A Historical Overview of Natural Products in Drug Discovery

Historically, natural products have been used since ancient times and in folklore for the treatment of many diseases and illnesses. Classical natural product chemistry methodologies enabled a vast array of bioactive secondary metabolites from terrestrial and marine sources to be discovered. Many of these natural products have gone on to become current drug candidates. This brief review aims to highlight historically significant bioactive marine and terrestrial natural products, their use in folklore and dereplication techniques to rapidly facilitate their discovery. Furthermore a discussion of how natural product chemistry has resulted in the identification of many drug candidates; the application of advanced hyphenated spectroscopic techniques to aid in their discovery, the future of natural product chemistry and finally adopting metabolomic profiling and dereplication approaches for the comprehensive study of natural product extracts will be discussed.

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It is hypothesized that secondary metabolism utilizes amino acids and the acetate and shikimate pathways to produce “shunt metabolites” (intermediates) that have adopted an alternate biosynthetic route, leading to the biosynthesis of secondary metabolites [ 29 ]. Modifications in the biosynthetic pathways may be due to natural causes (e.g., viruses or environmental changes) or unnatural causes (e.g., chemical or radiation) in an effort to adapt or provide longevity for the organism [ 29 ]. It is the unique biosynthesis of these natural products, produced by the countless number of terrestrial and marine organisms, which provides the characteristic chemical structures that possess an array of biological activities.

The biosynthesis and breakdown of proteins, fats, nucleic acids and carbohydrates, which are essential to all living organisms, is known as primary metabolism with the compounds involved in the pathways known as “primary metabolites” [ 26 ]. The mechanism by which an organism biosynthesizes compounds called ‛secondary metabolites’ (natural products) is often found to be unique to an organism or is an expression of the individuality of a species and is referred to as “secondary metabolism” [ 26 , 27 ]. Secondary metabolites are generally not essential for the growth, development or reproduction of an organism and are produced either as a result of the organism adapting to its surrounding environment or are produced to act as a possible defense mechanism against predators to assist in the survival of the organism [ 26 , 28 ]. The biosynthesis of secondary metabolites is derived from the fundamental processes of photosynthesis, glycolysis and the Krebs cycle to afford biosynthetic intermediates which, ultimately, results in the formation of secondary metabolites also known as natural products [ 26 ]. It can be seen that although the number of building blocks are limited, the formation of novel secondary metabolites is infinite. The most important building blocks employed in the biosynthesis of secondary metabolites are those derived from the intermediates: Acetyl coenzyme A (acetyl-CoA), shikimic acid, mevalonic acid and 1-deoxyxylulose-5-phosphate. They are involved in countless biosynthetic pathways, involving numerous different mechanisms and reactions (e.g., alkylation, decarboxylation, aldol, Claisen and Schiff base formation [ 26 ].

By comparison, the marine environment has very few reported applications in traditional medicine. The red algae Chondrus crispus and Mastocarpus stellatus were sources of a beverage, which was popular as a folk cure for colds, sore throats, chest infections including tuberculosis. The alga was also boiled in milk or water and used for kidney trouble and burns [ 22 , 23 ]. Furthermore, three spoonfuls of the juice of the red alga Porphyra umbilicalis (Linnaeus) Kützing, taken every morning followed by fasting for three weeks was found to be effective against cancers, in particular breast cancer [ 24 ]. P. umbilicalis has also been described in the Aran Islands for easing indigestion. and was also boiled and given to cows to relieve their springtime constipation [ 10 , 25 ].

As early as the 17th–18th century, lichens had been used as dyes and were far more valued than oriental spices. To date there are no lichen derived drugs approved on the market but their applications in folklore has been well documented [ 18 ]. Lichens have been used as the raw materials for perfumes and cosmetics, medicine from the time of the early Chinese and Egyptian civilizations [ 19 ]. Well known examples include Usnea dillenius ex Adanson which was traditionally used for curing diseases of the scalp and is still sold in pharmacies as an ingredient in anti-dandruff shampoos and in Ireland to treat sore eyes [ 19 ]. The lichen U. subfloridana Stirton was mixed with tobacco and butter, boiled and then cooled and applied as a lotion [ 14 ]. Parmelia omphalodes (Linnaeus) Acharius, which is abundant in the British Isles, was used in brown dyes. In the highlands it was traditionally sprinkled on stockings at the start of a journey to prevent inflammation of the feet [ 20 , 21 ] and in Ireland it was used as a cure for bad sores under the chin as well as for burns and cuts [ 14 ].

The fungus Piptoporus betulinus, which grows on birches was steamed to produce charcoal, valued as an antiseptic and disinfectant [ 15 ]. Strips of P. betulinus were cut and used for staunching bleeding and were also found to make very comfortable corn pads [ 16 ]. Another example is the fungus Agaricus campestris Linnaeux ex Fries (field mushroom) found in the northern and southern temperate zones and the Caribbean. A. campestris, had reportedly been stewed in milk to soothe cancer of the throat [ 17 ].

The plant, Alhagi maurorum Medik (Camels thorn) secretes a sweet, gummy material from the stems and leaves during hot days [ 8 ]. This gummy sap is called “manna” and consists mostly of melezitose, sucrose and invert sugar and it has been documented and claimed by the Ayurvedic people that the plant aids in the treatment of anorexia, constipation, dermatosis, epistaxis, fever, leprosy, and obesity [ 8 ]. It was also used by the Israelis who boiled the roots and drank the extract as it stopped bloody diarrhea. The Konkani people smoked the plant for the treatment of asthma, whilst the Romans used the plant for nasal polyps [ 8 ]. The plant Ligusticum scoticum Linnaeus found in Northern Europe and Eastern North America was eaten raw first thing in the morning and was believed to protect a person from daily infection [ 9 ]; the root was a cure for flatulence [ 10 , 11 , 12 ], an aphrodisiac [ 12 ] and was used as a sedative in the Faeroe Islands [ 10 , 13 ]. Atropa belladonna Linnaeus (deadly nightshade) is found in central and Southern Europe, Western Asia, North Africa, North America and New Zealand. Its notoriously poisonous nature (three berries are sufficient to kill a child) firmly excluded it from the folk medicine compilation and seemed to have been accepted as dangerous to handle or to experiment with [ 14 ].

The use of natural products as medicines has been described throughout history in the form of traditional medicines, remedies, potions and oils with many of these bioactive natural products still being unidentified. The dominant source of knowledge of natural product uses from medicinal plants is a result of man experimenting by trial and error for hundreds of centuries through palatability trials or untimely deaths, searching for available foods for the treatment of diseases [ 6 , 7 ]. One example involves the plant genus Salvia which grows throughout the southwestern region of the United States as well as northwestern Mexico and which was used by Indian tribes of southern California as an aid in childbirth [ 6 ]. Male newborn babies were “cooked” in the hot Salvia ashes as it was believed that these babies consistently grew to be the strongest and healthiest members of their respective tribes and are claimed to have been immune from all respiratory ailments for life [ 6 ].

The earliest records of natural products were depicted on clay tablets in cuneiform from Mesopotamia (2600 B.C.) which documented oils from Cupressus sempervirens (Cypress) and Commiphora species (myrrh) which are still used today to treat coughs, colds and inflammation [ 3 ]. The Ebers Papyrus (2900 B.C.) is an Egyptian pharmaceutical record, which documents over 700 plant-based drugs ranging from gargles, pills, infusions, to ointments. The Chinese Materia Medica (1100 B.C.) (Wu Shi Er Bing Fang, contains 52 prescriptions), Shennong Herbal (~100 B.C., 365 drugs) and the Tang Herbal (659 A.D., 850 drugs) are documented records of the uses of natural products [ 3 ]. The Greek physician, Dioscorides, (100 A.D.), recorded the collection, storage and the uses of medicinal herbs, whilst the Greek philosopher and natural scientist, Theophrastus (~300 B.C.) dealt with medicinal herbs. During the Dark and Middle Ages the monasteries in England, Ireland, France and Germany preserved this Western knowledge whilst the Arabs preserved the Greco-Roman knowledge and expanded the uses of their own resources, together with Chinese and Indian herbs unfamiliar to the Greco-Roman world [ 3 ]. It was the Arabs who were the first to privately own pharmacies (8th century) with Avicenna, a Persian pharmacist, physician, philosopher and poet, contributing much to the sciences of pharmacy and medicine through works such as the Canon Medicinae [ 3 ].

Natural products (secondary metabolites) have been the most successful source of potential drug leads [ 1 , 2 , 3 , 4 , 5 ]. However, their recent implementation in drug discovery and development efforts have somewhat demonstrated a decline in interest [ 1 ]. Nevertheless, natural products continue to provide unique structural diversity in comparison to standard combinatorial chemistry, which presents opportunities for discovering mainly novel low molecular weight lead compounds. Since less than 10% of the world’s biodiversity has been evaluated for potential biological activity, many more useful natural lead compounds await discovery with the challenge being how to access this natural chemical diversity [ 3 ].

2. Historically Important Natural Products

Traditional medicinal practices have formed the basis of most of the early medicines followed by subsequent clinical, pharmacological and chemical studies [5]. Probably the most famous and well known example to date would be the synthesis of the anti-inflammatory agent, acetylsalicyclic acid (1) (aspirin) derived from the natural product, salicin (2) isolated from the bark of the willow tree Salix alba L. [30]. Investigation of Papaver somniferum L. (opium poppy) resulted in the isolation of several alkaloids including morphine (3), a commercially important drug, first reported in 1803 ( ). It was in the 1870s that crude morphine derived from the plant P. somniferum, was boiled in acetic anhydride to yield diacetylmorphine (heroin) and found to be readily converted to codeine (painkiller). Historically, it is documented that the Sumerians and Ancient Greeks used poppy extracts medicinally, whilst the Arabs described opium to be addictive [30]. Digitalis purpurea L. (foxglove) had been traced back to Europe in the 10th century but it was not until the 1700s that the active constituent digitoxin (4), a cardiotonic glycoside was found to enhance cardiac conduction, thereby improving the strength of cardiac contractibility. Digitoxin (4) and its analogues have long been used in the management of congestive heart failure and have possible long term detrimental effects and are being replaced by other medicines in the treatment of “heart deficiency” [30]. The anti-malarial drug quinine (5) approved by the United States FDA in 2004, isolated from the bark of Cinchona succirubra Pav. ex Klotsch, had been used for centuries for the treatment of malaria, fever, indigestion, mouth and throat diseases and cancer. Formal use of the bark to treat malaria was established in the mid 1800s when the British began the worldwide cultivation of the plant [30]. Pilocarpine (6) found in Pilocarpus jaborandi (Rutaceae) is an L-histidine-derived alkaloid, which has been used as a clinical drug in the treatment of chronic open-angle glaucoma and acute angle-closure glaucoma for over 100 years. In 1994, an oral formulation of pilocarpine (6) was approved by the FDA to treat dry mouth (xerostomia) which is a side effect of radiation therapy for head and neck cancers and also used to stimulate sweat glands to measure the concentrations of sodium and chloride ( ) [31]. In 1998, the oral preparation was approved for the management of Sjogren's syndrome, an autoimmune disease that damages the salivary and lacrimal glands.

2.3. Natural Products from the Marine Environment

Though plants have proven to be a novel source for bioactive natural products the marine environment has a clear track record in also offering novel structural entities. “We are not marine organisms”, says Fenical, “so until about 1970, no one even thought of the ocean. It was left as a deep secret. It seemed ridiculous to me that the ocean — with such a vast habitat — had escaped anyone's notice. But there are good reasons. People fear the ocean; it has been considered a very hostile, inhospitable place” [76]. Given that 70% of planet earth’s surface is covered by ocean, pharmaceutical companies began to realize that the ocean would possess unique biodiversity and may be a possible source for potential drug candidates [77].

Exploration of the marine environment and organisms (algae, sponges, ascidians, tunicates and bryozoans) became possible due to modern snorkeling, the introduction of SCUBA (1970s), to the use of manned submersibles (1980s) and more recently the use of remotely operated vehicles (ROVs) (1990s). These progressive advancements in the past 40 years of exploration of the marine environment have resulted in the isolation of thousands of structurally unique bioactive marine natural products. To date, the global marine pharmaceutical pipeline consists of three Food and Drug Administration (FDA) approved drugs, one EU registered drug, 13 natural products (or derivatives thereof) in different phases of the clinical pipeline and a large number of marine chemicals in the pre-clinical pipeline [78]. Some examples include, Ziconotide (Prialt®, Elan Corporation) a peptide first discovered in a tropical cone snail, which was approved in December 2004 for the treatment of pain.

Plitidepsin (34) (Aplidin®, PharmaMa), a depsipeptide was isolated from the Mediterranean tunicate Aplidium albicans [79,80]. Plitidepsin (34) is effective in treating various cancers, including melanoma, small cell and non-small cell lung, bladder as well as non-Hodgkin lymphoma and acute lymphoblastic leukemia and is currently in Phase II clinical trials ( ) [78,81]. Ecteinascidin 743 (ET743; Yondelis™) (35) was isolated in very low yields from the ascidian Ecteinascidia turbinata [82,83]. The quantities of ET743 (35) required for advanced pre-clinical and clinical studies was achieved by adopting very large-scale aquaculture of E. turbinata in open ponds, however the semisynthesis of ET743 (35) has been well established ( ) [81,84,85]. In October 2007, Trabectedin (35) (also known as Ecteinascidin 743 or ET-743) (Yondelis, PharmaMar) became the first marine anticancer drug to be approved in the European Union [78]. Trabectedin (35) has been approved by the European Agency for the Evaluation of Medicinal Products (EMEA) and is completing key Phase III studies in the US for approval [78]. Spisulosine (36), isolated from the marine clam Spisula polynyma, exhibited substantial selective activity against tumor cells compared to normal cells [86]. It advanced to Phase I clinical trials against solid tumors but was withdrawn in late 2006 [87,88,89]. Cryptophycin (37) was selected for clinical trials in the mid 1990s then advanced to phase II trials but was terminated in 2002 due to toxicity and lack of efficacy ( ) [90].

2.5. Natural Products from Marine Sponges

Sponges (Porifera) are sessile organisms, which lack a nervous, digestive and circulatory system and maintain a constant water flow through their bodies to obtain food, oxygen and to remove wastes. All sponges are ‘current’ or ‘filter’ feeders and have few physical means of defense against predators. They are considered to be the first multicellular animals and have changed very little in approximately 500 million years. The first notable discovery of biologically active compounds from marine sources can be traced back to the reports of Bergmann on the isolation and identification of C-nucleosides, spongouridine (51) and spongothymidine (52) from the Caribbean sponge, Cryptotheca crypta in the early 1950s ( ) [111]. These compounds were found to possess antiviral activity and the synthesis of structural analogues led to the development of cytosine arabinoside (Ara-C) as a clinical anticancer agent, together with (Ara-A) as an antiviral agent 15 years later [111]. This was an important discovery since previously it was believed that for a nucleoside to possess biological activity, it had to have a deoxyribose or ribose sugar moiety. These investigations led to the identification of (Ara-C) as a potent antileukemic agent [112].

2.6. Natural Products from other Marine Sources

The class of synthetic derivatives known as the bryologs, such as 53, are derived from bryostatin 1 (54), an antineoplastic compound isolated from the bryozoan, Bulgula neritina [5,113]. Bryostatin 1 (54) has been isolated in sufficient quantities to permit more than 80 clinical trials to date, with 20 being completed at both phase I and phase II levels ( ) [78]. It has displayed positive responses acting as a single agent with effects ranging from complete to partial remission [28]. From 2007 to date there were four Phase I and eight Phase II clinical trials, all combination studies with biologicals or cytotoxins against multiple carcinomas. Currently, 54 is in two Phase I clinical trials and is being assessed as an anti-Alzheimer’s drug (Phase I trial approved) [78]. Halichondrin B (55) has been isolated from several sponges including, Halichondria okadai (Japan) [114]; Axinella sp. from the Western Pacific [115], Phakellia carteri from the Eastern Indian Ocean [116] and from Lissodendoryx sp., off the East Coast of the South Island of New Zealand ( ) [117]. Halichondrin B (55) has been successfully synthesized [118] along with several structural analogues including Halichondrin E-7389 (56) which has been selected for further development and is currently in phase III clinical trials for the treatment of breast carcinoma ( ) [113].

Patients are increasingly using complementary and alternative medicine,1,2 and doctors are responding to this in several ways, from being enthusiastic and interested to mystified and critical.3–5 Complementary and alternative medicine incorporates several different approaches and methodologies,6 with techniques ranging from spiritual “healing” in cancer to nutritional interventions for premenstrual tension, acupuncture for pain relief, and manipulation for backache. In this article we encourage you to reflect on your understanding of complementary and alternative medicine in relation to your clinical practice, share some of the current initiatives in undergraduate and postgraduate familiarisation and training in this type of medicine, and explore the implications of education, support, and development.

The BMA's attitude to complementary and alternative medicine became much more positive between its first and second reports on the subject in 1986 and 1993.7 Around 39.5% of general practice partnerships in England provide access to some form of complementary therapy for their NHS patients,8 but this raises questions about how the provision of such treatment can be integrated into conventional practice. If the care is provided on a delegated or referred basis, how much does a doctor need to know to make appropriate referrals and supervise delegated treatment? If doctors are to treat patients with complementary and alternative medicine what training do they require?

Summary points

• The growth in patients' use of complementary and alternative medicine has an impact on conventional medical practice

• To advise about complementary and alternative medicine, doctors need to understand its potential benefits and limitations

• Doctors are training in complementary and alternative medicine and report benefits both for their patients and themselves

• Patients' safety and the effective integration of complementary and alternative medicine and conventional medicine is influenced by the professionalism and ethics of the training available

• Doctors need to address training in and practice of complementary and alternative medicine within their own organisations

Undergraduate education

Until recently few medical students would have been familiar with complementary and alternative medicine, despite being interested in it.9–12 Over the past few years there has been a major increase in courses familiarising students with complementary and alternative medicine.13,14 The opportunity to integrate this training into the undergraduate curriculum has been facilitated by giving students options in special study modules15 and noting what they want to learn. At the University of Southampton the module in complementary and alternative medicine has been running for five years as part of the special study modules for medical students in their third year. It grew out of the students' request for familiarisation with this type of medicine (mirroring the demand for such therapy by patients). The medical school actively supports the presence of its small research unit in complementary and alternative medicine.

Southampton's module in complementary and alternative medicine is an opportunity to revisit basic assumptions about attitudes and values in medicine through a reflective learning process. Although it helps to ask whether it works and to review its evidence base, a broader set of learning objectives (box) has been established through a consultation and ranking exercise.16 Themes that students regularly identify include treatments chosen by patients not doctors, patients with the same disease choosing different treatments, privately funded treatments, variety of standards of care, and lack of regulation within professions practising complementary and alternative medicine.

Learning objectives established through a consultation and ranking exercise

• To facilitate and encourage medical students to reflect on the issues raised (in a scientific, clinical, and social context) by the growth and practise of complementary and alternative medicine

• To introduce students to the philosophy, historical development, and underlying concepts

• To give students the opportunity to understand several specific therapies in more depth

• To observe complementary and alternative medicine “in practice,” to enable students to formulate their own opinions about such medicine, and to discuss these opinions and issues with individual practitioners and their peer group

• To consider the evidence base and to discuss the relevance of techniques in relation to specific clinical situations

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Southampton's special study module is made up of eight half day sessions. Modules in other medical schools are structured differently. Although there is no formal way of setting or agreeing objectives between medical schools, there has been a “sharing” of activities.17 Southampton's current teaching plan (box) looks at key therapies and gives a context in which to explore and interpret the use and provision of complementary and alternative medicine in the community in relation to conventional medicine. Our evaluations show that the needs of the students are addressed by this module18 and that the aims are meet; comments from students include “I wish I was the patient,” “I was surprised by the range of different illnesses patients had,” and “It left me interested to find out more.”

Over the past three years at Southampton student nurses and student chiropractors have taken the module. This enables different professional views and values about both conventional and complementary and alternative medicine to be put forward, which in many ways parallels aspects of individualisation so important to complementary and alternative medicine. This multidisciplinary teaching has received positive feedback and encouraged us in developing further multiprofessional approaches to teaching complementary and alternative medicine.19

Postgraduate education

Several thousand doctors belong to medical organisations offering training, accreditation, and regulation in complementary and alternative medicine (see Appendix). Training focuses on two main levels, a basic or primary healthcare qualification, which gives an introduction to a subject and provides skills to work with a basic level of competence, such as the Faculty of Homoeopathy's primary healthcare certificate, or the British Medical Acupuncture Society's basic training. These usually involve four or more days of training combined with home study over a year. This leads on to intermediate training and full membership, usually involving a further two years of part time teaching and home study. Although many specialists in complementary and alternative medicine work in primary care, a third level of specialist training based on supervised experience is also emerging. Examinations and other assessments evaluate competence, and most medical organisations in complementary and alternative medicine are developing a programme of continuing professional development.

Homoeopathy is one of the most established complementary and alternative medicines in that it has been incorporated into the NHS since its inception. Five NHS homoeopathic hospitals now exist as well as a Faculty of Homoeopathy established by an act of parliament. The Faculty of Homoeopathy has 300 full members and 406 members at the primary healthcare level. The British Medical Acupuncture Society has grown greatly over the past decade and includes over 1700 basic and 500 full or accredited members, who incorporate acupuncture into their normal medical practice.

Outline of the module offered to third year medical students at Southampton

Session 1: introduction and overview of basic  principles of complementary and alternative  medicine

Session 2: hypnosis and herbalism

Session 3: acupuncture and osteopathy

Session 4: homoeopathy and aromatherapy

Session 5: clinical attachment or visit to a college of chiropractic

Session 6: clinical attachment

Session 7: clinical problem solving with  complementary and alternative medicine

Session 8: dilemmas and opportunities—assessment  and review

Doctors give a variety of reasons for undertaking a course in complementary and alternative medicine, from feeling a responsibility to respond to their patients' interests and needs to developing “another string to their bow.” Some are attracted to its study in its own right, others by a wish to focus some of their energy away from conventional medical practice, which they may find stressful and unfulfilling. Doctors studying complementary and alternative medicine often call on different personality traits20 and report a variety of positive benefits from training, including welcoming the opportunity to engage their feelings, trust their intuition, and enjoy therapeutic touch. Comments from attendees at one homoeopathic course were “I started to enjoy seeing patients again,” “Training had improved my conventional history taking,” and “Having another approach made treating heart-sink patients easier.”

Retraining leads to a re-examination of how practitioners relate to patients and a rethinking of their clinical work, as well as the professional organisation they feel at home in for support and development. Griffiths and Tann argue that a practitioner's values and personal theories translate through practice into the external theory of a profession,21 and in complementary and alternative medicine there are several emerging professional groups. Several doctors seem to be integrating complementary and alternative medicine into their clinical management,8 but a proportion of these have been on no or only brief training courses.22 The BMA and General Medical Council have recommended that doctors providing complementary and alternative medicine are adequately trained.7 Those doctors who engage patients more through their emotions need regular support and supervision to help with the practice and development of their professional work.23 Doctors integrating complementary and alternative medicine into their work and working as specialist practitioners of such medicine also need professional support to integrate their developing approach into practice, particularly if it is different from their colleagues. Unfortunately it is often the case that emerging professional groups lack infrastructure, practical support, and funding to provide supervision and mentoring when it is most needed.

Questions that might be asked about complementary and alternative medicine

• How do you feel about your patients using complementary and alternative medicine? What do you think their expectations or assumptions regarding your knowledge of complementary and alternative medicine might be?

• Are you mostly interested in fundamental questions about whether complementary and alternative medicine works and its mechanism of action or more curious about its safety, cost effectiveness, and how to optimally combine it with conventional treatments?

• Can you recall the last time a patient mentioned they were using complementary and alternative medicine? What was your attitude to this? Do you think your attitude has changed in the past five to 10 years. If so, why?

• Reflecting on your undergraduate training, were opportunities there to challenge basic assumptions and values of medicine to prepare you for a changing working environment?

• Why do you think some doctors choose to do a three year part time training in complementary and alternative medicine? If you were to undertake such a course would you think it would be a challenging experience and would you be well supported by your peers?

• If you had undertaken training in complementary and alternative medicine, how might it change your current working practice? Would your current professional organisations be adequate for your ongoing training, regulation, and representation needs?

• With an increased proportion of undergraduate teaching in complementary and alternative medicine occurring in optional modules, how will those who choose not to do them compensate for these lost opportunities in education? Will it be as part of their specialist or general practice training or through continuing professional development?

Debatable issues

Establishing a module in complementary and alternative medicine within the undergraduate curriculum made us call on those outside the circles of conventional medicine, with input from students and the medical school, to build a teaching team that shared core values. We have been impressed by the benefits students have had from attachments to local providers of complementary and alternative medicine, and this has brought a network of practitioners into contact with the medical school. Such contact could be an important step in the integration of complementary and alternative medicine with other medical services. The issues that are raised by complementary and alternative medicine model many dilemmas for communities relating to changes within medical practice, including prioritising funding, obtaining relevant evidence, respecting individual choice, and provision for minority groups. For doctors and students it raises questions about clarifying and working within their limits of competence, how patients' expectations alter, and a way that doctors can develop new skills. Looking ahead, we believe that there are opportunities for providing more multidisciplinary teaching, perhaps even an important common core element shared by all professionals in complementary and alternative medicine and conventional health care. From the patient's point of view, having specially trained doctors may be of great value in integrating complementary and alternative medicine and conventional medicine while making the training in complementary and alternative medicine yet more professional.

An opportunity exists for doctors to incorporate different approaches that can balance their own personal values and help in developing their individual model of health. This may be inspiring and allow doctors to re-engage enthusiastically with their patients. However, a move into an individualised way of working, with the possibility of using several different interventions for the same clinical condition, creates problems in the context of managed care.

The organisations providing education, development, and support for these doctors are stretched by, and may have conflicts in, providing, training, accreditation, and regulation in each discipline. These issues, along with the lack of statutory regulation in complementary and alternative medicine, will need to be addressed to allow the continued development of the professions in complementary and alternative medicine outside and within medicine.

Conclusion

If doctors are to have a role in gatekeeping or advising patients about complementary and alternative medicine they need some familiarisation with this type of medicine. Doctors and their professional organisations need to address the extent to which they will integrate the techniques of complementary and alternative medicine into their patient care. If they choose not to then it is likely that the provision of complementary and alternative medicine will continue to be patchy and largely outside the conventional care framework, perhaps through a growing network of parallel care providers involving larger numbers of non-medically qualified practitioners, which patients will continue to access directly. For doctors, familiarisation with and training in complementary and alternative medicine provides an opportunity to integrate different approaches into patient management and offers a framework to work with and develop other skills. These approaches enhance patients' care and meet some doctors' intuitive needs to balance the increase in the technological base of conventional medical approaches with a softer approach to clinical care. We believe that the integration of complementary and alternative medicine gives doctors and the health profession an opportunity to bring together the strengths and to balance the weaknesses inherent in different systems of health care, representing a coming together of the heart, head, and hand. Could this be a healing process in itself?

Acknowledgments

We thank the BMA for the Joan Dawkins education award and the British Homoeopathic Association for a charitable grant to assist with teaching costs; we also received support from the department of medical education at Southampton University's school of medicine. DKO is course organiser for the Southampton module in complementary and alternative medicine.

Appendix

British Society of Allergy Environmental and Nutritional Medicine, PO Box 7, Knighton LD7 1WT (tel 01547 550380, fax 01547 550339, www.bsaenm.org.uk)

British Society of Medical and Dental Hypnosis, 17 Keppel View Road, Kimberworth, Rotherham, South Yorkshire S61 2AR (tel/fax 07000 560309, email gro.hdmsb@yraterces, www.bsmdh.org)

British Medical Acupuncture Society, 12 Marbury house, Higher Whitley, Warrington, Cheshire WA4 4QW (tel 01925 730727, fax 01925 730492, email ku.gro.erutcnupuca-lacidem@nimdA, www.medical-acupuncture.co.uk)

Faculty of Homoeopathy, 15 Clerkenwell Close, London EC1R 0AA (tel 020 7566 7800, fax 020 7566 7815, www.trusthomoeopathy.org)

British Institute of Musculoskeletal Medicine, 34 The Avenue, Watford, Herts WD1 3NS (tel/fax 01923 220999, email moc.evresupmoc@mmib, www.bimm.org.uk)

Notes

Editorial by Berman

Footnotes

Competing interests: None declared.

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