Early Arabic and European records

Humans have always used plants in a multitude of ways in a tradition spanning human evolution. The selection of medicinal plants is a conscious process which has led to an enormous number of medicinal plants being used by the numerous cultures of the world.

An early European example is medicinal mushrooms, which were found with the Austrian/Italian ‘iceman’ of the Alps of Ötztal (3300 BCE). Two walnut-sized objects were identified as the birch polypore (Piptoporus betulinus), a bracket fungus common in alpine and other cooler environments. This species contains toxic natural products, and one of its active constituents (agaric acid) is a very strong and effective purgative, which leads to strong and short-lasting diarrhoea. It also has antibiotic effects against mycobacteria and toxic effects on diverse organisms (Capasso 1998). Since the iceman also harboured eggs of the whipworm (Trichuris trichiuria) in his gut, he may well have suffered from gastrointestinal cramps and anaemia. The finding of Piptoporus betulinus points to the possible treatment of gastrointestinal problems using these mushrooms. Also, scarred cuts on the skin of the iceman might indicate the use of medicinal plants, since the burning of herbs over an incision on the skin was a frequent practice in many ancient European cultures (Capasso 1998).

Classical Arabic, Greek and Roman records

The oldest written information in the European–Arabic traditions comes from the Sumerians and Akkadians of Mesopotamia, thus originating from the same area as the archaeological records of Shanidar IV. Similar documents have survived millennia in Egypt. The Egyptians documented their knowledge (including medical and pharmaceutical) on papyrus, which is paper made from Cyperus aquaticus, an aquatic sedge (also called papyrus) found throughout southern Europe and northern Africa. The most important of these writings is the Ebers Papyrus, which originates from around 1500 BC. This document was reputedly found in a tomb, and bought in 1873 by Georg Ebers, who deposited it at the University of Leipzig and 2 years later published a facsimile edition. The Ebers Papyrus is a medical handbook covering all sorts of illnesses and includes empirical as well as symbolic forms of treatment. The diagnostic precision documented in this text is impressive. Other papyri focus on recipes for pharmaceutical preparations (e.g. the so-called Berlin Papyrus).

Greek medicine has been the focus of historical pharmaceutical research for many decades. The Greek scholar Pedanius Dioscorides (Fig. 2.1) from Anarzabos (1 BC) is considered to be the ‘father of [Western] medicine’. His works were a doctrine governing pharmaceutical and medical practice for more than 1500 years, and which heavily influenced European pharmacy. He was an excellent pharmacognosist and described more than 600 medicinal plants. Other Greek and Roman scholars were also influential in developing related fields of health care and the natural sciences. Hippocrates, a Greek medical doctor (ca. 460–375 BC) came from the island of Kos, and heavily influenced European medical traditions. He was the first of a series of (otherwise largely unknown) authors who produced the so-called Corpus Hippocraticum (a collection of works on medical practice). The Graeco-Roman medical doctor Claudius Galen (Galenus) (130–201 AD) summarized the complex body of Graeco-Roman pharmacy and medicine, and his name survives in the pharmaceutical term ‘galenical’. Pliny the Elder (23 or 24–79 AD, killed in Pompeii at the eruption of Vesuvius) was the first to produce a ‘cosmography’ (a detailed account) of natural history, which included cosmology, mineralogy, botany, zoology and medicinal products derived from plants and animals.

Fig. 2.1 Pedanius Dioscorides.

Reproduced with permission from The Wellcome Library, London.

Classical Chinese records

Written documents about medicinal plants are essential elements of many cultures of Asia. In China, India, Japan and Indonesia, writings pointing to a long tradition of plant use survive. In China, the field developed as an element of Taoist thought: followers tried to assure a long life (or immortality) through meditation, special diets, medicinal plants, exercise and specific sexual practices. The most important work in this tradition is the Shen nong ben caojing (the ‘Drug treatise of the divine countryman’) which is now only available as part of later compilations (Waller 1998; see also Chapter 12, p. 177 et seq). This 2200-year-old work includes 365 drugs, most of botanical origin. For each, the following information is provided:

These scholarly ideas were passed on from master to student, and modified and adapted over centuries of use. Unfortunately, in none of the cases do we have a surviving written record. Table 2.1 summarizes some of the Chinese works that include important chapters on drugs.

Table 2.1 Chinese works that include important sections on drugs (after Waller 1998)

In the 16th century the first systematic treatise on (herbal) drugs using a scientific method was produced. The Ben Cao Gang Mu (‘Drugs’, by Li Shizhen, 1518–1593) contains information about 1892 drugs (in 52 chapters) and more than 11,000 recipes are given in an appendix. The drugs are classified into 16 categories (e.g. herbs, cereals, vegetables, fruits). For each drug the following information is provided (Waller 1998):

The recognition of the need to further develop the usage of a plant, to correct earlier mistakes and to include new information is particularly noteworthy. However, the numerous medicopharmaceutical traditions of the Chinese minorities were not included in these works and we, therefore, have no historical records of their pharmacopoeias.

Other Asian traditional medicine

Overall, the written records on other Asian medicine are less comprehensive than for Chinese medicine. The oldest form of traditional Asian medicine is Ayurveda, which is basically Hindu in origin and which is a sort of art-science-philosophy of life. In this respect it resembles Traditional Chinese Medicine, and like TCM has influenced the development of more practical, less esoteric forms of medicine, which are used for routine or minor illnesses in the home. Related types of medicine include Jamu, the traditional system of Indonesia, which will be described briefly below. All these forms of traditional medicine use herbs and minerals and have many features in common. Naturally, many plants are common to all systems and to various official drugs that were formerly (or still) included in the British Pharmacopoeia (BP), European Pharmacopoeia (Eur. Ph.) and US Pharmacopoeia (USP).

Kampo

Kampo, or traditional Japanese medicine, is sometimes referred to as low-dose TCM. Until 1875 (when the medical examination for Japanese doctors became restricted to Western medicine), the Chinese system was the main form of medical practice in Japan, having arrived via Korea and been absorbed into native medicine. Exchange of scholars with China meant that religious and medical practices were virtually identical; for example, the medical system established in Japan in 701 was an exact copy of that of the T’ang dynasty in China. In the Nara period (710–783), when Buddhism became even more popular, medicine became extremely complex and included facets of Ayurveda as well as of Arabian medicine. Native medicine remained in the background and, after concerns that it would be subsumed into Chinese medicine, the compendium of Japanese medicine, Daidoruijoho, was compiled in 808 on the orders of the Emperor Heizei. In 894, official cultural exchange with China was halted, and native medicine was temporarily reinstated. Knowledge gained from China, however, continued to be assimilated, and in 984 the court physician Yasuyori Tamba compiled the Ishinho, which consisted of 30 scrolls detailing the medical knowledge of the Sui and T’ang dynasties. Although based entirely on Chinese medicine, it is still invaluable as a record of medicine as practised in Japan at that time.

In 1184 the framework began to change when a reformed system was introduced by Yorimoto Minamoto in which native medicine was included, and by 1574 Dosan Manase had set down all the elements of medical thought which became a form of independent Japanese medicine during the Edo period. This resulted in Kampo, and it remained the main form of medicine until the introduction of Western medicine in 1771, by Genpaku Sugita. Although Sugita did not reject Kampo, and advocated its use in his textbook book Keieiyawa, it fell into decline because of a lack of evidence and an increasingly scholastic rather than empirical approach to treatment. Towards the end of the 19th century, despite important events such as the isolation of ephedrine (Fig. 2.2) by Nagayoshi Nagai, Kampo was still largely ignored by the Japanese medical establishment. However, by 1940, a university course on Kampo had been instituted, and now most schools of medicine in Japan offer courses on traditional medicine integrated with Western medicine. In 1983, it was estimated that about 40% of Japanese clinicians were writing Kampo herbal prescriptions and today’s research in Japan and Korea continues to confirm the validity of many of its remedies (Takemi et al 1985).

Fig. 2.2

The European Middle Ages and Arabia

After the conquest of the southern part of the Roman Empire by Arab troops, Greek medical texts were translated into Arabic and adapted to the needs of the Arabs. Many of the Greek texts survived only in Arab transcripts. Ibn Sina, or Avicenna from Afshana (980–1037), wrote a monumental treatise Qânûn fi’l tibb (‘Canon of medicine’; ca. 1020), which was heavily influenced by Galen and which in turn influenced the scholastic traditions especially of southern Europe. This five-volume book remained the most influential work in the field of medicine and pharmacy for more than 500 years, together with direct interpretations of Dioscorides’ work. While many Arab scholars worked in eastern Arabia, Arab-dominated parts of Spain became a second centre for classical Arab medicine. An important early example is the Umdat at-tabîb (‘The medical references’) by an unknown botanist from Seville. Thanks to the tolerant policies of the Arab administration, many of the most influential representatives of Arab scholarly traditions were Jews, including Maimoides (1135–1204) and Averroes (1126–1198). In Christian parts of Europe, the texts of the classical Greeks and Romans were copied from the Arabian records and annotated, often by monks. The Italian monastery of Monte Cassino is one of the earliest examples of such a tradition; others developed around the monasteries of Chartres (France) and St Gall (Switzerland).

A common element of all monasteries was a medicinal plant garden, which was used both for growing herbs to treat patients and for teaching about medicinal plants to the younger generation. The species included in these gardens were common to most monasteries and many of the species are still important medicinal plants today. Of particular interest is the Capitulare de villis of Charles the Great (Charlemagne, 747–814), who ordered that medicinal (and other plants) should be grown in the King’s gardens and in monasteries, and specifically listed 24 species. Walahfri(e)d Strabo (808 or 809–849), Abbot of the monastery of Reichenau (Lake Constance), deserves mention because of his Liber de cultura hortum (‘Book on the growing of plants’), the first ‘textbook’ on (medical) botany, and the Hortulus, a Latin poem about the medical plants grown in the district. The Hortulus is not only famous as a piece of poetry, but also because of its vivid and excellent descriptions of the appearance and virtues of medicinal plants. Table 2.2 lists the plants reported in the Capitulare de villis and in some other sources of the 10th and 11th centuries. Today, many of these plants are still important medicinally or in other ways. Many are vegetables, fruits or other foods. The list shows not only the long tradition of medicinal plant use in Europe, but also the importance of these resources to the state and religious powers during the Middle Ages. Although these were not necessarily of interest as scholarly writings, they were at least a practical resource.

A plan (which was not executed) for a medicinal herb garden for the Cloister of St Galls (Switzerland), dating from the year 820, has been preserved and gives an account of the species that were to be grown in a cloister garden. In general, pharmacy and medicine were of minor importance in the European scholastic traditions, as shown for example by the fact that in the Monastery of St Gall there were only six books on medicine, but 1000 on theology. Scholastic traditions, influenced by Greek–Arab medicine and philosophy, were practised in numerous European cloisters. In Arab-dominated Sicily, the first medical centre of medieval Europe was developed in Salerno (12th century). Until 1130, before the Council of Clermont, the monks combined medical and theological work, but after this date only lay members of the monastery were permitted to practise medicine. Simultaneously, the first universities (Paris 1110, Bologna 1113, Oxford 1167, Montpellier 1181, Prague 1348) were founded which provided training in medicine.

The climax of medieval medico-botanical literature was reached in the 11th century with De viribus herbarum (‘On the virtues of herbs’) and Macer floridus, a Latin poem from around 1070 AD, presumed to be by Odo of Meune (Magdunensis), the Abbot of Beauprai. In this educational poem, 65 medicinal plants and spices are presented. Other frequently cited sources are the descriptions of the medical virtues of plants by the Benedictine nun, early mysticist and abbess Hildegard of Bingen (1098–1179). In her works Physica and Causae et curae she included many remedies that were popularly used during the 12th century. Her writings also focus on prophetic and mystical topics. The works of both scholars are only available as later copies in other texts, which unfortunately give a rather distorted idea of the originals, as they are heavily re-interpreted.

Printed reports in the European tradition (16th century)

For over 1500 years the classical and most influential book in Europe had been Dioscorides’ De materia medica. Until the Europeans’ (re-)invention of printing in the mid-15th century (by Gutenberg), texts were hand-written codices, which were used almost exclusively by the clergy and scholars in monasteries. A wider distribution of the information on medicinal plants in Europe began with the early herbals, which rapidly became very popular and which made the information about medicinal plants available in the languages of lay people. These were still strongly influenced by Graeco-Roman concepts, but influences from many other sources came in during the 16th century (see Table 2.3).

Herbals were rapidly becoming available in various European languages and, in fact, many later authors copied, translated and re-interpreted the earlier books. This was especially so for the woodcuts used for illustration (see Fig. 2.4); these were often used in several editions or were copied. The herbals changed the role of European pharmacy and medicine and influenced contemporary orally transmitted popular medicine. Previously there had been two lines of practice: the herbal traditions of the monasteries and the popular tradition, which remains practically unknown. Books in European languages made scholastic information much more widely available and it seems that the literate population was eager to learn about these medicopharmaceutical practices. These new books became the driving force of European ‘phytotherapy’, which developed rapidly over the next centuries.

Fig. 2.4 Examples of early woodcuts: (a) marigold or Ringelblume (Calendula officinalis), one of the most important medicinal plants in historical and modern phytotherapy; (b) capsicum (chilli pepper; Capsicum frutescens).

Reproduced with permission from The University Library, Tübingen.

The trade in botanical drugs increased during this period. From the East Indies came nutmeg (Myristica fragrans, Myristicaceae), already used by the Greeks as an aromatic and for treating gastrointestinal problems. Rhubarb (Rheum palmatum and Rh. officinale, Polygonaceae) arrived in Europe from India in the 10th century and was employed as a strong purgative. Another important change at this time was the discovery of healing plants with new properties, during the exploration and conquest of the ‘New Worlds’ – the Americas, as well as some regions of Asia and Africa. For example, ‘guayacán’ (Guaiacum sanctum, Zygophyllaceae), from Meso-America, was used against syphilis, despite its lack of any relevant pharmacological effects.

Nicolás Monardes was particularly important in the dissemination of knowledge about medicinal plants from the New World. His principal work, Historia medicinal de las cosas que se traen de nuestras Indias Occidentales que sirven en medicina (‘Medical history of all those things which are brought from our Western India and may be used as medicines’) was published in 1574. Some parts had appeared as early as ca. 1530. Another influential scholar during this period was Theophrastus Bombastus of Hohenheim, better known as Paracelsus (1493–1541). His importance lies less in the written record he left but more in his medical and pharmaceutical inventions and concepts. He rejected the established medical system and, after a fierce fight with the medical faculty of Basel in 1528, fled to Salzburg. According to some sources, he had publicly burned the ‘Canon of medicine’ by Avicenna. He introduced minerals into medical practice and called for the extraction of the active principle from animals, plants or minerals, a goal that was not achieved until the beginning of the 19th century (see below). He regarded the human body as a ‘microcosm’, with its substances and powers needing to be brought into harmony with the ‘macrocosm’ or universe. According to Paracelsus, healing was due to ‘the power of life, which is only supported by the medical doctor and the medicine’. Although some of his ideas anticipated later ones, at the time they were largely rejected. The first pharmacopoeias were issued by autonomous cities, and became legally binding documents on the composition, preparation and storage of pharmaceuticals.

Fig. 2.3 Leonhard Fuchs.

Reproduced with permission from The University Library, Tübingen.

These pharmacopoeias were mainly intended to bring some order to the many forms of preparation available at the time and the varying composition of medicines, and to reduce the problems arising out of their variability.

Another development was the establishment of independent guilds specializing in the sale of medicinal plants, even though apothecaries had practised this for centuries. In 1617, the Worshipful Society of Apothecaries was founded in London, and in 1673 it formed its own garden of medicinal plants, known today as the Chelsea Physic Garden (Minter 2000). One of the most well-known English apothecaries (and astrologers) of the 17th century is Nicholas Culpeper (1616–1654), best known for his ‘English physician’ – more commonly called ‘Culpeper’s herbal’. This is the only herbal that rivals in popularity John Gerard’s General historie of plantes, but his arrogant dismissal of orthodox practitioners made him very unpopular with many physicians. Culpeper describes plants that grow in Britain and which can be used to cure a person or to ‘preserve one’s body in health’. He is also known for his translation A physicall directory (from Latin into English) of the London Pharmacopoeia of 1618 published in 1649 (Arber 1938).

European pharmacognosy and natural product chemistry in the 18th and 19th centuries

In the 17th and 18th centuries, knowledge about plant-derived drugs expanded, but all attempts to ‘distillate’ the active ingredients from plants were unsuccessful. The main outcome during this period was detailed observations on the clinical usefulness of medicinal products, which had been recorded in previous centuries or imported from non-European countries. The next main shift in emphasis came in the early 19th century when it became clear that the pharmaceutical properties of plants are due to specific molecules that can be isolated and characterized. This led to the development of a field of research now called natural product chemistry or, specifically for plants, phytochemistry. Pure chemical entities were isolated and their structures elucidated. Some were then developed into medicines or chemically modified for medicinal use. Examples of such early pure drugs include:

Fig. 2.6

Fig. 2.7 FW Sertürner.

Reproduced with permission from The Wood Library-Museum of Anesthesiology, Park Ridge, IL, London.

Fig. 2.8

Fig. 2.9

Also, early in the 19th century, the term ‘pharmacognosy’ was coined by the Austrian professor Johann Adam Schmidt (1759–1809) and was included in his posthumously published book Lehrbuch der Materia Medica (1811). This period thus saw the development of a well-defined scientific field of inquiry, which developed rapidly during the century.

One of the main achievements of 19th century science in the field of medicinal plants was the development of methods to study the pharmacological effects of compounds and extracts. The French physiologist Claude Bernard (1813–1878), who conducted detailed studies on the pharmacological effects of plant extracts, must be considered one of the first scientists in this tradition. He was particularly interested in curare – a drug and arrow poison used by the American Indians of the Amazon, and the focus of research of many explorers. The ethnobotanical story of curare is described further in Chapter 5.

Bernard noted that, if curare was administered into living tissue directly, via an arrow or a poisoned instrument, it resulted in death more quickly, and that death occurred more rapidly if dissolved curare was used rather than the dried toxin (Bernard 1966: 95–96). He was also able to demonstrate that the main cause of death was by muscular paralysis, and that animals showed no signs of nervousness or pain. Further investigations showed that, if the blood flow in the hind leg of a frog was interrupted using a ligature (without affecting the innervation) and the curare was introduced via an injury of that limb, the limb retained mobility and the animal did not die [Bernard 1966:95–96, 115 (orig. 1864)]. One of the facts noted by all those who reported on curare is the lack of toxicity of the poison in the gastrointestinal tract, and, indeed, the Indians used curare both as a poison and as a remedy for the stomach.

Bernard went on to say:

Later, the botanical source of curare was identified as Chondrodendron tomentosum Ruiz et Pavon, and the agent largely responsible for the pharmacological activity first isolated. It was found to be an alkaloid, and named D-tubocurarine because of its source, ‘tube curare’, so-called because of the bamboo tubes used as storage containers. In 1947 the structure of this complex alkaloid, a bisbenzylisoquinoline, was finally established (Fig. 2.10). The story of this poison is one of the most fascinating examples of transforming a drug used in an indigenous culture into a medication and research tool, and, although D-tubocurarine is now used less frequently for muscular relaxation during surgery, it has been used as a template for the development of newer and better drugs.

Fig. 2.10

The 19th century thus saw the integration of ethnobotanical, pharmacological and phytochemical studies, a process that had taken many decades but which allowed the development of a new approach to the study and the pharmaceutical use of plants. Ultimately, herbal remedies became transformed into chemically defined drugs.

The 20th century

One of the most important events that influenced the use of medicinal plants in the Western world in the last century was the serendipitous discovery of the antibacterial properties of fungal metabolites such as benzylpenicillin, by Florey and Fleming in 1928 at St Mary’s Hospital (London). These natural products changed forever the perception and use of plant-derived metabolites as medicines by both scientists and the lay public. Another important development came with the advent of synthetic chemistry in the field of pharmacy. Many of these studies involved compounds that were synthesized because of their potential as colouring material (Sneader 1996). The first successful use of a synthetic compound as a chemotherapeutic agent was achieved by Paul Ehrlich in Germany (1854–1915); he successfully used methylene blue in the treatment of mild forms of malaria in 1891. Unfortunately, this finding could not be extended to the more severe forms of malaria common in the tropics. Many further studies on the therapeutic properties of dyes and of other synthetic compounds followed.

The latter part of the 20th century saw a rapid expansion in knowledge of secondary natural products, their biosynthesis, and their biological and pharmacological effects. A large number of natural products or their derivatives were introduced as medicines, including many anti-cancer agents (paclitaxol, the vinca alkaloids; see Chapter 6, pp. 103), the anti-malarial agent artemisinin and the anti-dementia medication galanthamine, to name just a few (Cragg et al 2005, Heinrich 2010, Heinrich & Teoh 2004). Numerous examples of drugs which are natural products, their deriviates or a pharmacophore based on a natural product have been introduced. There is now a better understanding of the genetic basis of the reactions that give rise to such compounds, as well as the biochemical (and in many cases genetic) basis of many important illnesses. This has opened up new opportunities and avenues for drug development.