ovid databases by conducting a searchusing the name of the HM e.g. St Johns wort ORHypericum (see Table 2 below; Bensky and Gamble1991, 1993; Mills and Bone, 2000). The hierarchyof evidence was addressed, with meta-analysis andrandomized controlled human clinical trials (RCTs)reviewed where possible (Altman et al., 2001; Gagnieret al., 2006). Non-randomized controlled human trialsand animal trials were reviewed where RCTs were lack-ing. In vitro studies were only reviewed to assess safetydata, constituents responsible for activity, or to furtherdetermine use. A primary focus was on evidenceconcerning whole herbal extracts (rather than isolatedconstituents) as occurs in standard phytotherapeuticpractice. Studies using intravenous, topical or inhalantadministration were excluded, as this method does notreect the pharmacokinetics and subsequent pharmaco-dynamic activity from oral delivery in humans.

MOOD DISORDERS

Major depressive disorder (MDD)

MDD or unipolar depression involves depressed moodor reduced interest or pleasure and is accompanied byat least four other additional symptoms (e.g. weight orappetite change, fatigue, psychomotor agitation, insom-nia or hypersomnia, lack of concentration, suicidal idea-tion, feelings of worthlessness or guilt and low libido;American Psychiatric Association: 2000: 349). Accordingto the World Health Organization (WHO), the preva-lence of MDD is growing, with an estimated 120 millionpeople (approximately 5.8% of men and 9.5% of women)experiencing a depressive episode in any given year(WHO, 2006). By 2020 MDD is expected to pose thesecond greatest health burden of any health disorder interms of quality of adjusted life years (Murray and Lopez,1997). MDD is the psychiatric condition in which themost phytotherapy research has been conducted, withSJW representing the vast majority of the research.

Hypericum perforatum (St Johns wort). Two meta-analyses were conducted reviewing the treatment ofMDD with SJW against placebo and synthetic anti-depressants (Linde et al., 2005; Roder et al., 2004). Theresults of the Linde et al. (2005) Cochrane review, whichincluded 37 RCTs of SJW (dosage: 3001200 mg/day)in the treatment of MDD, found that although evidenceregarding SJW extracts was inconsistent, several trialssuggest that SJW extract and standard antidepressantshave similar benecial effects. Meta-analysis of six largerand six smaller trials of SJW in major depressionrevealed a 1.15 (95% CI:1.021.29) and a 2.06 (95%CI:1.652.59) effect size, respectively, although the au-thors commented that signicant heterogeneity of theresults was seen. A 2004 meta-analysis of SJW (dosage:3001200 mg/day) in the treatment of mild to moderatedepression (Roder et al., 2004) reviewed 30 trials andconcluded a signicant advantage of SJW over placebo(n = 2129, relative risk, RR = 0.66, 95% CI 0.570.78,mean response: 53.3% SJW vs 32.7% placebo). Themeta-analysis also demonstrated a similar efcacy tosynthetic antidepressants (n = 2231, RR = 0.96, 95% CI3.06.6, mean response 53.2% SJW vs 51.3% syntheticantidepressants).

Consistent with the meta-analyses, inspection ofindividual studies showed that SJW was found todemonstrate similar or greater efcacy than syntheticantidepressants in 16 trials. Six RCTs tested SJW againstplacebo and uoxetine in treating MDD, as commonlyassessed via the Hamilton rating scale for depression(HAM-D) and clinical global impression (CGI). Fourstudies demonstrated that SJW had similar (Behnkeet al., 2002; Bjerkenstedt et al., 2005) or superior (Favaet al., 2005; Schrader, 2000) effects to uoxetine.An analysis of the sub-sample of a 12-week 3-armstudy discovered that SJW (LI 160 900 mg/day) ameli-orated depression-based vegetative presentations, whileuoxetine (20 mg/day) was statistically equivalent toplacebo (Murck et al., 2005). A 2006 study found lowerremission rates for SJW in comparison with uoxetine,although intention-to-treat analysis (ITT) showed nodifference between the groups (Moreno et al., 2006). Incomparison with paroxetine, SJW was statistically more

Table 2. Herbal medicines reviewed

Herbal medicine

Bacopa monnieraBanxia houpu (TCM formula)Centella asiaticaCrataegus spp.Crocus sativusCymbopogon citratusDan zhi xiao yao (TCM formula)Echium amoenumEphedra sinicaEscholzchia californicaHange-koboku-to (Kampo formula)Hypericum perforatumKami-shoyo-san (Kampo formula)Lavandula spp.Melissa officinalisPassiflora incarnataPiper methysticumRhodiola roseaSaiboku-to (Kampo formula)Sho-ju-sen (Kampo formula)Suanzaorentang (TCM formula)Scutellaria laterifloraTing-chih-wan (TCM formula)Valeriana spp.Withania somniferaXiao Yao San (TCM formula)Zizyphus jujuba



effective in treating moderatesevere depression (seenext paragraph for data; Szegedi et al., 2005). Whentrialled against sertraline (Zoloft), SJW was discoveredin four RCTs to provide the same outcome of efcacy,as measured via HAM-D, the Beck Depression Inven-tory (BDI) and CGI scales (Brenner et al., 2000; Gastparet al., 2005; Hypericum Depression Trial Study Group,2002; van Gurp et al., 2002). Other comparative trialsdemonstrated SJWs statistical equivalence to imipra-mine (Woelk, 2000), citalopram (Gastpar et al., 2006),maprotiline (Harrer et al., 1994) and amitriptyline(Wheatley, 1997) in treating MDD.

There are insufcient data on the use of SJW fortreating moderate to severe depression (HAM-D > 20).Due to a highly publicized trial (Hypericum Depres-sion Trial Study Group, 2002) indicating that SJW wasno more effective than placebo (although slightly moreeffective than sertraline), the herbal medicine is com-monly now only recommended for mild to moderatedepression (Clement et al., 2006; Lawvere and Mahoney,2005; Linde et al., 2005; Shelton et al., 2001). It must benoted, however, that the sertraline arm of the trial alsodid not perform any better than placebo, denoting alack of assay sensitivity. Conversely a 6-week 2005 RCT(n = 251) comparing SJW extract WS 5570 (900 mg/day), paroxetine (20 mg/day) and placebo in moderateto severe depression (HAM-D 22), demonstratedSJWs therapeutic superiority as assessed by the HAM-D scale (14.4 decrease- SJW (SD 8.8) to 11.4 decrease-paroxetine (SD 8.6); Szegedi et al., 2005).

There is also little evidence on the efcacy and safetyof SJW in treating adolescents with MDD. Two smallopen-label trials of SJW were identied where it wastrialled in adolescents less than 17 years old (Findlinget al., 2003; Simeon et al., 2005). Although the resultsof these trials were promising, neither had a placebogroup or randomization, and there was a high percent-age of drop-outs due to continuing depression or non-compliance. No denitive afrmation of efcacy can bereached from these data.

The mechanism of SJWs antidepressant action, asassessed by in vitro and in vivo studies, appears toinvolve non-selective inhibition of the neuronalre-uptake of serotonin, dopamine, norepinephrine,GABA and L-glutamate, decreased degradation ofneurochemicals, and a sensitization of and increasedbinding to various receptors (e.g. GABA, glutamateand adenosine; Butterweck, 2003; Mennini and Gobbi,2004; Zanoli, 2004). Human studies have also foundthat SJW modulates salivary and serum cortisol levels,and has a slight effect on growth hormone (Franklinet al., 2006; Schule et al., 2001). Hyperforin, hypericinand various avonoids appear to be responsiblefor the neurochemical modulation (Butterweck, 2003;Laakmann et al., 1998; Zanoli, 2004). There is still con-troversy, however, regarding the optimum phyto-chemical standardization required to exert maximalantidepressant activity in SJW. Efcacy has been estab-lished in the LI 160 preparation (Lichtwer Pharma,Berlin), which is standardized to 0.3% hypericin,and in the WS 5573 and WS 5572 extracts (Schwabe,Germany), which are standardized to 0.5% and 5%hyperforin, respectively (Blumenthal, 2000). Althoughstudies have demonstrated hyperforins dose-dependentantidepressant activity, this does not necessarily indicatethat hyperforin is the only active constituent responsible

for SJWs efcacy, as hypericin-rich, low-dose hyperforinextracts have demonstrated similar antidepressanteffects. As occurs in all herbal medicines, synergybetween constituents may be a vital aspect of efcacy(Williamson, 2001), as evidence demonstrates thatthe absence of rutin, a simple avonoid constituent inSJW, reduces the antidepressant activity (Wurglics andSchubert-Zsilavecz, 2006).

The safety prole of SJW is very sound, with a sys-tematic review detailing that the degree of adverseeffects in 35 562 pooled patients was 0%5.7%, whichwas comparable to placebo (Knuppel and Linde, 2004).In a 2006 review of 16 post-marketing surveillancestudies (n = 34834: Schulz, 2006), SJW was deemed tobe 10-fold safer than synthetic antidepressants (adverseeffects- 0.1% to 2.4%). Apart from rare idiosyncraticreactions, most adverse effects involve reversible der-matological and gastrointestinal effects. Serotonin syn-drome has been documented in case studies (Knuppeland Linde, 2004; Rodriguez-Landa and Contreras, 2003),however, a direct pharmacodynamic interaction hasnot yet been established. Case studies have detailedpossible SJW-induced mania and psychosis, and will becovered later. Overall, SJW has demonstrated equalefcacy to pharmaceutical antidepressants, with a morefavourable side-effect prole and fewer drop-outs thanits synthetic counterparts. Consequently, SJW has beenrecommended as a rst-line treatment in milder formsof depression (Roder et al., 2004).

The main caveat to prescribing SJW is its potentialfor drug interactions, including a tendency to reducethe serum levels of many pharmaceuticals. Currentevidence suggests that this is due to hyperforin increas-ing the expression of the pregnane X receptor, whichincreases P-glycoprotein expression (the drug efuxpump; Dresser et al., 2003; Izzo, 2004; Moore et al.,2000). It should be noted that low hyperforin prepara-tions may not affect this response and hence may besafer (Izzo, 2004; Mueller et al., 2006).

Crocus sativus (Saffron). In traditional Persian medi-cine, saffron has been used to treat depression, withfour RCTs currently existing supporting this use. Twotrials using 30 mg of saffron demonstrated improvementof depression over placebo as assessed by the HAM-Dscale (Akhondzadeh et al., 2005; Moshiri et al., 2006).An equivalent therapeutic response was achieved intwo RCTs comparing saffron with the synthetic agents,imipramine and uoxetine (Akhondzadeh et al., 2004;Noorbala et al., 2005). These results are encouraging,although the short study time (6 weeks) and smallsample size (3040 patients) limit condence in theresults. One caveat in the adopting saffron into thephytotherapeutic materia medica is that the cost maybe prohibitive.

Rhodiola rosea (Roseroot). One of the most promis-ing plant medicines in the treatment of depression isRhodiola rosea, a stimulating adaptogen capable ofexerting antidepressant activity (Kelly, 2001; Kucinskaiteet al., 2004). Studies detailing efcacy in treatingdepression and fatigue are Russian in origin and wereunable to be located. One trial that could be accessed,investigated the inuence of roseroot on variousmental and biological parameters of 161 1921 yearolds, discovering a pronounced antifatigue effect


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(Shevtsov et al., 2003). This adaptogenic activity incombination with purported monoamine modulation,indicates a novel application in monopolar depres-sion (Stancheva and Mosharrof, 1987, cited by Kelly,2001).

Lavandula spp. (Lavender). Lavender has a longtraditional use in treating nervous system disorders(Felter and Lloyd, 2006 (1898)). One small study existsto date assessing Lavandula angustifolias antidepres-sant activity. A 4-week RCT was conducted comparinglavender tincture (1:5 50% alcohol, 60 drops) againstimipramine, in patients (n = 45) with a HAM-D ratingof at least 18 (Akhondzadeh et al., 2003). The resultsdemonstrated that although the herbal extract was lesseffective than its synthetic counterpart, the combina-tion of both was more effective than imipramine alone,indicating a synergistic effect.

Echium amoenum (Borage). Borage is used in tradi-tional Persian medicine as an anxiolytic and thymolepticremedy. An RCT evaluated the effectiveness of boragein ameloriating anxiety and depression (Sayyah et al.,2006). The RCT employed a single 375 mg dose ofEchium amoenum per day for 6 weeks against placebo,in 35 patients with depression and anxiety, assessed viaHAM-D and the Hamilton anxiety scale (HAM-A).Whilst the herbal medicine displayed no distinctiveanxiolytic activity, it showed superiority over placeboin reducing depression.

Dan zhi xiao yao. This TCM formula is modied fromthe Xiao yao san (Rambling powder) herbal prepara-tion which is commonly used in TCM to treat depres-sion by moving stasis (Bensky and Gamble, 1991); ithas the addition of Dan zhi (Cortex Moutan) used toclear heat in cases of irritable depression. A 2006 RCTcompared the formula with maprotiline in 63 patientsassessed with depression via the HAM-D, self-ratingdepression scale (SDS), self-rating anxiety scale (SAS)and the scale for TCM syndrome and symptom differ-entiation (Luo et al., 2006). There was no statisticaldifference between the maprotiline and Dan zhi xiaoyao groups, with both being highly effective in treat-ing depression (84% and 87% depression reduction,respectively).

Banxia houpu. Banxia houpu, a TCM formula consist-ing of Pinellia ternata, Poria cocos, Magnolia ofcinalis,Perilla frutescens and Zingiber ofcinale has been usedfor the treatment of depression-related diseases sinceancient times. Whilst no human clinical data exist todate determining efcacy, animal models have demon-strated antidepressant activity comparable to uoxetinein tail suspension and forced swimming tests (Li et al.,2003; Luo et al., 2000). An increase in serotonin (5-HT)and 5-hydroxyindoleacetic acid (5-HIAA) levels wasfound to the occur in mouse hippocampus and striatum.

In an animal model of depression where rats wereexposed to a variety of mild stressors for a prolongedperiod of time (Wang et al., 2005), banxia houpudecoction decreased the level of the triglycerides inserum, enhanced the activity of the natural killer cellsin the spleen, decreased the activity of superoxidedismutase in red blood and the activity of the nitricoxide synthase in serum and tissue, and reduced the

content of malondialdehyde in tissue via the effect onlipid peroxidation.

Dysthymic disorder (DD)

Dysthymic disorder is characterized in DSM-IV as apersistent low mood (although not meeting the criteriaof MDD) occurring for at least 2 years on most daysmore than not (American Psychiatric Association 2000:376,377). Only two studies were found on the herbaltreatment of dysthymia. A 2006 RCT (n = 150) using astandardized SJW extract PM235 (810 mg/day) observedthat whilst signicant improvement occurred in non-dysthymic depressed patients, no statistical improve-ment was discovered in ICD-10 depressed dysthymicpatients as assessed via HAM-D, a visual analoguescale (VAS) and BDI (Randlov et al., 2006). A non-randomized open study of patients with dysthymia (n =15) found that an Ayurvedic combination of herbs (GS-02) was effective in the majority of cases as assessed viaan intention-to-treat analysis (ITI) (Andrade et al.,2002), although the non-RCT design and small samplesize prohibited a denitive conclusion. As discussed inRandlov et al. (2006) it is possible that herbal interven-tion may not succeed in ameliorating low mood, asdysthymia may be an established melancholic person-ality trait in certain people, and is not necessarily apathological manifestation.

Seasonal affective disorder (SAD)

Controversy exists regarding the exact classication ofseasonally provoked mood disorders (Magnusson andPartonen, 2005), with SAD being the term commonlyadopted (American Psychiatric Association, 2000:425,426). To date, three trials have been performedusing herbal agents in SAD. Two open-label trials us-ing SJW alone and SJW plus light therapy found therewas a signicant reduction of winter-provoked depres-sion compared with placebo, although there was no sta-tistical difference between the two treatments (Martinezet al., 1994; Wheatley, 1999). However, a more rigorousRCT using Ginkgo biloba extract PN 246 to preventthe onset of SAD in 27 people, found no differencebetween the active and placebo group as dened byMontgomery-Asberg depression rating scale (M-ADS)and VAS (Lingaerde et al., 1999). Currently, the equi-vocal evidence available indicates no specic herbalintervention to condently treat SAD.

Bipolar disorder I/II (BD)

Bipolar II disorder is characterized in the DSM-IV as acondition whereby periods of MDD are accompaniedby one or more hypomanic episodes, while in contrast,bipolar disorder I is diagnosed by the occurrenceof one or more full-blown manic episodes with or with-out MDD (American Psychiatric Association, 2000:382,392). One study tested an herbal formula in treat-ing bipolar disorder. A recent 12-week double-blind,randomized, placebo controlled trial (Zhang et al., 2007)with 235 participants tested whether an adjunctiveTCM herbal therapy with an orthodox pharmaceutical



mood-stabilizer would increase therapeutic efcacy. Thedesign compared carbamazepine 300 mg/day, placeboand carbamazepine 3000 mg/day + Xiao yao san 36 g/day (an herbal formula traditionally used to treat de-pression and stress). The results revealed that Xiao yaosan with carbamazepine signicantly reduced depres-sion greater than placebo or cabamazepine alone, buthad no impact on further reducing mania than the phar-maceutical monotherapy. Although herbal interventionin bipolar conditions may have a future role, it is cur-rently recommended that HMs are trialled only as anadjunctive therapy in cases of pronounced mood oscil-lation, given the potentially harmful consequences frominadequately treated mania (Currier and Trenton, 2002;Mohr et al., 2005).

Cases of HM-induced mania have been documentedwith SJW (Fahmi et al., 2002; Guzelcan et al., 2001;Nierenberg et al., 1999; Stevinson and Ernst, 2004),Ephedra sinica (Boerth and Caley, 2003; Maglioneet al., 2005), Ginkgo biloba (Spinella and Eaton, 2002)and ginseng (type not specied) (Vazquez and Aguera-Ortiz, 2002). It should be noted, however, that high-dose SJW or concomitant pharmaceutical or recreationaldrugs were involved in most cases. Furthermore, causallinks could not be established in these cases due to alack of re-challenge with the herbal medicine involved.Although herbal-induced mania appears to occuridiosyncratically, monitoring is advised in cases of high-dosage, with use in patients with known bipolar dis-orders, and especially when Ephedra sinica is used.

ANXIETY DISORDERS

Generalized anxiety disorder (GAD) and non-specied anxiety

GAD is diagnosed in persons with excessive worry andanxiety, accompanied by more than three somatic symp-toms (e.g. tension, irritability) which occurs more daysthan not, for a period of at least 6 months (AmericanPsychiatric Association, 2000: 472). GAD is second onlyto MDD as the most commonly diagnosed psychiatriccondition in primary care (Antai-Otong, 2003). Al-though the DSM-IV categorizes the 1 year prevalenceof this condition as being approximately 3%, a samplesize of 10641 Australians being interviewed in 2002revealed a prevalence in the total sample of 2.8% for1-month GAD and 36% for 12-month GAD, indi-cating that anxiety is endemic and more research, treat-ment and education is needed urgently (Hunt et al.,2002). Anxiety represents the broadest area of researchof HM in psychological disorders, with around 10 indi-vidual phytomedicines possessing documented anxiolyticactivity. Kava is the HM that has been extensivelyresearched as the premiere anxiolytic, albeit with con-troversy existing regarding its safety due to cases ofhepatotoxicity.

Piper methysticum (Kava). The South Pacic medicinalplant Kava kava (kava) has traditional uses as a relax-ing soporic and is used extensively in modern phyto-therapy to treat a variety of ailments, in particularanxiety. A 2003 Cochrane review of randomized,double-blind, controlled trials of rigorous methodology

using kava monopreparations (60280 mg of kavalac-tones) in anxious conditions discovered 12 trials thatmet the inclusion criteria, seven of which were used ina meta-analysis using HAM-A as the outcome measure(Pittler and Ernst, 2006). Results of the review docu-mented a statistically signicant anxiolytic activity com-pared with placebo in all but one trial, demonstratingthat kava is an effective short-term treatment of anxi-ety. The meta-analysis of seven homogenous trialsusing HAM-A demonstrated that kava reduced anxi-ety signicantly over placebo (weighted mean differ-ence 3.9 over placebo on the HAM-A; 95% CI: 0.1 to7.7 p = 0.05; n = 380). Another meta-analysis based onsix placebo-controlled, randomized trials using kavaextract WS1490 in anxiety (assessed via HAMA-A)demonstrated similar ndings, with a mean improve-ment of 5.94 better than placebo (95% CI: 0.86 to12.8; Witte et al., 2005).

Although no trials using kava on adolescents orchildren were found, a 3-month randomized prospec-tive open study investigating kava in perimenopausalwomen with climacteric conditions has been con-ducted (Cagnacci et al., 2003). The 3-arm study con-sisted of a calcium supplementation control (n = 34),calcium plus 100 mg/day of kava (n = 15) or calciumplus 100 mg/day of kava (n = 19). The reduction ofanxiety with kava was signicantly greater than that incontrols as assessed via State trait anxiety index (STAI).Depression also declined at 3 months (5.03+/1.4)as assessed via Zungs depression scale, indicating athymoleptic effect that may be a future area of researchfor kava.

An insufciency of trials exists regarding the efcacyof kava compared with synthetic agents such as benzo-diazepines or antidepressants. One study assessed kavain comparison with the synthetic agents buspirone oropipramol in treating GAD using an 8-week (n = 129)randomized, controlled, double-blind, multi-centre clini-cal trial (Boerner et al., 2003). The study had a primaryoutcome measure of HAM-A, with secondary meas-ures including the Boerner anxiety scale, SAS, CGI, aself-rating scale for well-being, a sleep questionnaire, aquality-of-life questionnaire (QOL) and global judge-ments by investigator and patients. The results of thestudy found no signicant differences between kavaand buspirone or opipramol regarding all efcacy andsafety measures. 75% of patients were classied asresponders (50% reduction of HAM-A score) in eachtreatment group with 60% achieving full remission.An animal study using the elevated plus maze testdemonstrated anxiolytic activity similar to diazepam,as assessed via the elevated plus maze, the Wistar ratsincreasingly spending time in open arms and displayingmore risk behaviour (Rex et al., 2002).

Anxiety disorders are associated with low vagalcontrol of heart rate and increased risk of cardiacmorbidity and mortality. A novel study involving 13subjects evaluated kavas potential in improving vagalcontrol in suffers of GAD (Watkins et al., 2001). Thetwo indices of vagal control involved power spectralanalysis (baroreex control of heart rate (BRC) andrespiratory sinus arrhythmia). Results demonstrated thatsignicantly more patients treated with kava showedimproved BRC compared with the placebo group,reecting a favourable effect on reex vagal control ofheart rate in patients with GAD.


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The exact pharmacodynamic mechanism responsiblefor kavas action is still undened, with conicting evi-dence regarding the modulation of various GABAreceptors (Davies et al., 1992; Jussoe et al., 1994; Yuanet al., 2002). Other purported pharmacodynamics in-volve a down-regulation of -adrenergic activity (Singhand Singh, 2002). Further research is needed to clarifythe exact mechanism of kavas anxiolytic and hypnoticactivity.

Concerns of hepatotoxicity have emerged in recentyears prompting post-marketing, clinical and toxico-logy studies to be performed to assess the safety of kava.A 2002 review of kava was conducted to assess kavassafety prole via literature searches of four electronicdatabases, papers reference lists, spontaneous report-ing schemes of the WHO and national drug safetybodies and ten manufacturers of kava preparations(Stevinson et al., 2002). The data from short-term post-marketing surveillance studies and clinical trials sug-gest that adverse events are, in general, rare, mild andreversible. The review stated that although idiosyncratichealth events have occurred, no serious adverse eventswere noted except for case reports (not found in thetrials) of hepatotoxicity and theoretical potentiationof alcohol and benzodiazepines. Seventy-eight casesof hepatotoxicity have been documented to 2003,including 11 cases of hepatic failure leading to livertransplants and four deaths occurring. Many casesinvolved the concomitant ingestion of other compoundswith potential hepatotoxicity (e.g. medications and/oralcohol). There are several possible mechanisms forkavalactone hepatotoxicity: inhibition of cytochrome(CYP) P450, reduction in liver glutathione content orother enzymes needed to metabolize kavalactonesor inhibition of cyclooxygenase enzyme activity (all ofwhich may be caused by the kavalactones), concomi-tant drug or alcohol use, or a genetic CYP P450 insuf-ciency (Anke and Ramzan, 2004; Clouatre, 2004;Stevinson et al., 2002).

A recent in vivo trial sought to evaluate the potentialheptotoxicity of kava (Sorrentino et al., 2006). Wistarrats were fed 7.3 or 73 mg/kg body weight of ethanolkava extract for 3 and 6 months with no change in bodyweight, haematological and liver parameters, and macro-scopic and microscopic histological changes in themajor organs noted. A study of kava use (Av. 118 g/week, median duration of use = 12 years) in an ArnhemLand community in the Northern Territory of Australia(n = 340) was conducted in 2003 to assess anyhepatotoxicity (Clough et al., 2003). In kava users whowere not heavy alcohol users, only those who used kavawithin the previous 24 h displayed GGT levels higherthan nonusers, whereas higher ALP levels occurred onlyin those who last used kava 12 weeks and 24 h previ-ously. Liver function changes in users of aqueous kavaextracts at these moderate levels of consumption ap-pear to be reversible and began to return to baselineafter 12 weeks abstinence from kava. No evidence ofirreversible liver damage has been found, although thestudy indicated that liver function parameters can bealtered in humans with moderate kava use.

Unlike SJW, few human studies and case evaluationsof CYP 450 enzyme interaction have been conductedand hence potential kavadrug interactions need to bestudied further in-depth (Singh, 2005). One humanpharmacokinetic trial (n = 12) using probe drug cock-

tails of midazolam and caffeine, followed 24 h laterby chlorzoxazone and debrisoquin, determined thatkava caused CYP2E1 inhibition (approximately 40%)(Gurley et al., 2005). Kavapyrones from kava were foundin an in vitro assay to inhibit CYP3A4 (Unger et al.,2002). Whole kava extract (normalized to 100 Mtotal kavalactones) caused concentration-dependent de-creases in P450 activities, with signicant inhibition ofthe activities of CYP1A2 (56% inhibition), 2C9 (92%),2C19 (86%), 2D6 (73%), 3A4 (78%) and 4A9/11 (65%)following pre-incubation (Mathews et al., 2002). Anin vitro study evaluating CYP and pregnane X receptormodulation in rat hepatocytes treated with puriedkavalactones discovered that dihydromethysticin anddesmethoxyyangonin induced CYP3A23 via pregane Xtranscription activation (Ma et al., 2004). Regardlessof in vivo animal and in vitro trials assessing CYP450 and pregnane X modulation, to date no adverseevents have been documented in humans occurringfrom kavas potential pharmacokinetic interactionwith pharmaceutical medicines. Potential interaction ofkava with benzodiazepines causing increased sedationhas been posited (Singh, 2005; Stevinson et al., 2002),however, no clinical evidence currently supports thishypothesis.

The future of the therapeutic use of kava remainsuncertain, with safety concerns still restricting prescrip-tion in many countries. The risk-benet ratio is highlyfavourable towards kava due to respectable clinicalefcacy and relative low risk of potential liver toxicity(1 case/1 million monthly doses (Bauer, 2003). Ascurrent synthetic pharmacological treatment involvingbenzodiazepines possesses far greater adverse effects(Rickels and Rynn 2002; Stevinson et al., 2002), kavastill has an important place in the therapeutic pantheon.The solution appears to involve kava being removedfrom OTC use (to be available only via professionalprescription), the use of aqueous root preparationsstandardized for kavalactones (at daily doses of



future research (Hadley and Petry, 2003). A recentCochrane review of valerian for anxiety disorders foundonly one trial using a mono-preparation of valerian,and deemed that there is currently inadequate evidenceto support such therapeutic application (Miyasakaet al., 2006). The study examined in the review wasa three-arm 2002 RCT (n = 36) using valepotriates(81.3 mg mean daily dose) in comparison with placeboand diazepam control arms (Andreatini et al., 2002).The study revealed no signicant difference betweenthe groups in reducing anxiety as determined via theHAM-A and STAI-trait scales. However, the samplesize was small, and although valepotriates are con-sidered to be an active constituent of valerian, theydegrade easily and may not survive processing. Con-trary to a statement of the Cochrane review of Miyasakaet al. (2006), a valepotriate blend is not valerian asit is not a whole galenic extract of the plant, whichcontains many active constituents that produce asynergistic therapeutic action (Williamson, 2001).

A 6-week cross-over pilot study using valerian and avaleriankava combination in stress-induced insomnia(n = 24) determined that total stress severity was sig-nicantly relieved by both compounds, with no signi-cant differences between them (Wheatley, 2001). Whilststress parameters cannot be specically transferred toclinical anxiety, the results indicate that the compoundis perceived by subjects as calming and hence mayindeed exert an anxiolytic effect if such a diagnosticscale was employed. A large novel 8-week internet-based RCT (n = 391) using a valerian (6.4 valerenicacids/day) + placebo, kava (300 mg kavalactones/day) +placebo or double placebo was conducted to determineefcacy in treating comorbid anxiety and insomnia(Jacobs et al., 2005). The primary outcome measureused in rating change in anxiety was STAI-State. Theresults suggested that neither kava nor valerian relievedanxiety insomnia more than placebo. Although theseresults may be accurate, the design of the trial presentsseveral potential problems, with internet recruitmentfor trials resulting in samples of questionable repre-sentativeness, and the STAI-state having inadequatetestretest reliability to be a sensitive measure of thera-peutic change in anxiety. Robust RCTs assessing wholeextracts of valerian appropriately administered (e.g. 1 gthree times daily) to an adequate sample size are neededto determine if clinical efcacy exists in the treatmentof anxiety.

Hypericum perforatum (St Johns wort). Although SJWis prescribed commonly for its antidepressant activity,emerging data indicates that the HM may also possessanxiolytic activity, supporting the traditional use in avariety of nervous system complaints (Culpeper, 1652:139,140; Felter and Lloyd, 2006 (1898)). Two animalstudies document anxiolytic and anti-panic activity viaa lightdark test and observation of inhibitory avoid-ance and one-way escape (Beijamini and Andreatini,2003; Vandenbogaerde et al., 2000). The anxiolyticactivity is proposed to involve a modulation ofGABA and potentiation of benzodiazepine receptoragonism. No anxiety-specic human trial was located,although a RCT comparing imipramine and SJW indepression revealed a statistically signicant changeon the Hamilton Anxiety-Somatization subscale (Woelk,2001).

Scutellaria lateriora (Scullcap). Scullcap is a HMthat has traditional use as a sedative in variousnervous system disorders in Native American andEclectic medicine (Felter and Lloyd, 2006 (1898)). Todate, two studies have documented anxiolytic activity.In an animal maze-test model, scullcap displayed anxioly-tic effects via increasing the number of unprotectedhead dips and entries into open-eld area and arms,with the compounds baicalin and baicalein purportedto be involved in this activity via GABA(A) binding(Awad et al., 2003). A double-blind, placebo-controlledcross-over study of healthy adults (n = 19) revealedthat scullcap dose-dependently reduced symptoms ofanxiety and tension after acute administration comparedwith control (Wolfson and Hoffmann, 2003).

Melissa ofcinalis (Lemon Balm). Lemon balm hastraditional usage as a mild sedative and spasmolyticagent (Bone, 2003: 308; Felter and Lloyd, 2006 (1898)).An RCT was conducted with 20 participants whowere given single doses of 300, 600 and 900 mg of lemonbalm or a matching placebo at 7-day intervals. Self-rated calmness, as assessed by Bond-Lader mood scaleswas elevated at the earliest time points by the lowestdose, whilst alertness was signicantly reduced at alltime points following the highest dose (Kennedy et al.,2002). A double-blind, placebo-controlled, randomized,balanced cross-over experiment (n = 18) using twoseparate single doses of a standardized lemon balmextract (300 mg, 600 mg) and placebo (Kennedy et al.,2004), determined that acute dosing of Melissa ofcinalisdemonstrated a signicant increase in self-rated calm-ness and reduced alertness in subjects via a denedintensity stressor simulation (DISS) test. A later double-blind, placebo-controlled, randomized, balanced cross-over experiment utilizing a standardized productcontaining lemon balm and valerian extracts in healthyvolunteers (n = 24) assessed mood and anxiety via aDISS test (Kennedy et al., 2006). The results demon-strated that a 600 mg dose of the combination amelio-rated the negative effects of the DISS the level ofanxiety. A combined valerian and lemon balm prepa-ration (2 2 tablets/day of 160 mg valerian root dryextract (4-5:1) and 80 mg lemon balm leaf dry extract(4-6:1)) was investigated in a 4 week open, multi-centrestudy in children less than 12 years (n = 918) sufferingfrom restlessness and nervous dyskoimesis (Muller andKlement, 2006). The primary symptoms of dyssomniaand restlessness were reduced from moderate/severeto mild or absent in most of the children, with 70.4%of the patients with restlessness improving. Both par-ents and investigators assessed efcacy as very goodor good (60.5% and 67.7%, respectively).

Eschzoltzia californica (California poppy). Californiapoppy has been used by Native Americans and Ecleticphysicians as a sedative, analgesic and anxiolytic (Felterand Lloyd, 2006 (1898)). An animal model conrmedanxiolysis in a familiar environment test (Rolland et al.,1991). Administration of California poppy (25 mg/kg)increasing the numbers of steps climbed (an anti-conict test) and the amount of time the animals spentin the lit area. California poppy possesses an afnitywith benzodiazepine receptors, with umazenil (abenzodiazepine receptor antagonist) suppressing thesesedative and anxiolytic effects (Rolland et al., 2001).


710 J. SARRIS

Crataegus spp. (Hawthorn berry/leaf). Although haw-thorn is usually prescribed in phytomedicine for car-diovascular complaints, an arena in which it possessesrobust evidence of efcacy (Pittler et al., 2003; Rigelskyand Sweet, 2002), emerging data indicate a use inanxiety, especially where somatic cardiovascular symp-toms present (e.g. tachycardia). An RCT administering500 mg of hawthorn extract to mildly hypertensivepatients (n = 36) discovered in a secondary outcomemeasure a nonsignicant trend (p < 0.10) towardsreduction of anxiety, compared with placebo (Walkeret al., 2002). A later double-blind, randomized, placebo-controlled trial involving adults presenting with mild-moderate GAD as assessed via DSM-III-R (n = 264),were prescribed two tablets containing xed quan-tities of Crataegus oxyacantha (300 mg), Eschscholtziacalifornica (80 mg) and magnesium (300 mg elemental)twice daily for 3 months (Hanus et al., 2004). Total andsomatic Hamilton scale scores, subjective patient-ratedanxiety and physicians CGI were used as outcomemeasures. The results demonstrated the formula mark-edly ameliorated anxiety in comparison with placeboas determined by HAM-A and subjectively assessedanxiety.

Cymbopogon citratus (Lemongrass). A traditionalBrazilian herbal medicine, lemongrass (abafado) iscommonly prepared as a tea from the dried leaves.Lemongrass infusion was evaluated for hypnotic andanxiolytic activity in 50 participants (Leite et al., 1986).The rst phase of the trial tested the effect of lemongrassextract on sleep parameters, and found no differencecompared with placebo. A subgroup (n = 18) with hightrait-anxiety scores were evaluated on an anxiety-inducing test after lemongrass administration. Therewere no differential anxiolytic effects after acuteadministration compared with placebo.

Centella asiatica (Gotu Kola). Gotu Kola has beenused for centuries in Ayurvedic and traditional Pan-Pacic medicine for a variety of therapeutic applica-tions, including treatment of anxious and depressivecomplaints (Bone, 2003: 255). A double-blind, placebo-controlled study was undertaken to evaluate theanxiolytic activity of gotu kola via the acoustic startleresponse (ASR) in 40 healthy participants (Bradwejnet al., 2000). Subjects were randomly assigned toreceive either a single 12 g orally administered dose ofgotu kola or placebo. Compared with placebo, gotukola signicantly attenuated the peak ASR amplitude30 and 60 min after treatment indicating anxiolyticactivity in humans.

Zizyphus jujuba (Sour date seed). Sour date seed isused in TCM to nourish the heart and calm the spirit(the Western equivalent of anxiolysis) and often isprescribed as the formula suanzaoren to aid in sleep orcalm the mind (Bensky and Gamble, 1991: 404). Aninitial study of suanzaoren supported this traditionaluse demonstrating sedative activity (Chen et al., 1985).Animal studies later revealed that aqueous extract ofthe seed potentiated sleep induced via hexobarbital-Naand diazepam (Morishita et al., 1987) and pentobarbital-Na (Li et al., 2001). The jujubosides are regarded asactive constituents in the activity of sour date seed,displaying in an animal model inhibition of glutamate-

mediated pathways in the hippocampus (Zhang et al.,2003). Other studies using suanzoaren in animalmodels have documented modulation of central mono-amines and have posited the main locus of activityto involve the limbic system and a decreased turnoverof central monoamines and central catecholaminergicactivity (Hsieh et al., 1986a; Hsieh et al., 1986b). Whileinitial in vivo studies are promising, to date no humanclinical trials using Zizyphus jujuba appear to havebeen conducted.

Withania somnifera (Ashwagandha). Classied inAyurvedic medicine as a rasayana, a medicine used toenhance physical and mental performance and wardoff disease, ashwagandha has been adopted into West-ern herbal material medica for its use in nervous systemand endocrine disorders (Bone, 2003: 73,74). An animalstudy observed adaptogenic effects of ashwagandha ina stress-inducing procedure, via the attenuation of stress-related parameters (cortisol levels, mental depression,sexual dysfunction (Bhattacharya and Muruganandam,2003). The purported active constituents, the glyco-withanolides, were administered orally in an in vivo rattrial once daily for 5 days, and were discovered to in-duce an anxiolytic effect comparable to that producedby lorazepam relevant tests (elevated plus-maze, socialinteraction and feeding latency in an unfamiliar envi-ronment, tests; Bhattacharya et al., 2000).

Bacopa monniera (Brahmi). Although Brahmi isusually studied for its reputed cognitive enhancingactivity, the HM has traditional use in treating anxiety,insomnia and insanity (Bone, 2003: 80). One studywas located assessing Brahmi effect on anxiety, the 2001RCT using 300 mg of Bacopa monniera revealing amarked reduction of state anxiety compared with pla-cebo after 12 weeks of treatment (Stough et al., 2001).

Ginkgo biloba (Maidenhair). Although Ginkgo bilobais commonly used therapeutically to treat dementia,cognitive decline, peripheral arterial disease and tinnitus,studies have noted that mood modulation can occur incognitively impaired subjects. A 2006 RCT (n = 107)was conducted using Ginkgo biloba EGb 761 extract(480 mg or 240 mg per day) or placebo for 4 weeks inadults with GAD or adjustment disorder with anxiousmood as assessed via DSM-III-R (Woelk et al., 2007).Intention-to-treat (ITT) analyses were performed onthe primary outcome measure HAM-A, and the sec-ondary outcome measures the CGI, the Erlangen anxi-ety tension and aggression scale (EAAS), the list ofcomplaints (B-L), and the patients global rating ofchange. The subjects HAM-A total scores decreasedby 14.3 (8.1), 12.1 (9.0) and 7.8 (9.2) in the480 mg per day Ginkgo biloba group, the 240 mg Ginkgobiloba group and the placebo group, respectively. Theresults indicated specic dose-dependant anxiolysis com-pared with placebo in both the higher-dose and lower-dose group.

TCM and Kampo formulations. Oriental herbal medi-cine practice consists of using pre-established formula-tions of various herbal medicines, many of which aremany centuries old. A caveat is that the therapeuticoutcome from specic herbal formulations is oftenbased on the skill of the practitioners diagnostic and



prescriptive skills in matching individual formulas tohealth patterns. The creation of clinical trials using TCMand Kampo formulas is challenging. Regardless, clinic-ally studied evidence of the psychopharmacological useof oriental medicines is increasing, as detailed below.

Saiboku-to, an oriental herbal medicine has beenevaluated for its attenuation of anxiety in mice, usinga light/dark test and histaminergic-induced anxiety(Yuzurihara et al., 2000). Saiboku-to exhibited anxiolyticactivity in both models, the authors postulating thatthe activity was due to an anti-histaminergic effect. Sho-ju-sen, a Japanese traditional Kampo herbal medicine,triggered no signicant change in anxiolytic parameters,as observed via the plus-maze or activity test followinga single administration of the formula (Kuribara et al.,2001). When the Kampo formula was administered for5 days it did demonstrate anxiolysis compared withdiazepam, assessed via a signicant prolongation of thetime the mice spent in the open arms of the maze. Thissuggests that long-term treatment of Sho-ju-sen maybe necessary to ameliorate anxiety. Benzodiazepinereceptor modulation is believed responsible for thisactivity. Ting-chih-wan, an oriental medicine formula,demonstrated anxiolytic activity in an animal model,via a black and white test and elevated plus-maze(Lin et al., 2003). This action was conrmed by theauthors as involving a decreased catecholaminergicactivity, caused by an increase in the turnover rateof catecholamines in the brain and decreased con-centrations of 5-HT in the brain stem, by activatingsomatodendritic 5-HT1A auto-receptors and inhibitingpostsynaptic 5-HT receptors.

Panic disorder/agoraphobia

Panic attacks can occur in the context of other mooddisorders, medical conditions or substance-related dis-orders. The disorder is marked by the presentation ofchronic periods of intense fear in the absence of realdanger, with at least four cognitive or somatic symp-toms (e.g. shaking, tachycardia, sweating) (AmericanPsychiatric Association, 2000: 430-431). To date, noRCTs with HM exist. Four case studies, however, havebeen documented using Kampo herbal medicines Kami-shoyo-san (TJ-24) and Hange-koboku-to (TJ-16) inpatients with panic disorder and agoraphobia (Mantaniet al., 2002). The Kampo medicines, which principallyconsist of peony, bupleurum and dang gui, relieved panicattacks, anticipatory anxiety and agoraphobia. Ananimal model evaluated the antipanic/anxiolytic effectof standardized SJW extract (LI 160) on rats tested inthe elevated T-maze (Beijamini and Andreatini, 2003).Repeated administration of SJW (300 mg/kg) inducedan anxiolytic effect (decreased inhibitory avoidance)and an anti-panic effect (increased one-way escape).

Social phobia

Social anxiety disorder is characterized by persistentfear of social or performance situations in which markedstress and or embarrassment occurs. There is avoidanceof these situations and signicant interference withthe social functioning (American Psychiatric Associa-tion, 2000: 450451). HM in the treatment of social

phobia has been documented (Boerner, 2001). A casestudy of a 37 year old female patient suffering fromGAD and both simple and social phobias achievednearly complete remission after 6 months of treatmentwith 3 tablets of LI 150 kava extract (equivalent to135 mg of kava pyrones per day). One RCT triallingHM in social phobia was found. A placebo-controlledpilot study using SJW (exible-dose 6001800 mg daily)for 20 people with social phobia (as assessed via theLiebowitz Social Anxiety Scale), found no signicantdifferential impact over placebo, although a trendtowards improvement was demonstrated (Kobak et al.,2005b).

Obsessive-compulsive disorder (OCD)

The primary features of OCD are unreasonablerecurrent obsessions or compulsions that are sufcientlysevere to consume time and cause marked distress(American Psychiatric Association, 2000: 456,457). A12-week open-label exploratory study was conductedevaluating SJW (450 mg 0.3% hypericin 2/day) in thetreatment of OCD patients (n = 12) as assessed via theY-BOCS, the Patient Global Impressions of Improve-ment Scale, HAM-D and the CGI (Taylor and Kobak,2000). The results demonstrated a signicant change of7.4 points in Y-BOCS after 12 weeks, with ve patients(42%) being rated much or very much improved, six(50%) were minimally improved, and one (8%) hadno change on the clinician-rated CGI. A recent studysought to validate these results in a 12-week RCT(Kobak et al., 2005a). SJW (LI 160) at a exible doseof 6001800 mg/day or placebo was administered to60 adults with OCD. SJW did not ameliorate OCD onthe Y-BOCS (3.43) in comparison with placebo (3.60),or differentially affect clinician rating. As in the caseof social phobia, anxiolytic herbal medicines such askava, valerian or passionower may provide a moresuitable therapeutic intervention, as OCD presentswith anxious symptomatology (American PsychiatricAssociation, 2000: 457).

Depression with anxious symptoms (AnxD)

No diagnosis of AnxD is identied in DSM-IV (Ameri-can Psychiatric Association, 2000), and GAD cannotbe diagnosed as present unless symptoms cannot beexplained by the presence of MDD. However, anxietysymptoms are endemic in depression (Kessler et al.,2003), and true comorbidity of depressive and anxiousconditions commonly occurs (Hunt et al., 2004; Sartoriuset al., 1996). In cases where there is a combination ofdepression and anxiety, adjunctive anxiolytic medica-tions with antidepressants, have been suggested as astrategy to address acute anxiety, as the thymolepticeffect of antidepressant medications often take 2 to 3weeks to occur (Baghai et al., 2006; Nemeroff, 2003).An increase in compliance may also occur in the useof stimulating antidepressants, which often cause side-effects such as agitation, restlessness and insomnia(Degner et al., 2004). Currently only one human trialexists in this area. An open, practice-orientatedstudy using high-dosage SJW and valerian extracts totreat AnxD demonstrated marked success, with the


712 J. SARRIS

combination therapy ameliorating anxiety more effec-tively than SJW mono-therapy (Muller et al., 2003). Asthe valerian SJW combination demonstrates, a combi-nation of antidepressant agents such as SJW or roserootand known sedative/anxiolytics such as kava, passion-ower, California poppy, scullcap or sour date seed,may provide a synergistic herbal formula to addressdepression that co-occurs with or involves symptoms ofmildmoderate anxiety.

SOMATOFORM DISORDERS

The essential feature of the somatoform disorders isthe presence of physical (somatic) symptoms that causeclinically signicant distress or social/occupational im-pediment and are not explained by a general medicalcondition or substance (American Psychiatric Associa-tion, 2000: 485). The diagnosis of somatoform dis-orders is problematic, as it is difcult to distinguishbetween a subjective rating that is not open to directobservation, and it is difcult to distinguish betweena psychosomatic and a purely physical presenta-tion (Bradeld, 2006; Kroenke and Rosmalen, 2006;Lecrubier, 2006). Two RCTs treating somatoform dis-orders were located. A 6-week multi-centre RCT (n =151) found that SJW extract (600 mg/day) was signi-cantly superior to placebo in reducing somatoformsymptoms as assessed via HAMA-SOM scale (Volzet al., 2002). A later double blind placebo-controlledstudy (n = 184) tested SJW extract in patients withsomatization disorders. The results using six outcomemeasures, demonstrated that 45.4% of the SJW groupwere classied as responders, compared with 20.9% whotook placebo (Muller et al., 2004).

SCHIZOPHRENIA AND PSYCHOTICDISORDERS

Schizophrenia and other psychotic disorders are seriousmental disorders with a profound impact on cogni-tion, emotion and behaviour, and include symptomssuch as hallucinations, thought disorder and delusions(American Psychiatric Association, 2000: 297299).Interestingly, sufcient trials using Chinese herbal medi-cine (CHM) preparations for schizophrenia have beenconducted for completion of a Cochrane databasesystematic review (Rathbone et al., 2005). Six studiesevaluated CHM in combination with antipsychoticdrugs against an antipsychotic alone. One trial found areduction in a global rating of not improved/worsefrom the CHM/antipsychotic combination (n = 123, RR0.19 CI 0.10.6, NNT 6 CI 511). Two studies (n = 103)found short-term data from the CGI scale favouredthe CHM/antipsychotic group (WMD 0.46 CI 0.9 to0.1) compared with those given only antipsychotics.Signicantly fewer patients withdrew from treatmentin the CHM/antipsychotic group than from the anti-psychotic drug groups, with subjects displaying fewerside effects such as constipation. The authors of theCochrane review concluded that CHM when combinedwith antipsychotic drugs may be of benet in treatingschizophrenia.

Ginkgo biloba has been studied for its efcacy andsafety in combination with haloperidol in treating schizo-phrenia. A 12-week 2001 RCT (n = 109) discoveredthat the addition of Ginkgo biloba (360 mg/day) tohaloperidol increased its efcacy and reduced side ef-fects such as extrapyramidal symptoms, compared withhaloperidol and placebo (Zhang et al., 2001). Ginkgobilobas mechanism of action is posited as involvingantioxidant activity. A 12-week clinical trial (n = 54)demonstrated that a haloperidolGinkgo biloba com-bination reduced superoxide dismutase (antioxidantmarker), while improving psychotic symptoms comparedwith control as assessed on the Scale for Assessment ofPositive Symptoms (Zhou et al., 1999).

There have been some reports of HM causing acutepsychosis. A 2004 review found 17 case reports detail-ing purported SJW-induced psychosis (Stevinson andErnst, 2004). In 12 cases the diagnosis was mania orhypomania. Causality between SJW and psychosis wasnot denitive, as positive re-challenges were not under-taken. Psychotic events have also been documentedin Ephedra sinica use, although in most cases a pre-existing psychiatric condition and/or concomitant medi-cation/drug use was apparent (Maglione et al., 2005)

DISCUSSION

Apart from a high-standard of evidence existing forthe use of kava and SJW as psychotropic medicines,currently there is little robust clinical evidence for theuse of HMs in psychiatric disorders. The HMs withpotentially signicant use in psychiatric medicine thaturgently require further research are Rhodiola roseaand Crocus sativus (saffron) for MDD; Passioraincarnata, Scutellaria lateriora and Zizyphus jujubafor GAD; and Piper methysticum for phobic disorders,panic disorder and OCD. Whilst MDD and GADare commonly researched, the use of HM in phobic,psychotic/schizophrenic, somatoform and bipolar/cyclothymic conditions has attracted less research, andis a potential area of exploration. Although it is notrecommended that that HM intervention is the rst-line treatment in psychosis and schizophrenia, adjunc-tive treatment with HM may increase therapeuticoutcomes.

Outside of European healthcare models, integrationof psychotropic HMs into conventional medical prac-tice appears to still be some way off. The main reasonswhy Western medical practitioners do not prescribeHMs, are conceivably due to the lack of training inphytotherapy, a perception that HMs are ineffectiveor potentially dangerous, and that synthetic agentsare viewed as therapeutically more precise (Pirottaet al., 2000). In the past two decades, no substantialadvance has occurred in the development of new classesof synthetic antidepressant and anxiolytic medica-tions (Berton and Nestler, 2006), with SSRIs andbenzodiazepines currently remaining rst-line treat-ments in depression and anxiety disorders, respectively(Berton and Nestler, 2006; Rickels and Rynn, 2002).As fewer than 50% of all patients show full remissionwith synthetic pharmaceutical treatments (Berton andNestler, 2006), and the medications commonly elicitsignicant side effects (Degner et al., 2004) and are



potentially addictive in the case of benzodiazepines(Rickels and Rynn, 2002), an alternate treatmentprotocol is needed.

There is a need for a more integrative approach totreat mental health conditions, a part of which may beto prescribe HMs. SJW and kava have demonstratedunequivocally that plant medicines can provide effectivetreatment in mental health disorders, and it is likelythat other HMs that have traditional use in treatingmental disorders will prove valuable. Prescribing HMsin combination with standard pharmaceuticals mayprovide an answer. In the case of SJW, the commonopinion is never to co-prescribe with SSRIs in fear ofevoking serotonin syndrome (Knuppel and Linde, 2004;Miller, 1998; Schulz, 2006), and in the case of kava,never to prescribe with benzodiazepines as a theoret-ical additive-sedative effect may occur (Singh, 2005).In both cases, as reviewed above, there is no clinicalevidence to conrm this. Co-prescription of certain HMswith synthetic agents may in fact create a benecialsynergistic effect (Borgert et al., 2005; Williamson, 2001).This allows for a lower dose of synthetic pharmaceut-icals to be taken, thus reducing potential side effectsas demonstrated in the Rathbone review of CHM(Rathbone et al., 2005). Another application of co-

prescription is in aiding the withdrawal from anti-depressants and benzodiazepines. SJW or roseroot canbe titrated upwards, while antidepressant medication isgradually reduced. Sedative or anxiolytic HMs such askava, valerian or sour date seed can potentially be usedin safe doses when withdrawing from benzodiazepines.Although these concepts may be controversial, researchinto HM-pharmaceutical co-prescription is an area ofpromising future exploration.

Conicts of interest

The author of the paper is currently conducting aclinical trial on SJW and kava. The product used in thistrial is funded by Mediherb (Australia). No personalfunding is being received by the author for the review,or the study currently being conducted.

Acknowledgements

The author of the paper gratefully acknowledges the signicant con-tributions of Professor David Kavanagh (University of Queensland)in proong and structuring the review. Thanks are also extended toKerry Bone for his review of the paper.

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