Botanical and Diet-Based Biological Therapies and Their Use by Older Persons: Part I
Complementary and alternative medicine therapies are being used with increasing frequency by mature and elderly persons. In fact, the use of alternative medicine in some form or another is widespread in the United States, with usage rates reported as high as 30%.1 Many complementary and alternative therapies are available, including: mind-body interventions (meditation, hypnosis, dance, music and art therapy, and biofeedback); biologically based therapies (herbal and dietary); manipulative and body-based methods (osteopathy, chiropractic, and massage); and energy therapies (electromagnetic fields and pressure application). This two-part series reviews available literature about the use, and possible misuse, of common botanical and diet-based biological therapies. A 1997 survey estimated that 12.1% of adults had used some form of herbal remedy in the prior 12 months, with an out-of-pocket expense exceeding $5 billion.2 A recent survey of persons 66-100 years of age revealed that the primary reasons for use include pain relief, improved quality of life, and maintenance of health and fitness. The same survey concluded that “knowledge” regarding complementary therapies was extremely low across the surveyed population.3
Questions concerning regulation, quality, safety, and efficacy of these therapies are abundant in the literature, and data regarding their use in older persons are particularly lacking.4 Many studies have methodologic flaws including publication bias, lack of placebo control, lack of standard treatment arms, small numbers of subjects, and brief terms for follow-up.5 The safety of certain herbs has also been questioned, including their potential for adverse effects on the cardiovascular, gastrointestinal, neurological, and renal systems. Especially bothersome are the lack of data regarding their potential for causing drug interactions. Due to polypharmacy, the older patient population is at increased risk for drug-drug interactions and drug-herb interactions. Questions about credentialing of complementary and alternative medicine “practitioners” have been raised with concern over a lack and uniformity of licensing and credentialing processes similar to that of other health care professions.6
Ginkgo biloba and Panax ginseng are commonly used in individuals who hope to prevent deterioration in their cognition. Ginkgo biloba has been studied for many different uses including memory loss, intermittent claudication, vertigo, and tinnitus. The proposed mechanism of action relates to its apparent ischemic protective and antioxidant effects through flavonoids. These are believed to reduce oxidative metabolism in brain neurons and serve as free radical scavengers to prevent lipid peroxidation.7 Ginkgo has also been demonstrated to reduce neutrophil infiltration and increase blood flow, which is believed to prevent the progression of ischemia. Antioxidant and reported membrane-stabilizing activity may increase cerebral hypoxia tolerance.8 Ginkgolide B has been shown to inhibit platelet-activating factor; ginkgo may inhibit age-related muscarinic and adrenoreceptor loss, as well as beta-amyloid deposition.9 The quality of ginkgo products on the market varies dramatically; standardized extract contains at least 24% flavone and 6% terpene lactones.
There is a wealth of literature available on the use of ginkgo, most of which is flawed for reasons stated in the introduction. Using standardized scales for cognition, a study of 212 subjects randomized to take either placebo or ginkgo found a significant positive effect for ginkgo. This effect was comparable to that noted for donepezil, an acetylcholinesterase inhibitor.10 In 202 patients for whom data were collected in a placebo-controlled, double-blind, randomized trial using a standardized Alzheimer’s Disease Assessment Scale, ginkgo extract was found to be safe and capable of improving cognitive and social functioning.11 A 1998 meta-analysis of four articles meeting stringent inclusion criteria also found a small but significant positive effect of ginkgo on objective measures of cognition in Alzheimer’s disease.12 A recent evidence-based review by the American Academy of Neurology states that ginkgo biloba remains a “practice option.”13 The 2003 Cochrane Database of Systematic Reviews found benefits in cognition, activities of daily living, and mood and emotional function for ginkgo without an increase in adverse events.14 The adverse effects are believed to be related to the inhibition of platelet-activating factor (PAF).
The biological actions of PAF are multiple, including platelet aggregation, increased microvascular permeability, systemic vasodilation, increased cerebral blood flow, and granulocyte activation.15,16 All ginkgolides are believed to be capable of inhibiting PAF, and there are reports in the literature of bleeding events in patients taking ginkgo biloba. Specifically, there have been case reports of subdural hematomas, spontaneous hyphema, subarachnoid hemorrhage, bleeding associated with liver transplantation, and bleeding postoperatively from laparoscopic cholecystectomy.17-21 Therefore, caution is advised in the use of Ginkgo in conjunction with other anticoagulant agents such as warfarin, aspirin, and clopidogrel, or in those at high risk of damage from bleeding. A consensus opinion has recommended discontinuing Ginkgo prior to surgery, although the interval suggested varies greatly from 36 hours to 14 days prior.9 Ginkgo biloba has recently been associated with the onset of seizures in seven reports; this has prompted health care providers to use caution in patients predisposed to seizure or who are taking other medicines that may cause seizure or reduce one’s seizure threshold.22
Panax ginseng has been evaluated to a limited degree for symptoms ranging from lack of stamina, fatigue, debility, and decreased capacity for work and concentration, to cognitive impairment. Ginseng’s main active components consist of approximately 25 ginsenosides, or steroidal saponins; these have a variety of tissue and receptor targets, complex pharmacology, and multiple potential actions.23 Ginseng’s proposed effect on cognition is believed to result from nicotinic receptor stimulation by non-ginsenoside components of the herb.24 Ginseng has also been shown to function as an acetylcholine agonist.25 The results of clinical trials have been mixed to date. There is a concern that the various ginseng species are not easy to analyze in the literature because of confusing and complex terminology. A 2003 study of Panax ginseng’s effect on “quality of life” failed to demonstrate an overall improvement in health-related quality-of-life measures, although several other studies demonstrated beneficial effects in certain instrument summary component scores.26 Another report of the effects of ginseng on cognitive performance, mood, and energy found the evidence for ginseng to be “exceedingly weak.”27 A review of 57 randomized controlled trials of ginseng found 16 randomized controlled trials capable of meeting stringent review criteria, and from further analysis the authors concluded that although ginseng may have “beneficial” effects on psychomotor performance and cognitive behavior, no “compelling evidence” existed for any of ginseng’s claimed indications.28
Studies performed in China that used higher concentrations of ginseng derived from the ginseng root than are commonly available reported increases in endurance training in athletes. Little is known about this use in the general population or adverse effects from higher concentrations of ginseng root, and additional studies are warranted. Serious adverse effects of ginseng are rare and found only in scattered case reports. A single case report links a standard dose of ginseng to a subtherapeutic international normalized ratio (INR) in a patient previously therapeutic on warfarin.29 Diffuse effects such as insomnia, diarrhea, vaginal bleeding, headache, schizophrenia, and the Stevens-Johnson syndrome have also been reported.30 A 2002 systematic review of adverse effects of ginseng found the most commonly experienced adverse effects to be headache and gastrointestinal (GI) disorders. Although case reports of more serious adverse effects exist, causality is difficult to determine from available evidence.31
ST. JOHN’S WORT
Depression is extremely common in the elderly and is associated with a decreased quality of life and a range of symptoms from anhedonia to pseudodementia. Hypericum perforatum, or St. John’s wort, has been used as a mild antidepressant, sedative, and anxiolytic for many years. The mechanism of action of St. John’s wort is attributed to hyperforin, which inhibits serotonin, norepinephrine, and dopamine reuptake. However, similar to other herbal remedies, at least 10 other compounds may be contributory to the effects of St. John’s wort.32 Although initial reviews of clinical trials yielded positive results, closer review of these studies revealed multiple flaws. A 1999 study of 149 outpatients with mild-to-moderate depressive episodes compared 800 mg of St. John’s wort extract LoHyp-57 to 20 mg of fluoxetine, demonstrating similar effects.33 Unfortunately, no placebo arm was used in this study or others similarly comparing it to selective serotonin reuptake inhibitors (SSRIs).
A review of 23 randomized trials with a total of 1757 outpatients suffering from mild-to-moderate depression measured a “pooled estimate of response rate” and number of patients dropping out due to side effects. Hypericum extracts were found to be significantly superior to placebo, with fewer patients experiencing side effects than with standard antidepressants.34 However, the authors reported that the evidence was difficult to interpret because the definition of depression was not uniform, different herbal preparations were used, and limited numbers of patients were included in each of the trials. In a recent large, randomized, placebo-controlled trial, St. John’s wort extract failed to demonstrate superiority to placebo in treating major depression.35 An abstract presented at a recent international conference concluded that hypericum had a significant beneficial effect in patients with mild-to-moderate depression who are nondysthymic; patients with dysthymia were reportedly less likely to respond to treatment. It should be noted that measures of depression are subject to large placebo effects, requiring large groups of patients for comparative studies.36 Adverse effects of St. John’s wort stem from its ability to induce the cytochrome P450 3A4 enzyme, utilized in the metabolism of at least 50% of marketed medications. Multiple medications are affected, including cyclosporine, tacrolimus, indinavir, nevirapine, amitriptyline, simvastatin, fexofenadine, oral contraceptives, and digoxin.37 Reports of lethargy/incoherence, mild serotonin syndrome, and decreased concentrations of theophylline and digoxin have been reported in the literature.38 Photosensitivity, fatigue, and GI upset have also been noted.
Genitourinary complaints are frequent in older persons and include both incontinence and difficulty urinating. Benign prostatic hypertrophy (BPH) is a frequent problem affecting the older man. Serenoa repens, or saw palmetto, has been used to treat BPH with some success. Saw palmetto has anti-androgenic effects believed to be capable of inhibiting the binding of dihydrotestosterone (DHT) to its prostate receptor, thus helping to decrease prostate hyperplasia.39 It also has anti-estrogenic effects that may inhibit stromatic prostate mass growth in BPH. A study of 1098 men with moderate BPH compared finasteride with saw palmetto extract and found an equivalent improvement in International Prostate Symptom Score, improved quality of life, and increased peak urinary flow rate.40 A Cochrane Database review of 16 randomized trials noted that saw palmetto reduced nocturia and increased peak urinary flow with comparable effectiveness to finasteride.41 A recent randomized controlled trial also reported that saw palmetto was effective in men with symptomatic BPH with few side effects.42
The common cold is one of the most prevalent acute illnesses in the United States and accounts for considerable morbidity. The recent public outcry over limited influenza vaccination will undoubtedly lead to a search for alternatives including herbal remedies. Echinacea purpurea has been approved by the German Commission E, a German herbal regulatory authority, for use in the common cold, cough/bronchitis, fevers and colds, urinary tract infections, wounds, and burns. It is believed that all varieties of echinacea have immunomodulating activity secondary to alkamides, glycoproteins, flavonoids, and water-soluble immuno- stimulating polysaccharides. It has been shown to have multiple effects on wound healing as well as direct effects on phagocytosis, cytokine production, and the number of white blood cells, among others. Echinacea has been at the center of a large number of clinical trials that have generally been of poor quality, and thus difficult to interpret. A recent randomized, double-blind, placebo-controlled trial in 128 patients with cold symptoms found no statistical difference in total symptoms, individual symptoms, or time to resolution.43
Herbal and other biologically based diet remedies are being sought out and used for a variety of indications by persons of all ages, including older persons. The literature available is massive but generally of limited quality. Medical practitioners need to be aware of the potential for their patients to use these products as well as the potential for adverse effects. If a physician confirms that a patient is using these remedies, he or she should pursue the patient’s reason for taking them, and explore other, possibly more effective, medical options as appropriate. In certain cases, these agents may prove beneficial and the risk–benefit should be weighed for the particular patient. With the cost of health care and certain medications rising, we may expect to see more patients looking for over-the-counter remedies including herbs and other biological diet-based agents for relief. We need to be prepared to educate our patients as to the scientific data behind these remedies so that they are not blinded by the multiple unsubstantiated claims available to them in many different media. Although there are numerous other possibly beneficial products available, little is known about many of them. Future studies will hopefully provide guidance and help the medical profession better utilize these forms of therapy as either alternative or complementary treatment options.