Treatment

In chronic bronchitis there is overactivity of the mucus-secreting glands and goblet cells. The vast excess of mucus coats the bronchial walls and clogs the bronchioles. Exacerbating this, many ciliated columnar cells are replaced by goblet cells in response to the chronic irritation. Therefore the excessive mucus is also less able to be cleared from the lungs. Hence, the use of expectorants is emphasised in the treatment of chronic bronchitis, despite the fact that an easily productive cough can be a feature of this disease. (In some patients sputum may be scanty and tenacious, which also requires treatment with expectorants.)

Treatment

Essential aspects of the treatment of bronchiectasis are as follows:

Pathophysiology

Asthmatic lungs are characterised by epithelial cell loss, goblet cell hyperplasia, increased collagen deposition, mast cell degranulation and inflammatory cell infiltration.³¹ Asthma is now primarily classified as an inflammatory disorder. The desquamation allows allergens to penetrate more easily and exposes irritant receptors.

There has been an increased understanding over the past two decades that asthma is a chronic, immunologically mediated condition with a disturbance of the normal airway repair mechanism, which results in inflammatory changes and airway remodelling.³² The airway inflammation and remodelling together likely explain the clinical manifestations of asthma. The mechanisms by which the external environmental cues, together with the complex genetic actions, propagate the inflammatory process that characterise asthma are beginning to be understood. There is also an evolving awareness of the active participation of structural elements, such as the airway epithelium, airway smooth muscle and endothelium in this process. In tandem with this has come the realisation that inflammatory cells respond in a coordinated, albeit dysfunctional, manner via an array of complex signalling pathways that facilitate communication between these cells; these structural elements within the lung and the bone marrow serve as reservoirs for and the source of inflammatory cells and their precursors. Although often viewed as separate mechanistic entities, innate and acquired immunity often overlap in the propagation of the asthmatic response.³²

Classically, asthma, specifically allergic asthma, has been attributed to a hyperactive Th2 cell immune response. However, the Th2 cell-mediated inflammation model has failed to adequately explain many of the clinical and molecular aspects of asthma.³³ In addition, the outcomes of Th2-targeted therapeutic trials have been disappointing. Thus, asthma is now believed to be a complex and heterogeneous disorder, with several molecular mechanisms underlying the airway inflammation and AHR that is associated with it. The original classification of Th1 and Th2 pathways has recently been expanded to include additional effector Th cell subsets. These include Th17, Th9 and Treg cells. Emerging data highlight the involvement of these new T helper cell subsets in the initiation and augmentation of airway inflammation and asthmatic responses.³³

That regulatory T cells (Tregs) have a crucial role in controlling allergic diseases such as asthma is now undisputed. The cytokines most commonly implicated in Treg-mediated suppression of allergic asthma are transforming growth factor-beta (TGF-beta) and interleukin (IL)-10. In addition to naturally occurring Tregs, adaptive Tregs, induced in response to foreign antigens, have been shown in recent studies. The concept of inducible/adaptive Tregs (iTregs) has considerable significance in preventing asthma, if such cells are generated early enough in life.³⁴

Other inflammatory cells implicated in asthma include natural killer T cells, although their role is controversial,^35,36 mast cells, neutrophils and eosinophils.³⁷ Platelets and endothelial cells also play a role.

As touched on above, some experts are arguing for a re-evaluation of the therapeutic implications informed by a pathophysiological understanding of asthma. A case is made that asthma has its origins in the airways themselves, involving defective structural and functional behaviour of the epithelium in relation to environmental insults, with wall thickening.³⁸ Specifically, a defect in barrier function and an impaired innate immune response to viral infection may provide the substrate upon which allergic sensitisation takes place. Once sensitised, the repeated allergen exposure will lead to disease persistence. These mechanisms could also be used to explain the observed airway wall remodelling and the susceptibility of the asthmatic lung to exacerbations provoked by respiratory viruses, air pollution episodes and exposure to biologically active allergens. It seems that the problem lies in placing allergy at the centre of disease pathogenesis, when in practice other environmental factors may be equally if not more important in the induction and then progression of asthma. Instead a defect of epithelial barrier function exists that, as in atopic dermatitis, allows greater access of environmental allergens, microorganisms, and toxicants to the airway tissue. Evidence indeed indicates that both the physical and functional barrier of the airway epithelium is defective in asthma with disrupted tight junctions, reduced antioxidant activity, and impaired innate immunity. Viewing asthma primarily as an epithelial disease, with the conceptual adoption of a chronic wound scenario, also provides a route to understand the observed airway wall remodelling and the varying asthma phenotypes over its life course.³⁹

A host of inflammatory mediators have been identified in the pathophysiology of asthma. However some mediators may be more involved in triggering the inflammatory process than others. In this context, important mediators are the Th2 cytokines and probably histamine, platelet activating factor (PAF), major basic protein, leukotrienes especially (leukotriene B4)⁴⁰ and to a lesser extent prostaglandins.³⁷ Patients with ASA have increased PAF responsiveness, reduced prostaglandin levels and increased leukotrienes compared with normal controls.^41,42 TGF-beta is a key player in airway remodelling.

The host of inflammatory cells and mediators involved in the pathogenic process means that treatment directed at a single mediator or cell is unlikely to be successful. A multi-faceted approach to treatment is required. This is compatible with herbal therapy, which has traditionally used combinations of plants to treat diseases.

The above considerations also explain the current preference in conventional medicine for steroid use in asthma. These drugs have a broad suppressing effect on many inflammatory mechanisms. In this context the ‘magic bullet’ is more like an ordinary shotgun.

Factors associated with asthma

Differentiation should be made between the causes that initiate or sustain the underlying condition, which are probably factors that result in injury to the lining of the lungs, and the triggers that precipitate the asthmatic attack. While avoidance of the latter group is of course important, it is only attention to the former that will reduce the progression of the disease. There is no better illustration of this issue than the subject of dairy products. Traditional knowledge suggests that consumption of dairy products can lead to a state of unhealthy mucous membranes in sensitive patients. However, these patients may not give a positive skin test to dairy products, and these products may not provoke an acute asthmatic attack. In the classical sense there is no allergy to dairy products. Yet the avoidance of this food group will, in time, give appropriate patients considerable relief from their asthmatic condition. Key factors amenable to treatment are reviewed below.

Allergens

The most significant allergen in the long-term development of asthma is now considered to be the house dust mite. However, this does not necessarily mean that the degree of house dust mite exposure will correlate with the day-to-day severity of asthma. This is because sensitivity to the house dust mite feeds the underlying pathological process. Unfortunately, chemical and physical methods aimed at reducing exposure to house dust mite allergens have yielded disappointing results.⁴³

Other common factors involved in asthma development may include cats, cockroaches, grass pollens and molds, but the situation is complex, as for dust mite.⁴⁴ Association with severe asthma in children was seen between non-feather bedding, especially foam pillows and the current ownership of furry pets, or ownership at birth.⁴⁵ A Finnish study of school children aged 7 to 13 found that moisture and mold problems in the school building were linked to respiratory infections and asthma.⁴⁶

Of course, all the above allergens can trigger an asthma attack, as can many foods, especially dairy products, eggs and nuts. Dust mite contamination of wheat flour caused anaphylactic reactions and cooking had no effect. It was suggested that flour be stored in the refrigerator.⁴⁷ Royal jelly should be used cautiously as it is now a well-known trigger of asthma attacks.

Air quality

Maternal or parental smoking has been linked to asthma incidence and severity.⁴⁸ Air pollution parameters such as NO₂, ozone and particulates have also been associated with the incidence of asthma.⁴⁹

Exposure to dust, irritants and allergens at the workplace can also cause asthma. Usually withdrawal from the irritant or allergen results in remission, but in some cases where exposure is prolonged the asthma becomes self-sustaining despite such withdrawal.

Sinusitis

Sinusitis has been associated with asthma in several studies,^50,51 although this has received less attention recently. This is not considered to be due to aspiration of sinus contents.⁵² In one study 79% of asthma cases had chronic rhinitis or rhinosinusitis.⁵³ In 69% of cases the nasal symptoms coincided with or preceded the onset of asthma. In 59% of associated cases, nasal symptoms coincided with acute asthmatic episodes. Treatment of the nasal condition improved the asthma. The link between sinusitis and asthma is strongest in patients with intrinsic asthma. Evidence supports the concept that rhinosinusitis and asthma may be the expression of an inflammatory process that appears in different sites of the respiratory tract at different times.⁵⁴

Poor digestion

A number of researchers in the 1930s found a high incidence of hypochlorhydria in asthmatic patients.⁵⁵ In these studies the test meal method was used. This method is now considered inappropriate for the assessment of histological hypochlorhydria. However it does assess for functional hypochlorhydria, that is a deficiency of vagal stimulation of acid production. Hydrochloric acid therapy improved the asthma.⁵⁵ Since this kind of gastric deficiency is due to deficient vagal output, the use of bitter herbs that act through a vagal reflex to increase gastric digestion is indicated (see Chapter 2).

Gastro-oesophageal reflux (GOR) has been linked to asthma in several studies. In fact there is evidence that GOR is an important aetiological factor for some asthmatics. Monitoring of oesophageal pH revealed GOR in seven out of nine patients with persistent asthma.⁵⁶ In another study 61% of patients with intrinsic asthma exhibited GOR.⁵⁷ From studies on children it was concluded that asthma symptoms were more often elicited by exposure of the distal oesophagus to gastric acid, possibly by a vagal reflex, than by aspiration of gastric juice.⁵⁸ However, other studies have implicated the importance of aspiration.^59,60 In support of the reflex hypothesis, subjects with GOR (but not asthma) showed a significantly greater bronchial reactivity to histamine than normal matched controls.⁶¹

Treatment of GOR by surgery or drugs can result in improvement or cure of asthma, although results are mixed and suggest that targetting of individual patients is necessary.⁶² (Also see Chapter 2, under Mucilages.)

Diet

Particular foods are well-known causes of asthma attacks. However, the contribution of diet to the underlying pathophysiological processes of asthma is not well studied. It has been postulated that dietary changes may have contributed to the rise in asthma mortality.⁶³ In particular, increased consumption of polyunsaturated fatty acids has resulted in the doubling from 8% to 15% of the linoleic content of body fat.⁶³ Such a change could be regarded as pro-inflammatory.

Coffee consumption was found to be inversely correlated to the prevalence of bronchial asthma in an Italian study.⁶⁴ Epidemiological studies found that consumption of oily fish may protect against asthma in childhood⁶⁵ and adults,⁶⁶ and a connection between low magnesium intake and increased asthma risk has also been suggested.⁶⁷ Consumption of apples (five per week) was found to improve lung function.⁶⁸ This benefit was attributed to the flavonoids found in apples.

A systematic review and meta-analysis found weak but supportive protective evidence with respect to dietary vitamins A, D and E, zinc, fruits and vegetables and a Mediterranean diet.⁶⁹

Infection and infestation

Viral infections are known to exacerbate asthma. Viral infection in the upper airways frequently triggers deterioration in airways hyperreactivity in asthmatics.⁷⁰ Most hospital admissions for asthma occur over the winter months and soon after the start of school terms.⁷⁰ Viral infections also worsen asthma in adults.^71,72

There is also some evidence to suggest that viral infections may also contribute to the development of asthma, especially in children. About 92% of children hospitalised with respiratory syncytial virus (RSV) bronchiolitis in the first year of life subsequently developed symptoms suggestive of asthma within 5 years.⁷³ Of this group, 71% had clinical evidence of asthma.⁷³ Recurrent upper respiratory tract infections are associated with asthma risk in children⁷⁴ and 37% of children with viral lower respiratory tract infections in infancy subsequently developed asthma.⁷⁵ With the development of molecular diagnostics, human rhinovirus wheezing illnesses have been recognised more recently as a stronger predictor of school-age asthma than RSV.⁷⁶

In contrast, bacterial infection has been linked to adult-onset asthma. The first study linking repeated or prolonged exposure to Chlamydia pneumoniae with wheezing, asthmatic bronchitis and asthma was published in 1991.⁷⁷ Patients with evidence of C. pneumoniae exposure comprised 81% of 26 patients with asthmatic bronchitis, 100% of asthmatic bronchitics 40 years and older, and 8 out of 10 patients with asthma. However, findings from later studies have been inconsistent.⁷⁸ Associations between Mycoplasma species and chronic asthma are relatively well-established.⁷⁸

A group of 12 adult patients with asthma and chronic fungal skin infection were found to have hypersensitivity to Trichophyton spp.⁷⁹ Several patients had many of the features of late-onset intrinsic asthma. A Russian study in children with bronchial asthma living near a microbiological factory found that most were hypersensitive to Candida.⁸⁰ Asthma has also been associated with parasitic infestation with Strongyloides stercoralis.⁸¹

Salt intake and dehydration

Regional sales of table salt in England and Wales are strongly correlated with deaths from asthma in men and children.⁸² A study of 138 men found a close relation between AHR and 24 h urinary sodium excretion.⁸³ Other studies have yielded conflicting results. A large randomised controlled trial of slow sodium supplementation showed an increase in AHR in men, but not women,⁸⁴ and a low salt intake was correlated with improved asthma in men.⁸⁵ Several mechanisms for this association have been postulated, such as an increase in circulating Na,K-ATPase inhibitors or a decrease in catecholamine concentration.⁸⁶ Data supporting dietary salt restriction for reducing AHR in asthmatics are encouraging.⁸⁷

Exercise-induced asthma may be related to dehydration of the intrathoracic airways during hyperpnoea.⁸⁸ A high salt intake may interfere with rehydration of the airways. Mouth breathing as a result of sinusitis may also cause airway dehydration.

Hormonal factors

Glucocorticoid insufficiency related to various adrenal and extra-adrenal mechanisms has been associated with asthma in a Russian study.⁸⁹ Reduced nocturnal catecholamine and cortisol levels, which are a natural part of circadian rhythm, may be linked to the nocturnal exacerbation commonly associated with asthma.⁹⁰ Stress-induced corticosteroid resistance or insensitivity in asthma is receiving research attention,⁹¹ as is hyporesponsiveness of the HPA (hypothalamic-pituitary- adrenal) axis (see also below).⁹²

It was postulated that an increase in brain norepinephrine can reflect depression of the HPA axis.⁹³ In asthmatic children such an increase was found compared with controls.⁹³

Premenstrual asthma has been observed, which was improved by progesterone injection.⁹⁴ Dynamic changes in hormone concentrations during the perimenstrual period are thought to be responsible for the rise in emergency admissions of asthmatic women at this time. Hormonal variation may prove to be a significant and independent risk factor for acute exacerbations of asthma.⁹⁵ Although the observed 4-fold increase in emergency admissions suggested that hormonal variation may influence the timing of an asthma attack, the severity of symptoms was no worse than that among women who presented at any other time in their menstrual cycle.

Stress

Low-income patients were more likely to report exacerbation of asthma when upset or anxious.⁹⁶ Parents of children who developed asthma were more likely to have problems in coping and parenting.⁹⁷

Stress and associated muscular tension might influence lung function. One study suggested that an intrinsic impairment of the ability of inspiration to stretch airway smooth muscle is a major feature of asthma.⁹⁸ In other words, defective deep breathing could be a factor in airway narrowing. This would suggest a role for relaxation and breathing techniques in asthma.

Antioxidant status

The role of oxidative stress in asthma is gaining increasing research attention.⁹⁹ Activation of the Nrf2/ARE pathway could prove to be of therapeutic benefit.¹⁰⁰ Patients with acute asthma had decreased antiperoxide plasma activity compared with normal controls.¹⁰¹ Moreover the severity of the asthma was inversely associated with the above parameter. In patients with steroid-dependent asthma the free radical process was more intensive.¹⁰¹ Low selenium concentrations in whole blood have been correlated to increased asthma risk in New Zealand.¹⁰²

Traditional factors associated with asthma

Herbal diuretics

Plants have been used as diuretic remedies thoughout history (Pliny the Elder mentions that many plants have diuretic properties in his Naturalis Historia¹). However, the early indications for such use were often different: urinary stones, nephritis, cystitis, strangury, urinary retention and incontinence.² The excruciating pain of urinary stones would of course be well known and would have driven many urgent treatments. Because of the severity of such conditions, diuretic remedies would have been more drastic than nowadays. Remedies would have been given in much higher doses, for shorter duration, and stronger agents were used. The diuretic effects of purgatives, for example, were well understood and these may well have been used in desperate attempts to relieve the symptoms of ascites in advanced liver failure – a not uncommon condition given the frequency of hepatitis. (This reputation of laxatives, although easily experienced, remains unsupported in clinical research, although it has been found in vivo that anthraquinone derivatives induce experimental diuresis associated with the inhibition of ATPases in the kidney medulla.³) Another drastic treatment of dropsy forms the basis of one of medicine’s best historical stories. When William Withering found that the active principle of one effective remedy for dropsy was the cardioactive foxglove he initiated a whole new medical tradition as well as confirming that dropsy was a symptom of heart failure rather than of the kidneys (see also Chapter 2).

Inducing appreciable consistent diuresis generally involves drastic pharmacological activity and modern diuretic drugs are powerful agents. Examples of plants with direct diuretic effects producing consistent activity in controlled conditions in the literature are rare, and there are some studies that specifically show a negative effect in these circumstances.^4–7 There is, for example, the suggestion that essential oils may prove to have direct effects on tubular function: a paper on the effects of aqueous parsley seed extract has implicated tubular inhibition of the sodium/potassium pump, albeit with relatively large doses in rats, that would lead to a reduction in sodium and potassium reabsorption and an osmotic water flow into the urinary lumen.⁸ Other examples where a diuretic effect has been observed experimentally include a study showing significant increase in 24-hour urine volume, urine and serum sodium levels in nine mild hypertensives administered a whole-plant preparation of Phyllanthus amarus.⁹ In another study, Aerua lanata flowers at doses of 10 g induced significant diuresis in 70% of subjects in uncontrolled clinical conditions.¹⁰ A study on a product based on asparagus and parsley root has also shown limited diuretic effect in the management of congestive heart failure.¹¹ The benefits of the Indian remedy Terminalia arjuna bark extract at 500 mg every 8 hours, as adjuvant therapy to conventional medications, have been attested in a double blind, crossover trial on 12 patients with chronic congestive heart failure (although this is most likely a cardiac rather than a renal effect).¹²

There is some evidence of diuretic effects of various popular diuretics in experimental animals, but often at very high doses (40 mL/kg¹³ and 1 g/kg^14,15), levels outside any therapeutic range. Other plants with experimental diuretic effects in animals that have been observed at various dosages include Taraxacum (dandelion),¹⁶ members of the Equisetum family,¹⁷ Orthosiphon leaf¹⁸ and Orthosiphon seeds,¹⁹ various Solidago species,^20,21Agrimonia eupatoria (agrimony),²²Lactuca virosa (wild lettuce)²³ and Parietaria (pellitory).²⁴ Diuretic activity (including renal vasodilation and urinary sodium excretion) has been observed in experimental studies on Clerodendron trichotomum,²⁵ and Rehmannia radix.²⁶ However, studies on Alpinia speciosa²⁷ and Polygonum punctatum²⁸ showed no diuretic properties in spite of other pronounced pharmacological activities, and the main effect in rats of administering oral doses of Opuntia ficus-indica infusions was a marked loss of potassium, with only modest diuresis and sodium loss at lower concentrations.²⁹

In more recent pharmacological studies, several common herbs have exhibited interesting diuretic activity that might prove clinically relevant, including fennel (see fennel monograph). Others have been the subject of an extensive 2007 review.³⁰ A few clinical trials have also been undertaken. Powdered cherry stalk (Cerasus avium) at 2 g caused a mild increase in urine volume in 13 healthy volunteers in an open label trial.³¹ In another open label, pilot study, three 8 mL doses in 1 day of a hydroethanolic extract of fresh dandelion leaf given to 17 healthy volunteers caused a significant (p<0.05) increase in the frequency of urination in the 5-hour period after the first dose.³² There was also a significant (p<0.001) increase in the excretion ratio in the 5-hour period after the second dose of extract. The third dose failed to change any of the measured parameters. The herb Eclipta alba leaf powder 3 g/day caused a remarkable increase in urine volume (34%) and urine sodium (24%) in a placebo-controlled 60-day trial involving 60 mildly hypertensive patients.³³

The modest research evidence apart, the experience of even mild herbal prescriptions having sometimes dramatic diuretic effects is well known to practitioners and this is one of the most common reactions to treatment that patients report. One conclusion that can be drawn is that diuretic responses are variable, perhaps reflecting other indeterminate susceptibilities in the individual patient.

Aquaretics and diuretic depuratives

Two variations on the diuretic theme have emerged from earlier Western traditions. In German practice, the concept of ‘aquaretic’ has been used to describe diuretic agents that excrete water from the body, most probably associated with potassium, but not other electrolyte, excretion.³⁴ They may exert their effect due to increased blood flow to the kidney. Most herbal diuretics in tradition are likely to be of this class. They are thus not easily comparable with modern diuretics that interfere with resorption at the distal tubule of the nephron, leading to wider electrolyte elimination, and thus may be less effective in treating hypertension and oedematous conditions. They are speculated to act on the glomerulus, increasing fluid loss from the body in a physiological manner by increasing the formation of primary urine.³⁵

In the case of hypertension, the main benefit of herbal aquaretics may be in replacing the potassium lost through the use of modern diuretic prescriptions. High potassium levels relative to sodium have been shown to be a feature of herbal drugs with traditional diuretic activity.³⁶ Compared to a ratio in the average diet of 2:1, herbal remedies such as Urtica (nettle tops), Equisetum (horsetail), Betula (birch), Sambucus (elder), Agrimonia (agrimony), Phaseolus vulgaris (bean pods), Matricaria (chamomile) and tilia (lime flowers) had ratios greater than 150:1 potassium to sodium, especially in decoction form. It is difficult with current information to link high potassium levels to any aquaretic or diuretic effect, but given that diuresis is almost by definition accompanied by potassium loss, to have an effective potassium supplement seems convenient.

The herb combination that has been most studied in the context of aquaretic activity is asparagus root (Asparagus officinalis) with parsley herb (Petroselinum crispum).¹¹ In uncontrolled trials, this combination caused significant weight loss in overweight patients and significantly lowered blood pressure in patients with hypertension, without changing other biochemical parameters.¹¹

In the case of oedema, phytotherapeutic strategies should emphasise activity on other body functions (see below) rather than any diuretic impact.

A second concept of ‘diuretic depurative’ is more compatible with the general meaning of diuretics in Western herbal tradition; it implies that the remedy removes metabolites and waste products as well as water, that is as an aid to excretion.

There is one very gentle diuretic mechanism that may underlie the effect of several plants.

Osmotic diuresis

The principle of osmotic diuresis has been established since the end of the 19th century when Ustimowitsch, Falck and Richet stressed the influence of urinary solutes on urine flow, although over a century earlier Segalas and Wohler observed that an extra load of urea, or any other substance that is excreted by the kidney, causes a diuresis.³⁷

The osmotic plant-based diuretic mannitol is used, by intravenous injection, in acute oliguric renal failure.³⁸ Mannitol is found in some plants, including the popular diuretic Elymus repens (couch grass); however, its absorption from the gut wall is limited and it is unlikely to play a significant role in the effect of couch grass. Nevertheless, a number of similar sugar molecules may account for a gentle diuretic effect of many herbal remedies, as well as, more generally, fruits and vegetables. For example, the plant starch inulin is used in commercial preparations to measure glomerular filtration rate and in experiments of kidney microperfusion as a marker of tubular water reabsorption. A number of plant extracts of inulin have been shown to have a comparable effect.³⁹

The kidneys and oedema

Although clearly active in the elimination of water from the body and the control of fluid levels within the tissues, the impact of the kidneys in oedema is not always obvious, compared with a failing heart, a cirrhotic liver or lymphatic or venous insufficiency in their relevant syndromes. Nevertheless, in all such cases prescription of conventional diuretic drugs is commonplace and it is widely assumed that the kidney is centrally involved in most cases.

This assumption has mixed support in the scientific literature. For example, renal complications of liver cirrhosis are certainly implicated in the development of ascites. These complications include inadequate renal prostaglandin production and the negative effect on the kidney of raised nitric oxide production. Such complications may actually reduce the effect of diuretics, but they remain indicated in the treatment of ascites as long as they are effective.⁴⁰ In phytotherapy, however, the main effort now would be on using hepatics and other treatments for the liver.

Although undoubtedly effective symptomatically, the value of diuretics used alone for congestive heart failure in the long term has been challenged, because of their possible excitation of the renin-angiotensin system. Concomitant prescription of ACE inhibitors has been proposed and positively evaluated, because they suppress this excitation.⁴¹ As seen below, herbal diuretics are unlikely to raise the same concerns but may be only second-tier treatments compared to the cardioactive glycosides.

The localised oedema of lymphatic and venous insufficiency is treated in phytotherapy with particular remedies said to act on the vessel walls. These may have incidental diuretic effects.

In phytotherapy, there are few traditional strategies that are likely to bear directly on the kidney cortex itself, with emphasis placed instead on activity lower down the urinary system. Nevertheless, little is known about the full impact of plant constituents on this organ and, although there are very few cases where actual nephrotoxicity occurs, a general caution in using herbal treatments is advisable where the kidneys are already damaged.⁴²

Beneficial effects of plant remedies on the kidney

Kidney disease such as glomerulonephritis and cystic disease presents awesome and possibly overwhelming odds for the phytotherapist. By definition the kidney in such cases, especially where the basement membrane is involved, is vulnerable to further damage with any new active metabolite and the practitioner needs to proceed with extreme caution. Nevertheless, there is experimental and case report evidence, mainly from China and Japan, suggesting that some herbal remedies might have beneficial effects in such cases, including such conditions as nephrotic syndrome (Chinese herbs Astragalus and Angelica (see monographs),⁴³ diabetic nephropathy (Abemoschus manihot⁴⁴) and other kidney diseases.^45–49Andrographis paniculata has shown experimental ability to reduce pyuria and haematuria as complications of urinary stone destruction (see Andrographis monograph)⁵⁰ and magnesium lithospermate B, a component of Lycopus and Lithospermum species, has shown potential as a therapeutic agent for inhibiting the progression of renal dysfunction.⁵¹ The use of various Chinese bitter (‘cooling and drying’) herbs has been shown to improve biochemical markers associated with free radical damage in patients with chronic glomerulonephritis compared with matched controls.⁵²

Other plant materials have shown apparent antinephrotoxic activity and may provide the basis for strategies following the adverse effects of heavy metals, antibiotics, analgesic and other prescription drugs, Amanita mushroom and aflatoxins and industrial agents. Protective effects of Arctostaphlos uva-ursi, Orthosiphon stamineus and Polygonum aviculare have been noted against the nephrotoxic effects of mercuric chloride,⁵³ and beneficial effects against the nephrotoxin aminoglycoside in elderly patients have also been noted in controlled studies for Cordyceps sinensis.⁵⁴ Aqueous rhubarb extract (at 150 mg/day) reduced proteinurea and glomerulosclerosis in rats exposed to experimental chronic renal fibrosis in controlled models.⁵⁵ More recently curcumin and Withania have demonstrated nephroprotective activity in vivo (see monographs) and there have been some interesting reviews of this topic.^56–59

Terminology

As noted above, most plants used primarily for their effects on the urinary system are collectively referred to as ‘diuretics’ in many texts. Nevertheless, this covers a broad range of traditional activities and probably very variable actual diuretic effects so the terms ‘aquaretics’ and ‘diuretic depuratives’ (see above) may be more accurate. However, the conventional terminology will be used here, as demarcation between the two categories is currently inadequate.

Urinary tract demulcents

These agents will exert a soothing effect on the lining of the urinary tract and are indicated for inflammation and infections such as urethritis and cystitis. They may also be of value for inflammation higher up the urinary tract and the irritation of kidney stones. Some urinary tract demulcents such as marshmallow leaf act by a reflex effect (reflex demulcents). Others, specifically couch grass and corn silk probably have a direct effect.

Antilithics

These herbs decrease the likelihood of urinary stone formation and may also act to weaken and slowly dissolve existing stones. Antilithic herbs include Crataeva, horsetail, gravel root (Eupatorium purpureum), parsley piert (Aphanes arvensis) and pellitory of the wall (Parietaria species). Gravel root may act particularly against uric acid stones, whereas the other herbs act on mineral stones. Some antilithics such as Crataeva⁶³ can help the expulsion of small stones.

Bladder tonics

These herbs have a toning effect on the smooth muscle of the bladder. They are therefore useful in the treatment of hypotonic bladder, as can occur with the urinary outlet obstruction caused by benign prostatic hyperplasia, and other neurological conditions of the bladder. During bladder infection, bacteria may remain with the residual urine that is left in the bladder after each voiding. Bladder tonics decrease this residual volume and therefore assist greatly with the flushing of the bladder. In this context they can be particularly valuable in the resolution of recurrent cystitis. The best established bladder tonic is Crataeva bark.⁶³

Kidney tonics

In Western herbal terminology kidney tonics are herbs which tonify the function of the kidneys and may be useful in poor kidney function in conjunction with diuretic depuratives. They may also help protect the kidney during diseases such as glomerulonephritis. Unfortunately there is little reliable information about herbs that might have this role. In the European tradition, Solidago virgaurea (golden rod) stands out⁶⁴ and there could also be a role for horsetail in this context.

In traditional Chinese medicine the term ‘kidney tonic’ is also used, but it has no relationship with the anatomical kidney. The ‘kidney tonics’ of Chinese medicine are typically adrenal cortex tonics. It is important that they are not confused with the above.

Recurrent urinary stones

A theme that emerges from the research is the complexity of mineral and electrolyte disturbance, involving other body systems, which can underlie urinary stone formation. For example, the pathogenesis of renal calculi may involve relative changes in concentrations of other urinary trace elements, notably copper and phosphorus,⁶⁵ that clearly reflect wider metabolic changes.

In industrialised countries, about 80% of stones that form in the kidneys are composed of calcium salts and usually occur as calcium oxalate and less commonly calcium phosphate.^66,67 The remaining 20% of stones are largely composed of uric acid, struvite or cystine.

Because urine is supersaturated with calcium, crystal formation occurs readily if urine calcium rises, as when there is fluid depletion or increased calcium excretion. Calcium is also less soluble as the urine becomes more alkaline. Factors in urine that inhibit crystallisation processes include:⁶⁸

About 50% of patients with calcium stones have excessive calcium in their urine. The most common cause of this is a genetically determined increased calcium absorption in the intestine. Excessive urinary calcium can also be caused by a diet rich in sodium or animal protein. Low levels of citrate in the urine is another factor, which affects between 20% and 60% of patients.⁶⁶ Factors involved here can include urinary tract infection, a high sodium intake, chronic diarrhoea, potassium loss, excessive physical exercise and an excessively acid-forming diet (rich in high protein foods). High excretion of oxalate in the urine is largely of dietary or genetic origin. Ironically, the dietary factor most often responsible for oxalate stones is a low calcium intake. However, reducing the intake of oxalates is probably a safer option than increasing dietary calcium beyond normal levels,⁶⁸ although calcium supplementation has been shown to be beneficial in stone prevention.⁶⁹

High protein consumption may be a factor in stone formation, since the resultant sulphates formed generate an acid load in the urine that is buffered by bone.⁶⁷ Animal protein also has a high purine content, which will increase uric acid excretion. An inverse relationship occurs between renal potassium and calcium excretion, which brings attention to the role of potassium-rich fruits and vegetables as preventatives.⁶⁷ Obesity and insulin resistance are linked to both calcium and uric acid stones.^67,70

Recurrent oxalate stone formers are significantly less likely to be colonised with the gut-dwelling bacterium Oxalobacter formigenes.⁷¹ This organism is able to degrade dietary oxalate. Probiotic use of lactic acid bacteria that metabolise oxalate might also provide a valid alternative to this organism.

Lifestyle and diet are best aimed at preventing stone formation, and, since the recurrence rate of stones is 75% over 20 years, the following guidelines could be followed by all patients with a history of kidney stones.⁶⁶

Regular weight-bearing exercise will help store calcium in bones, which would otherwise be excreted in the urine. However, exercise should not be excessive since this increases dehydration and can cause lactic acidosis, both factors in stone formation. Fluid intake should be adequate, especially in warm climates, but commercial drinks are to be avoided (these are sometimes loaded with phosphate and sugar).

The diet should be based on fruit, vegetables and unrefined carbohydrates. Animal protein (including cheese) intake should not be excessive and dietary salt should be restricted.⁷² Fruit, which is rich in potassium and citrate, should be emphasised, together with foods rich in magnesium such as fermented soya products, legumes, nuts and green leafy vegetables. Calcium intake, specifically dairy foods, should be moderate, but should also not be restricted unless there are other reasons for this, such as dairy protein allergy. Restriction of calcium can lead to excessive oxalate absorption.⁷³ If there is a history of oxalate stones, then foods rich in oxalate are best avoided. These include rhubarb, spinach, strawberries, ginger, almonds, cashews and beetroot. A probiotic supplement may be relevant here as well.

There is substantial evidence of interaction between urinary urates and oxalates, so that higher urinary levels of the former, following disturbances of purine metabolism including gout, can lead to ‘salting out’ of calcium oxalate stones; drugs such as allopurinol, which reduce urinary urate, also reduce oxalate stones.⁷⁴ This calls into question the use, in the case of incipient or actual oxalate calculi (for example, in cases of severe small intestinal disease as above), of some plants such as the fruits of Apium graveolens (celery) and Petroselinum crispum (parsley), Eupatorium purpureum (gravel root), Betula spp. (birch) and Urtica dioica (nettle leaf), that are considered to increase urinary excretion of urates.

Other studies suggest that urate stones themselves may be linked to low blood urate levels following enhanced tubular secretion of urate within the kidney. In such cases, agents increasing urate excretion would be clearly contraindicated and alkalinisation of urine may be the most effective treatment,⁷⁵ since overly acidic urine is the key feature of these types of stones. It may be the factor that connects the disorder with metabolic syndrome.^76,77

In pregnancy, hyperuricuria and hypercalciuria, changes in metabolic inhibitors of lithiasis formation, urinary stasis, relative dehydration and the presence of infection all increase the likelihood of stone formation.⁷⁸

Herbal remedies and urinary stones

In seven plants (Verbena officinalis, Lithospermum officinale, Taraxacum officinale, Equisetum arvense, Arctostaphylos uva-ursi, Arctium lappa and Silene saxifraga) studied for their effects on experimental risk factors for urinary stones (citraturia, calciuria, phosphaturia, pH and diuresis), moderate solvent action on uric stones was linked to the alkalinising capacity of the herb infusion and to a possible urinary antiseptic activity.⁷⁹

Other Asiatic herbal products have been shown to reduce experimental renal stone formation.^80–82 In Ayurveda, Crataeva nurvala is highly acclaimed for its use in the management of urinary tract disorders, especially kidney stones. Research has demonstrated a range of activity on urinary structures, including improved performance in clinical studies of benign prostatic hyperplasia⁸³ and with urinary stones^84,85 and in reducing oxalate stone formation,⁸⁶ with the steroid lupeol being a possible active constituent.⁸⁷ A pharmacological study found that Crataeva influenced small intestinal Na,K-ATPase, which in turn influenced the transport of minerals.⁸⁸ This is a reminder that oxalate problems may well originate from the digestive tract (see above).

Herbal teas in general have been recommended as alternatives to the usual black tea consumption because of the latter’s association with increased risk of formation of calcium oxalate stones, but this is unlikely to reflect a general benefit of plant extractives as such.⁸⁹

Herbal treatment can augment the above dietary and lifestyle measures designed to prevent kidney stones and can also be used to treat existing stones. The regime is largely the same for these two treatment scenarios. In the case of managing existing stones, therapy is aimed at passing small stones and/or gradually weakening or dissolving larger stones:

• A key herb is Crataeva, which research has shown can assist the passage of small stones and prevent the formation of new stones (see the detailed information above). Other antilithic herbs such as horsetail and golden rod are indicated, as are aquaretics which will render the urine more dilute (as will copious fluid intake). Dandelion leaf is also useful, given that it is rich in potassium.

• Anthraquinone-containing herbs such as cascara and yellow dock can help by binding calcium in the urine and making it less likely to precipitate. The herb madder (Rubia tinctorum) was particularly used for this effect in Europe, but has now been banned due to concerns over carcinogenicity.

• Infection can provide a focus for stone formation; hence the treatment strategies for cystitis should also be followed if infection is thought to play a role. This includes immune supporting herbs such as Echinacea root and antibacterial herbs such as cranberry and buchu. However, there is some clinical evidence to suggest that cranberry may slightly increase the risk of oxalate stone formation.⁹⁰

• If a stone is lodged and causing pain then urinary tract demulcents and spasmolytic herbs such as cramp bark and wild yam are additionally indicated. The prescription-only spasmolytic Ammi visnaga was traditionally used in Egypt to aid the passage of urinary stones. While stones are causing damage to the urinary tract mucosa, immune-enhancing herbs and urinary tract antiseptics will lower the risk of infection. A species of oak Quercus salicina (Q. stenophylla) has been used to treat urinary stones in Japan since 1969. Clinical trials have demonstrated efficacy in assisting the passage of both renal and ureteral stones.^91,92

Example liquid formula

Dose: 8 mL with water twice a day (if Crataeva 1:2 liquid is available it can be used instead of the dandelion leaf in the above formulation).

Urinary infections

Urinary infections are very common, affecting for example up to 20% of women at some time in their lives. Practitioner experience is that herbal remedies can be effective treatments for conditions such as urethritis, cystitis, ureteritis and even pyelonephritis (especially if chronic). Infections of the prostate gland (i.e. prostatitis) are also potentially amenable, although two general caveats are raised here. There are usually legal and ethical issues in the way of tackling urinary infections of venereal origin without referral to conventional sexually transmitted disease clinics. From a clinical point of view also, a urinary infection that has progressed beyond the walls of the tubules, as in pyelitis and prostatitis, can present other treatment challenges. That being said, the judicious use of the urinary antiseptics described below is often productive and there are many cases of recurrent cystitis that have been permanently corrected with phytotherapy.

Several plant constituents have at least theoretical antiseptic effects when eliminated in the urinary tract and a number of plants have firm clinical reputations for long-term efficacy in uncomplicated urethritis and cystitis, especially when caused by Gram-negative bacteria such as Escherichia coli (accounting for 80% of adult cases), Staphyloccocus saprophyticus, Klebsiella and Proteus.

When urinary tract infections are complicated by pregnancy, diabetes, immunosuppression or other abnormalities, prudence will determine that these are considered before simple urinary antiseptics are applied. Except in pregnancy and severe kidney disease, however, the treatments are rarely contraindicated. They may also show effectiveness in urinary tract conditions linked to fungal (e.g. Candida) and parasitic infections (for example, following malaria, leishmaniasis, trichomoniasis and bilharziasis) and for those without obvious infective cause. In the last case at least alkalinisation of the urine is a helpful accompaniment, conventionally with half a teaspoon of sodium bicarbonate in water every 3 to 4 hours but also with increased consumption of fruit juice (and vegetable juice especially).

Urinary infection probably requires adhesion of the bacteria to the otherwise glassy surface of the urinary tract and those usually responsible have mechanisms to do this. Constituents of berries of the heather family, notably Vaccinium macrocarpon (cranberry) and V. myrtillus (blueberry, bilberry), appear at least in vitro to interfere with this adhesion mechanism,⁹³ especially in the case of Escherichia coli (responsible for 80% of such infections). This may be due to the D-mannose in the berries preferentially adhering to the bacterial surface, or to proanthocyanins. There have been a number of clinical trials pursuing this effect and recently an updated Cochrane report chose 10 that were of methodologically good quality for systematic review and four for meta-analysis. The conclusion from the latter was that cranberry juice products can be effective in reducing urinary tract infections, although perhaps favouring women and having less impact in the elderly.⁶² They pointed to more work being needed, particularly in establishing effective dosage and other elements of treatment regime.

The benefits of cranberry may be pointers to the clinical benefits seen with its relative, Arctostaphylos uva-ursi (bearberry), although in this case it is the leaves that are used and it is the conversion of the glycoside arbutin into the antiseptic hydroquinone in the urinary tract that is seen as the likely mechanism.⁹⁴ Another traditional urinary antiseptic Chimaphila umbellata (pipsissewa) also contains arbutin.⁹⁵ (Also see the bearberry monograph.)

Another plant constituent with clinical antiadhesive properties, at least in the gut and in synthetic form, is berberine from the Berberis genus including Berberis aquifolium (Oregon grape) and Hydrastis canadensis (golden seal), both used traditionally for cystitis.⁹⁶ These also have separate activity against E. coli, Klebsiella spp. and other urinary pathogens (see berberis monograph).

It is also possible that herbs may help in the condition known as interstitial cystitis. This difficult condition, marked by inflammatory infiltration in the bladder wall but no obvious infection, is generally thought to be an autoimmune disorder. However, an infective cause has not been ruled out,⁹⁷ and in spite of its name, it appears that there is no increased bladder permeability.⁹⁸ There do appear to be changes in neurotransmitter sensitivity (increasing resistance to atropine and histamine and a switch towards purinergic transmission in parasympathetic nerve terminals)⁹⁹ and impairment of bladder perfusion in patients has also been observed, especially when the bladder was full.¹⁰⁰ It is for these reasons that in herbal treatments urinary antiseptics can be combined with other agents with an apparent benefit on the bladder wall (e.g. Equisetum, Zea, Crataeva nurvula and Althaea).

A major and debilitating problem is recurrent acute bacterial cystitis (otherwise known as recurrent cystitis), where the woman suffers repeated acute infections, often close to one another. As already noted the bacteria that cause cystitis can cling to and invade the cells lining the bladder wall and there they can remain dormant and resistant to antibiotic attack. Their activation leads to the next infection. Up to 20% of young women with cystitis develop recurrent infections of the urinary tract.¹⁰¹

Recurrent cystitis responds positively to herbal treatment, which is recommended on a continuing basis to prevent the acute attacks. After freedom from acute infections for 3 to 4 months, the herbal treatment can be reduced and eventually discontinued if the response is still favourable. Dietary measures (especially cranberry intake) should then continue, including reduced refined carbohydrate intake and dairy products. Adequate fluid intake should be ensured. Also, during acute cystitis any use of herbs needs to be combined with copious intake of fluid to flush the bladder. Cystitis is an infection, so it is always a good idea to support the immune system. For this either Echinacea root or the Ayurvedic herb Andrographis paniculata can be used. In a clinical trial Andrographis prevented the typical development of urinary tract infections in patients undergoing shock wave therapy for kidney stones (see andrographis monograph). Andrographis is appropriate at around 6 g/day during acute cystitis and about 3 g/day of Echinacea root can be used to prevent recurrent cystitis.

Other herbs to consider in cystitis include urinary tract demulcents such as couch grass and corn silk and licorice (Glycyrrhiza glabra), which may reduce bacterial adherence to the bladder wall (see licorice monograph).

Nocturnal enuresis (bedwetting)

Childhood sleep (nocturnal) enuresis (bedwetting) is the inappropriate voiding of urine by a child who has reached the age at which satisfactory control is expected. Since a large proportion of young children wet their beds, it is inappropriate to use the term enuresis until at least 5 years of age. At least 90% of children with nocturnal enuresis are reliably dry during the day.¹⁰²

More than 80% of children with nocturnal enuresis have never been dry at night for a prolonged period, but nearly all will have had an occasional dry night. This can be referred to as intermittent enuresis. True primary enuresis, in which the child has never had a single dry night, is very rare. Secondary (or acquired) enuresis is less prevalent than intermittent enuresis, and is where enuresis develops after the age of 5 years in a child who has previously been reliably dry at night for at least 1 year.¹⁰²

Nocturnal enuresis is more common in boys, first-born children, lower social classes and in children who have experienced stress in early life.¹⁰² Given the association with families, genetic factors may be involved with this disorder. Disorders such as diabetes, renal failure, urological abnormalities and epilepsy are rarely the cause, but should be excluded.

Stress is probably a factor, especially in relapses. Obviously the condition itself can be stressful. A child with nocturnal enuresis may have a smaller functional bladder capacity (that is, the child has the habit of emptying the bladder when it contains a relatively small volume of urine).¹⁰³ Urinary tract infection is not common, but should be tested for. Constipation can be an unrecognised factor and should be attended to.¹⁰⁴ Food allergies may be present (especially dairy, wheat or yeast) and soft drinks, tea and coffee should be avoided. Sleep apnoea should be considered and appropriate measures taken if relevant (including herbal treatment for adenoids and sinus conditions).

It is now generally agreed that nocturnal polyuria, detrusor overactivity and high arousal thresholds are, in various combinations, central to enuresis pathogenesis.¹⁰⁵

In addition to the measures described above, the following considerations can be useful. If the child shows symptoms consistent with food allergies or intolerances, then a relevant exclusion diet should be tested. Intake of refined carbohydrates should be reduced and a natural whole food diet followed as much as possible.

Restriction of fluid intake is not helpful. In fact increasing fluid intake during the day to generate higher urine flow rates increases the awareness of bladder filling and, by encouraging urine holding, achieves an increase in functional bladder size.¹⁰⁶

Many research projects have confirmed the merits of conditioning using alarms. Body-worn alarms are usually preferred.^106,107 Rewarding dry nights can reinforce behaviour. It might be particularly valuable to reward dry nights without making an obvious connection, so that a subconscious impression is encouraged.

Key herbs to consider are as follows:

Receptor activity

Although herbal remedies are not exactly comparable to conventional drugs in terms of directness of action, it is most likely that the primary effect of plant constituents on the nervous system is similar in terms of the synaptic junctions between nerve and nerve and nerve and muscle or other tissue. The receptor sites involved, whether on the presynaptic or postsynaptic membranes, are the communication junctions in the nervous system where its modulation is generally effected. The transmitter chemicals involved are among the most powerful molecules in the body and play a major part in the functions of other body systems; as seen in the relevant chapters of this book, plant constituents have been widely shown to engage with receptors in the hormonal, immunological and other control systems in the body. These systems form a whole, whose study, psychoneuroimmunology, has attracted the attention of the more imaginative medical researchers since the 1960s. The ability of plant constituents to engage cell receptors is also a particular feature of activity within the digestive system, which in clinical reality for herbal remedies is probably the most accessible interface in the chemical control of the nervous system.

There are ample opportunities for herbal constituents to interact with synaptic function in the nervous system. Various herbal extracts have been shown in vitro to act on adrenergic and cholinergic,¹ muscarinic, 5-HT_1A and 5-HT₂ receptors, dopamine (D₁ and D₂), the benzodiazepine and the gamma-aminobutyric acid (GABA) binding sites.^2,3 Notable examples of such activity follow; the literature cited reflects the fact that much published research in this area emanates from China and Japan. While these experimental examples might not always reflect real clinical effects, some are given here to reflect the wide spectrum of possible activities of herbal remedies.

Analgesic activity

Analgesics present a major challenge to the modern phytotherapist. Painkillers are by definition relatively powerful agents. Natural analgesics are likely to have been identified early in human history for their immediate benefits in pain relief and/or for their psychoactive properties. Obvious examples are the opium poppy (morphine alkaloids), the nightshade family (atropine alkaloids), willow (see monograph), poplar and birch barks among other sources of salicylates and phenols, as well as the many psychoactive plants (coca, cannabis, psilocybin, mescaline, etc.). Most are now only legally prescribed by doctors, if at all, and it would appear that there is little scope for relatively gentle remedies to compete with the improved targeting of synthetic analgesics.

There are, however, a number of traditional remedies with general and specific analgesic reputations that have been less well exploited in modern times and which are relatively well tolerated in clinical use. Although not as powerful as some of the modern synthetic analgesics, they do show sufficient activity to be taken seriously and are particularly likely to be helpful in pain linked to inflammation and to visceral and vascular spasm. The research papers cited in the following examples demonstrate that even in the demanding area of analgesia there is ample evidence to support useful clinical intervention by the phytotherapist. None of the following remedies are safe for widespread use by the public; their use is to be confined to the experienced clinician who can take account of all factors, including the increased likelihood of adverse effects.

Anxiolytic activity

Modern research is investigating a number of medicinal plants for anxiolytic activity. The key anxiolytic herbs covered by monographs in this text are Piper methysticum (kava) and Valeriana officinalis (valerian). Withania (Withania somnifera), hawthorn (Crataegus species) and Ginkgo (Ginkgo biloba) have also demonstrated clinical anxiolytic effects, and these trials have been included in their respective monographs.

Another anxiolytic herb with a growing body of evidence is passionflower (Passiflora incarnata). The unusual common name is not a reference to earthly passions. It comes instead from the Christian symbolism (Christ’s Passion) seen in the flower by the Spanish conquistadores when they first encountered the vine growing in South America. This was later elaborated by the scholarly monk Jacomo Bosio, who maintained that the flowers contained a profound symbolism of Christ’s final days on earth.⁵⁷ For example, the five stamens were the number of wounds, the three pistil stigmas represented nails and the 72 filaments were the number of thorns in the crown given to Jesus.

Despite this focus on the flower, the part of the plant used medicinally is the aerial part or the vine. Phytochemicals found here that contribute to the anxiolytic activity are not fully understood, but they include flavonoids, maltol and flavonoid-related molecules such as benzoflavone.⁵⁸

There are now several clinical trials providing evidence to support the value of passionflower for anxiety symptoms. In a pilot, randomised, double blind, controlled trial, passionflower extract was as efficacious as oxazepam for the management of generalised anxiety disorder. However, herbal treatment resulted in a lower incidence of impairment of job performance. The daily dosage of the undefined passionflower extract was 45 drops.⁵⁹ A passionflower and valerian combination improved symptoms of insomnia in uncontrolled trials.^60,61 The side effects characteristic of benzodiazepine tranquilisers were not observed.⁶¹ In a controlled trial with comparison against chlorpromazine (an antipsychotic drug), electroencephalographic (EEG) recordings showed a sedative activity after 6 weeks’ treatment with the herbal combination.⁶⁰ In a randomised, double blind, placebo-controlled study, a single dose of passionflower extract (equivalent to about 7 g of dried herb) demonstrated a calming effect in healthy female volunteers, as assessed by a self-rating scale for alertness.⁶²

Passionflower has also been used to help drug withdrawal symptoms. A randomised, double blind, controlled, 14-day trial compared clonidine plus passionflower extract against clonidine plus placebo in the outpatient detoxification of opiate addicts. Both treatments were equally effective at treating the physical symptoms of withdrawal, but the group receiving passionflower showed superiority over clonidine alone in terms of the management of mental symptoms.⁶³

Many patients suffer from anxiety before surgery, but any premedication must be sufficiently strong without causing undue sedation or interacting with general anaesthesia. A recent clinical study found that a single dose of passionflower prior to outpatient surgery reduced anxiety without increasing sedation.⁶⁴ In a double blind, randomised, placebo-controlled trial, 60 patients received either 500 mg of passionflower herb as a tablet or a matching placebo as a premedication 90 minutes before surgery. The passion flower tablet was standardised to contain 1.01 mg of benzoflavone. A numerical rating scale of 1 to 10, with 10 being the worst possible anxiety, was used to assess anxiety and sedation before and 10, 30, 60 and 90 minutes after premedication. Psychomotor function was assessed at arrival in the operating theatre and 30 and 90 minutes after tracheal extubation. Anxiety scores were similar for both groups at baseline, being 4.6±1.7 for the passionflower group and 5.1±2.0 for the placebo control group. After 90 minutes these had changed to 0.97 for the herbal treatment versus 3.88 for control treatment (p<0.001). There were no significant differences between the groups in the level of sedation before surgery and the recovery of function after surgery. Discharge times were also similar and no side effects were observed.

A clinical study presented as a poster at the European College of Neuropsychopharmacology Congress held in Vienna during October 2007 found that a combination of St John’s wort (Hypericum perforatum) and passionflower was helpful for the symptoms of depression with anxiety.⁶⁵ Each tablet in the combination contained 450 mg of St John’s wort extract (about 2.7 g of herb) and 350 mg of passionflower extract (about 1.4 g of herb) and it was given at a dose of 2 per day. In the trial, 162 patients received either the herbal tablets or a matching placebo for 8 weeks using a randomised, double blind design. Herbal treatment resulted in a highly significant reduction in the Hamilton depression score in the mildly depressed patients (15.64±0.93 to 8.05±1.69) versus an increase for placebo. Results were similar for anxiety scores, indicating that the anxiety that often accompanies mild depression also responded to the herbal combination, no doubt due largely to the passionflower.

Preliminary findings from a clinical trial suggest passionflower improves subjective sleep quality, a result entirely consistent with its traditional reputation as a mild hypnotic. A double blind, placebo-controlled trial conducted in Australia investigated the efficacy of passionflower on sleep.⁶⁶ Forty-one healthy volunteers (18 to 35 years) without extreme sleep problems received passionflower or placebo for 1 week, then after a 1-week washout they received the other treatment for 1 week. They drank a cup of tea 1 hour before bedtime. The tea was prepared from 2 g passionflower or placebo (parsley, Petroselinum crispum; 2 g) in 250 mL of boiling water, infused for 10 minutes. There was a significant improvement in sleep quality when taking passionflower (5.2% mean increase relative to placebo; p<0.01). No significant effects were found for other parameters, although the participants had initially low levels of anxiety.

Antidepressant activity

Herbs with antidepressant activity form part of the herbal category known as the nervine tonics (or nervous system trophorestoratives). The best known example is St John’s wort (Hypericum perforatum), which is the subject of a lengthy monograph in this book.

In addition, there is some encouraging research that has highlighted some unlikely herbal candidates for antidepressant activity, namely lavender (Lavandula officinalis) and saffron (Crocus sativa). Also, perhaps not unexpectedly, the tonic herb Rhodiola now has some reasonable evidence for a supporting role in depression.

Lavender has a strong reputation as a herb for the nervous system. In aromatherapy it has been used to calm anxiety and boost mood for some time. The use of lavender oil in depression is also supported by evidence from clinical studies.⁶⁷ A small double blind clinical trial was conducted to compare the oral use of 60 drops/day of a lavender 1:5 tincture with the drug imipramine.⁶⁸ A third group of patients also took both treatments. While the lavender tincture showed some benefit, it was not as effective as the imipramine for depression. Perhaps a higher dose of lavender might have yielded better results, as the dose used in the trial was quite low. But the interesting finding was that the combination of lavender with imipramine worked better than imipramine alone, without any accentuation of the drug’s side effects.

The evidence for saffron is more extensive, with a number of clinical trials showing promising results, although again these are all small, involving around 40 patients each. Trials tested its efficacy against a placebo and against conventional antidepressants, both a tricyclic (imipramine) and a selective serotonin re-uptake inhibitor (fluoxetine).

Two double blind placebo-controlled trials found that saffron extract at a dose of just 30 mg/day was significantly better (p<0.001) than placebo in improving the mood of patients with mild to moderate depression.^69,70 There were no more side effects in the saffron group than in the placebo. There was a dramatic drop in the Hamilton depression rating scale for the patients taking the saffron that was evident at 2 weeks and continued to fall until the end of the trial at 6 weeks. In all, it fell from around 23 to 9 in the group taking saffron, versus a fall of only around 23 to 18 in the placebo group.

In the comparative clinical trials, saffron was found to be as effective as the conventional drugs tested. In the trial comparing saffron with imipramine, patients taking the drug experienced the typical side effects of a dry mouth and excessive sedation.⁷¹ No such side effects occurred for saffron. Saffron was compared with fluoxetine in two published trials^72,73 and found to have a similar remission rate for depression to the drug, of around 25%. There were no significant differences between the two patient groups in terms of side effects.

Saffron is a very expensive spice and dye commonly used in Indian and Middle Eastern cuisine. The reason why it is expensive is that just a small part (the stigma) of each flower of this attractive Crocus is harvested by hand.

Research from Sweden has supported the role of Rhodiola rosea in depression.⁷⁴ In an experimental model of depression Rhodiola performed as well as St John’s wort and the antidepressant drug imipramine. The activity was dose dependent and several key phytochemicals in Rhodiola including rosavin were shown to be active.

This research led to a clinical trial of Rhodiola extract in mild and moderate depression. In a randomised, double blind, placebo-controlled design, male and female patients aged 18 to 70 years with Hamilton Rating Scale for Depression (HAMD) scores of 21 to 31 were divided into three groups.⁷⁵ Over 6 weeks Group A (31 patients) received 340 mg/day of Rhodiola extract, Group B (29 patients) received 680 mg/day of extract and Group C (29 patients) were assigned a matching placebo. Both the Hamilton and the Beck Depression Inventory (BDI) were used to assess treatment outcomes at 6 weeks. The BDI is a series of questions developed to measure the intensity, severity and depth of depression.

In terms of overall depression, there were highly significant reductions (p<0.0001) in both the HAMD and BDI scores 6 weeks after Rhodiola treatment that was not evident in the placebo group. The average HAMD score in Groups A and B fell from around 25 to around 18 for both groups, indicating that a dose-response effect was not seen for this outcome. In contrast, a dose-response relationship was observed for the BDI scale, with values falling from around 11 to 8 in Group A and from about 11 to 5 in Group B. In terms of the HAMD subgroup scores, significant reductions were seen for insomnia, emotional instability and somatisation (physical symptoms caused by mental or emotional factors), but not for self-esteem (except in the high dose Group B). No serious side effects were seen.

In discussing a mechanism of action for Rhodiola, the authors emphasised its adaptogenic and antistress activities.⁷⁴ In depression it is theorised that stress hormones such as cortisol and indeed the HPA (hypothalamic-pituitary-adrenal) axis are overactivated and do not switch off appropriately via the normal negative feedback (see later in this section). The influence of certain stress chemicals released by cells (stress kinases) is thought to play a key role in this overactivity. In particular, they inhibit the sensitivity of receptors in the brain to cortisol. In an experimental model, Rhodiola extract decreased the release of stress kinases and cortisone in response to stress. This suggests that Rhodiola inhibits the stress-induced activation of stress kinases in depressed patients and so restores the impaired sensitivity of their brain receptors to cortisol. This ‘resistance’ of the cortisol receptors is a noted feature in many patients with major depression (see also p. 338).

Analgesics

Herbal sedatives and hypnotics

In conventional pharmacological terms, sedatives reduce nervous activity and hypnotics promote sleep. There is obviously overlap in practice between the two categories, and both imply a degree of depression of nervous activity and consequent dangers (as seen most obviously in the barbiturates). There is a third category of calming agent that was postulated as an ideal anxiolytic strategy: the tranquilliser. This was originally defined as a treatment whose effect was confined to the reticular activating system that determined the level of arousal in the central nervous system (CNS), and did not otherwise sedate. Although the benzodiazepines were hailed as tranquillisers on their discovery, this ideal has been clearly compromised and these remedies are now seen to have appreciable sedative and hypnotic effects as well.

Many traditional herbal remedies have various degrees of sedative and tranquillising activity, and some have had this effect supported in experimental and clinical studies. However, it is probably misleading to apply the strict pharmacological definitions to them; their effects are much broader in clinical experience, with strong sedation rare. For the purposes of this text, therefore, the terms ‘herbal sedatives and hypnotics’ will be used to describe remedies that are actually relaxing, with little evidence of depressive activity.

Spasmolytics and relaxants (anxiolytics)

Most medical preoccupation has been with the nervous system as an entity in itself, with the goal of better analgesics, sedatives, tranquillisers and antipsychotics. Traditional interest in such areas was of course also strong and many plants were favoured for their powerful psychoactive properties. However, probably the most widespread use of neuroactive plants, or nervines, nowadays is for their effects on innervated structures rather than on nervous tissue alone.

The spasmolytic is a modern descriptor of the effect of an agent on visceral muscle in vitro, often the isolated guinea pig ileum. The technique is widely used as a model to indicate muscarinic or related receptor activity as above, but is a property with little therapeutic application. By contrast, herbal spasmolytics or relaxants are remedies used to reduce the symptoms of tension in the body. Pre-Cartesian insights into the human condition had no separation between body and mind and this particular holistic view is a constant feature of Asian medicine still. Apart from the obvious psychoactives, remedies were not seen to be acting on the nervous system as such; rather there were many remedies that treated various manifestations of turbulence in the body linked to what nowadays would be described as ‘stress-related’ conditions.

Even though using other terms, early texts described such conditions as classic hypertension (‘Liver qi rising’), nervous headaches, palpitations, breathless attacks and hyperventilation (‘constriction of the chest’), nervous dyspepsia, dysphagia, irritable bowel and urinary frequency.

The remedies selected for these conditions were seen as somatic in emphasis. The markers for application and effectiveness were physical symptoms. Nowadays modern phytotherapists refer to many of them as antispasmodics or spasmolytics or, more recently, ‘visceral relaxants’. They are offered to the modern stressed patient as a welcome antidote to the culture of tranquillisers and sedatives, treatments working from the ‘neck down’ to reduce the physical effects of tension without befuddling the brain or impugning their sanity. Western remedies such as those listed later have all developed reputations as useful management measures in helping patients handle and even overcome psychosomatic disorders, perhaps combined with appropriate breathing exercises and adrenaline-reducing aerobic activity. Some Chinese remedies such as Uncaria rhynchophylla were targeted at such conditions and hold out the promise of modern applications.

Nervine tonics (nervous trophorestoratives)

Herbal medicine has had to adapt significantly from its traditional roots. There is evidence that in many earlier cultures there were different perspectives on anxiety and depression syndromes. Whether there was genuinely less opportunity for the modern diagnosis in highly structured communities living on the edge of survival or whether such symptoms were not recognised as such is arguable. There is, however, less emphasis on treatments to relieve stress and mood conditions in most traditional texts.

There were also no powerful synthetic agents that relieved pain and distress. It is thus an entirely modern notion that herbs could provide gentle back-up for sufferers with nervous or mental problems.

In the West, where such adjustments have been made over many decades, the group of remedies that has emerged to meet modern needs is sometimes referred to as ‘nervines’. In recognition of the common observation that many conditions of tension are linked with fatigue, debility and depression, there is also a category of remedies that were seen to restore energies and build up strength. These have sometimes been referred to as ‘trophorestoratives’. It was a general principle that some tonifying element be included in most nervine prescriptions, so as to aim for lasting value rather than just short-term alleviation.

Anxiety

There are several types of anxiety defined in the various diagnostic manuals including panic disorder, phobias, social anxiety disorder, obsessive-compulsive disorder, separation anxiety and post-traumatic stress disorder. However, the condition classified as generalised anxiety disorder (GAD) is probably the most common form suffered by patients seeking phytotherapy. This is with good reason, since this often milder form of anxiety is more amenable to subtle treatments.

The DSM-IV (American Psychiatric Association 2000) defines GAD as troublesome excessive anxiety and worry (apprehensive expectation) occurring more days than not for at least 6 months and not associated with any other condition.⁷⁸ Three or more of the following will be present: restlessness or feeling on edge, being easily fatigued, difficulty in concentration, irritability, muscle tension and sleep disturbances.

One interesting discussion suggests that several factors have led contemporary psychiatry away from neuroses and anxiety disorders and towards depression as a social paradigm of distress.⁷⁹ These included a perception that anxiety disorders have less relevance, the downfall of the benzodiazepines and the failure to replace them with better anxiolytics, and the development of newer antidepressants. The article suggests that having promoted cognitive-behavioural therapy as the treatment for anxiety disorders, these conditions have become more the domain of clinical psychologists.

The discussion does touch on an important consideration: that patients suffering from anxiety must be viewed as a whole. Aspects of lifestyle and diet should be considered and extremes corrected where possible, for example excessive use of alcohol, recreational drugs or sexual indulgence, imbalanced diet, excessive tea and coffee intake, and cigarette smoking. Such corrections will need to be carefully considered, since often these factors can be used by the patient to allay anxiety and their abrupt withdrawal could exacerbate symptoms. Appropriate professional guidance and counselling, with the introduction of simple techniques for relaxation, can be beneficial.

Aspects of herbal treatment to be considered for the patient with GAD are as follows:

Anxiolytic herbs should not in general make the patient drowsy or affect their capacity to drive or use machinery. However, some sensitive patients may complain of this. These are usually people who are sleep-deprived or ‘living on their nerves’ and the herbs are probably only making them aware of how tired their bodies are. Due attention to rest and sleep usually eliminates this effect over a few weeks.

Note: Terminology to describe the classification of medicines is often applied loosely and inconsistently in modern usage. Sedatives (according to the Oxford Dictionary) soothe the nervous system. Implied in the term, however, is a resultant state of sedation. In contrast, anxiolytics allay anxiety, without necessarily inducing a state of sedation. In modern parlance, sedatives are often used to describe substances that induce sleep. But the correct term for this is hypnotic. That said, it is obvious that most sedatives will assist someone with disturbed sleep (but probably work better as such when taken throughout the day, rather than just before bed).