The JBH consumed in overdose was analyzed by a Colorado State University laboratory and found to contain a single plant-derived ingredient: the alkaloid 1-tetrahydropalmatine, representing 36% of the table,(1, 3) the rest being neutral starch. Thus, JBH differs from most herb products in that it is a purified chemical compound, and so has some of the same potential problems that occur with pharmaceutical products. Most users of JBH had assumed it was a typical herb compound, made up of dozens of natural components, even though the English-language label plainly states that it contains 30% alkaloid and 70% starch. The single alkaloid composition of JBH apparently was not understood by most of the prescribers and consumers of the product, which may have led to less caution with its use.

HISTORY AND SOURCE

Tetrahydropalmatine (THP) was first described as a constituent of a Chinese herb in a German report published in 1923.(4) For purposes of historical reference, this was the same year that a German study(5) about another alkaloid from a Chinese plant -ephedrine -- established a new drug of choice for treatment of asthma. (A second ingredient in the same plant -- pseudoephedrine -- is today produced synthetically to yield the primary sinus congestion remedy that does not cause drowsiness.) Virtually all over-the-counter herb remedies for hayfever and sinus congestion contain the original source material or a related species of Ephedra. These alkaloids are part of a long history of deriving useful remedies from East Asian herbs. In fact, the first isolation of an alkaloid was morphine from opium poppy, long used in Chinese medicine; the finding was reported in 1817 by a German researcher.(5) THP belongs to this rich tradition of pharmacological research, though it has not, until re cently, been well publicized.

Many alkaloids affect the nervous system. This is because, like plant alkaloids, neurotransmitters contain an active nitrogen molecule that influences binding to receptor sites. The impact of alkaloids on the nervous system may vary with dosage; for example, a low dose may stimulate the nervous system while a high dose may sedate it. In fact, some alkaloids are fatal in overdose by inducing paralysis of the respiratory control center. Because of the complexity of the nervous system, alkaloids can have paradoxical effects, causing stimulation or sedation not only at different doses, but among different individuals who use them, or even under different circumstances of use. Caffeine and ephedrine are alkaloids best known for their strong stimulatory action, while morphine and reserpine are well-known for their sedative actions.

The original source of THP in pharmacological research(6) was the tuber of Corydalis turtschaninovii Bess., commonly called corydalis (Chinese: yanhusuo or yuanhu). It is also derived from at least seven other related species.(7) As many as thirteen species of Corydalis have been identified as being used by herbalists in Asia though not all of them are called yanhusuo. Several of these plants have been used continuously in Chinese herbal medicine for over a thousand years.

Isolation and characterization of THP from various sources continued for about a decade after the initial work, primarily in China and Japan, as part of a concerted effort to use Western methods of analysis to reveal the nature of traditional remedies. By 1960, the isolated compound had already gained use in clinical trials for treatment of pain, and alternative sources of THP, such as various species of Stephania, notably Stephania rotunda, had been identified.(8) Corydalis species contain dl-tetrahydropalmatine, while Stephania species contain only l-tetrahydropalmatine;(9,10) both genera of plants produce other alkaloids that have similar pharmacological actions, though different potencies.(4)

CHEMICAL CHARACTERISTICS OF TETRAHYDROPALMATINE

THP is an isoquinoline alkaloid, one of many such compounds that are known for analgesic and tranquilizing properties. Within that large group, this compound belongs to the protoberberine series. Alkaloids in this series are used extensively in the Orient,(8) mainly for the treatment of infections (e.g., berberine), cancer (e.g., berbamine), and pain (e.g. stephanolide and THP). They are characteristically yellow, have four linked benzene rings with a nitrogen atom joining two ring pairs, and are modified variously via two oxygen atoms at each end. THP may owe some of the strength of its physiologic effects, compared to closely related structures, to its symmetry and to its solubility in fat (a property conferred by the four terminal methyl groups shielding each oxygen atom). Corydalis yields a total of 0.59% to 0.74% total alkaloids(11), of which there are about a dozen.(7) dl-Tetrahydropalmatine content of corydalis is not specified, but is estimated to represent only about 0. 2% by weight of the corydalis tuber. Stephania rotunda roots have a total alkaloid content of about 1.2% and may have as much as 0.5% by weight l-tetrahydropalmatine.

ACTION OF TETRAHYDROPALMATINE

The physiological effects of THP are essentially the same as those of the herb corydalis, which is analgesic, sedative, tranquilizing, and slightly hypnotic.(12) The herb contains a number of other protoberberine series alkaloids with similar effects, as well as protopine series alkaloids.(4) Corydaline, a methylated analog of THP, is present in similar amounts and has the most similar activity, with perhaps even greater analgesic effect.

Corydalis is used extensively by practitioners of Chinese herbal medicine both in Asia and the West, where it is recognized (by those practitioners and their patients) as a safe and often effective remedy for common pain syndromes, especially abdominal pain. It is most frequently utilized in the form of slices of the dried tuber used to make a tea, powdered and combined with other herbs in tablets and capsules, or as a powder or granule derived from the hot water extract of the dried tuber. Isolated L-tetrahydropalmatine (derived from Stephania species) is also widely used in the product Jin Bu Huan (literally: "more valuable than gold." a name given to several folk remedies that are analgesic and hypnotic. including the crude herb Stephania japonica). dl-Tetrahydropalmatine from corydalis is sold in tablets in the product called Yuan Hu Zhi Tong Pian.

Experiments on rabbits, mice, rats, dogs, and monkeys(8) showed that dl-tetrahydropalmatine at high dosage produced a significant hypnotic action. The compound is able to tame monkeys; it markedly decreases both spontaneous and passive activity in mice but is unable to abolish the righting reflex, suggesting the absence of anesthetic action. Subcutaneous injection of the agent to dogs results in sedation, tranquilization, lack of desire to escape, and tame behavior 5-20 minutes after medication; drowsiness is observed 30 minutes later. The effects last as long as 80 minutes. Nevertheless, the animals' senses are still present and they are easily awakened. In relation to these pharmacological findings, it is interesting to note that individuals reporting informally to the Institute for Traditional Medicine (ITM) about their experience with oral ingestion of THP in the form of the Chinese product JBH state that the time from ingestion to onset of effects is about 20 minutes, and that the duration of effects is typically about 90 minutes. (Insomniacs who wish for longer action are disappointed by this, but those who have suffered morning drowsiness from long-acting pharmaceutical drugs like this quality of JBH.)

dl-Tetrahydropalmatine potentiates or antagonizes the action of various drugs that influence the central nervous system.(8) It significantly potentiates the hypnotic action of cyclobarbital and it increases sensitivity to the convulsant effect of strychnine, yet it antagonizes the central stimulant action of caffeine and amphetamine and the convulsant effect of pentylenetetrazole. It also inhibits the neck and back scratching action of mice given the hallucinogen mescaline. In pharmacology experiments. the analgesic action of THP was shown to be less than that of morphine. Its tranquilizing action is stronger than that of morphine but less than that of chlorpromazine. It has been reported that l-tetrahydropalmatine has the analgesic and sedative actions, but that d-tetrahydropalmatine in similar doses produces a brief stimulation. Experiments with d-tetrahydropalmatine have been limited and, thus far, significant differences between the isolated dl-form and the combined dl-form have not been clearly demonstrated.

The mechanism of action of THP has been investigated.(8,12,13,14) It depresses cortical and subcortical electrical activity, especially in the motor areas of the brain. The action on neurotransmitters was shown to be different from that of either reserpine or morphine. While some protoberberine compounds bind to M-cholinergic receptors in the brain, THP and several closely related alkaloids do not. Other studies have shown that dl-tetrahydropalmatine and l-tetrahydropalmatine deplete the levels of three neurotransmitters: dopamine, norepinephrine, and serotonin, with a corresponding increase in most of their metabolites. This finding suggests that the compound acts as a short-lasting monoamine depleter. The other berberine compounds, some of which could bind to M-cholinergic receptors, do not have an effect on mono-amines in the brain. In other words, the action of THP is unique.

Pharmacokinetic studies(8) show that intragastric administration of THP to mice at a dose of 60 mg/kg results in rapid and nearly complete absorption (90%) within thirty minutes. When injected subcutaneously, the compound mainly enters fatty tissue, and is also found in the lungs, liver, and kidneys. Over time, more of the compound is transferred to fat. It can easily cross the blood-brain barrier, and concentration in the brain peaks within a few minutes, is somewhat reduced after 30 minutes, and quite low after two hours (corresponding, roughly, with the observed impact of the compound on behavior in animals). It should be noted that the common alkaloid berberine also accumulates in brain tissue; in China, pregnant women are not prescribed high doses of berberine because the material can accumulate in fetal brain tissue. THP should therefore not be recommended for use during pregnancy, even though, at this time, there is no reason to believe it will cause harm when used in us ual amounts. It appears that most of the alkaloid is metabolized prior to excretion in rabbits, since little is found in urine or feces, but most of it is excreted unmetabolized in the urine of rats within 12 hours. Therefore, the metabolism of the compound differs with the species of animal, though the effects do not differ substantially.

TOXICOLOGY STUDIES

Toxicity of corydalis and THP has been evaluated in China.(8) The LD(50) (dose lethal to 50% of animals tested) of whole corydalis extract given intragastrically to mice was determined to be equivalent to 100 g/kg, indicating extremely low toxicity (in other studies, comparing different species of corydalis, it was found that the LD(50) could be lowered to 35 g/kg by selecting the most toxic species; this is low toxicity). The LD(50) of THP in mice was shown to be 146 mg/ kg by intravenous route, the same as that found for several related alkaloids from corydalis. If the figure of about 0.65% alkaloid content of corydalis is assumed, and if the 100 g/kg LD(50) for the whole material is taken, then the average oral LD(50) of the alkaloids should be about 650 mg/kg (by the gastric route). The figure of about 150 mg/kg for individual alkaloids by intravenous route appears in agreement, given the usual finding of higher toxicity of intravenous versus gastric routes.

Cats and rabbits receiving intravenous injection of dl-tetrahydropalmatine in the dosage range 20 mg/kg to 60 mg/kg show some slight changes in respiration but no toxic effects. A single intragastric dose of 85 or 100 mg/kg or subcutaneous dose of 80 mg/kg given to rats does not result in significant toxicity. Similar doses given to rats over a period of two weeks does not produce signs of toxicity. Extreme sedation and deep hypnosis, however. could be obtained by giving a single intragastric dose of 180 mg/kg to rats.(8)

The dosage of THP actually given to humans for pain relief in clinical practice in China is 60- 100 mg per dose by injection, and 60-120 mg per dose orally. The dose can be repeated up to four times per day (total ingestion of nearly 0.5 gram).(8) With such doses, it is reported that neuralgia, dysmenorrhea, simple headaches, headache due to brain concussion, and pain due to internal organ disease (especially gastric ulcer) respond well, but post-surgical pain is not much affected. The treatment does not cause significant tolerance or addiction. The lack of addictive quality has been repeatedly noted in informal reports to ITM.

For insomnia, a dose of 100-200 mg THP at bedtime was reported helpful and no side effects were observed the day after in the Chinese studies/ Side effects of normal dosage administration have been reported to include vertigo, fatigue, and nausea. The doses being used in the human studies thus correspond to about 1.3 to 4.2 mg/kg. The patent JBH is made in the form of 80 mg tablets, of which about 29 mg is THE Since most Americans report that one to four tablets produce adequate response a single dose of 29-116 mg appears useful. This is substantially lower than the amount used by Chinese patients in clinical studies; according to those studies, and given the body weight differences usually involved, doses of up to eight tablets at one time would be reasonable for adults wanting bedtime sedation.

Based on the available laboratory and clinical reports from China,(8) the dosage ratio between a potentially fatal amount (about 150 mg/kg by injection and probably in excess of 200 mg/kg orally or intragastrically in small animals) and a clinically effective amount (in humans) is 50:1 or better. A fifty-fold difference between therapeutic and poisonous levels is more characteristic of foods than modern drugs. (For example, even coffee is more toxic -- because of its caffeine content -- than corydalis or THP). However, an infant or young child who swallowed pills of JBH could obtain an intermediate dose that would be potentially dangerous, as has been shown by experience. The product is currently packed in individual vials of 12 tablets; a 25-pound child consuming all 12 tablets could get more than 20 times the normal "therapeutic" level. The vials are not child-proof. ITM has received several informal reports of adults consuming 12 to 24 tablets of JBH through misunderstanding of the instructions for use. It appears that the adult response to overdose is mental agitation rather than the deep sleep that occurs with young children. In addition, some adults experience a paradoxical response to small or moderate doses, with mental agitation or even hallucinations being reported. The effects are always short-term, lasting a few hours at most. whether the dosage is low or high.

VARIABILITY

The content of alkaloids in Corydalis and Stephania, as in other herbs, is found to vary with the particular species collected as well as with the growing location and other factors, such as soil content, sun exposure, and rain, all of which influence the plant metabolism. At least eight species of Corydalis are used as sources of the market material within China (additional species are also used in Korea and Japan): it is likely that only one or possibly two species enter the U.S. (This is because the U.S. market affords the "best" quality of an herb and therefore the material from the species with the best reputation is selected by most of the importers.) Variability of JBH tablets has been suggested informally in reports to ITM: some people claim that individual boxes of JBH are "good" or are "ineffective." It is possible that there is variability in the manufacturing process or that storage conditions may make the finished product less potent (perhaps from excessive heat or longer duration of storage). There might also be some variability in response among patients depending upon the fat levels in the body, if, in fact, the distribution to fat tissues influences the amount of the compound that reaches the brain or the duration of adequate dosage in the brain. The variability in response attributed to the JBH product might actually be due to different circumstances of use.

OTHER APPLICATIONS

In China, further applications of corydalis and THP are being investigated.(8,15,16,17) Studies conducted thus far demonstrate a mild hypotensive action, an ability to counter arrhythmia induced by ouabain and picrotoxin, an inhibition of mycobacteria, and the ability to prevent and treat silicosis. The antiarrhythmic effect is the one of greatest interest, since it is consistent and substantial. The perceived value of THP is so high that tissue culture of the Stephania species is being investigated as a means of enhancing total production. Corydalis compounded with calcium salts from natural sources (such as sea shells) has been used clinically in the Orient and the West to treat gastric ulcer; in addition to relieving pain, it appears to have a curative effect. A prepared formula of this nature (Gastropathy Capsules) is sometimes imported from China. In the U.S. corydalis is being used experimentally by acupuncturists in complex herb formulas for the treatment of endometriosis .

In China, corydalis is usually used in the amount of 3 to 12 grams per day in the form of decoction, and about 0.9 to 2 grams per day as a powder. Based on the alkaloid content of the herb, the total alkaloids consumed by either of these methods (assuming 100% extraction by decoction) would be from 6 to 72 mg per day; lower than that used clinically (in China) for pain or for inducing sleep in a single dose. This lower level is useful, nonetheless, because other herbs consumed at the same time can help produce certain desired effects (including pain relief through other mechanisms), and it has been suggested that the total alkaloids have superior pain-relieving action compared to a single alkaloid from the plant. Drowsiness is not reported by individuals using corydalis by this method.

LIVER HYPERSENSITIVITY

The Rocky Mountain Drug and Poison Control Center has developed a database on adverse reactions to JBH, including about 10 cases (as of April 1994) of possible liver hypersensitivity.(8) Persons who are sensitive to THP develop severe liver inflammation even with modest dosage if the alkaloid is consumed repeatedly over a period of time. The inflammation subsides over a period of several weeks after ingestion of THP is stopped. Some American practitioners of Chinese medicine have observed individual cases of raised liver enzymes -- the characteristic sign of liver inflammation -- in patients who were using JBH regularly for several months and have reported such incidents to ITM during 1993. It has not been established that JBH was the cause in each case, since the individuals consuming JBH on a regular basis may have been using it in response to undiagnosed liver problems that lead to pain and/or insomnia. However, it was recently reported by Dr. Graham Woolf that three women in Los Angeles who purchased JBH from the same store were each hospitalized for acute hepatitis that was evidently caused by the ingestion of this compound.(2) Most people use JBH intermittently or for a relatively brief period; with this type of usage pattern, such liver reactions are unlikely to arise or become serious.

According to Chinese experience, THP does not result in any liver toxicity in animals.(8) Toxicology reports(19,20) in Chinese medical journals contain no mention of any cases of liver inflammation or toxic reaction to THP, nor are other isoquinoline alkaloids obtained from herbs reported to cause such problems. In fact, some of the herbs with isoquinoline alkaloids are used to treat viral hepatitis, including corydalis.(20) One of the importers of JBH, Dr. Bing Wong, said that those who become sick may have taken the wrong dosage. "Don't worry," he says, "the Chinese herbs never have side effects."(21) However, a small number of reports of liver and kidney hypersensitivity to Western and Chinese herbs have been appearing in the Western literature during the past few years, suggesting that herbs long regarded as entirely safe may cause health problems for a few individuals. An appropriate response to this situation, short of banning the use of the herb or product, has not yet b een established by the FDA or by the trade associations dealing with herbs.

SAFETY CONSIDERATIONS

ITM has advised Chinese medical practitioners in the U.S. to caution their patients to keep herb materials out of the reach of children since product labeling to this effect is usually absent. In most cases, it is highly unlikely that children will consume such materials, especially in quantities that are potentially harmful, because of their form and taste. However, JBH pills are very small and almost tasteless, while the small vials are possibly inviting to inquisitive minds and relatively easy to open. The dosage of alkaloids in the pills is relatively high (many times that found in crude herb materials), which makes them much more convenient for the individual who wishes to take them for pain or insomnia, but also more dangerous in relation to possible overdose. It should also be noted that while the package insert properly describes the content as "alkaloids" and gives approximately the correct amount of alkaloids (the insert says 30%, but Colorado State University chemists measured 36% alkaloids in several boxes analyzed), it misidentifies the plant source of the alkaloids as Polygala sinensis (another plant that is known in China by the name Jin Bu Huan, but which does not contain alkaloids). In recently published Chinese literature, the term "alkaloid" is sometimes used to indicate the active component even when it is not an alkaloid, due to poor translation work.(20) Mislabeling of herb products raises an alarm among health workers who may be faced with treating a person who has used the product -- how is one to respond when the substance ingested can't be quickly and accurately identified?

Corydalis, in the form of a crude herb or a simple hot-water extract, as is commonly used by practitioners of traditional Chinese medicine, appears to be safe from the point of view of experience and information derived from pharmacology experiments, even if taken in amounts far higher than normally recommended. Most preparations of the herb or the extract are intended to be taken in the dosage form of large numbers of tablets or capsules for ordinary conservative dosing (e.g., Gastropathy Capsules, 6-9 capsules per day; Corydalis Analgesic Tablets, 12 pills per day; American-made tablets containing corydalis as an ingredient, 6-15 tablets per day). This makes substantial overdosing quite difficult, even for children.

Highly concentrated preparations also appear safe when used in the proper dosage; for example, reactions to THP in JBH, by adults consuming six or fewer tablets, have been limited to rare cases of heightened insomnia, hallucinatory phenomena at night, and nausea; in all cases, these reactions were temporary. Yet, while these pills are safe compared to most over-the-counter drugs, they remain potentially dangerous in overdose because of their concentration and form.

RESPONSE TO JIN BU HUAN

FDA had largely ignored JBH during the time it has been available in the U.S. due to the lack of complaints about it. Following up on the incidents of accidental overdose by children in Colorado, FDA agents in California visited several Chinese herb importers and distributors and told them to discontinue sale of the product. In August 1993, FDA added JBH to a list of Chinese patent medicines that were banned for importation into the U.S.(22) More recently (April 1994), FDA wrote to the Council for Responsible Nutrition, the American Botanical Council, the Herb Research Foundation, the American Herbal Products Association, the National Nutritional Foods Association, and several other organizations, asking them to identify suppliers of JBH and requested that those suppliers desist from selling the product. AHPA has issued an alert recommending discontinuance of all sales of JBH, with the proviso that this action should remain in effect "until claims of toxicity have been investiga ted."(24) An informal poll of AHPA active members found no embers selling JBH.(25) As a result of FDA discussions with Chinese herb importers and distributors, JBH has become virtually unavailable. The problems of mislabeling of the product -- both with the incorrect plant source and with medical claims -- coupled with the packaging method that does not deter accidental ingestion by children and newly published information about liver hypersensitivity will likely result in continued FDA restriction on its distribution.

REFERENCES

(1.) Horowitz. R. S., et al., Jin Bu Huan Toxicity in Children, Center for Disease Control and Prevention. Morbidity and Mortality Weekly Report 1993; 42 (33): 633-635.

(2.) Woolf. G. M., et al., Jin Bu Huan Toxicity in Adults, Center for Disease Control and Prevention. Morbidity and Mortality Weekly Report 1993; 42 (48): 920-922.

(3.) Horowitz, R. S., Personal communication; Rocky Mountain Drug and Poison Control Center. Denver. June 7, 1993.

(4.) Hsu. H. Y., Chen, Y. P., and Hong, M., The Chemical Constituents of Oriental Herbal Drugs. 1992. Oriental Healing Arts Institute, Long Beach, California.

(5.) Leake. C. D., An Historical Account of Pharmacology to the Twentieth Century. 1975. Charles C. Thomas, Springfield, Illinois.

(6.) Tu, G. S. (editor-in-chief), Pharmacopoeia of the People's Republic of China (English Edition 1988). People's Medical Publishing House, Beijing, China.

(7.) Zhu, M., et al., Studies on Yuanhu. II. Quantitative and Qualitative Evaluation. Chinese Traditional and Herbal Drugs, 1986; 17(4): 150-152.

(8.) Chang, H. M. and But, P. P. H. Pharmacology and Applications of Chinese Materia Medica. 1987. World Scientific Publishing Co., Singapore.

(9.) Tian. C. G. and Wu, J., Alkaloids from Stephania disciflora. Chinese Traditional and Herbal Drugs, 1988; 19(9): 392-393, 399.

(10.) Fang, S. D., et al.. Alkaloids of Stephania officinarum. ACTA Botanica Sinica 1990; 32(5): 368-371.

(11.) Yen, K. Y., The Illustrated Chinese Materia Medica. 1992. SMC Publishing Inc. Taipei, Taiwan.

(12.) Zhu, D. Y., Recent advances on the active components in Chinese medicine. ACME, 1987: 1(2): 251-286.

(13.) Hou, Y. F. and Liu, G. Q., Effects of tetrandrine, berbamine, and some other tetrahydroisoquinolines on ((3)HI) Quinclidinyl benzilate binding to m-cholinergic receptors in rat brain. ACTA Pharmaceutica Sinica, 1988; 23(11): 801-805.

(14.) Liu, G. Q., et al., Effects of some isoquinoline alkaloids on monoamines in rat brain. ACTA Pharmaceutica Sinica, 1985; 20(8): 566-570.

(15.) Wang, Y. and Li, D. X., Antiarrhythmic action of l-tetrahydropalmatine. ACTA Pharmacologica Sinica, 1987; 8(4): 337-340.

(16.) Luo, H. W., Gao, J. W., and Zhang, J. R., Structure-Antibacterial activity relationship of tanshinones and related compounds. Journal of China Pharmaceutical University, 1988; 19(4): 258-262.

(17.) Xu, D. Y., Advances in research on drugs for treating silicosis. Industrial Health and Occupational Diseases, 1987; 13(3): 182-185.

(18.) Horowitz, R. S., Personal communication; Rocky Mountain Drug and Poison Control Center, Denver. April 25, 1994.

(19.) Chang, H. M. (editor-in-chief), Abstracts of Chinese Medicine, quarterly (1986-1994). Chinese Medicinal Materials Research Centre, Shatin, Hong Kong.

(20.) Wang, Y. M. and Hu, Y. J., Toxicity and side effects of some Chinese medicinal herbs, in Advances in Chinese Medicinal Materials Research, 1985. World Scientific Publishing Co., Singapore.

(21.) Associated Press wire service report, March 17, 1994.

(22.) FDA Import Alert #66-10. Chinese Herbal Medications. Revised Aug. 6, 1993.

(23.) Lumpkin, Murray M. Center for Drug Evaluation and Research (FDA), letter to trade and research associations, April 8, 1994.

(24.) News release by American Herbal Products Association, April 21, 1994, Austin, Texas.

(25.) Hinrichs, Jeffrey (AHPA). Personal communication to Mark Blumenthal (ABC) April 8, 1994.

Article copyright American Botanical Council.

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By Subhuti Dharmananda