Abstract
I. A 17-year-old female student with major depression indicates to her psychiatrist that she would prefer commencing St John's Wort rather than a selextive serotonin re-uptake inhibitor (SSRI). The patient mentions a preference for ‘natural substances’ and has read that St John's Wort is an effective anti-depressant with few side effects. She asks her psychiatrist for more information about this treatment.
II. A 56-year-old man with unstable manic depressive illness tells his doctor that he has been successfully prescribed a herbal mixture by a naturopath for rheumatism. The patient inquires how the herbal remedy and psychotropic agents might interact.
III. The daughter and carer of a 73-year-old man with dementia is canvassing physical treatments that might optimise his cognitive ability. On being advised that tacrine is not suitable, she asks her father's psychiatrist whether Gingko biloba is worth a trial.
How would you, reader, respond in these situations: answer the questions confidently, profess ignorance or seek to change the topic? Have you ever had similar experiences? Are you in favour of patients taking herbal remedies or strongly opposed to their use?
Herbal medicines and other ‘alternative treatments’ appear to be commonly used in most western countries [1–5]. The largest survey in the world literature on the use of alternative medicines and alternative medicine practitioners was a South Australian study [2], which found that almost half the State's population uses alternative medicines and that a fifth consults alternative practitioners. Studies from Victoria [1] and New South Wales [3] have yielded very similar figures. In the South Australian survey [2], herbs were the most popular form of alternative medication after vitamins.
In most of the studies, the proportion of users taking herbal preparations for psychiatric reasons is unclear or not stated. Nevertheless, a large number of available herbal medicines are for psychiatric conditions and it is reasonable to assume that there is a market for these products. Herbal ‘sedatives’ and ‘anxiolytics’ accounted for 10% of sales of herbal drugs in Europe in 1994 [6]. In Germany, St John's Wort is prescribed more commonly for depression than fluoxetine [7]. The willingness of Australian consumers to use herbal treatments for psychiatric illness was suggested by a recent community survey [8]. Shown a vignette of a person with depression, 29% of respondents rated conventional antidepressants as potentially helpful and 42% rated them as harmful. By contrast, the treatment category that included vitamins, minerals, tonics and herbal medicines was considered potentially helpful by 57% of respondents and harmful by 3%. Similarly, for schizophrenia, the treatment category with herbal medicines was rated more helpful and less harmful than antipsychotic drugs.
There is increasing interest in the psychiatric literature in herbal medicines (e.g. [9],[10]). The purpose of this paper is to provide information about the efficacy, safety and regulatory aspects of herbal treatments in mental disorders to enable psychiatrists to become more knowledgeable and objective about this treatment modality as well as to stimulate thought, discussion and research. Herbal remedies in the Australian context will be a theme. We include discussion of terminology and basic principles relating to herbal medicine because many readers may be unfamiliar with these.
Definition and terminology (see Appendix I)
A herb is a flowering plant the stem of which is above the ground, does not become woody, and dies down after flowering [11]. A broader definition is a plant valued for its medicinal properties, flavour, scent or the like [12]. The term ‘phytotherapy’ was coined by the French physician Henri Leclerc (1870–1955) to describe the practice of herbal medicine [13]. Over 20 000 herbs have been identified as potentially useful for medicinal purposes [14]. Herbs used for psychiatric and neurological disorders are called ‘nervines’. Herbal medicine can be distinguished from homeopathy. Homeopathic approaches, which began with the German physician Samuel Hahnemann (1755–1843), use plant concentrations so small that there are few or no active ingredients [15].
Herbalism versus orthodox medicine
Herbal medicine differs from orthodox medicine in several ways [16]. First, orthodox medicine tends to view disease as a malfunction of an organ or body system. In contrast, herbal medicine conceptualises the body as a series of interconnecting functions and disease as an imbalance of these functions. It follows that in orthodox medicine a drug generally targets a particular organ or body system whereas in herbal medicine, notwithstanding a nomenclature that includes terms like ‘nervine’, the herb is primarily given to correct an overall imbalance. A second point of distinction is that while orthodox medicine uses plants as ingredients for many drugs, it aims to isolate and produce active, generally single, chemical entities from them. Traditional herbalism values the ingredients of the whole plant although nowadays not all herbalists are as strict in this regard. Third, orthodox medicine emphasises experimentation, particularly controlled trials, to support the use of its treatments. Herbal medicine, however, has relied mainly on expertise accumulated by observation of individual cases and passed down generations. This situation also appears to be changing, as exemplified by the large number of controlled trials of St John's Wort in depression [17]. Finally, the lag in onset of improvement with herbal remedies is often said to be longer than with orthodox approaches.
The differences between herbal medicine and orthodox medicine may partly explain the scepticism of many medical practitioners about herbal treatments. Herbal medicine concepts such as the ‘Doctrine of Signatures’ [18] are very removed from modern medical science and thinking. The Doctrine is the belief that the shape of a plant or plant part point to the condition for which it should be used. Thus, the porosity of the leaves of St John's Wort has suggested to some herbalists (among them Paracelsus) that topical application of this herb will heal ‘holes’ or wounds of the skin [12].
Herbal treatments in Australia
Plants had been used by Aborigines for medicinal purposes for thousands of years by the time of the first European settlement [19]. Within days of the foundation of the colony, clinical experiments with wild currants, eucalyptus and other greens were being undertaken [20]. Scurvy and dysentery, rather than mental illness, provided the impetus to search for new herbal remedies. The major forms of herbal medicine practised and used in Australia today are Western herbal medicine (WHM), traditional Chinese medicine (TCM) and ‘Ayurveda’, a form of Indian herbal medicine [Cowper A: personal communication]. There are no data on their comparative popularity.
The most straightforward of the three schools in theoretical basis and nervine classification is WHM. In WHM, three types of nervine are recognised: nervine tonics are said to strengthen and restore the nervous system; nervine relaxants to soothe the body and mind; and nervine stimulants to directly stimulate nerve activity [21].
Traditional Chinese medicine distinguishes four categories of herb that work primarily on the mind: the categories translating as ‘substances that settle and calm the spirit’, ‘substances that nourish the heart and calm the spirit’, ‘substances that extinguish wind and stop tremors’ and ‘substances that open the orifices’ [22]. Traditional Chinese medicine believes that other categories of herb may also have effects on the mind but are less specific. Examples are bupleurum (Bupleurum scozoneraefollium) and cyperus (Cyperus rotundus), which are used to treat depression [22].
According to Ayurveda, there are three biological humors, Vata, Pitta and Kapha, each of which has a counterpart in the mind, Prana, Tejas and Ojas [22]. The key to mental health is considered to be a balance of Prana, Tejas and Ojas. Ayurveda recognises six tastes found in herbs that may affect this balance: sweet, sour, salty, pungent, bitter and astringent. For example, bitter herbs increase Prana, pungent herbs increase Tejas and sweet herbs increase Ojas.
An individual herb may be employed as a nervine by more than one school of herbal medicine. A corollary is that a herb classified as a nervine by one school may not be regarded as a nervine by another.
For example, skullcap is classed as a nervine by WHM but TCM considers it a ‘heat-clearing herb’ with negligible effects on the mind [22].
Apart from the major schools of herbal medicine, there are idiosyncratic schools also relevant to psychiatry. One example is ‘Bach Flower Remedies’, developed by a medical practitioner in the 1930s and continuing to enjoy popularity [23]. Thirty-eight types of personality and/or mood disturbance are recognised, each of which is treated by a different herb. We thus find Agrimony recommended for those in whom ‘a cheerful mask hides inner torture…(who are) restlessness at night with thoughts going round and round’, Mimulus for those who are ‘shy, tongue-tied, fear situations (other people, darkness, death)’ and Pine for persons who are ‘overconscientious and overwork but filled with self-reproach and never content’ [23].
Psychiatric applications
Unfortunately, reports and texts about herbal medicines seldom utilise standard medical classification systems or provide sufficient information about cases for the reader to offer even a tentative diagnosis. A large number of publications about herbal treatment are in German, thus inaccessible to many people. Nevertheless, the literature suggests that herbal medicines have been used for a range of psychiatric disorders, including psychoses [24],[25], depression [26], anxiety disorders [27], alcohol and substance abuse [28], attention deficit hyperactivity disorder [29], Alzheimer's disease [30],[31], chronic pain syndromes [32], erectile dysfunction [33] and sleep disorders [34]. Use of herbal preparations for subclinical cases or non-specific ailments (‘stress’, ‘tension’, etc.) seems to be particularly common. Herbal medicines have also been used to treat side effects of orthodox psychotropic agents [35].
One of the better known herbs in psychiatry's history has been Rauwolfia serpentina, used in India for centuries for a variety of conditions. The active principle, reserpine, was introduced into Western psychiatry as an antipsychotic in the 1950s, very soon after chlorpromazine was synthesised. Although effective as an antipsychotic, reports of secondary depression lessened its popularity. Indeed, the ability of reserpine to induce depression and deplete brain amines became one of the pillars of the monoamine theory of affective disorders [36],[37].
A further interesting chapter relating to herbs and psychiatry concerned the use of hallucinogens (herbal and other) to facilitate psychotherapy. Mescaline, derived from the Mexican plant peyotl, was one such hallucinogen [38]. In non-Western cultures, ‘therapist’ or ‘patient’, or both, sometimes induce altered states of consciousness with herbs or other compounds, to aid the therapeutic process. It is also worth noting the ongoing investigations about the potential value of marijuana in terminal illness, as an analgesic and to counteract the nausea and appetite loss associated with chemotherapy [39]. Unfortunately, a rational appraisal of marijuana's therapeutic use has been impeded by the debate about the legal status of its recreational use [40].
Nervines commonly used for psychiatric disorders in developed countries today include chamomile, Gingko biloba, hops, motherwort, passionflower, rosemary, skullcap, St John's Wort, Valeriana officinalis and Wood Betony [41],[42]. St John's Wort, Gingko biloba and Valeriana officinalis have attracted considerable attention recently.
St John's Wort (Hypericum perforatum)
The health craze in Europe and the United States regarding St John's Wort (SJW) [43] appears to be reaching Australia. Used to treat a range of disorders for over 2000 years, it is the apparent value of SJW as an antidepressant that has captured most recent attention. Interest in English-speaking countries in the anti-depressant properties of SJW was raised by the publication of a meta-analysis in the British Medical Journal in 1996 [44]. St John's Wort is not native to Australia but was introduced for medicinal purposes into the goldfields of Victoria during the 1880s [45]. It has now been declared a noxious weed in most states.
There have been numerous open trials and 24 randomised, double-blind studies of SJW in depression: eight double-blind studies comparing SJW to other active medication and 16 double-blind studies comparing SJW to placebo [17],[44]. Across all reports, 50 to 80% of patients improved with SJW, a rate similar to that achieved with conventional antidepressants. St John's Wort was most beneficial for mild to moderately severe depression. However, the studies had significant limitations. Most of the trials were small and used heterogenous patient groups. Classification of depression was not uniform and none of the studies lasted longer than 12 weeks. Dosages of anti-depressant in the comparison trials were subthera-peutic or in the low therapeutic range [44].
The herb appears to be well tolerated. In an open study of 3250 patients taking hypericum, side effects were reported by 2.4% of subjects [46]. The most commonly noted adverse events were gastrointestinal symptoms (0.6%), allergic reactions (0.5%), fatigue (0.4%) and restlessness (0.3%). Other adverse reactions reported were emotional vulnerability, pruritus, weight gain and dizziness. Phototoxicity (an increased reactivity of the skin to ultraviolet radiation) is a potential problem with SJW. Severe phototoxicity has been reported in cattle and sheep grazing on the plant, but not in humans on therapeutic (antidepressant) doses. In Australia, there have been three recent reports of adverse events involving SJW to the Adverse Drug Reaction Advisory Committee (ADRAC) [17].
The exact mechanism of action of SJW is unknown. It inhibits uptake of serotonin, noradrena-line and dopamine, has a potent affinity for GABA receptors and inhibits monoamine oxidase [17]. It has recently been postulated that the antidepressant properties of SJW may be due to its effect on inter-leukin-6 [47].
Gingko biloba
Gingko biloba is the last remaining member of the Gingkoaceae family. Gingko fruits and seeds have been valued in China for their medicinal properties since 2800 B.C., but it is only in the last 20 years that Gingko has been used extensively in Western medicine [48]. Gingko biloba extract (GBE) was the major selling herbal product in Germany in 1994 [6]. The extract has been used for a range of disorders, mainly circulatory, and most recently has been studied in dementia. There have been fewer controlled trials of GBE in dementia (nine in total) than of SJW for depression but the early results are promising [31],[49]. In one study [31], GBE appeared capable of stabilising, and in some cases improving, the cognitive performance and social functioning of outpatients with Alzheimer's disease for 6 months to 1 year. Side effects of Gingko biloba tend to be few and minor. Gastrointestinal disturbance, headache and allergic skin reactions have been reported infrequently. The available evidence [10] suggests that GBE improves vascular perfusion by modulating vessel wall tone, decreases thrombosis by antagonising platelet activating factor and has antioxidant properties which are neuroprotective.
Valeriana officinalis (valerian)
The dried rhizomes and roots of this herb are the plant parts used medicinally. Several studies have demonstrated a mild hypnotic action in sufferers of insomnia and normal sleepers as well as a mild sedative effect [50–52]. There is one report of an anxiolytic effect [53]. Galen was one of the earliest prescribers of valerian for insomnia. There are suggestions that valerian might have beneficial effect on sleep latency, frequency of waking, night-time motor activity and overall sleep quality. Side effects appear to be minimal. Research on the mechanisms of action of valerian point, variously, to its affinity for GABA-A and 5-HTA receptors [10],[54], and inhibition of GABAcatabolism [55].
Toxicity and drug interactions
The conviction that ‘natural products are safe’ has not been borne out by experience. Of the nervine herbs, ‘Ma Huang’ has been associated with several cases of psychosis and death [56],[57], and ‘Jin Bu Huan’ with acute hepatitis [58]. A recent report [59] suggested that GBE may have contributed to a sub-arachnoid haemorrhage in a 61-year-old man, by increasing the bleeding time. Between 1991 and 1995 there were 1297 reports of adverse events to the National Poisons Information Service in London relating to ‘traditional and herbal remedies and dietary supplements’ [60]; of these, there was a possible or confirmed association in 785 (61%) cases. In the period from 1972 to 1997, there were only 154 notifications to ADRAC about ‘complementary and alternative medicines’ [61]. Given the widespread use of such medicines and the UK data, this low number suggests that adverse events due to alternative medicines are significantly under-reported in Australia.
There is negligible information about interactions between nervine herbs and conventional psychotropic drugs. The subject is important because more patients than we suspect may be taking herbal remedies and pychotropics concurrently or may switch from one to the other. For example, combining SJW with other antidepressants is not recommended because SJW extract appears to have monoamine oxidase inhibitor (MAOI) and selective serotonin re-uptake inhibitor (SSRI) properties [17].
‘Evidence-based herbalism’
The World Health Organization Guidelines for the Assessment of Herbal Medicines [62] state that requirements for proof of efficacy of herbs should take into account ‘experience with individual cases recorded in reports from physicians, traditional health practitioners or treated patients’. The guidelines also suggest that these requirements should depend on the kind of indication and that for ‘minor disorders and nonspecific indications, some relaxation is justified…(considering) the extent of traditional use’.
Should the same standard of proof apply to herbal drugs that applies to orthodox drugs? Some believe that any softening of approach for herbal treatments is unacceptable: ‘The Australian public expects a high standard…it is hypocritical to expect a totally different standard for herbal remedies’ [63]. Many proponents of herbal medicine appear to be resisting the trend towards evidence-based practice and outcome measurement. They point to the limitations of controlled trials (e.g. [13]). or argue that such trials are inappropriate for alternative treatments (e.g. [18]), or ponder the state of modern medicine were it not for less exacting standards of proof [32]. Increasingly, however, as suggested by discussion on SJW and GBE, some promising herbal preparations are being subjected to more searching examination.
Regulatory aspects
In Australia the Minister for Health and Family Services established the ‘Complementary Medicines Evaluation Committee’ (CMEC) in 1997 to advise the Government on the regulation of non-orthodox medicines. At present, the vast majority of herbal preparations are categorised under the Register of Therapeutic Drugs as ‘listed drugs’. ‘Listed drugs’ are required to satisfy less rigorous efficacy and safety criteria compared to ‘registered drugs’. In turn, as stipulated by the ‘Therapeutic Goods Advertising Code’, listed drugs can not be marketed to the public as a treatment for certain conditions, including ‘psychiatric diseases, ailments or defects’. The Code requires marketing to convey the message that herbs provide, at best, symptomatic relief for minor problems. The recommended phrasing for advertising herbal products in relation to psychiatric conditions includes: ‘helps relieve nervous tension/stress’, ‘helps reduce effects of mild anxiety’, ‘beneficial during times of stress’, ‘calming effect’, ‘calms the nerves’ and ‘improves stress adaptation’.
The CMEC is keen to develop a general standard to ensure herbal products marketed in Australia are of consistent quality. At present, herbal and other listed drugs lack standardised preparation and are more prone to contamination, substitution, adulteration, incorrect packaging, wrong dosage, and inappropriate labelling and advertising [61]. For example, in the case of S JWthere is presently no way of knowing that the correct species of hypericum is used, that the plant is harvested at the right time of year, that appropriate plant parts are chosen, dried and stored properly, and that the extraction process is uniform. All of these are known to effect biological activity. The CMEC is presently monitoring the development of the European Pharmacopoeia draft herbal standard which proposes limits for foreign matter, heavy metals, pesticide residues, fumigation agents and radioactivity. The standard also provides directions for confirming the identity of material through microscopic, macroscopic and chromatographic methods. A poignant reminder of the need to correctly identify plant species was provided by an editorial about St John's Wort in the BMJ, which inadvertently published a photo of the wrong species of plant [7],[64].
There are also regulatory issues pertaining to herbal medicine associations. The three main organisations concerned with herbal medicine in this country are the National Herbalists' Association of Australia, the Australian Traditional Medicine Society, and the Australian Natural Therapists' Association. Accreditation and registration need to be addressed by all three organisations if the interests of their members are to be furthered and if they are to be better accepted by the medical profession.
Implications for the practice of psychiatry
The use of herbal treatments by the community has implications for psychiatry in several domains and raises a number of issues requiring wider debate.
Because of the widespread use, in taking a psychiatric history we should enquire routinely about herbal treatments. The taking of herbal remedies has implications for compliance with other treatments and potential drug interactions. Asking about herbal medicines may also convey to patients our recognition of an alternative treatment system and perhaps a sense of being broad-minded, remove a possible burden for patients of surreptitiously taking ‘unap-proved’ drugs and, by doing these, strengthen the therapeutic alliance. Herbs should also be considered as a possible cause of drug-induced organic syndromes and any significant adverse events should be reported to ADRAC.
When discussing treatment options, should we be mentioning herbal medicines? If so, we need to know something about them. If we are prepared to work in association with ‘phytotherapists’, what model of integration would be acceptable? Any integrative model is predicated partly on each party possessing some knowledge about the other's work. Finally, if clinically indicated and supported by sound research, should we be prescribing herbs? If not, how can this be justified? Indeed, initiation of herbal treatments for psychiatric disorders by non-medical persons may preclude patients receiving treatments of demonstrated effectiveness (perhaps resulting in failure to prevent suicide) and may also lead to failure to recognise medical disorders that mimic mental illness [42].
Further studies are required. In 1978 the German Government established a commission to examine data concerning approximately 1400 herbal drugs. The findings of ‘Commission E’, which are ongoing, constitute the largest body of data on herb efficacy and safety available today [30]. Nevertheless, there remain gaps in knowledge. Studies outside Germany and reporting of research findings in refereed, English-language medical journals should occur. Encouragingly, the National Institute of Mental Health recently funded a US$4 million trial comparing SJW, SSRI and placebo in depression. Studies of herbal drugs will need to use recognised diagnostic systems and instruments of known reliability and validity and be of adequate duration. Herbal products will also need to be standardised.
Securing research funds is a priority. Historically, the pharmaceutical industry has had little incentive to research natural products because they could not be patented according to intellectual property law. This is believed to be one of the reasons for the demise of reserpine as a potential therapeutic agent [37]. However, pharmaceutical companies are coming to regard plant derivatives as potential templates for novel compounds that can be patented. Recent years have thus seen the acquisition of several phytomedi-cinal companies by multinational drug companies and a growing proportion of leading pharmaceutical companies (now over half of the top 250 companies) with research programs investigating the plant world for new drugs [16].
Should we be discussing herbal approaches in our teaching of physical treatments in undergraduate medicine and psychiatric training? Our answer would be yes, if only briefly. Unlike the situation in Australia, in Germany medical and pharmacy students receive extensive instruction in this area.
Finally, it may be advisable for our College, and other psychiatric Colleges and Associations, to adopt a position about the use of herbal treatments in psychiatry.
Conclusions
Since its inception, psychiatry has been interested in ‘unconventional’ treatments, perhaps partly due to the shortcomings of orthodox methods and the seemingly intractable nature of many psychiatric disorders. In relation to herbal medicine, on the one hand modern psychiatry can ill-afford to embrace any therapy which is not validated by quality research. On the other hand, we should not bury our head in the sand and pretend that our patients do not try other treatments, that an alternative healthcare system does not exist, that herbal drugs ‘never work’ and that all research into herbs is flawed. We can no longer regard herbal medicine as a curiosity, as something only taken by ‘primitive people’ or used by fringe cultures. Herbal remedies are taken by a large part of the population and psychiatrists ought to know about developments in this area, at least to be able to give informed advice to patients and families, such as those described in the opening vignettes.
Footnotes
Acknowledgements
Con Spiliopoulos, Helen Cameron, Patrick Purcell and Anne Cowper are thanked for their assistance.