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.