Herbs Affecting the Central Nervous System

CONSIDERATION OF SPECIFIC HERBS

Ephedra or Ma Huang (Ephedra spp.)

Ephedra, commonly referred to by its Chinese name ma huang, has received much publicity recently. The herb consists of the dried green stems of several species of Ephedra native to Central Asia. These include E. distachya L., E. equisetina Bunge., and E. sinica Stapf. Ma huang has been used in China for the treatment of bronchial asthma and related conditions for more than 5000 years.

The therapeutic use of ephedra is due to its content of several closely related alkaloids of which ephedrine is both the most active and the one present in largest amount. A typical ephedra plant contains about 1.5% total alkaloids of which some 80% is ephedrine. American species of Ephedra, one of which is E. nevadensis S. Wats., often referred to as Mormon tea, contain no active alkaloids. Ephedrine was carefully researched here in the United States during the 1920s and was a standard over-the-counter (OTC) medication for many years. Like all other effective medications, it may also produce undesirable side effects.

The alkaloid's vasoconstricting effect makes it a useful nasal decongestant, but it also raises blood pressure and increases heart rate. It is an effective bronchodilator, but it also stimulates the central nervous system (CNS) with side effects ranging from nervousness to insomnia. This stimulation is greatly increased by consumption of caffeine or caffeine beverages such as coffee, tea, or cola. Consequently, ephedrine has been replaced to a large extent in over-the-counter cold and cough products by related chemicals such as pseudoephedrine or phenylpropanolamine. These have a similar action but much reduced CNS effects.

In recent years, ephedra and caffeine combination products have been promoted as appetite depressants and metabolic stimulants for weight loss, as athletic performance enhancers and, in very large doses, legal euphoriants or intoxicants. There is a considerable literature about the effects of ephedra on weight loss with some modestly favorable results. As one of my pharmacologist friends quipped, "You're bound to lose weight if you take ephedra and caffeine because you'll be so hyper the soup will slop out of the spoon before it reaches your mouth." That is, of course, a slight exaggeration.

Detailed studies of the herb's effect on athletic performance or its euphoriant activities do not exist. But that is of little moment because ephedra should not be taken chronically for any purpose unless the consumer is under the direct care of a competent physician. Many of the herbal products do not list the concentration of ephedrine present. Some manufacturers almost certainly "spike" their dosage forms with additional quantities of synthetic ephedrine.

As a result, the Food and Drug Administration (FDA) convened a special advisory group on ephedra in October 1995. That committee of experts made a number of recommendations regarding the sale of ephedra products, including strict dosage limitations, appropriate warning labels preventing chronic use, prohibition of sale to persons under age 18, and warnings to individuals with specific health risks.

These recommendations were never implemented, although in April 1996 the FDA did issue a warning cautioning consumers not to buy any high-dose ephedra products marketed as "legal highs." By August 1996, the FDA had compiled a list of some 800 adverse reactions, including 22 deaths and a number of serious cardiovascular and nervous system effects, including heart attack, stroke, and seizures, which they attributed to the consumption of ephedra, often in combination with caffeine-containing herbs. (The numbers in both categories have increased significantly since that time.) Consequently, another special advisory group meeting was held, but after lengthy discussion, no consensus was reached, and no concrete recommendations were made.

Food and Drug Commissioner David A. Kessler, who attended the meeting, said the agency would consider the matter and act quickly on ephedra's marketability, almost certainly before the end of 1996. He subsequently resigned, and no action was taken prior to the self-imposed deadline.

Finally, in June 1997, the FDA requested comment on a series of proposed restrictions on the sale of ephedra as a dietary supplement. These included a limitation of 8 mg per dose of ephedra alkaloids, labels warning consumers not to take more than 24 mg of ephedra alkaloids per day, labels advising at-risk persons not to consume ephedra, and limitation of consumption to a maximum of 7 days. As of June 1999, these proposed regulations have never been implemented.

Several states have acted, or are considering action, to control ephedra products. Most authorities continue to believe that small doses of ephedra, equivalent to not more than 40 mg of ephedrine per day, consumed on an occasional, not a chronic, basis for the relief of bronchial asthma, are safe for otherwise normal persons.

Another concern often expressed about ephedra is the possibility that the contained ephedrine may be illegally converted to methamphetamine or "speed," a common drug of abuse, by basement chemists. Although this is possible, it is not likely because of the difficulty in separating the product from the accompanying plant material. A much more likely starting product is pseudoephedrine which is readily available in pure form. Indeed, large-scale sales of that alkaloid are now monitored by the Drug Enforcement Administration (DEA).

Ephedra remains a prime example of an age-old dilemma in medicine. Must a useful therapeutic agent be banned because of its abuse potential? In many cases, this has proven to be necessary. Whether ephedra herb falls in this category remains to be seen.

Ginkgo (Ginkgo biloba L.)

An important breakthrough in herbal medicine took place in October 1997 when the Journal of the American Medical Association published the results of the first clinical trial conducted in the United States of the effect of Ginkgo biloba extract (GBE) on patients suffering from mild to severe dementia caused by Alzheimer's disease or multiple clots in the blood vessels. The generally positive results showing modest improvement in the cognitive performance and social functioning of the demented patients basically confirmed results previously obtained in European studies. Some 36 clinical trials with GBE had been conducted there between 1975 and 1996.

The ginkgo tree is well-known, particularly to residents of our large cities where its resistance to pollution and its overall toughness has caused it to be much planted as an ornamental along the very busy streets. This resistance to stress has enabled the species to survive for at least 70 million years; it is often referred to as a living fossil.

The seeds of the tree, after removal of the smelly, outer fleshy layer, have been used in China, both as a medicine and a food, for thousands of years, but it is the dried green leaves, not the seeds, that yield the herbal medicine that has become so popular today. Research beginning in the 1930s identified a number of constituents in the leaves, and in 1965 a product containing 24% flavone glycosides and 6% terpenes (ginkgolides A,B,C, and bilobalide) was first marketed for the treatment of conditions resulting from cerebral and peripheral circulatory disturbances. The product subsequently became very popular as an approved drug in Germany where sales in 1996 exceeded $163 million.

GBE is used primarily to treat cognitive deficiency, a condition caused by inadequate blood flow and nerve degeneration in the brain and expressed by symptoms such as vertigo, tinnitus, headache, short-term memory loss, reduced vigilance and concentration, and confusion. It is also useful in peripheral vascular disorders, having been shown to increase pain-free walking distance in patients with intermittent claudication. Evidence is also accumulating to support the value of GBE in alleviating sexual problems in males, particularly in those whose erectile dysfunction has been induced by the consumption of various antidepressant drugs.

Just how does GBE function to produce all of these beneficial effects? As is often the case with herbs, no single compound and no one mechanism is responsible. The ginkgo flavonoids reduce harmful brain effects by preventing the activity of enzymes that produce damaging free radicals. They also act as antioxidants scavenging any free oxygen radicals that are formed. In addition, they affect calcium transport which has a powerful influence on brain metabolism.

The sesquiterpene bilobalide reduces increased water and electrolyte levels in damaged brain tissue. The diterpene ginkgolides are potent platelet activating factor (PAF) inhibitors. PAF can contribute to brain damage not only by inducing thrombosis but also by increasing the permeability of blood vessels, allowing liquid to seep through them into brain tissue. This is likely to result in nerve damage.

In contrast to many synthetic drugs (halperidol, fluoxetine, and tacrine) for the treatment of dementia, GBE exerts its beneficial action with a much lower incidence of side effects. Only 1.67% of 10,632 patients treated with ginkgo experienced mild stomach upsets, headache, or allergic reactions in comparison to 5.42% of 2,325 patients treated with synthetic drugs who suffered these or more serious reactions.

The customary daily dose of GBE is 120-240 mg taken in 2 or 3 separate doses. A minimal 8-week course of treatment is recommended for cognitive deficiency. Contraindications to ginkgo therapy are not known, but because it does inhibit PAF, the herb should be administered cautiously in patients undergoing anticoagulant therapy utilizing either other herbs, e.g., garlic (Allium sativum L.), ginger (Zingiber officinale Roscoe), feverfew [Tanacetum parthenium (L.) Schultz Bip.], or synthetic drugs (warfarin).

Consumption of unprocessed ginkgo leaves in any form, including teas, should be avoided because they contain several potent allergens known as ginkgolic acids. These compounds, removed during processing of GBE, are chemically related to urushiol, the active principle in poison ivy [Toxicodendron radicans (L.) Ktze.]. Current regulations in Germany limit the concentration of ginkgolic acids in ginkgo preparations to a maximum of 5 parts per million. No standard has been established in the United States, but quality products do not exceed that level.

The GBE preparations long marketed worldwide are concentrated about 50-fold and contain 24% flavone glycosides and 6% terpenes, often designated 24/6. Recently, one company has made available a 27/7 product prepared by a method that increases the ginkgolide B concentration. Studies show that it produces a higher concentration of ginkgolides in the blood for a longer period of time, thus enhancing the effects of the herb.

In contrast to such improved products, it is believed that there are many substandard GBE preparations on the market today. Because of the extensive processing required, ginkgo is relatively expensive to produce, and the standard 50-60 mg tablets usually retail in the $10-$15 range for 60 capsules, depending on the brand. So-called bargain herbs, sometimes selling for a dollar or two for the same quantity, are very likely not bargains at all.

Sometimes one sees ginkgo advertisements touting it as a "smart pill" that improves the cognitive function of persons in the absence of any pathological condition. There is practically no evidence to show that the herb produces significant beneficial effects in the normal human brain.

St. John's Wort (Hypericum perforatum L.)

Depression, at least in its milder forms, is a condition that seems to afflict many Americans, occasionally if not chronically. In this country, the disease is the fourth most likely reason for one to consult a family physician and costs our economy more than chronic respiratory illness, diabetes, arthritis, or hypertension. The treatment and rehabilitation expenses in the United States exceed $12 billion annually; but the true cost, including loss of earnings, absenteeism, and loss of productivity, totals nearly $44 billion annually.

Depression is characterized by a number of subjective complaints ranging from despondency and loss of interest to irritability and sleep and digestive disorders. One authority has noted that the depressed patient suffers from melancholia about the present, guilt about the past, and anxiety about the future. Mild to moderate depressive symptoms occur in 13-20% of the population; major depression, often characterized by suicidal tendencies, plagues 1.5-5%.

More than a dozen prescription drugs are routinely used to treat America's depression. All of them are synthetic, and they all produce more or less unpleasant side effects ranging from skin rashes to overtly violent behavior. Meanwhile, in Germany the most popular prescription drug of any type, natural or synthetic, for the treatment of depression is a concentrated extract of the flowers and leaves of St. John's wort, often simply called hypericum. More than 200,000 prescriptions per month are filled for a single brand (Jarsin) there compared to about 30,000 per month for fluoxetine (Prozac). This figure does not include sales of other hypericum products, whether prescribed or self-selected. Actually, 80-90% of the sales in Germany are prescriptions, which allows their cost to be reimbursed by the health insurance system.

During the past two years, St. John's wort has become extremely popular in the United States. In 1996, it was not even listed among the best-selling herbs. Now it is one of the five most popular botanicals. Favorable publicity on television, and subsequently in the popular press, had much to do with this phenomenal increase in use.

Many clinical trials show St. John's wort to be especially useful in treating mild to moderate depressive states. Studies in 3,250 patients found improvement or total freedom from symptoms in about 80% of the cases treated, with only 15% not responding. These results are typical of all drug therapies for depression. However, the side effects were far fewer than those observed with conventional antidepressants. The incidence was less than 2.5% and consisted mainly of gastrointestinal disturbances and allergic reactions.

The herb's multiple constituents apparently function in several different ways. Initially, St. John's wort was thought to act as a monoamine oxidase (MAO) inhibitor. This effect has now been shown to be insignificant. Some evidence supports its effect as a selective serotonin reuptake inhibitor (SSRI).

It may also inhibit COMT (catechol-O-methyltransferase), an enzyme capable of destroying biological amines. Still another mechanism seems to suppress interleukin-6 release, affecting mood through neurohormonal pathways. The advantage of this combined action is fewer side effects for the patient because the total response is not due to a single type of activity.

Some authorities have warned against exposure to sunlight while consuming hypericum because it may induce photosensitivity with its dermatitis and associated inflammation. However, while light-skinned animals grazing on great quantities of the herb have had such reactions, photosensitivity is very uncommon in people taking it in normal amounts. It has occurred in patients injected intravenously with very large amounts of hypericin-50 to 70 times the normal oral dose.

Although St. John's wort is marketed as a drug in Germany and has been approved there by the German equivalent of our Food and Drug Administration for the treatment of depression, anxiety, and nervous unrest, it is sold in the United States only as a dietary supplement. The most effective preparations are capsules containing an extract of the herb standardized on the basis of 0.3% hypericin. Dosage is 300-900 mg daily. Improvement of mild to moderate depression should result after 2 to 6 weeks of treatment.

Kava (Piper methysticum G. Forst.)

The first Europeans to observe the kava plant and its ritualistic consumption by natives of Oceania were Dutch explorers Jacob Le Maire and William Schouten. In 1616, they encountered the plant in the Hoorn Islands, now a part of the French territory Wallis and Fatuna. Later travelers in the Pacific region provided a wealth of detail regarding this highly valued and widely used pepper plant.

Long cultivated and known by a number of common names, including kava-kava, ava, yagona, and yangona, the plant is now classified by botanists as Piper methysticum, meaning "intoxicating pepper." In religious and social rituals that naturally vary somewhat from island to island, the rhizome of the plant is grated (originally chewed by young people with sound teeth), mixed with water in a bowl, strained, and the resulting beverage drunk to produce a feeling of well-being.

Observers and even scientists long disagreed on the effects of kava. Captain James Cook, who observed its use during his world voyage of 1768-1771, thought the symptoms resembled those of opium. Lewis Lewin, a pioneer pharmacologist in the field of mind-altering drugs, referred to it in the 1880s as a narcotic and sedative, but noted these effects followed a period of quiet euphoria. Modern authorities call kava a psychoactive agent; it reduces anxiety much like the potent, synthetic benzodiazapines (e.g., Valium) and is a potent muscle relaxant. Kava does promote relaxation and sociability, but its effects are very different from those produced by either alcohol or synthetic tranquilizers. It does not produce a hangover, and, even more significant, it does not cause dependency or addiction.

Naturally, people were interested in finding out how kava produced these interesting effects. It was once thought that chewing the root converted its starch into sugar which then fermented to produce alcohol. Although this sounds far-fetched, chicha, a corn-based beer brewed by natives in Peru and Bolivia, is prepared in just this fashion. Lewin said a resinous material was the active component. Finally in the 1950s and 60s, two teams of German scientists headed by H.J. Meyer in Freiburg and R. Hänsel in Berlin found that the various activities of the kava plant were due to some 15 different chemical compounds known as pyrones. Collectively named kavapyrones or kavalactones, the compounds were found to increase the sedative action of barbiturates, to have both analgesic and local anesthetic effects, to cause muscles to relax, and to have antifungal properties.

Shortly after these findings, preparations of kava extract began to appear on the European market, usually standardized to provide a daily dosage in the range of 60-120 mg of kavapyrones. German Commission E, the group responsible for evaluating the safety and efficacy of botanical medicines, reviewed the data on kava and, in 1990, approved its use for conditions such as nervous anxiety, stress, and restlessness. It is frequently marketed as an anxiolytic. Use of kava is contraindicated during pregnancy, nursing, and in cases of depression caused by internal factors.

With an herb as potent as this one, there is naturally concern about side effects. Observations on 4,049 patients consuming 105 mg of kavapyrones daily for 7 weeks noted 61 cases (1.5%) of undesired effects. These were mostly mild and reversible gastrointestinal disturbances or allergic skin reactions. A 4-week study of 3,029 patients taking 240 mg of kavapyrones daily produced a slightly greater incidence (2.3%) of similar side effects. This would be expected because of the larger dosages used.

Long-term consumption of very large quantities of kava may result in a yellow coloration of the skin, nails, and hair, allergic skin reactions, visual and oculomotor equilibrium disturbances. For this reason, Commission E recommends that kava not be consumed for longer than 3 months without medical advice. Driving and operating machinery during consumption should be avoided.

The results of 5 controlled, double-blind clinical trials carried out with a total of 410 subjects over periods ranging from 28 to 84 days, using daily doses of kavapyrones between 30 and 210 mg, were all positive. For example, in 1995, 100 patients suffering anxiety and stress symptoms were given 210 mg of kavapyrones daily. After 8 weeks, the treated subjects were clearly improved in comparison to those receiving a placebo. As for side effects, 15 persons receiving the placebo reported them in comparison to only 5 taking kava extract.

Kava products have been steady but unspectacular sellers in Europe for several decades. Until recently, no one in the United States seemed much interested in them. Ironically, when the Food and Drug Administration began to express concern over the safety of ephedra, a stimulant herbal product, herb marketers became enthusiastic about kava, a depressant. Both herbs have psychoactive properties, but the effects are almost exactly opposite.

Kava and its contained pyrones are, without question, effective medications. They are also subject to abuse. The kava scenario in this country is just beginning. It is too early to predict whether it will continue to be marketed freely or will eventually be subjected to rigid controls.

Valerian (Valeriana officinalis L.)

The dried rhizome and roots of this tall perennial herb have enjoyed a considerable reputation as a minor tranquilizer and sleep aid for more than 1000 years. They contain from 0.3% to 0.7% of an unpleasant-smelling volatile oil containing bornyl acetate and the sesquiterpene derivatives valerenic acid and acetoxyvalerenic acid. Also present is 0.5% to 2% of a mixture of lipophilic iridoid principles known as valepotriates. These bicyclic monoterpenes are quite unstable and occur only in the fresh plant material or in that dried at temperatures under 40°C. In addition, various sugars, amino acids, free fatty acids, and aromatic acids have been isolated from the drug.

Identity of the active principles of valerian has been a subject of controversy for many years. Initially, the calmative effect was attributed to the volatile oil; indeed, this kind of activity was long associated with most herbs containing oils with disagreeable odors. Then, beginning in 1966 with the isolation of the valepotriates, the property was attributed to them for a 20-year period. This was done in spite of the fact that they were highly unstable and were contained in most valerian preparations only in small amounts. Finally, in 1988, it was shown that although valerian did produce CNS depression, neither the tested valepotriates, nor the sesquiterpenes valerenic acid or valeranone, nor the volatile oil itself displayed any such effect in rats. Although the active principles of valerian remain unidentified, it seems possible that a combination of volatile oil, valepotriates, and possibly certain water-soluble constituents may be involved.

Because the valepotriates possess an epoxide structure, they demonstrate alkylating activity in cell cultures. This caused concern that the herb might possess potential toxicity. However, those valepotriates decompose rapidly in the stored drug and also are not readily absorbed.

Source: V. E. Tyler (Purdue Univ.)