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SYNEPHRINE:

Is Chih-shih (Zhishi) Toxic?

by Subhuti Dharmananda, Ph.D., Director, Institute for Traditional Medicine, Portland, Oregon

BACKGROUND

In the Spring 1999 issue of Herbalgram (the quarterly publication of the American Botanical Council), there appeared a letter by three medical doctors-Firenzuoli, Calapai, and Gori-from Italy (1). Their letter presented data from a laboratory animal experiment which they had conducted with an extract of Citrus aurantium (the source of the Chinese herbs zhishi and zhiqiao), concluding that: "This is a further example of medicinal plants potentially dangerous to humans...."

This report comes about in response to yet another herbal weight loss method, this time based on using the fruit from Citrus aurantium, a common orange tree. Weight loss products have been highly destructive to the reputation of herbs. Ma-huang, an herb traditionally used for treating surface fevers without sweating, was turned into a variety of weight loss products in the U.S., several of which have been blamed for causing severe adverse reactions and death. Germander, a Western herb that was used in weight loss products distributed in England and France, caused liver inflammation in several people, sometimes with only a few weeks of consuming the herb. Stephania (derived from Aristolochia fangji) and magnolia bark were included in a complex weight loss program in Belgium and, subsequently, were blamed for nearly 100 cases of rapid-onset renal failure (magnolia bark is no longer blamed, though it has not been formally absolved); duration of use was as little as a few months. Now, a common citrus used in Chinese medicine, chih-shih (zhishi) is being promoted as a means of reducing appetite, and, as per the letter from the Italian doctors, is being held out as yet another example of how medicinal plants are a danger to humans. Traditionally, chih-shih is used to treat indigestion, gastric ulcer, and loss of appetite.

The authors tested what they termed as a "a special extract" of Citrus aurantium, which apparently differs markedly from the crude herb, the crude herb decoction, or any other common preparation of the herb used in traditional or folk medicine. Their extract, which may be similar to those used in weight loss products, was standardized to contain 6 percent synephrine, a constituent commonly used in assaying the quality of medicinal citrus products. But, the extract has a relatively huge amount of an alkaloid that otherwise appears only in small amounts in the herb. In fact, their preparation represents about a 25-fold concentration compared to what is normally found in Chinese herbal citrus products, a level that can only be attained using extraction methods appropriate to concentrating the alkaloid fraction.

Synephrine is a drug product in Europe (oxedrine; Sympatol) that was originally produced as a synthetic derivative of amphetamine for use as a sympathomimetic (i.e., stimulates the sympathetic nervous system). Testing showed that when given by i.v. infusion to healthy volunteers at a rate of 4 mg/minute, synephrine increased systolic and mean arterial blood pressure, increased cardiac index, and decreased peripheral vascular resistance (5); it is a cardiac performance enhancer. These effects are not reported in the literature for the crude herb, its decoction, or other traditional preparations of citrus materials used in Chinese medicine (see Table 1), but have been recognized as effects of the injection (chih-shih aqueous extract or isolated synephrine), which has been used in China to treat shock (3), alone with ginseng saponins.

An extract of Citrus aurantium, marketed under the trademark Advantra Z, is reported by the manufacturer to be standardized to contain 4% adrenergic alkaloids (see below), with synephrine as the dominant one, accompanied by octopamine, hordenine, and tyramine. This extract, or similar ones, are used in making diet products such as Herbal Phen Fuel (named after phentermine, a diet drug that has recently been taken off the market due to adverse cardiac effects) and X-treme FX (meaning: extreme effects); both of these commercial products, which combine the synephrine-rich extract with other substances (additional herb extracts), are said to "burn fat" by stimulating metabolism.

Synephrine occurs in virtually all citrus products, and is consumed by humans in small amounts if citrus is included the diet. A wide variety of citrus materials containing synephrine are used in Chinese medicine and have generally been regarded as non-toxic; indeed, synephrine is used as a marker for chemical identification and relatively high synephrine content is a measure of herb quality. Positive effects of synephrine, mainly for anti-allergy applications, has been reported in the literature. The crude herb materials that contain synephrine, such as citrus (chenpi) and chih-shih (zhishi), have been reported to have anti-allergy effects (6, 7), which are also partly due to their flavonoid content (e.g., hesperidin, nobiletin). In Chinese literature, these herbs are described as non-toxic. A combination of zhiqiao, chenpi, and foshou is included in a Chinese remedy called Weisu Granules, used for treating stomach upset and abdominal distention (14).

Following is a description of synephrine and the citrus materials, their pharmacology, clinical applications, and toxicology. The results of the Italian study appear to represent an unusual toxic reaction at the dosage reportedly given (a relatively low dose). Nonetheless, synephrine and highly concentrated citrus products should not be used for the specific purpose of losing weight, as the dosage required to attain these effects could be sufficient to yield adverse reactions, especially after prolonged use.

SYNEPHRINE

Synephrine is an alkaloid similar in structure to ephedrine (see Figure 1), the main active component of ma-huang. There are only two substitutions to get from ephedrine to synephrine: one of the ring carbons is hydroxylated (OH replaces H), and a side chain methyl group (CH3; Me) is replaced by hydrogen. Like many other alkaloids, synephrine interacts with the nervous system, and like ephedrine, it has a stimulant action; both compounds affect alpha-adrenergic receptors and, to a lesser extent, beta-adrenergic receptors. Other alkaloids in Citrus aurantium have similar actions. Both ephedrine and synephrine can raise blood pressure and have other effects on the cardiac function which may be beneficial for selected patients when a proper dosage is administered, but may be harmful for others. Synephrine is found mainly in the medicinal products derived from citrus; it is also present in small amounts in the Chinese herb evodia. The alkaloids appear to be present in slightly higher quantities in the unripe fruit than in the ripe fruit (2). The amount of synephrine in blue citrus (qingpi), an immature citrus fruit, is 0.26% and in citrus (chenpi), a mature citrus fruit, the level is 0.22% (3). In an evaluation of four different dried citrus fruits used in Japanese herbal medicine, the content of synephrine did not show much difference (4). Some citrus materials that have been assayed in China have a higher synephrine content; in one study, synephrine levels in citrus fruits and peels ranged from as little 0.1% to a very high 2.0% (9), while most reports place the level at about 0.25%.

Ephedrine, as a drug, is usually administered in doses of about 15-30 mg per time, up to 45-90 mg/day, with higher amounts sometimes used to treat asthma (up to about 150 mg/day; ephedrine has been replaced by other drugs, so is rarely used now for this purpose). Due to concerns about adverse reactions to ephedrine, the U.S. FDA has proposed limiting its dosage in non-drug herbal products, with a maximum recommended level of just 8 mg each time, and only up to 24 mg/day. The crude herb source of ephedrine, ma-huang, is usually recommended in Chinese texts to be used in the amount of 1.5-9 grams per day, with up to 12 grams per day for short term use. The commonly marketed material typically contains about 0.7% ephedrine (there are also similar alkaloids present in the herb, bringing the total alkaloid content to about 1%). The daily ingestion of ephedrine in traditional teas (assuming full extraction of the ephedrine present in the herb; a more reasonable estimate would be about 80%) is 10-80 mg. Thus, the lower end of the Chinese traditional dosage level (1.5-3.0 grams/day) is what the FDA is suggesting be permitted, while the upper end of the dosage level corresponds to typical drug dosing (see: Ephedrine: Actions and dosage).

Synephrine is only rarely used as a drug in China, sometimes in high doses to treat shock, similar to the use of high doses of ephedrine for emergency cases of asthma. It is given by intravenous drip or push, with a dose of 20-60 mg. Using chih-shih aqueous extract in injection form, the dose used in Chinese medical practice corresponded to 20-60 grams of the herb, which could contain 60-180 mg of synephrine (3). These doses of the citrus alkaloids are similar, on a milligram basis, to those of ephedrine. Similarities in chemical structure, dosage, and effects between synephrine and ephedrine suggest that they may be compared directly. Synephrine was also suggested in Chinese and Western medical literature to be a potential treatment for bronchial asthma, as is ephedrine.

SYNEPHRINE DOSAGE IN CLINICAL USE
AND LABORATORY EXPERIMENTS: EFFICACY AND SAFETY

Citrus species, such as chenpi, zhishi, zhiqiao, and qingpi, are typically prescribed by Chinese physicians in the amount of 3-9 grams per day, which is a dosage range similar to that for ma-huang. With a synephrine level of about 0.25%, and assuming that all is extracted by decoction (as with ephedrine, an 80% yield would be more realistic), a daily dose of the herbs would provide about 7.5-22.5 mg of synephrine, somewhat lower than the amount of ephedrine used in Chinese herb teas.

Although it is difficult to make direct comparisons of these doses in humans with the doses given to laboratory animals, the milligram per kilogram value for this dosage range of synephrine (using a 70 kg human body weight) is 0.11-0.33 mg/kg. As an example of dosing that has been used previously for laboratory animal experiments, synephrine administered to guinea pigs with PAF (platelet activating factor)-induced stomach mucosal damage was provided at a dose of 5-20 mg/kg (7). There was increasing beneficial effect (repair of mucosal damage) over this dosage range, which is about 50 times the typical human intake. A number of flavonoids are reputed to help heal stomach ulceration by improving production of stomach mucus (see: The role of dietary and herbal flavonoids in gastro-intestinal health); this is also a possible effect of the citrus flavonoids.

In a study of synephrine in mice using immobility tests (tail suspension, forced swimming; testing sympathetic nervous system responses), doses of 1-10 mg/kg overcame the immobility response, and at 30 mg/kg, the mobility returned to normal (8). Spontaneous motor activity was not affected by synephrine doses of 0.3-10 mg/kg. In mice, a dose of 20 g/kg of foshou (Citrus medica) by IP injection increased spontaneous motor activity for 2 hours and delayed death due to strychnine, pentylenetetrazole, or caffeine (3); the dosage corresponds to about 50 mg of synephrine. In a study of qingpi (Citrus reticulata), an injection of extract corresponding to 1g/kg (about 2.5 mg/kg synephrine) was reported similar to a dose of 10 ug/kg of norepinephrine; the same level of response was reported for 0.5g/kg of zhishi. Synephrine isolated from the methanolic extract of qingpi was administered intravenously to cats at 1 mg/kg, which abolished histamine-induced bronchial constriction (11).

In these short-term tests, the range of synephrine dosage was more than 100 fold from 0.3 to 50 mg/kg, with effective doses in the range of 1-10 mg/kg (or higher) for reported beneficial effects. This is about 10-30 times the human dosage (on a mg/kg basis) obtained from medicinal citrus teas.

The Italian authors of the Herbalgram letter had administered a synephrine-rich extract at 2.5-20 mg/kg for 28 days, which, at 6% synephrine, would yield a daily dose of 0.15-1.2 mg/kg of synephrine (by oral route). This amount appears to correspond to the human dosage range quite closely, though the upper dosage used in their experiment is almost four times the upper level ingested by humans taking decoctions of the herb. According to the authors, this amount of synephrine (along with other substances in the extract, which were not specified) when given over a period of several weeks (up to four weeks) caused reduction in food and water intake, weight loss, electrocardiograph abnormalities, and, in up to 50% of the cases at the highest dosage, death. But, the extract also caused death in 10% of cases at the lowest dosage, which is within the human dosage range. These effects were noted within 28 days of daily administration.

According to the toxicology report of Pharmacology and Applications of Chinese Materia Medica (3), "zhishi has a low toxicity and a wide safety range." For zhishi the LD50 (single dose that causes death in 50% of animals) for this herb in mice had been reported earlier as being 71 grams/kg (3). At 0.25% synephrine in the herb, this corresponds to 177 mg/kg. How could such a seemingly safe material, requiring a very high dosage to be toxic, become so dangerous at 1/100th that dosage when used for just a few weeks? For comparison, the LD50 of ephedrine has been established at 50-350 mg/kg depending on the animal tested and route of administration. This is about the same level as that for synephrine. While dietary products made with high levels of ephedrine have proven dangerous, the herbal teas used in Chinese medicine have not; as described above, the dosage of ma-huang and citrus materials used in Chinese medical practice is about the same.

POSSIBLE EXPLANATIONS FOR TOXICITY OF THE SPECIAL EXTRACT

There can be a number of explanations for the seemingly extreme adverse reactions to the special Citrus aurantium extract used in the Italian study. One would be that the special extract used was prepared in such a way (not necessarily intentionally) so as to isolate a group of compounds having a much higher toxicity than the crude herb or individual components. In the normal process of making hot water extracts, it is common to concentrate substances by a factor of 4-6, but this special extract had a concentration of synephrine that was about 25 times higher than the crude material. It is likely that the extraction process also brought out certain other substances at unusually high levels. The procedure for obtaining a good yield of synephrine would almost certainly concentrate similar substances, such as N-methyltyramine, an alkaloid that is also present in the fruit that has properties similar to synephrine. N-methyltyramine serves as a precursor to production of synephrine (via removal of one hydroxyl group); it is one of the compounds blamed for the toxicity in cattle and horses from feeding on the weed Palicourea (12).

Also, there are tiny amounts of methylhesperidin and its chalcone derivatives in the citrus fruits; these are more toxic than the component hesperidin (see below) that is present in much higher amounts. Methylhesperidin can have, at high levels, negative effects similar to those reported for the special citrus extract used in the study, including inhibition of appetite and cardiac effects. Perhaps some of these compounds were also concentrated in the extract.

Second, the delivery of the very highly concentrated extracts to the animals might have caused a more intense anorectic response than one would obtain when taking more dilute forms of the herb extract or when taking the same daily dose in several divided doses, as is common practice in China and with herbal prescribing elsewhere. In that case, nutritional deficiencies secondary to anorectic response might have contributed to the observed results of cardiac instability. The special extract, with 6% synephrine, is more highly concentrated than the Advantra Z used in diet products that has a total alkaloid content of 4%, suggesting that differences in composition and effects may result from the different extraction methods utilized.

OTHER INGREDIENTS IN THE CITRUS PRODUCTS

While synephrine makes up only about 0.25% of the Chinese medicinal citrus products, there are much larger amounts of other components. For example, in chenpi (Citrus reticulata peel), there are essential oils (1.5-2.0%; with limonene as the dominant constituent; in zhishi, limonone and linalool are main components) and flavonoids (with hesperidin, the main flavonoid, at 8.4% and others bringing the total to about 10%). While essential oils are unlikely to accompany alkaloids in an extraction process, flavonoids sometimes can, depending on their structure of the compounds involved and the methods used in the extraction process.

Hesperidin, like synephrine, has been made into a drug in China. A tablet of hesperidin, alone or with other substances added, is given in China for treating coronary disease and various bleeding disorders (such as retinal hemorrhage, menorrhagia, and hemophilia). Hesperidin derivatives were reported to have strong cardiovascular effects (3). Methylhesperidin is the main component of Chinese drugs called Maitong (meaning: to open the vessels) and Maishujing (meaning: vessel dilator), the latter with 10 mg/tablet of methylhesperidin, used to treat hypertension. While these compounds are safe to use at the dosage indicated, considerably higher amounts could be toxic. By intravenous injection, methylhesperidin was 8 times as toxic as hesperidin, probably due to the presence of chalcone derivatives of methylhesperidin in the isolate. Neohesperidin dihydrochalcone administered to animals at high levels results in slight growth depression accompanied by reduction in food intake (13). In the preparation used in the Italian study, 6% was synephrine, but what was the other 94%?

CONCLUSIONS

The toxicity report, submitted as a letter without many details, probably should have had a differently worded conclusion, one that would not suggest that the findings served as an example of the potential dangers of herbs. The danger that was revealed had to do with a specialized extract that differed markedly from usual herbal materials. It is, nonetheless, useful to warn people about using medicines, herbal or synthetic, to try to substitute for good habits in diet and exercise (see: The use of herbs for obesity: An ITM position paper). In this case, there is little doubt that if enough synephrine-and other substances isolated along with it-is provided in a product, it can cause harm, as is apparently the case with the high doses of chemically similar ephedrine in some weight-loss products.

On the other hand, using the citrus substances in traditional Chinese herbal medicine, or their similar use in European herbal medicine (Citrus aurantium is mentioned in the German Commission E reports), should not be discouraged by these results. Specialized highly-concentrated extracts should not be portrayed simply as herbs; they are unique substances derived from herbs. If an extract similar to the one described in the letter is being used as a weight loss product, then that product should be identified as being potentially harmful.

TABLE 1: Traditional Uses of Citrus Products. In Thousand Formulas and Thousand Herbs (10), the following descriptions are given:

REFERENCES

1. Firenzuoli F, Calapai G, and Gori L, Physicians discuss orange extract (letter), Herbalgram 1999; 46: 76-77.
2. Hong-Yen Hsu, Chen Yuh-Pan and Hong Ming, The Chemical Constituents of Oriental Herbs, 1982, Oriental Healing Arts Institute, Long Beach, CA.
3. Chang HM and But PPH (eds.), Pharmacology and Applications of Chinese Materia Medica, (2 vols.), 1986 World Scientific, Singapore.
4. Hosoda K, et al., Studies on the preparation and evaluation of kijitsu, the immature citrus fruits. IV. Biological activities of immature fruits of different citrus species, Yakugaku Zasshi 1991; 111(3): 188-192.
5. Hofstetter R, Kreuder J, von Bernuth G, The effect of oxedrine on the left ventricle and peripheral vascular resistance, Arzneimittelforschung 1985; 35(12): 1844-1846 [German].
6. Usio Sankawa and Chun Yuito, Anti-allergic substances from Chinese Medicinal Plants, in Advances in Chinese Medicinal Materials Research, 171-180.
7. Miyamoto K, Abdu P, and Furukawa T, Pharmacological effects of chenpi and synephrine, International Journal of Oriental Medicine 1990; 15(2): 57-69.
8. Song DK, et al., Antidepressant-like effects of p-synephrine in mouse models of immobility tests, Neuroscience Letters 1996; 214 (2-3): 107-110.
9. Tang W and Eisenbrand G, Chinese Drugs of Plant Origin, 1992 Springer-Verlag, Berlin.
10. Huang Bingshan and Wang Yuxia, Thousand Formulas and Thousand Herbs of Traditional Chinese Medicine, vol. 1, 1993 Heilongjiang Education Press, Harbin.
11. Zhu Youping, Chinese Materia Medica: Chemistry, Pharmacology, and Applications, 1998 Harwood Academic Publishers, Amsterdam.
12. Kemmerling W, Toxicity of Palicourea marcgravii, Zeitung Naturforsch 1996; 51(1-2): 59-64 [German].
13. Lina BA, Dreef-van der Meulen HC, and Leegwater DC, Subchronic oral toxicity of neohesperidin dihydrochalcone in rats, Food Chemical Toxicology 1990; 28(7): 507-513.
14. Sa Liming, Determination of synephrine in Weisu Granules by TLC-scanner, Chinese Traditional Patent Medicine 1993; 15(10): 13-14.