The central nervous system

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Chapter 17 The central nervous system

Drugs acting on the central nervous system (CNS) include the centrally acting (mainly opioid) analgesics, anti-epileptics and anti-Parkinson agents, as well as those for psychiatric disorders. Drugs of plant origin are important in all these areas, although not usually for self-medication. They are also of historical interest; for example, the antipsychotic drug reserpine, isolated from Rauvolfia species, revolutionized the treatment of schizophrenia and enabled many patients to avoid hospitalization before the introduction of the phenothiazines (such as chlorpromazine) and the newer atypical antipsychotics (olanzapine and risperidone). Unfortunately, reserpine depletes neurotransmitter levels in the brain (it is used as a pharmacological tool in neuroscience for this reason) and so can cause severe depression, and it has recently been implicated in the development of breast cancer. There are no other currently useful antipsychotics obtained from plants and they will not be covered here. Similarly, the useful anti-epileptics are synthetic, with the possible exception of the cannabinoids, from Cannabis sativa, which are currently under investigation.

However, for milder psychiatric conditions, phytotherapy can provide useful support. The prevalence of mental health problems, particularly depression and anxiety, in the general population is around one in six people, and around 40% of people with mental health problems will have symptoms of both anxiety and depression. Depression is more common in women than men; around one-half of women and one-quarter of men will be affected by depression at some time. However, other than in mild cases, these disorders are not suitable for self-treatment, and medical supervision is necessary. Sleep disturbances, such as insomnia and early morning awakening, are characteristic of depression and anxiety, although they can also occur independently of mental health problems. Around one-third of adults are thought to experience insomnia, and most do not seek treatment from a physician. Phytotherapy has a role to play in helping to re-establish a regular pattern of sleep. Valerian (Fig. 17.1), for example, has been advocated as a means of alleviating the symptoms of benzodiazepine withdrawal.

Fig. 17.1

Migraine is a common disorder, but can be debilitating. Opioid analgesics are used, and the synthetic 5-HT₁ (5-hydroxytryptamine) antagonists (sumatriptan, rizatriptan) are highly effective, although they are not used for the prophylaxis of migraine. Ergotamine is a potent drug used as a last resort in attacks of migraine. Feverfew is sometimes used to prevent attacks, and will be discussed briefly.

In cases of dementia and Alzheimer’s disease, natural compounds have played a key role in their symptomatic treatment. Galantamine (from the snowdrop, Galanthus nivalis) and derivatives of physostigmine (e.g. rivastigmine) are clinically used as cholinesterase inhibitors. Some plant extracts, such as sage and rosemary, have similar but milder effects and are being investigated for memory improvement. Ginkgo biloba has cognition-enhancing properties and can be used for mild forms of dementia.

Hypnotics and sedatives

The difference between a sedative and hypnotic is generally a question of dose. Plant products used in this way are not as potent as synthetic drugs, but neither do they have many of the disadvantages. However, as with synthetic hypnotics, these medicines are generally intended for short-term use.

Hops, Humulus lupulus L. (Humuli lupuli strobuli)

Humulus lupulus (Cannabaceae), often referred to by its common name of hops, has been used traditionally for insomnia, neuralgia and excitability. It is cultivated in several European countries, including England, France and Germany. The part of the plant used pharmaceutically is the female flower heads (known as ‘strobiles’). These are composed of overlapping bracts, which enclose the ovary. Hops have a characteristic odour.

Constituents

The main active constituents of hops are the bitter principles found in the oleo-resin. These include the α-acid humulone and the β-acid lupulone, and their degradation products, such as 2-methyl-3-buten-2-ol (Fig. 17.2). Other constituents include flavonoids, chalcones, tannins and volatile oils.

Fig. 17.2

Therapeutic uses and available evidence

Modern pharmaceutical uses of hops include sleep disturbances and restlessness. Sedative and hypnotic activities have been documented in vivo (mice) for extract of hops, and for the bitter acid degradation product 2-methyl-3-buten-2-ol. Clinical studies provide some evidence of the hypnotic effects of hops given in combination with the herbal sedative, hypnotic valerian (Zanoli and Zavatti 2008). Antibacterial and antifungal activities have been documented in vitro for certain constituents of hops. Hops are non-toxic, as their use in beer would suggest. Cheers!

Lemon balm, Melissa officinalis L. (Melissae folium)

Melissa officinalis L. (syn. ‘balm’ and ‘sweet balm’, Lamiaceae) has been used traditionally for its sedative effects, as well as for gastrointestinal disorders. The dried leaves are the parts used pharmaceutically. The herb is described in Chapter 17.

Constituents

The volatile oil of melissa contains numerous constituents, mainly monoterpenes, particularly aldehydes (e.g. as citronellal, geranial and neral) and sesquiterpenes (e.g. β-caryophyllene). Flavonoids, including quercetin, apigenin and kaempferol, and polyphenols (e.g. hydroxycinnamic acid derivatives) are also present in the herb. Melissa is listed in the Eur. Ph, which states that the drug contains not less than 4.0% of total hydroxycinnamic derivatives, expressed as rosmarinic acid, calculated with reference to the dried drug.

Therapeutic uses and available evidence

Sedative and antispasmodic effects have been documented for melissa extracts using in vivo studies (mice, rats). It is used for nervous or sleeping disorders and functional gastrointestinal complaints. There has been no clinical investigation of the sedative effects of melissa alone in individuals with sleeping disorders. However, clinical trials have explored the effects of melissa in combination with other herbal sedatives (e. g. valerian and hops) and provide some evidence to support the sedative and hypnotic effects of such preparations. Antihormonal effects of balm, mainly antithyroid, have been documented and, recently, cholinergic activity has been found for extracts using human cerebral cortical cell membrane homogenates. Dried lemon balm is usually taken internally in the form of a herbal tea, at a dose of 2–4 g three times a day. Melissa extracts are also applied topically in cases of Herpes simplex labialis resulting from HSV-1 infection (see anti-infectives). Lemon balm is regarded as non-toxic, although it should not be used to excess because of the reputed antithyroid activity. For review, see Ulbricht et al 2005.

Kava, Piper methysticum Forst. (Piperis methystici rhizome)

Piper methysticum (Piperaceae), also known as kava-kava or kawa, has been used in the Pacific Islands, notably Fiji, for hundreds of years. It is a small shrub with heart-shaped leaves and thick, woody roots and rhizomes, which are ground or chewed to release the actives. These are then fermented to make the ceremonial drink Kava, which induces a relaxed sociable state, and is given to visiting dignitaries (including the Pope and the Queen of England). Kava is used medicinally for its tranquillizing properties and numerous other disparate complaints. Recent safety concerns have resulted in Kava products being withdrawn from sale at present (2011), but moves are being made to try to re-introduce it into the EU (Sarris et al 2011).

Constituents

The main components of kava are the kavalactones (also known as kavapyrones), including kavain, dihydrokavain, methysticin, yangonin and desmethoxyyangonin.

Therapeutic uses and available evidence

In vitro studies have previously provided some conflicting data on receptor interactions of kava extract and isolated kavalactones. Current thinking is that kavalactones potentiate GABA_A receptor activity. Other receptor binding studies demonstrate no interaction with benzodiazepine receptors. The efficacy of kava extracts in relieving anxiety is supported by data from several randomized, placebo-controlled, clinical trials, for example an aqueous kava preparation produced significant anxiolytic and antidepressant activity and appeared equally effective in cases where anxiety is accompanied by depression (Sarris et al 2009). Overall, studies indicate reductions in anxiety after 4–12 weeks of treatment with kava extracts at dosages equivalent to 60–240 mg of kavalactones daily.

Kava extracts are generally well tolerated when used at recommended doses for limited periods. However, kava-induced liver injury has been demonstrated in several patients worldwide, and it has been suggested that this is due to inappropriate quality of the kava raw material (Teschke et al 2011). There may also be a pharmacogenomic component to the toxicity (Sarris et al 2011) and assessment of the causal role of kava is complicated by other factors, including concomitant drugs linked with liver toxicity, and alcohol. There is circumstantial evidence for the roles of toxic metabolites, inhibition of cyclooxygenase (COX) enzymes and depletion of liver glutathione, and pharmacogenomic effects are likely, particularly for cytochrome P450 genes. Experimental and clinical cases of hepatotoxicity show evidence of hepatitis, but the question remains whether this inflammation is caused by components of kava directly, or is due to downstream effects (Zhang et al 2011). A recent study in hepatocytes has shown that kavain has minimal cytotoxicity and methysticin moderate concentration-dependent toxicity, whereas yangonin displayed marked toxicity (Tang et al 2011).

Passion flower, Passiflora incarnata L. (Passiflorae herba)

Passion flower (Passiflora incarnata L., Passifloraceae) is also known by the common names passion vine, maypop and others. The plant is a climbing vine, native to South America, but now also grown widely including in the USA and India. The dried leafy aerial parts, which normally include the flowers and fruits, are used pharmaceutically. The flower shows a distinctive shape of a cross, and gives the name passion (which refers to Christian connotations rather than romantic). There are numerous curling tendrils and the leaves are three-lobed. The active constituents have not yet been clearly established. The edible passion fruit is from P. edulis.

Constituents

The active constituents are not known, but the flavonoids are thought to be important, particularly chrysin and related compounds. These include schaftoside, isoschaftoside, orientin, homoorientin, vitexin, isovitexin, kaempferol, luteolin, quercetin, rutin, saponaretin and saponarin. Alkaloids of the harman type are present in low amounts (the presence of harmine, harmaline, harmol and harmalol has been disputed) as well as β-carbolines. P. edulis contains similar types of compounds and cycloartane triterpenoids such as the cyclopassifloic acids and cyclopassiflosides. Passion flower is included in the Eur. Ph. The drug should contain not less than 1.5% of total flavonoids, expressed as vitexin, assayed by a colorimetric method.

Therapeutic uses and available evidence

The historical medicinal uses of passion flower include treatment of insomnia, hysteria, nervous tachycardia and neuralgia. Modern pharmaceutical uses include nervous restlessness and insomnia due to nervous tension, and, specifically based on the THMPD, for the temporary relief of symptoms associated with stress and of mild anxiety.

Animal studies (mice, rats) have documented CNS-sedative effects or reductions in motility for aqueous ethanolic extracts of passion flower and for the constituents maltol and ethylmaltol. Anxiolytic activity has been reported in mice (Sampath et al 2010) and modulation of the GABA system is known to be involved (Appel et al 2010, Elsas et al 2010). Sedative effects are attributed at least in part to the flavonoid, particularly chrysin, content. There are few clinical studies of passiflora; however, a preliminary double-blind randomized trial using 36 patients with generalized anxiety showed the extract to be as effective as oxazepam, but with a lower incidence of impairment of job performance. It has been advocated as an adjunctive therapy for opiate withdrawal symptoms (for review, Miyasaka et al 2007). Generally, passiflora is well tolerated with few side effects; however, isolated reactions involving nausea and tachycardia in one case, and vasculitis in another, have been reported.

Valerian, Valeriana officinalis L. (Valerianae radix)

Valeriana officinalis (Valerianaceae), commonly known as valerian, all-heal, and by many other vernacular (common) names, is among the most well documented of all medicinal plants, particularly in northern Europe. It is an herbaceous plant, reaching about 1 m in height, and is cultivated in many European countries, as well as in Japan and North America. Valerian has a long history of traditional use. Historically, it was used in the treatment of conditions involving nervous excitability, such as hysterical states and hypochondriasis, as well as in insomnia. The parts used pharmaceutically are the root, rhizomes and stolons, which are yellowish grey to pale greyish-brown. The rhizomes may be up to 50 mm long and 30 mm in diameter, whereas the roots may be around 100 mm long and 1–3 mm in diameter. Valerian root has a characteristic smell, which is usually described as unpleasant.

Constituents

The main components of valerian are the volatile oil and the iridoid valepotriate constituents. The volatile oil contains monoterpenes and sesquiterpenes, such as β-bisabolene, caryophyllene, valeranone, valerianol, valerenol, valerenal, valerenic acid and derivatives (Fig. 17.1). The valepotriate compounds include valtrate, didrovaltrate and isovaltrate. The valepotriates readily decompose on storage and processing to form mainly baldrinal and homobaldrinal, which are also unstable. Valerian also contains alkaloids, including valerianine and valerine, and amino acids such as arginine, γ-aminobutyric acid (GABA), glutamine and tyrosine.

Valerian root is listed in the Eur. Ph., which requires that it contains not less than 5 ml/kg volatile oil for the whole drug, and not less than 3 ml/kg for the cut drug, calculated with reference to the dried drug. It should also contain not less than 0.17% of sesquiterpenic acids, expressed as valerenic acid.

Therapeutic uses and available evidence

In Europe valerian and its various preparations (tablets, tinctures) have been approved for the temporary relief of symptoms of mild anxiety and to aid sleep, and are generally based on traditional use. The sedative effects of valerian root are well documented. In vivo studies (in mice) have demonstrated CNS-depressant activity for the volatile oil, the valepotriates and the valepotriate degradation products. The sedative effects of valerian root are thought to be due to the activities of these different components, particularly valerenal and valerenic acid (constituents of the volatile oil), and the valepotriate compounds. Therefore, the profile of these constituents, and their concentrations, in a specific valerian preparation will determine its activity. Biochemical studies have indicated that certain components of valerian, particularly valerenic acid, may lead to increased concentrations of the inhibitory neurotransmitter GABA in the brain by inhibiting its catabolism, inhibiting uptake and/or by inducing GABA release. Increased GABA concentrations are associated with decreased CNS activity, which may, at least partly, explain valerian’s sedative activity. It is not clear whether valerian root extracts have effects on the binding of benzodiazepines to receptors. Modern medicinal uses for valerian root preparations are for insomnia, stress and anxiety. Clinical trials have tested the effects of valerian preparations on subjective (e.g. sleep quality) and objective (e.g. sleep structure) sleep parameters, and on measures of stress. Some, but not all, of these studies provide evidence to support the traditional uses of valerian. Several preparations contain valerian root in combination with other herbs reputed to have hypnotic and/or sedative effects, such as hops (Humulus lupulus) and melissa (Melissa officinalis) (see Salter and Brownie 2010 for review). It is recommended that valerian preparations should not be taken for up to 2 hours before driving a car or operating machinery; also, the effect of valerian preparations may be enhanced by alcohol consumption. There are isolated reports of hepatotoxicity associated with valerian-containing products, although causality has not been established.

Antidepressants

St John’s wort, Hypericum perforatum L. (Hyperici herba)

St John’s wort (Hypericaceae) has a history of medicinal use, particularly as a ‘nerve tonic’ and in the treatment of nervous disorders. It is commonly used to treat mild and moderate forms of depression and is registered in the UK for the treatment of ‘slightly low mood and mild anxiety’.

It is an herbaceous perennial plant native to Europe and Asia. The name St John’s wort may have arisen as the flowers bloom in late June around St John’s day (24 June). Herbal products containing St John’s wort have been among the top-selling herbal preparations in developed countries in recent years. The dried herb (consisting mainly of the flowering tops, including leaves, unopened buds and flowers) is the part used pharmaceutically.

Constituents

St John’s wort contains a series of naphthodianthrones, which include hypericin and pseudohypericin, and the prenylated phloroglucinols, such as hyperforin and adhyperforin. Initially, hypericin was considered to be the antidepressant constituent of St John’s wort, although evidence has now emerged that hyperforin (Fig. 17.3) is also a major constituent required for antidepressant activity. Further research is necessary to determine which other constituents contribute to the antidepressant effect. The Eur. Ph. states that the drug should contain not less than 0.08% of total hypericins, expressed as hypericin, calculated with reference to the dried drug. Most products containing standardized extracts of St John’s wort are still standardized on hypericin content, as hyperforin is fairly unstable. St John’s wort also contains other biologically active constituents, such as flavonoids. The leaves and flowers also contain an essential oil, of which the major components are β-caryophyllene, caryophyllene oxide spathulenol, tetradecanol, viridiflorol, α- and β-pinene, and α- and β-selinene.

Fig. 17.3

Therapeutic uses and available evidence

The precise mechanism of action for the antidepressant effect of St John’s wort is unclear. Results of biochemical and pharmacological studies have suggested that St John’s wort extracts inhibit synaptosomal uptake of the neurotransmitters, serotonin (5-hydroxytryptamine, 5-HT), dopamine and noradrenaline (norepinephrine) and GABA. Studies involving small numbers of healthy male volunteers have indicated that St John’s wort extracts may have dopaminergic activity and effects on cortisol, which may influence concentrations of certain neurotransmitters. Previous in vitro studies suggested that St John’s wort inhibited monoamine oxidase, although other studies failed to confirm this. Experimental studies involving animal models of depression provide supporting evidence for the antidepressant effects of St John’s wort. Evidence from randomized controlled trials indicates that preparations of St John’s wort extracts are more effective than placebo, and possibly as effective as conventional antidepressants, in the treatment of mild to moderate depression (for overview, see Linde 2009, Nahrstedt and Butterweck 2010). Generally, a few weeks’ treatment is required before marked improvement is seen. St John’s wort is not recommended for the treatment of major depression.

Standardized extracts of St John’s wort are generally well tolerated when used at recommended doses for up to 12 weeks. Adverse effects reported are usually mild, and include gastrointestinal symptoms, dizziness, confusion and tiredness and, rarely, photosensitivity (due to the hypericin content). However, clinical trials of St John’s wort suggest a more favourable short-term safety profile than some conventional antidepressants. Concern has been raised over interactions between St John’s wort preparations and certain prescribed medicines, including anticonvulsants, cyclosporin, digoxin, HIV protease inhibitors, oral contraceptives, selective serotonin reuptake inhibitors, theophylline, triptans and warfarin. Patients taking these medicines should stop taking St John’s wort and seek medical advice (except in the case of oral contraceptives) as dose adjustment of the prescribed medicines concerned may be necessary. St John’s wort should not be used during pregnancy and lactation.

Stimulants

CNS stimulants are now rarely employed therapeutically, with the exception of caffeine, although they were important in the treatment of barbiturate poisoning (e.g. picrotoxin) or as a tonic (strychnine). Cola nut extract is used in many herbal tonics and, of course, in the ubiquitous soft drink of the same name. Guarana is an ingredient of some ‘energy’ drinks and ‘healthy’ nutritional products. Both cola nut and guarana contain caffeine as the active constituent. Cocaine is more useful medicinally as a local anaesthetic, but its use as a recreational drug is an increasing problem throughout the world.

Caffeine

Caffeine is a methylxanthine derivative found in tea, coffee and cocoa (Fig. 17.4). It is a mild stimulant, and is added to many analgesic preparations to enhance activity, although there is no scientific basis for this practice. High doses may lead to insomnia and a feeling of anxiety, and can induce withdrawal syndrome in severe cases.

Fig. 17.4

Cola nut, Cola spp. (Colae semen)

Cola, or kola nut [Cola nitida (Vent.) Schott et Endl., Cola acuminata (Beauv.) Schott et Endl., Sterculiaceae], is native to West Africa and extensively cultivated in the tropics, particularly Nigeria, Brazil and Indonesia. The seed is found in commerce as the dried, fleshy cotyledons, without the testa. They are red-brown in colour, convex on one side and flattened on the other, up to 5 cm long and about 2.5 cm in diameter. The cotyledons of C. acuminata are generally smaller and divided into 4 or 6 segments.

Cola contains the xanthine derivative caffeine (Fig. 17.4), with traces of theobromine and theophylline. Tannins and phenolics, including catechin, epicatechin, kolatin, kolatein, kolanin, and amines, including dimethylamine, methylamine, ethylamine and isopentylamine, are also present, together with thiamine and other B vitamins.

Caffeine is a mild stimulant and has diuretic properties; cola extracts are also astringent and antidiarrhoeal due to the tannin content. Cola extracts are an ingredient of many tonics for depression and tiredness, and to stimulate the appetite. Cola extract is safe, apart from any effects due to high doses of caffeine (see above).

Guarana, Paullinia cupana Kunth. ex H. B. K

Guarana (Sapindaceae) is a vine indigenous to the Amazonian rain forest. The seeds are ground to a paste and used in cereal bars, or extracted and made into a stimulant drink. The effects are similar to those of cola (see above).The main active constituent is caffeine, which was formerly known as guaranine, and other methyl xanthines. It also contains tannins.

Cocaine

Cocaine (Fig. 17.5) is a tropane alkaloid extracted from the leaf of coca [Erythroxylum coca Lam. and E. novogranatense (Morris) Hieron, Erythroxylaceae]. These are shrubs growing at high altitudes in the South-American Andes. The leaf is still chewed by the local people (along with lime to assist buccal absorption), in order to alleviate symptoms of altitude sickness and fatigue. Cocaine is rarely used medicinally, except as a local anaesthetic in eye surgery, but is now a major illicit drug responsible for many health problems and associated crime. The supply and use of cocaine is strictly regulated in most countries.

Fig. 17.5

Analgesics

Two types of analgesics are usually recognized: those that act via the CNS (the opioids) and will be discussed briefly here; the non-opiate and non-steroidal antiinflammatory drugs, which include aspirin, and which will be covered in Chapter 20. It is very common for the two types to be used in combination, for example aspirin with codeine. The opioid analgesics and their derivatives have never been surpassed as painkillers in efficacy or patient acceptability despite their disadvantages. They are obtained from the opium poppy (Papaver somniferum) and the most important are still the alkaloids morphine and codeine. Numerous derivatives such as oxycodone, dihydrocodeine, fentanyl, buprenorphine and etorphine have been developed which have different therapeutic and pharmacokinetic profiles, or can be administered via a different route (buccal tablets such as those containing buprenorphine, or transdermal patches, such as with fentanyl). The pharmacology of the opiates is covered in depth in many textbooks and these should be referred to for further information.

Opium, Papaver somniferum L. (Opii crudum; opii pulvatus normatus)

The opium poppy (Papaver somniferum, Papaveraceae) is an annual that is native to Asia, but is cultivated widely for food (the seed and seed oil), for medicinal purposes and as a garden ornamental. It has been used since time immemorial as a painkiller, sedative, cough suppressant and antidiarrhoeal, and features in ancient medical texts, myths and histories. The flowers vary in colour from white to reddish purple, but are usually pale lilac with a purple base spot. The capsules are subspherical, depressed at the top with the radiating stigma in the centre, below which are the valves through which the seeds are dispersed. The seeds are small, greyish and kidney-shaped. The latex, which exudes from the unripe capsule when scored, dries to form a blackish tarry resin, which is known as opium. For pharmaceutical use it can be treated to form ‘prepared opium’, but opium or the whole dried capsule (known as ‘poppy straw’) are now used commercially to extract the alkaloids. The supply and use of these products is strictly regulated in most countries. Poppy seeds are used in cooking.

Constituents

Alkaloids represent about 10% of the dried latex. The major alkaloid is morphine (Fig. 17.6), with codeine and thebaine and lesser amounts of very many others including narceine, narcotine, papaverine, salutaridine, oripavine and sanguinarine.

Fig. 17.6

Therapeutic uses and available evidence

Opium has potent narcotic and analgesic properties. The total alkaloidal extract is known as ‘papaveretum’ and is used for pre-operative analgesia (now with the narcotine removed due to its reported genotoxicity). Morphine is a very potent analgesic, used for severe pain in the short term (e.g. kidney stone), or for terminal illness, and is the starting material for the production of diamorphine (heroin). Codeine is less potent than morphine, although it is a very useful analgesic for moderate to severe pain, in for example for migraine, dental and gynaecological pain. All the opioid analgesics have side effects, which include nausea, constipation and drowsiness; they cause respiratory depression and have a potential for dependence, which varies according to their capacity to induce euphoria. A withdrawal syndrome is common after illicit use (especially with heroin), but less of a problem with medical use.

Migraine

The aetiology of migraine is not fully known and various drugs are used in its treatment. The analgesics mentioned above (particularly codeine) can be used to relieve an attack, although their capacity to induce nausea can cause problems, and aspirin can cause stomach discomfort. The newer synthetic drugs sumatriptan, naratriptan and others are highly effective in acute attacks, and β-blockers and pizotifen taken regularly are used to prevent recurrences. If all else fails, ergotamine can be used in limit doses for acute attacks. There is, however, one herb that has been investigated as a preventative, and this is feverfew.

Ergotamine

Ergotamine is an alkaloid extracted from ergot (Claviceps purpurea), a parasitic fungus that grows on cereals, usually rye. It can be used to treat severe migraine that cannot be controlled with other drugs, but it can cause severe adverse reactions and there are restrictions as to the maximum daily and weekly doses. It is not suitable for children.

Feverfew, Tanacetum parthenium (L) Schultz Bip. (Tanaceti parthenii herba)

Feverfew [syn. Chrysanthemum parthenium (L.) Bernh., Asteraceae] is a perennial herb reaching 60 cm, with a downy erect stem. It has been a common garden plant for many centuries and was found in peasants’ gardens throughout Europe. It is still a popular medicinal plant in many parts of the world, to treat rheumatism and menstrual problems. The aerial parts are used. The leaves are yellowish-green, alternate, stalked, ovate and pinnately divided with an entire or crenate margin. The flowers, which appear in June to August, are up to about 2 cm in diameter and arranged in corymbs of up to 30 heads, with white ray florets and yellow disc florets and downy involucral bracts.

Constituents

The sesquiterpene lactones are essential for the biological activity, the major one being parthenolide (Fig. 17.7), with numerous others reported from the species (e.g. santamarine). It also contains small amounts of essential oil (0.02–0.07%), with α-pinene and derivatives, camphor and others.

Fig. 17.7

Therapeutic uses and available evidence

The main use of feverfew today is as a prophylactic and treatment for migraine. The fresh leaves may be eaten, usually with other foods to disguise the nauseous taste, or a standardized extract taken daily to prevent migraine attacks. Although some clinical studies have shown efficacy, others have not, and further work is needed to identify which extracts may be effective (Pittler and Ernst 2004).

Feverfew extracts inhibit secretion of serotonin from platelet granules and proteins from polymorphonuclear leukocytes (PMNs). Since serotonin is implicated in the aetiology of migraine and PMN secretion is increased in rheumatoid arthritis, these findings substantiate the use of feverfew in these conditions. Parthenolide is considered to be the main active constituent. It is a potent inhibitor of NF-kB. The sesquiterpene lactones as a class have an effect on a large number of other targets, including the inhibition of prostaglandin production and arachidonic acid release. This explains the antiplatelet and antifebrile actions to some extent, but in fact feverfew extract with the parthenolide removed also has antiinflammatory activity (Sur et al 2009). Feverfew may produce side effects such as dermatitis, and soreness or ulceration of the mouth. Also, contact dermatitis has been described, especially by workers handling material from this species, caused by the exposure to the allergenic sesquiterpene lactones.

Drugs used for cognitive enhancement and in dementia

There are few effective treatments for improving memory, especially in dementia. Acetylcholinesterase-inhibiting drugs are available to treat Alzheimer’s disease with varying degrees of success. Rivastigmine is a reversible, non-competitive inhibitor of acetylcholinesterase. It is a semi-synthetic derivative of physostigmine, an alkaloid found in the Calabar bean (Physostigma venenosum), a highly poisonous plant indigenous to West Africa. Galantamine (= galanthamine), an alkaloid extracted from the snowdrop (Galanthus nivalis) was introduced around 2001 (Fig. 17.8, Heinrich and Teoh 2004). These drugs appear to slow down progression of the disease for a period of time, but do not cure it, and have side effects making them unacceptable to many patients.

Fig. 17.8

Ginkgo, Ginkgo biloba L. (Ginkgo folium)

Ginkgo, the maidenhair tree (Ginkgoaceae), is an ancient ‘fossil’ tree indigenous to China and Japan and cultivated elsewhere. It is very hardy and is reputed to be the only species to have survived a nuclear explosion. The leaves are glabrous and bilobed, each lobe being triangular with fan-like, prominent, radiate veins. The leaves are used medicinally and the fruits are eaten.

Constituents

Ginkgo contains two major classes of actives, both of which contribute to the activity: ginkgolides A, B and C, and bilobalide, which are diterpene lactones; and the biflavone glycosides such as ginkgetin, isoginkgetin and bilobetin (Fig. 17.9). Ginkgolic acids are present in the fruit but normally only in very minor amounts in the leaf.

Fig. 17.9

Therapeutic uses and available evidence

The most important use of ginkgo is to reduce or prevent memory deterioration, due to ageing and milder forms of dementia, including the early stages of Alzheimer’s disease (e.g. Ihl et al 2010). It’s enhancement of cognitive processes is thought to be by improving blood circulation to the brain and also due to its antiinflammatory and antioxidant effects. Many clinical studies have been carried out (not all of high quality), and the extract has been shown to improve the mental performance in healthy volunteers and geriatric patients where this was impaired (for review, see Weinmann et al 2010). The effects on the CNS are not yet well defined, but include effects on neurotransmitter uptake, neurotransmitter receptor changes during ageing, cerebral ischaemia and neuronal injury. Inhibition of nitric oxide may play a part. The usual dose of ginkgo (standardized) extracts is 120–240 mg daily. Ginkgo has been reported to cause dermatitis and gastrointestinal disturbances in large doses, although rarely. Allergic reactions in sensitive individuals are more likely to be due to ingestion of the fruits due to the ginkgolic acids, which are usually absent from leaf extracts and ginkgo products, or present only in very small amounts.

References

Appel K., Rose T., Fiebich B., Kammler T., Hoffmann C., Weiss G. Modulation of the γ-aminobutyric acid (GABA) system by Passiflora incarnata L. Phytother. Res.. 2010. doi:10.1002/ptr.3352. [Epub ahead of print]

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