Herbal Therapeutics: The Top 12 Remedies, Part 2

Last month, the author reviewed sales statistics and other indicators of the public's growing interest in the medicinal use of herbs. Having thus set the stage for his series, he began to introduce the characters. Here he profiles six more: garlic, echinacea, saw palmetto, grape seed extract, kava, and evening primrose.

SECOND OF THREE PARTS

By R. W. Watkins, MD, MPH, FAAFP

Dr. Watkins is assistant clinical professor of family medicine at UNC School of Medicine in Chapel Hill, North Carolina, and has a private practice in Summerfield, North Carolina.

The use of herbs by patients in an attempt to self-manage both acute and chronic illness is a skyrocketing trend that physicians need to monitor closely. In the March issue of EMERGENCY MEDICINE, we looked at the conditions fostering the trend and at what is known about the properties of the three best-selling herbs on the U.S. market–ginkgo biloba, St. John's wort, and ginseng. Here we will review current knowledge of six more of the most-used herbs: garlic, echinacea, saw palmetto, grape seed extract, kava, and evening primrose.

GARLIC

Garlic photo © 2002 www.stevenfoster.com

Allium sativum. Garlic has a colorful medical history. It is mentioned as a remedy in Sanskrit records more than 5,000 years old. Ancient physicians Hippocrates, Galen, Pliny, and Dioscorides all used garlic for a number of maladies. It was called upon for everything from parasitic infections to respiratory problems, poor digestion, and low energy.

Louis Pasteur confirmed its antimicrobial action in 1858, and Albert Schweitzer used it as a weapon against amoebic dysentery during his years in Africa.

Most of the activity of garlic is attributed to its allicin content. Intact garlic cells contain alliin, an odorless amino acid. When the cells are broken and exposed to air, alliin meets the enzyme allinase, producing allicin, an unstable, odoriferous compound that provokes tears when onions are sliced or garlic is crushed. Fresh garlic contains approximately 1% alliin. One milligram of alliin is converted to 0.458 mg allicin, which in turn is converted to other sulfur compounds such as ajoene and allyl sulfides.

Garlic's clinical indications are numerous. First, there are the cardiovascular effects. There is some controversy over whether garlic is an effective treatment for hyperlipidemia, with several studies showing no benefit. But the bulk of evidence in the more than 250 publications on garlic's role in the treatment of cardiovascular disease shows that it does modestly improve total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels. In studies lasting 4 to 25 weeks, there is usually a lowering of total cholesterol levels by 4% to 12%. Garlic seems to have no effect on high-density lipoprotein (HDL) cholesterol.

Garlic may be beneficial in the treatment of hypertension. There is some evidence that it reduces blood pressure by 2% to 7% after four weeks of treatment. Several recent studies have shown that at relatively low doses of 300 mg per day, garlic may affect the vasculature by improving aortic elasticity. At 900 mg per day of a standardized powder, it has been found to slow the rate of progression of atherosclerosis. Thus, even though garlic may not give patients the cholesterol reductions of a statin, it may be protective in ways we are not yet able to measure. For instance, a very recent article showed that ajoene might possess potent anti-inflammatory properties.

There is a growing body of evidence from population studies suggesting that garlic, at least in the diet, has anti-carcinogenic properties, specifically against cancers of the colon, stomach, and prostate. One possible scenario for garlic's prevention of stomach cancer may be its inhibitory effect on H. pylori. Some even more recent evidence shows that it may be helpful in the prevention of breast cancer as well.

As mentioned previously, garlic has historically been used to treat a variety of infections including bacteria, viruses, worms and parasites, and fungi. Recent studies have confirmed garlic's utility in fungal infections. Topical treatment of tinea infections with ajoene 0.4% cream was effective for 79% of patients. And when a 0.6% gel was used, it was as effective as terbinafine 1% cream in cases of tinea corporis and tinea cruris.

Dosage of garlic varies with the preparation. In the treatment of hypertension and hyperlipidemia, most clinical trials have used 600 to 1200 mg per day of a standardized powder containing 1.3% alliin divided into three doses. A fresh garlic preparation containing 4 grams (about one medium-sized clove) has also been used. In epidemiologic studies looking at prevention of stomach and colorectal cancer, subjects ate anywhere from 3.5 grams to almost 30 grams of fresh or cooked garlic per week.

Based on current knowledge, it seems prudent to assume that any garlic preparation that is odorless is probably worthless. The active components identified to date are all sulfur derivatives and they are far from odorless.

Safety issues with garlic are mainly related to its inhibition of platelet aggregation and prolongation of bleeding times. Patients on warfarin should be monitored closely and surgical patients should stop garlic supplements at least a week prior to surgery if possible.

Garlic is nontoxic at the doses commonly used, but it can cause upset stomach occasionally in higher doses. Garlic enters the milk of nursing mothers and may cause colic in infants. Rashes have occasionally been reported and the literature includes several cases of severe dermatoses, as well as a couple of cases of anaphylaxis.

Recently, more concern about garlic has arisen because of its ability to induce cytochrome P-450 enzyme 3A4. Thus, many of the same concerns raised about St. John's wort are echoed in warnings about garlic's possible interference with medications, especially cyclosporine and protease inhibitors.

ECHINACEA

Echinacea photo © 2002 www.stevenfoster.com

Echinacea purpurea. Echinacea is a wildflower native to North America. It is also commonly known as the purple cone flower or American cone flower. Native Americans used echinacea more than any other remedy for numerous and diverse conditions including snakebite, abscesses, burns, infections, joint pains, and toothache. Modern research on the properties of the herb began in Germany in the 1930s.

Echinacea was part of the National Formulary of the United States until 1950. With the advent of antibiotics, its use fell out of favor, but with today's problems of antibiotic resistance, interest in its benefits has been rekindled. In terms of volume, echinacea accounts for about 10% of yearly herbal remedy sales.

Echinacea is a relatively well-researched substance and has been the subject of over 400 scientific studies worldwide. The actions of echinacea are mainly due to a number of polysaccharides called fructofuranosides, such as heteroxylan and arabinogalactan, and also to a group of lower-molecular-weight polysaccharides, including alkylamides and echinacosides. These compounds contribute to tissue regeneration and the regulation of the inflammatory response in a number of ways and have been shown to have a mild, direct cortisone-like effect.

Echinacea stimulates phagocytosis and lymphocyte activity, particularly T cells, and increases production of interferon. Natural killer cell activity is also increased. Echinacea seems to promote the release of tumor necrosis factor and interleukin-1 and can limit the effects of the bacterial enzyme hyaluronidase, known as "spreading factor" for its ability to break down cell walls and promote the spread of infection.

Clinically, echinacea is used in an oral form, usually with an extract of the parts that grow above ground (aerial portions), for preventing and treating the common cold and other upper respiratory infections. The bulk of evidence shows that echinacea is probably effective in limiting colds in severity and duration if started early in the course of illness. The evidence for its role in prevention is less compelling. Echinacea is also used for a variety of other infections, including urinary tract infections, vaginal candidiasis, and other recurrent infections, and at times when the immune system needs to be fortified.

Dosage, again, varies with the preparation of the herb. Many studies have used the juice of the aerial portion of E. purpurea preserved in 22% ethanol (standardized to contain a minimum of 2.4% fructofuranosides) in doses of 2 to 3 ml three times daily. Some others have tested a solid (dry powdered) extract (standardized to 3.5% echinacosides) at 300 mg three times daily. Whatever the source of the echinacea, including a blended tea in one study, higher doses given earlier in the disease course have been associated with better outcomes.

Echinacea is on the whole extremely well tolerated. In rats and mice, the LD50 of intravenous juice of E. purpurea is more than 50 ml/kg and the LD50 of the polysaccharide component is between 1000 and 2500 mg/kg. Most problems reported in the literature center on allergic reactions, which can include urticaria, erythema nodosum, acute asthma exacerbations, anaphylaxis, and angioedema. In addition, certain individuals may be at increased risk for these allergic reactions: those with atopy and those who are allergic to plants and flowers in the Asteraceae family, which includes ragweed, daisies, marigolds, and chrysanthemums. The only other people who should probably avoid echinacea are those with systemic diseases of the autoimmune variety, such as rheumatoid arthritis, collagen disorders, or multiple sclerosis, and those who are on immunosuppressive therapies.

SAW PALMETTO

Saw palmetto photo © 2002 www.stevenfoster.com

Serenoa repens. Native Americans used saw palmetto berries in the treatment of genitourinary tract problems. Early in the 20th century, a decoction of the berries was first used to treat benign prostatic hypertrophy (BPH), and until midcentury, saw palmetto tea was part of the United States Pharmacopeia and the National Formulary. In Germany and France, patients with uncomplicated BPH are more likely to receive saw palmetto extract (SPE) than any other form of treatment.

The active constituents of SPE are fatty acids from the berries that inhibit the 5-alpha reductase enzyme and prevent the intraprostatic conversion of testosterone to dihydrotestosterone (DHT). However, 5-alpha reductase, serum testosterone, DHT, and prostate-specific antigen (PSA) levels do not seem to be affected by SPE in vivo. Saw palmetto does not seem to affect overall prostate size, but inhibits epidermal growth factor and shrinks the inner prostatic epithelium. The herb might also exert its effect through the anti-inflammatory attributes of its fatty acid components in the lipo-oxygenase and cyclo-oxygenase pathways.

Numerous double-blind, placebo-controlled studies, as well as many open trials, have proved SPE to be a safe and efficacious treatment for BPH. A recent meta-analysis of 44 studies concluded: "Randomized studies of Serenoa repens appear to show saw palmetto to be a useful option for improving lower urinary tract symptoms and flow measures." Saw palmetto has shown comparable efficacy to finasteride (Proscar) and is better tolerated, with fewer side effects.

The dosage used in most of the literature is 160 mg, twice a day, of a standardized extract of the berries containing 85% to 95% fatty acids and sterols. Standardized, safe formulas are widely available. Recently, independent testing by ConsumerLab.com (January 2000) found that 17 out of 21 leading brands of SPE passed the 85% level, illustrating the benefit of using standardized extracts when available. Crude berries, fluid extracts, or tinctures may not yield the same results as were obtained in the scientific studies.

Saw palmetto extract is, in general, extremely well tolerated and adverse events are comparable to placebo. Most complaints are gastrointestinal in nature—nausea, vomiting, constipation, or diarrhea. Dizziness is sometimes reported. Initially, there were some concerns about erectile dysfunction with the use of SPE. However, clinical studies have shown that rates of impotence in men using saw palmetto are comparable to placebo and far lower than in those using finasteride. There are no known drug or food interactions.

GRAPE SEED EXTRACT

Grape photo © 2002 www.stevenfoster.com

Vitis vinifera. The first recorded mention of a key ingredient in grape seed extract was in 1534 in the mission logs of Jacques Cartier as he was exploring the St. Lawrence River. It seems he and his men became ice-bound during a particularly bitter Canadian winter. His men had begun suffering from scurvy when a friendly native happened by and taught them how to make a tea from pine bark that produced an immediate improvement in the crew's health.

Jacques Masquelier, upon reviewing Cartier's logs, felt that there must be a rich source of vitamin C in pine bark, and went about investigating the possibilities. What he found were other substances he called oligomeric proanthocyanidin complexes (OPCs) and procyanidolic oligomers (PCOs). Masquelier patented the method of extracting PCO from pine bark in France in 1951 and gave it the trade name Pycnogenol. In 1970, he was successful in extracting PCOs from grape seeds. Sales in France of the grape seed extract are 400 times greater than those of the more expensive pine bark products. Other sources rich in PCOs are cranberry, blueberry, bilberry, hawthorn berries, black currants, green and black teas, and red wine. From any source, these plant flavonoids seem to exert a number of health-promoting effects.

Chemical analysis has revealed that PCOs have an antioxidant capacity some 50 times greater than vitamin C or E. Thus, one of the most important roles of PCOs is as free radical scavengers. They are known to take out hydroxyl free radicals and lipid peroxides and may, therefore, be protective against other free radicals of both water- and fat-soluble types. They also seem to inhibit a number of enzymes that can degrade connective tissues (hyaluronidase, elastase, and collagenase).

The primary clinical indications for grape seed extract are the treatment of such vascular disorders as venous insufficiency and capillary fragility and possibly retinal maladies such as diabetic retinopathy and macular degeneration. There have been several small preliminary studies indicating that PCOs might also improve night vision in healthy subjects. Many patients report improvement in allergy symptoms, but a recent clinical trial showed no benefit. It has been proposed that the constituent of cranberry juice that may help prevent recurrent UTIs might be PCOs.

For antioxidant support and for general health, a regimen of 50 mg per day is reasonable. The average daily intake of flavonoids in the American diet is about 25 mg per day. Daily intakes greater than 30 mg have been associated with reduced rates of cardiovascular mortality.

When PCOs are used for therapeutic purposes, such as venous insufficiency, the dose should be increased to 150 to 300 mg per day. In terms of percentage of the active constituent (PCO), grape seed extracts contain 92% to 95%, while pine bark extracts usually contain 80% to 85%. And the grape seed products are considerably less expensive.

Safety concerns are extremely limited and there have been no adverse reactions or significant side effects reported to date.

KAVA

Kava photo © 2002 www.stevenfoster.com

Piper methysticum. The people of the South Pacific, who were among the few populations on earth to not have discovered alcohol by the time Western explorers came to their islands, had used kava in celebrations and ceremonies for thousands of years. The first recorded exposure of a Westerner to the herb was Captain James Cook during his first voyage to the South Sea Islands in 1768. He is given credit for naming the herb "intoxicating pepper." Famed pharmacologist Louis Lewin conducted the first scientific studies on the herb in 1886. Bill Clinton took part in a kava ceremony as part of his 1992 presidential campaign, but no one is sure if he actually ingested the drink.

The pharmacologic actions of kava are believed to be due, for the most part, to compounds called kavalactones found in the fat-soluble resin of the root. The kavalactone content of the root can vary between 3% and 20%, so standardized preparations are preferred for clinical treatments, as they are with many herbs. Kavalactone content in the standardized products ranges from 30% to 70%.

Kava has muscle relaxant, anticonvulsant, and analgesic properties. It appears to interact primarily with the GABA receptors and dopamine A2. To a much lesser extent it interacts with opioid and histamine receptors, most prominently in the limbic system. Although it has some analgesic properties, it does not seem to affect the opiate receptors strongly since naloxone does not appear to reverse its effects.

A specific kavalactone, kawain, appears to decrease thromboxane 2 production and inhibit cyclo-oxygenase, indicating that kava may have significant inhibitory effects on platelet aggregation.

Kava has clinical indications for the short-term treatment of anxiety and possibly insomnia. Multiple clinical trials, most using a standardized extract of 70% kavalactones, have shown kava to be superior to placebo and comparable in effect to low-dose benzodiazepines for the treatment of anxiety. There are also several recent studies that show kava may be helpful in anxiety and neurovegetative symptoms related to perimenopause.

For the short-term treatment of anxiety, 45 to 70 mg of kavalactones a day should be taken in three doses. It may take two to four weeks to see an effect in some patients. The sedative dose is 180 to 210 mg kavalactones one hour before bedtime. Keep in mind that the typical bowl of kava contains approximately 250 mg of kavalactones and several bowls may be imbibed during a ceremony or gathering.

Adverse reactions are possible, particularly if doses are used that are higher than recommended. Gastrointestinal complaints, headache, and dizziness are possible at the recommended doses. Two studies have shown that unlike alcohol, benzodiazepines, or other sedative drugs, kava does not seem to depress mental functions or impair the ability to drive or operate machinery. In one study, healthy subjects were given kava, oxazepam, or placebo in a double-blinded fashion. Word recognition tests and event-related potentials were measured by electroencephalography. Both treatment groups experienced reduction of anxiety, but the mental function of the kava group actually improved. That said, there have been cases of motor impairment in people drinking large amounts of kava tea, including one case report of an arrest for "driving under the influence."

In addition, high doses of kava, over a prolonged period of time (at least several months), may result in the so-called kava dermopathy, or what Pacific islanders refer to as kani, a thickening, scaling, and yellowing of the skin.

Liver toxicity is also a concern, although it has usually been seen in patients using high doses for extended periods of time. However, there are two case reports in the literature of acute hepatitis in patients taking normal doses for only three or four weeks. It is speculated that these individuals were "poor metabolizers" with genetic polymorphisms in their cytochrome P450 2D6 isoenzymes.

European authorities have recently received about 25 reports of kava-associated cirrhosis, hepatitis, and liver failure, prompting Switzerland to ban the sale of preparations containing the herb and a few other countries to restrict it late last year.

The U.S. Food and Drug Administration is investigating and has asked practitioners to report "any adverse events associated with the use of kava products." The National Center for Complementary and Alternative Medicine has advised the public, meanwhile, to consult a health care practitioner before using the herb. What seems clear at this point is that those with known liver disease, those who drink alcohol more than occasionally, and anyone taking hepatotoxic drugs or central nervous system depressants should not use kava. There is one case report of a 54-year-old man hospitalized for lethargy and disorientation who was taking alprazolam (along with cimetidine and terazosin). When he became more alert after a few hours in the emergency department, he stated that he had been taking kava for three days.

EVENING PRIMROSE

Evening primrose photo © 2002 www.stevenfoster.com

Oenothera biennis. Evening primrose oil contains gamma-linolenic acid (GLA), an essential fatty acid in the omega-6 family of oils that is subsequently metabolized to dihomogammalinolenic acid (DGLA). Both the acid and its metabolite serve to counter inflammation in a number of maladies as precursors of the favorable series 1 prostaglandins (PGE1) and prostaglandin E2 (PGE2). In addition, DGLA is converted to 15-hydroxy-DGLA, which is thought to competitively inhibit the production of other inflammatory prostaglandins and leukotrienes from arachidonic acid.

There is some evidence that the body may not be able to convert linoleic acid to GLA efficiently in certain conditions, including old age, high alcohol intake, atopic eczema, cyclic mastalgia, high cholesterol, or high saturated fat intake, and deficiencies of vitamin B6, zinc, magnesium, biotin, or calcium. In these conditions, GLA may be truly deficient and supplementation may result in clinical improvement. This may be more likely in patients with diabetes and especially those suffering from diabetic neuropathy.

Other and, in fact, better sources of GLA are borage oil (22% GLA) and black currant seed oil (17% GLA). Evening primrose oil is actually much higher in linoleic acid (65% to 80%) than GLA (2% to 16%). Thus, many of the studies focusing on GLA, most of which used evening primrose oil, may be confounded by the fact that they were looking at effects of linoleic acid, not GLA as such. In addition, studies have shown that, over the long run, GLA supplementation actually increases tissue levels of arachidonic acid while at the same time decreasing levels of eicosapentaenoic acid (EPA), the precursor of the beneficial omega-3 series of prostaglandins. If the goal is to reduce inflammation, it is contrarian to raise arachidonic acid levels and decrease EPA levels. In other words, balance is the key.

That being said, evening primrose oil deserves special attention as the ninth best-selling herbal preparation in the United States. One of the main reasons for its popularity is the belief that it is an effective treatment for premenstrual syndrome (PMS). Studies have credited it with some improvement in irritable bowel symptoms in these patients, but otherwise found it ineffective in the treatment of PMS.

Another women's health concern that has spurred the use of evening primrose oil is cyclic mastalgia. The oil has been found to relieve symptoms in just under 50% of women with cyclic mastalgia and in 27% of women with non-cyclic symptoms. The study showed that it was not as effective as danazol, but was comparable to bromocriptine with substantially fewer side effects. There was no placebo group in this study, but a double-blind, placebo-controlled study involving 73 women showed similar results: reduced pain in 50% of women, compared with 19% in the placebo group. Evening primrose oil has not been helpful in trials involving women suffering from recurrent breast cysts or fibroadenomas.

Evening primrose oil has shown promise in reducing signs and symptoms in patients with rheumatoid arthritis. The effect may take several months to be seen and as indicated above, in the long term, treating inflammatory conditions with evening primrose oil is controversial. Many experts believe treating with omega-3 fatty acids makes more sense physiologically and there is certainly more literature to back up this stance.

Evening primrose oil is one of the few treatments that may be helpful in diabetic neuropathy. In one double-blind placebo-controlled study, 111 patients were given either 480 mg per day of GLA as evening primrose oil or placebo. After 12 months, the treatment group had significantly fewer symptoms. Positive results were also seen in a smaller group of patients with diabetic neuropathy in another study. A number of animal studies have shown GLA's ability to protect against diabetes-induced nerve injuries.

Gamma-linolenic acid is widely used in Europe for the treatment of eczema, but that indication gets no clear endorsement from the literature. A review of nine double-blind studies from 1989 showed GLA to have a positive effect on itching due to atopic eczema. Another study showed benefits in skin changes as well as itching. However, a number of other studies have shown no beneficial effects in GLA-treated patients. More and better designed studies need to be done before GLA can be recommended in patients with atopic dermatitis.

Given the fact that essential fatty acids are needed for normal brain development and function, they could be key to a rational therapeutic approach in the treatment of attention deficit and hyperactivity disorder. A recent double-blind placebo-controlled trial found that a supplement containing fish oil and evening primrose oil might indeed be helpful in improving this condition. However, the study has been criticized for its high dropout rate.

Dosage of evening primrose oil for the treatment of cyclic mastalgia has ranged from 3 to 4 grams a day (roughly 300 to 400 mg of GLA). Diabetic neuropathy is usually treated with higher doses in the range of 4 to 6 grams a day of the oil. For PMS, most studies have used dosages of 2 to 4 grams daily. In the studies dealing with rheumatoid arthritis, treatment dosages ranged from 540 mg to 2.8 grams daily. Children with atopic eczema were given 2 to 4 grams per day. Evening primrose oil and other sources of GLA should be taken with food to increase absorption. Benefits may not be seen for several months in chronic conditions.

Most adverse reactions to evening primrose oil are gastrointestinal in nature (indigestion, nausea). As with any oil supplement, higher doses can cause loose stools and abdominal cramps. One fairly recent report stated that evening primrose oil might increase the risk of complications in pregnancy, such as arrest of descent, oxytocin augmentation, and conditions requiring vacuum extraction. There is some question whether or not evening primrose oil lowers the seizure theshold, specifically in those with schizophrenia taking concomitant phenothiazines. Anyone with a known seizure disorder therefore should use evening primrose oil with caution. No other food or drug interactions are known to occur.

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