Ineffective remedies

Ginkgo biloba (maidenhair tree) was tested in a small (n = 27) trial involving people with ‘winter depression’. The results did not suggest that this approach was superior to placebo (Reference Lingaerde, Foreland and MagnussonLingaerde et al, 1999). It has, however, been shown to be effective for conditions such as dementia (Reference Ernst, Pittler and StevinsonErnst et al, 2001).

Promising remedies

Lavandula angustifolia (common lavender) was compared with imipramine in a small randomised controlled trial (RCT) including 45 individuals with moderate depression (Reference Akhondzadeh, Fallah-Pour and AfkhamAkhondzadeh et al, 2004). Both treatments seemed similarly effective but the study had significant methodological shortfalls (e.g. it was not designed as an equivalence trial). Another trial designed along the same lines suggested that Crocus sativus (saffron crocus) and imipramine were similarly effective (Reference Akhondzadeh, Kashani and FotouhiAkhondzadeh et al, 2003). Unfortunately, the same limitations applied.

Effective remedies

The only herbal remedy that has been shown beyond reasonable doubt to be effective as a treatment for mild to moderate depression is Hypericum perforatum (St John's wort). The active ingredients of this herbal medicine are probably hypericin and/or hyperforin. Its antidepressive activity seems to be due to inhibition of both serotonin reuptake and monoamine oxidase.

An authoritative systematic review and meta-analysis included 30 RCTs involving individuals mostly (but not exclusively) with mild to moderate depression (Reference Roder, Schaefer and LeuchtRoder et al, 2004). The methodological quality of these trials was variable but many scored highest marks. Twenty five of them, involving a total of 2129 patients, compared St John's wort with placebo. The results strongly favoured the former over the latter (risk ratio = 0.66, 95% CI 0.57–0.78, number needed to treat = 42). Five trials, involving a total of 2231 patients, compared St John's wort with conventional antidepressants (including selective serotonin reuptake inhibitors (SSRIs)). The risk ratio of 0.96 indicates equivalence of these approaches. A subsequent Cochrane Review (Reference Linde, Mulrow and BernerLinde et al, 2005) reported similarly encouraging results.

So why use this herbal remedy if it is not better than conventional drugs? One answer could be that many patients prefer ‘natural’ treatments. A perhaps more convincing answer is that its adverse effects profile is preferable. In fact, St John's wort is associated with similar frequency and severity of adverse effects as placebo. There are, however, two caveats. Extracts of St John's wort powerfully interact with the cytochrome P450 enzyme system and thus increase the plasma level of a wide range of other drugs (Reference Mills, Montori and WuMills et al, 2005). It seems to follow that it is safe only for people who use no other medication. The second caveat is the suspicion that St John's wort can trigger psychoses, particularly in patients who concomitantly take SSRIs (Reference Izzo and ErnstIzzo & Ernst, 2001).

Ineffective remedies

No anxiolytic effects of valerian (Valeriana officinalis) extract were noted in an RCT involving 66 people with generalised anxiety disorder (Reference Adreatini, Sartori and SeabraAdreatini et al, 2002).

Promising remedies

A large RCT found that a combination of Crataegus oxyacantha (hawthorn), Eschscholzia californica (Californian poppy) and magnesium was more effective than placebo in reducing anxiety in 264 individuals with generalised anxiety disorder (Reference Hanus, Lafon and MathieuHanus et al, 2004). There is some evidence for the efficacy of Matricaria recutita (German chamomile) in the treatment of anxiety (Reference Wong, Smith and BoonWong et al, 1998), but the study was methodologically weak. Short-term anxiolytic effects were noted after administration of Melissa officinalis (lemon balm) to healthy volunteers (Reference Kennedy, Little and ScholeyKennedy et al, 2004). Passiflora incarnata (passion flower) generated encouraging anxiolysis in an RCT with 36 people who had generalised anxiety disorder (Reference Akhondzadeh, Naghavi and VazirianAkhondzadeh et al, 2001). Even though these results are encouraging they do require independent replication before firm recommendations can be made.

Effective remedies

The only herbal remedy that is demonstrably effective in reducing anxiety is Piper methysticum (kava). Our Cochrane Review included 11 RCTs, involving a total of 645 patients (Reference Pittler and ErnstPittler & Ernst, 2003). The methodological quality of these studies was variable but some were excellent. Without exception, these trials showed anxiolytic effects of kava that were superior to placebo.

Despite these clearly positive efficacy data, kava cannot currently be recommended for clinical use. This is because it has been associated with (sometimes severe) hepatotoxicity (Reference ErnstErnst, 2004). Recently there has been much debate about whether this association is causal or not. At present, however, this herbal remedy remains banned from the UK market.

Research difficulties

Herbal medicines are mixtures of many active ingredients. They differ from synthetic drugs in several ways (Table 2). Often it is more than one herbal active ingredient that brings about the clinical effects we observe in patients. In many instances we have not yet identified any or all of the active ingredients. Moreover, the quality of herbal remedies varies considerably (Reference Garrard, Harms and EberlyGarrard et al, 2003) owing to a range of factors: plant species, soil, climate, storage, extraction method, etc. This complexity complicates research.

Table 2 Herbal medicines v. synthetic drugs

Herbal	Synthetic
Active ingredients often not known	Active ingredient known
Pure compound not available	Pure compound available
Raw material limited	Raw material unlimited
Quality variable	Quality constant
Mechanism often unknown	Mechanism known
Toxicology often unknown	Toxicology known
Long tradition of use	Short tradition of use
Wide therapeutic window	Narrow therapeutic window
Adverse effects rare	Adverse effects frequent

The clinical effects of herbal medicines are usually moderate and often appear only after prolonged periods of administration. Clinical trials therefore need to be large and long-term. These facts tend to render clinical trials more expensive. Even though the sector as a whole achieves a sizeable turnover (Reference WrightWright, 2005), single herbal manufacturers are usually relatively small and, compared with ‘big pharma’, they are typically not financially powerful. To make things worse, normally there is no patent protection of herbal extracts. Thus, there is little money to support expensive trials and even less impetus to spend it on research. This already bleak situation will be further aggravated by recent legislation: the European Directive on Traditional Herbal Medicinal Products, which came into force in October 2005, does not require proof of efficacy through clinical trials for registering herbal medicines under this scheme. Thus the incentive to conduct such research approaches zero.

Is there a way out of this dilemma? One solution would be to follow the American example and set aside ‘ring-fenced’ public funds for supporting research into herbal medicine. Research that emerges from initiatives funded by the National Institutes of Health is usually of outstanding methodological quality. Perhaps the UK authorities should consider this approach and develop a strategy along similar lines.

Product safety

From a clinical perspective, we need to consider not just efficacy but also (and perhaps foremost) safety (Box 1). Consumers often assume herbal medicines to be safe; a survey conducted in Israel, for instance, showed that 56% of them believed they cause no side-effects at all (Reference Giveon, Liberman and KlangGiveon et al, 2004). Unfortunately, this is not true. Most herbal remedies have been associated with (usually mild and transient) adverse effects (Reference Ernst, Dukes and AronsonErnst, 2000). In addition, a systematic review showed that herbal medicines taken for non-psychiatric indications can cause psychiatric adverse effects, including delirium, coma, confusion, hallucinations, mood disturbances and seizures (Reference ErnstErnst, 2003). Research also confirms that many herbal medicines have the potential to interact with prescribed drugs (Box 2). The notion that ‘natural’ equals ‘safe’ can therefore be dangerously misleading.

In conclusion, the scientific knowledge about the potential benefits or harms of herbal treatments for anxiety or depression is incomplete and the information patients receive can be highly misleading. Psychiatrists should be aware of the essential facts and advise their patients accordingly.