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Remedies used in nonorthodox medicine
M.N.G. Dukes
50
Remedies used in nonorthodox medicine
HERBAL REMEDIES
Natural mutagens
An encouraging sign of the growing realization that 'natural' remedies can exert serious side effects was the publication in the Medical Letter of April 6th 1979, of a review of toxic reactions to plant products sold in health food stores in the United States (24R). The British Medical Journal has also devoted editorial attention to what it terms these 'popular poisons' (25r). The realization that these problems can exist is, however, only the first step; factual knowledge in this field is still extraordinarily limited, and there is still very little attempt being made to study systematically the adverse effects and interactions of the many herbal remedies on sale.
Schimmer (26) has studied the mutagenic potential of a number of plants used in herbal medicine, and has reviewed earlier work on this topic. Natural mutagens are found to include a range of furocumarins and furochrornones (e.g. psoralens, xanthotoxins, bergapten) as well as the substances listed in Table 1. The natural mutagens belong to various chemical groups, including the alkaloids, terpenes and phenylpropane derivatives; although to date most such compounds have been inadequately studied in this respect there would seem to be every reason to limit the use of those substances the mutagenic potential of which has already been identi-
Table 1. Some natural mutagens Mutagenicity demonstrated
9. ~
Pyrrolizidine Cryptopleurin Vincristine Scopolamine Colchicine Berberin AUylisothiocyanate 1, (Sinigrin) J MAM (Cycasin) Citronellal Hymenovin Safrol, lsosafrol Quercetin Aloeemodin
~
+
+
+
+
•
+
+
+
+
Distribution in higher plants
+
+
+
+ +
+
+
+
+
+
+
+ +
+ +
+
+ +
Senecio, Crotalaria, Echium, Cynoglossum Cryptocarya Vinca Solanaceae Colchicum Berberis, Hydrastis Brassicaceae Cycas, Encephalartos Cymbopogon, Melissa Hymenoxys Lauraceae, Rut aceae,Zingiberaceae Widespread (e.g. Tilia, Sambucus) Aloes, Rheum
M.N. G. Dukes
342 fled, since few of them would appear to be of essential importance in medicine.
Datura stramonium The tree daturas contain a series of alkaloids of which hyoscine is the most prominent. Datura has featured for many centuries in both folk medicine and mystical rites, primarily because of its anticholinergic properties and its consequent hallucinogenic potential. From Denmark, Fensbo and Harbeck (22 C) have described a case of poisoning due to a herbal tea based on Datura stramonium, probably intended as an asthma remedy; earlier cases of severe stramonium poisoning when the seeds were taken for their hallucinogenic effects were known from the USA (22r). More recently, a number of cases of datura poisoning have been reported in Britain, involving drug addicts who had eaten or brewed the leaves of certain datura trees which grow in West Cornwall; the symptoms were typically those of atropine-type poisoning (23Cr). The outdated use of Datura stramonium in asthma cigarettes was discussed in SEDA-3 (p. 388).
Wintergreen Methyl salicylate was first isolated from the leaves of the wintergreen, and products based on synthetic methyl salicylate are commonly still known by the traditional name. Used externally as a rubifacient and counter-irritant, methyl salicylate apparently does little harm, but Speer has recently recorded a case of an allergic reaction involving severe urticaria and angioedema (27c); one previous case of contact dermatitis attributed to this substance seems to have been recorded (27r); if (improperly) taken internally, oil of wintergreen or methyl salicylate can of course cause salicylate poisoning (SED 8, 158). Pennyroyal The pennyroyal or squawmint (Mentha pulegium) is the source of an oil related to turpentine which is sometimes used as an insect repellant or fragrance. Pennyroyal can also be used to prepare a herbal tea and has a long-standing reputation as a medicine; it is believed to act as a sedative and diaphoretic and to induce menses, and for the latter reason has been used as an abortifacient. It is
probably capable of irritating the uterus and bladder, triggering reflex contractions. In the US three cases of poisoning have been reported. Two women who took 7.5 ml of pennyroyal oil to induce abortion experienced nausea, dizziness and other symptoms but recovered after treatment. A third woman who for u n k n o w n reasons took 30 ml of the oil was admitted to hospital in a comatose state and died a week later of hepatic and renal failure (29cr). Gossypol Gossypol is a phenol extracted in China from the roots, stems and seeds of the cotton plant. According to Chinese data (12 C) it is a highly effective contraceptive for the male, producing a drastic reduction in the sperm count by mechanisms which are not yet determined. There appears to be no effect on serum hormone levels, and the contraceptive effect is reported to be reversible. Some men taking gossypol experience transient nausea and loss of appetite, and serum levels of potassium may fall; perspiration may be impeded. De Peyster and Wang in the US (13) have studied gossypol in the Ames test and found no evidence of mutagenic activity. However, no systematic testing of the product for safety appears to have been carried out and, whilst cottonseed meal has been widely used as a source of dietary protein, the fact that gossypol is known to be retained for long periods in body fat justifies a somewhat cautious approach to this product, however promising its contraceptive potential may be (13r).
Synthetic contaminants in herbal remedies The case of Chuifong Toukuwan has featured in these volumes twice before as an example of a so-called traditional Chinese herbal remedy which in fact was fortified with corticosteroids and non-steroidal antiinflammatory agents (SEDA-1, 376; SEDA3, 388). If one takes account of a recent analysis published in the Netherlands (7) and two clinical papers from Britain (6 c, 8r), one can conclude that this product has at various times been found to contain phenylbutazone, phenacetin, aminopyrine, mercuric sulphide, indomethacin, dexamethasone, hydrochlorothiazide and diazepam. Chrysanthemum crystals have been found
Remedies used in non.orthodox medicine o n sale in G e r m a n y as a Chinese r e m e d y claimed t o have sedative, a n t i - i n f l a m m a t o r y a n d h e p a t o p r o t e c t i v e p r o p e r t i e s . O n analysis a s a m p l e was f o u n d t o c o n t a i n d e x a m e t h a sone (5r).
GINSENG Siegel ( 9 C R ) , w h o e s t i m a t e s t h a t t h e r e are c u r r e n t l y 5 t o 6 million ginseng t a k e r s in t h e U n i t e d States, h a s s t u d i e d 133 A m e r i c a n ginseng users. All h a d b e e n t a k i n g ginseng regularly f o r at least o n e m o n t h b e f o r e rec r u i t m e n t . Most h a d b e e n using P. ginseng or quinquefolius ( A m e r i c a n ginseng) b u t o t h e r material, i n c l u d i n g Siberian ginseng a n d desert ginseng, was also e n c o u n t e r e d . In the great m a j o r i t y o f cases t h e p r o d u c t h a d b e e n t a k e n orally, b u t a f e w i n d i v i d u a l s h a d used ginseng cigarettes, c o s m e t i c creams, snuffs or injections. They were q u e s t i o n e d over t h e n e x t t w o years as t o t h e s e n s a t i o n s w h i c h t h e y e x p e r i e n c e d , a n d t h e y were also e x a m ined b o t h p s y c h o l o g i c a l l y a n d physically every six m o n t h s . T h e r e p o r t e d e f f e c t s r e s u l t i n g f r o m longt e r m use are listed in T a b l e 2. Siegel speaks of a 'Ginseng Abuse Syndrome' (GAS) and m a y be q u o t e d literally as regards his i m p r e s sions and c o n c l u s i o n s :
343 '... it is clear that most subjects experienced symptoms of CNS excitation and arousal. Fourteen subjects (10%) experienced GAS defined as hypertension together with nervousness, sleeplessness, skin eruptions, and morning diarrhoea. Oed_ema was seen in five of these subjects. All 14 GAS subjects employed P. ginseng roots in the oral route, and all also used caffeinated beverages. Six other subjects experienced GAS, but these persons used either Siberian ginseng or injection routes, which were considered atypical, and they axe not discussed here. Nevertheless, fully 22 subjects experienced hypertension, which was verified by monthly examinations. Subjects here used no other stimulants except for caffeine. The average daily dosage for the GAS subjects was 3 g of root material, but the range was 0 to 15 g. Most users attempted to titrate the dosage to minimize undesired side effects, e.g., nervousness and tremor. One user reported that abrupt withdrawal precipitated hypotension, weakness, and tremor. The GAS reappeared periodically throughout the first 12 months of ginseng use but was rarely seen or reported at the 18- and 24-month follow-up examinations. Concomitantly, there was a reduction in daily dosage to an average of 1.7 g at the 18-month follow-up. Roughly 50% of the GAS subjects discontinued use by the 24-month examination compared with 21% for the clinical population as a whole. Occasional diarrhoea and nervousness were still reported by eight GAS subjects at the end of two years. The most common psychological finding among these subjects was an elevation of mood. Ten GAS
Table 2. Effects reported by long-term ginseng users during a two-year period Reported effect Stimulation Feeling of well-being Increased motor and cognitive efficiency Morning diarrhoea Skin eruptions Demulcent effects on throat Sleeplessness Nervousness Hypertension Euphoria Oedema Enhanced sexual performance Decreased appetite Depression Hypotension Amenorrhoea
Number of subjects (N=133) 133 93 89 47 33* 26 26 25 221" 18 14 9 7 6 5 4
Use (wk) before effect Immediate 3 2 3 3 Immediate 3 1 13 < 1 4 2 1 24 3 16
Preoarations used* C, E, R, T C, E, R, T C, E, R, T C, E, R, T C, R, T T, C, C, C, E, C,
Ci E, R E, R E, R R R
C, R E, E, C,
E, R R R R
* Abbreviation C indicates capsules; E, extracts; R, roots; T, teas; and Ci, cigarettes. 1 Confirmed by examination.
M. N. G. Dukes
344 subjects became euphoric, restless, agitated, and insomniac. High doses (15 g) resulted in feelings of depersonalization and confusion for four subjects. One subject experienced anaphyiaxis following injection of 2 ml of an extract, and this was followed by confusion and hallucinations. No abnormal personality function was detected with psychometric instruments, but depression was reported following doses higher than 15 g. These effects are similar to organic brain syndromes associated with corticosteroids and cortieotropin and may be related to ginseng's interference with cortisone and corticotropin levels.'
lactic reactions to this foreign material on the other would appear predominant, though it remains difficult to obtain estimates of the actual frequency of complications. There have been reports of aggravation of existing metabolic disorders, activation of latent infection and development of lymphadenopathy. One serological study has shown the formation of antibodies in approximately 50% of cases treated with cellular therapy.
AMYGDALIN (LAETRILE) Siegel's study is of value in view of the singular lack of well-documented clinical observations from other quarters, but one must bear in mind that it is evidence of a type which one would not generally regard as valid when dealing with a normal prescription drug; the product, dose and route of administration varied, and there was no control group or control period; one does not get a picture of the normal state of health of the individuals concerned, many of whom must have taken the product to counter the very phenomena (e.g. nervousness, depression) which are here recorded as effects. The high incidence of central nervous stimulation is, however, striking, and Siegel's hypothesis that the effects are akin to those of corticosteroid poisoning is a reasonable starting point for further investigation. The incidence of amenorrhoea in a few cases recalls earlier reports of hormonal effects (SEDA-3, 397). A final question with respect to Siegel's study concerns the source of the ginseng used; like other herbal remedies ginseng is likely to vary in composition according to the area and season in which it is harvested, and the mode of extraction and processing employed; some ginseng products are entirely devoid of active principles (10), whilst others have been found to be 'fortified' with synthetic products. The warning given earlier in this series and repeated by Siegel that ginseng may well interact with prescription drugs, must be emphasized.
CELLULAR THERAPY (SEDA-1, 376- 7,) Baenkler (4 R) has reviewed the risks attached to cellular therapy, the various schools of which were discussed in an earlier volume in this series. The risk of viral infection on the one hand and allergic or anaphy-
The evolving drama of amygdalin has been recorded in previous volumes in this series (SEDA-2,384; SEDA-3,390); the controversy - particularly in the United States as regards the right of patients to have access to this treatment has led to an intensification of research which is bound to throw further light upon the topic. The National Cancer Institute was due to commence a clinical trial of the product in the course of 1979 (14r). -
Animal studies The animal toxicity studies in dogs reported in SEDA-3 (p. 391) have now been complemented by an investigation by Khandekar (15) in rats. This was initially intended to determine the efficacy of amygdalin against Walker 256 carcinosarcomata. Doses of 250, 500 and 750 mg/kg were given intraperitoneally daily for five days, whilst a comparable series of animals were treated with cyclophosphamide or saline only, and a further group received both amygdalin and cyclophosphamide. Amygdalin proved ineffective against the development of the turnout, but there was a strikingly high dosedependent mortality in the amygdalin-treated animals (31%, 44% and 57% respectively), and the mode of death and elevated serum cyanide levels in the dying animals strongly suggested cyanide poisoning as the cause of death. The importance of the study from the clinical point of view lies in the fact that the product was not given orally; it has been argued (20 r) that whilst oral amygdalin may be broken down enzymatically with the release of cyanide, this may not occur when the drug is given directly into the system. This argument would not appear to hold good where intraperitoneal administration is concerned, though it may be valid for intramuscular use (see below).
345
Remedies used in non-orthodox medicine
Acute human toxicity Also relevant to the question of enzymatic breakdown is a report by Ortega and Creek on a child with a neuroblastoma which had been treated with cyclophosphamide; the patient, a boy of 3, was lost to follow-up and was subsequently found to be undergoing treatment with Laetrile given both orally and intravenously. Because of difficulties with intravenous injection, the mother began to administer the parenteral product as an enema; following a second daily enema containing 3.5 g Laetrile, the patient developed vomiting and diarrhoea, and after the third enema severe cyanide poisoning developed; the diagnosis was confirmed when cyanide blood concentrations a little below the lethal level were detected. These authors point out that after rectal administration one might expect hydrolysis of amygdalin to occur under the influence of beta-glucosidases, as after oral administration (16Or). A further case of poisoning due to accidental ingestion of Laetrile by a small child has been reported by Braico e t al.; death from cyanide intoxication resulted (17 C). A report by Rubino and Davidoff (18 c) serves as a reminder that, alongside Laetrile and various other brands of amygdalin, plain apricot seeds have acquired something of a reputation as a tonic or remedy, and that these too can cause acute cyanide poisoning. Finally, a report from Morse e t aL (21 c) illustrates the fact that cyanide poisoning can and does occur in patients undergoing treatment in so-called 'Laetrile clinics' such as exist in Mexico. Interaction with ascorbic acid In SEDA-3 the point was made that the dietary rituals sometimes adopted by amygdalin users may themselves prove detrimental. In view of the fact that megadoses of vitamin C are a component of one so-called 'antineoplastic diet', Backer and Herbert (19) performed in vitro studies to determine whether ascorbic acid would increase the hydrolysis of amygdalin and thus increase the risk of cyanide poisoning. Their findings suggest that though such an effect does occur it is not particularly marked, only a small fraction of the total available cyanide being released. Human pharmaeokinetics Ames e t al. (20 Cr) determined amygdalin concentrations in the urine and plasma of two patients taking Laetrile b n their own initiative. Fol-
lowing intramuscular administration to a male patient of a dose which according to the labelling contained 6 g of amygdalin, 4.25 g was recovered in the urine. The amygdalin was found to be excreted primarily as the unchanged molecule, and in view of the fact that in the past the amygdalin content of such products has been found to be considerably below that stated on the label, Ames e t al. consider that urinary recoveries following parenteral (i.m.) administration may approach 100%. In a woman who had taken 500 mg Laetrile orally, 55% of the label dose was recovered in the urine. The most important finding in this study is certainly the fact that amygdalin is after intramuscular administration excreted primarily as the unchanged molecule. The very limited scope of the study, however, and uncertainty as to the true amygdalin content of the products administered leaves some doubt as to the extent of the differences in the fate of intramuscularly and orally administered amygdalin.
Nomenclature It will be noted that in reviewing the literature one encounters some studies in which the products dealt with are designated 'amygdalin', in others 'laetrile' or 'Laetrile'; the terms are not necessarily synonymous and claims are sometimes advanced as to the superiority of products branded 'Laetrile'. In the absence of comprehensive analytical data and the evidence repeatedly advanced as to product variation it is impossible to draw firm conclusions as to the general validity of much of the work done; certainly one must beware of comparing and collating data from various studies as if they all related to the same product.
APHRODISIACS ( S E D A - 3 , 3 9 0 ) Amyl nitrite Though amyl nitrite has receded into the background as a coronary vasodilator it has in recent years acquired some popularity as an 'orgasm expander'; the products illegally traded for this purpose may also contain other volatile nitrites (1R). When used in cardiology the drug is notorious for its unpleasant adverse reactions including headaches, orthostatic symptoms and reflex tachycardia, and it does not appear to confer any pleasurable sensation on the patient. It
346 would seem that persons misusing the volatile nitrites are sometimes inhaling them throughout the day; whether this will be accompanied by harmful long-term sequelae is not known. Lead and other metals Brearley and Forsythe (2 or) have described a case of lead poisoning in a Bangladeshi immigrant to Britain; the manifestations included irritabihty, intestinal ileus and sideroblastic anaemia. Four aphrodisiac powders in his possession, brought from Bangladesh, were analyzed; one was a powder containing 46% of lead w/w; other powders variously contained smaller quantities of lead, silver or stannous sulphide. Traditionally many medicines in the Indian subcontinent which have a reputation as aphrodisiacs are based on silver or gold, but this case suggests that substitution with base metals, including lead, is practised.
SURMA Surma is a fine powder which is applied to the conjunctival surface of the eyelids in Asian countries and by Asian immigrants in Europe. Its name is derived from the Urdu word for antimony, but oriental pharma-
M. N. G. Dukes copoeias contain prescriptions for Surma which include salts of antimony, zinc and lead; lead sulphide seems to be currently employed, often in combination with camphor or menthol to induce lacrimation. Although used primarily as a cosmetic, it is also considered to be a remedy for eyestrain and soreness. As of 1 9 7 9 S u r m a has been prohibited in the United Kingdom, following reports of lead encephalopathy and increased blood lead levels among Asian children in Britain (28R).
MINERAL WATER (SEDA-3, 390) According to press reports, the US Health authorities have altered the labelling of two popular brands of mineral water to include a warning that they may be detrimental to health (3r). The step has been taken because of the arsenic content; that of Apollinaris water is 5 parts per milhon, that of Vichy Celestins 24 per 100 milhon. The Netherlands Health Authorities permit a maximum content of 5 parts per 100 million. In view of the exceptionally small quantities present in these brands of mineral water and the known ability of the body to adapt itself to chronic intake of arsenic it would seem most unlikely that mineral water can in this respect prove harmful.
REFERENCES 1. Cohen, S. (1979): The volatile nitrites. J. Amer. med. Ass., 241, 2077. 2. Brearley, R.L. and Forsythe, A. M. (1979): Lead poisoning from aphrodisiacs: potential hazard in immigrants. Brit. reed. J., 4, 1748. 3. Anonymous (1979): Attic in Amerika tegen mineraalwater. NRC Handelsblad, 28 september. 4. Baenkler, H. W. (1978): Gefahren der Zellulartherapie. Z. allg. Med., 54, 1228. 5. Anonymous (1978): Chrysanthemum Crystals: Gef'abrliche 'Wunderdroge'. Dtsch. Apoth. Ztg, 118, 1809. 6. Forster, P. J. G., Calverley, M., Hubball, S. and McConkey, B. (1979): Chuei-Fong-Tou-Geu-Wan in rheumatoid arthritis. Brit. med. J., 3, 308. 7. Uitdehaag, C. M.J., Hekster, Y.A., van de Putte, L. B. A., Waas, R. J. M., Bertels, B., Huysse, H., Slijkhuis, C. and Smits, H. M. (1979): Chinese pillen, Cushing-syndroom en geneesmiddelenonderzoek. Ned. T. Geneesk., 123, 1009. 8. Martin, V. (1979): 'Herbal' medicines and rheumatoid arthritis. Brit. reed. J., 3, 504. 9. Siegel,R. K. (1979): Ginseng abuse syndrome. J. Amer. med. Ass., 241, 1614.
10. Liberti, L. E. and Marderosian, A. D. (1978): Evaluation of commercial ginseng products. J. Pharm. ScL, 67, 1487. 11. Preissig, R. (1979): Personal communication. 12. National Coordinating Group for Male Contraceptives (1978): A new male contraceptive gossypol. Chin. Med. J. (Peking), 8, 455. 13. de Peyster, A. and Wang, Y. Y. (1979): Gossypol - proposed contraceptive for men passes the Ames test. New Engl. J. Med., 301,275. 14. Cleton, F. J. (1979): Laetrlle en kanker. Ti]dschr. Kanker, 3, 1. 15. Khandekar, J. D. (1979): Studies of amygdalin (Laetrile) toxicity in rodents. J. Amer. med. Ass., 242, 169. 16. Ortega, J. A. and Creek, J. E. (1979): Acute cyanide poisoning following administration of Laetrile enemas. J. Paediat., 93, 1059. 17. Braieo,K.T., Humbert, J. R., Terplan, K. L. and Lehotay, J. M. (1979): Laetrile intoxication. New Engl. J. Meal., 300, 238. 18. Rubino, M. J. and Davidoff, F. (1979): Cyanide poisoning from apricot seeds. J. Amer. reed. Ask, 241,359.
Remedies used in non-orthodox medicine 19. Backer, R.C. and Herbert, V. (1979): Cyanide production from laetrile in the presence of megadoses of ascorbic acid. J. Amer. reed. Ass., 241, 1891. 20. Ames, M. M., Kovach, J. S. and Flora, K. P. (1978): Initial pharmacologic studies of amygdalin (Laetrile) in man. Res. Commun. Chem. Path.
Pharmacol., 22, 1. 21. Morse, D.L., Boros, L. and Findley, P. A. (1979): More on cyanide poisoning with Laetrile.
New Engl. J. Med., 301,892. 22. Fensbo, C. and Harbeck, C. (1979): Datura stramonium anvendt som urtete. Ugeskr. Laeg., 141, 1150. 23. Belton, P. A. and Gibbons, D. O. (1979): Da-
347 tura intoxication in West Cornwall. Brit. med. J.,
1,585. 24. Anonymous (1979): Toxic reactions to plant products sold in health food stores. Med. Letter, 21, 29. 25. Editorial (1979): Liver injury, drugs, and popular poisons. Brit. med. J., 4, 574. 26. Schimmer, O. (1978): Natiirliche Mutagene in h6heren Pflanzen. Dtsch. Apoth. Ztg, 48, 1818. 27. Speer, F. (1979): Allergy to methyl salicylate. Ann. Allergy, 36. 28. Editorial (1979): Surma and lead poisoning. Lancet, L 28. 29. Gunby, P. (1979): Plant known for centuries still causes problems today. J. Amer. med. Ass., 241, 2246.
50
Remedies used in nonorthodox medicine
HERBAL REMEDIES
Natural mutagens
An encouraging sign of the growing realization that 'natural' remedies can exert serious side effects was the publication in the Medical Letter of April 6th 1979, of a review of toxic reactions to plant products sold in health food stores in the United States (24R). The British Medical Journal has also devoted editorial attention to what it terms these 'popular poisons' (25r). The realization that these problems can exist is, however, only the first step; factual knowledge in this field is still extraordinarily limited, and there is still very little attempt being made to study systematically the adverse effects and interactions of the many herbal remedies on sale.
Schimmer (26) has studied the mutagenic potential of a number of plants used in herbal medicine, and has reviewed earlier work on this topic. Natural mutagens are found to include a range of furocumarins and furochrornones (e.g. psoralens, xanthotoxins, bergapten) as well as the substances listed in Table 1. The natural mutagens belong to various chemical groups, including the alkaloids, terpenes and phenylpropane derivatives; although to date most such compounds have been inadequately studied in this respect there would seem to be every reason to limit the use of those substances the mutagenic potential of which has already been identi-
Table 1. Some natural mutagens Mutagenicity demonstrated
9. ~
Pyrrolizidine Cryptopleurin Vincristine Scopolamine Colchicine Berberin AUylisothiocyanate 1, (Sinigrin) J MAM (Cycasin) Citronellal Hymenovin Safrol, lsosafrol Quercetin Aloeemodin
~
+
+
+
+
•
+
+
+
+
Distribution in higher plants
+
+
+
+ +
+
+
+
+
+
+
+ +
+ +
+
+ +
Senecio, Crotalaria, Echium, Cynoglossum Cryptocarya Vinca Solanaceae Colchicum Berberis, Hydrastis Brassicaceae Cycas, Encephalartos Cymbopogon, Melissa Hymenoxys Lauraceae, Rut aceae,Zingiberaceae Widespread (e.g. Tilia, Sambucus) Aloes, Rheum
M.N. G. Dukes
342 fled, since few of them would appear to be of essential importance in medicine.
Datura stramonium The tree daturas contain a series of alkaloids of which hyoscine is the most prominent. Datura has featured for many centuries in both folk medicine and mystical rites, primarily because of its anticholinergic properties and its consequent hallucinogenic potential. From Denmark, Fensbo and Harbeck (22 C) have described a case of poisoning due to a herbal tea based on Datura stramonium, probably intended as an asthma remedy; earlier cases of severe stramonium poisoning when the seeds were taken for their hallucinogenic effects were known from the USA (22r). More recently, a number of cases of datura poisoning have been reported in Britain, involving drug addicts who had eaten or brewed the leaves of certain datura trees which grow in West Cornwall; the symptoms were typically those of atropine-type poisoning (23Cr). The outdated use of Datura stramonium in asthma cigarettes was discussed in SEDA-3 (p. 388).
Wintergreen Methyl salicylate was first isolated from the leaves of the wintergreen, and products based on synthetic methyl salicylate are commonly still known by the traditional name. Used externally as a rubifacient and counter-irritant, methyl salicylate apparently does little harm, but Speer has recently recorded a case of an allergic reaction involving severe urticaria and angioedema (27c); one previous case of contact dermatitis attributed to this substance seems to have been recorded (27r); if (improperly) taken internally, oil of wintergreen or methyl salicylate can of course cause salicylate poisoning (SED 8, 158). Pennyroyal The pennyroyal or squawmint (Mentha pulegium) is the source of an oil related to turpentine which is sometimes used as an insect repellant or fragrance. Pennyroyal can also be used to prepare a herbal tea and has a long-standing reputation as a medicine; it is believed to act as a sedative and diaphoretic and to induce menses, and for the latter reason has been used as an abortifacient. It is
probably capable of irritating the uterus and bladder, triggering reflex contractions. In the US three cases of poisoning have been reported. Two women who took 7.5 ml of pennyroyal oil to induce abortion experienced nausea, dizziness and other symptoms but recovered after treatment. A third woman who for u n k n o w n reasons took 30 ml of the oil was admitted to hospital in a comatose state and died a week later of hepatic and renal failure (29cr). Gossypol Gossypol is a phenol extracted in China from the roots, stems and seeds of the cotton plant. According to Chinese data (12 C) it is a highly effective contraceptive for the male, producing a drastic reduction in the sperm count by mechanisms which are not yet determined. There appears to be no effect on serum hormone levels, and the contraceptive effect is reported to be reversible. Some men taking gossypol experience transient nausea and loss of appetite, and serum levels of potassium may fall; perspiration may be impeded. De Peyster and Wang in the US (13) have studied gossypol in the Ames test and found no evidence of mutagenic activity. However, no systematic testing of the product for safety appears to have been carried out and, whilst cottonseed meal has been widely used as a source of dietary protein, the fact that gossypol is known to be retained for long periods in body fat justifies a somewhat cautious approach to this product, however promising its contraceptive potential may be (13r).
Synthetic contaminants in herbal remedies The case of Chuifong Toukuwan has featured in these volumes twice before as an example of a so-called traditional Chinese herbal remedy which in fact was fortified with corticosteroids and non-steroidal antiinflammatory agents (SEDA-1, 376; SEDA3, 388). If one takes account of a recent analysis published in the Netherlands (7) and two clinical papers from Britain (6 c, 8r), one can conclude that this product has at various times been found to contain phenylbutazone, phenacetin, aminopyrine, mercuric sulphide, indomethacin, dexamethasone, hydrochlorothiazide and diazepam. Chrysanthemum crystals have been found
Remedies used in non.orthodox medicine o n sale in G e r m a n y as a Chinese r e m e d y claimed t o have sedative, a n t i - i n f l a m m a t o r y a n d h e p a t o p r o t e c t i v e p r o p e r t i e s . O n analysis a s a m p l e was f o u n d t o c o n t a i n d e x a m e t h a sone (5r).
GINSENG Siegel ( 9 C R ) , w h o e s t i m a t e s t h a t t h e r e are c u r r e n t l y 5 t o 6 million ginseng t a k e r s in t h e U n i t e d States, h a s s t u d i e d 133 A m e r i c a n ginseng users. All h a d b e e n t a k i n g ginseng regularly f o r at least o n e m o n t h b e f o r e rec r u i t m e n t . Most h a d b e e n using P. ginseng or quinquefolius ( A m e r i c a n ginseng) b u t o t h e r material, i n c l u d i n g Siberian ginseng a n d desert ginseng, was also e n c o u n t e r e d . In the great m a j o r i t y o f cases t h e p r o d u c t h a d b e e n t a k e n orally, b u t a f e w i n d i v i d u a l s h a d used ginseng cigarettes, c o s m e t i c creams, snuffs or injections. They were q u e s t i o n e d over t h e n e x t t w o years as t o t h e s e n s a t i o n s w h i c h t h e y e x p e r i e n c e d , a n d t h e y were also e x a m ined b o t h p s y c h o l o g i c a l l y a n d physically every six m o n t h s . T h e r e p o r t e d e f f e c t s r e s u l t i n g f r o m longt e r m use are listed in T a b l e 2. Siegel speaks of a 'Ginseng Abuse Syndrome' (GAS) and m a y be q u o t e d literally as regards his i m p r e s sions and c o n c l u s i o n s :
343 '... it is clear that most subjects experienced symptoms of CNS excitation and arousal. Fourteen subjects (10%) experienced GAS defined as hypertension together with nervousness, sleeplessness, skin eruptions, and morning diarrhoea. Oed_ema was seen in five of these subjects. All 14 GAS subjects employed P. ginseng roots in the oral route, and all also used caffeinated beverages. Six other subjects experienced GAS, but these persons used either Siberian ginseng or injection routes, which were considered atypical, and they axe not discussed here. Nevertheless, fully 22 subjects experienced hypertension, which was verified by monthly examinations. Subjects here used no other stimulants except for caffeine. The average daily dosage for the GAS subjects was 3 g of root material, but the range was 0 to 15 g. Most users attempted to titrate the dosage to minimize undesired side effects, e.g., nervousness and tremor. One user reported that abrupt withdrawal precipitated hypotension, weakness, and tremor. The GAS reappeared periodically throughout the first 12 months of ginseng use but was rarely seen or reported at the 18- and 24-month follow-up examinations. Concomitantly, there was a reduction in daily dosage to an average of 1.7 g at the 18-month follow-up. Roughly 50% of the GAS subjects discontinued use by the 24-month examination compared with 21% for the clinical population as a whole. Occasional diarrhoea and nervousness were still reported by eight GAS subjects at the end of two years. The most common psychological finding among these subjects was an elevation of mood. Ten GAS
Table 2. Effects reported by long-term ginseng users during a two-year period Reported effect Stimulation Feeling of well-being Increased motor and cognitive efficiency Morning diarrhoea Skin eruptions Demulcent effects on throat Sleeplessness Nervousness Hypertension Euphoria Oedema Enhanced sexual performance Decreased appetite Depression Hypotension Amenorrhoea
Number of subjects (N=133) 133 93 89 47 33* 26 26 25 221" 18 14 9 7 6 5 4
Use (wk) before effect Immediate 3 2 3 3 Immediate 3 1 13 < 1 4 2 1 24 3 16
Preoarations used* C, E, R, T C, E, R, T C, E, R, T C, E, R, T C, R, T T, C, C, C, E, C,
Ci E, R E, R E, R R R
C, R E, E, C,
E, R R R R
* Abbreviation C indicates capsules; E, extracts; R, roots; T, teas; and Ci, cigarettes. 1 Confirmed by examination.
M. N. G. Dukes
344 subjects became euphoric, restless, agitated, and insomniac. High doses (15 g) resulted in feelings of depersonalization and confusion for four subjects. One subject experienced anaphyiaxis following injection of 2 ml of an extract, and this was followed by confusion and hallucinations. No abnormal personality function was detected with psychometric instruments, but depression was reported following doses higher than 15 g. These effects are similar to organic brain syndromes associated with corticosteroids and cortieotropin and may be related to ginseng's interference with cortisone and corticotropin levels.'
lactic reactions to this foreign material on the other would appear predominant, though it remains difficult to obtain estimates of the actual frequency of complications. There have been reports of aggravation of existing metabolic disorders, activation of latent infection and development of lymphadenopathy. One serological study has shown the formation of antibodies in approximately 50% of cases treated with cellular therapy.
AMYGDALIN (LAETRILE) Siegel's study is of value in view of the singular lack of well-documented clinical observations from other quarters, but one must bear in mind that it is evidence of a type which one would not generally regard as valid when dealing with a normal prescription drug; the product, dose and route of administration varied, and there was no control group or control period; one does not get a picture of the normal state of health of the individuals concerned, many of whom must have taken the product to counter the very phenomena (e.g. nervousness, depression) which are here recorded as effects. The high incidence of central nervous stimulation is, however, striking, and Siegel's hypothesis that the effects are akin to those of corticosteroid poisoning is a reasonable starting point for further investigation. The incidence of amenorrhoea in a few cases recalls earlier reports of hormonal effects (SEDA-3, 397). A final question with respect to Siegel's study concerns the source of the ginseng used; like other herbal remedies ginseng is likely to vary in composition according to the area and season in which it is harvested, and the mode of extraction and processing employed; some ginseng products are entirely devoid of active principles (10), whilst others have been found to be 'fortified' with synthetic products. The warning given earlier in this series and repeated by Siegel that ginseng may well interact with prescription drugs, must be emphasized.
CELLULAR THERAPY (SEDA-1, 376- 7,) Baenkler (4 R) has reviewed the risks attached to cellular therapy, the various schools of which were discussed in an earlier volume in this series. The risk of viral infection on the one hand and allergic or anaphy-
The evolving drama of amygdalin has been recorded in previous volumes in this series (SEDA-2,384; SEDA-3,390); the controversy - particularly in the United States as regards the right of patients to have access to this treatment has led to an intensification of research which is bound to throw further light upon the topic. The National Cancer Institute was due to commence a clinical trial of the product in the course of 1979 (14r). -
Animal studies The animal toxicity studies in dogs reported in SEDA-3 (p. 391) have now been complemented by an investigation by Khandekar (15) in rats. This was initially intended to determine the efficacy of amygdalin against Walker 256 carcinosarcomata. Doses of 250, 500 and 750 mg/kg were given intraperitoneally daily for five days, whilst a comparable series of animals were treated with cyclophosphamide or saline only, and a further group received both amygdalin and cyclophosphamide. Amygdalin proved ineffective against the development of the turnout, but there was a strikingly high dosedependent mortality in the amygdalin-treated animals (31%, 44% and 57% respectively), and the mode of death and elevated serum cyanide levels in the dying animals strongly suggested cyanide poisoning as the cause of death. The importance of the study from the clinical point of view lies in the fact that the product was not given orally; it has been argued (20 r) that whilst oral amygdalin may be broken down enzymatically with the release of cyanide, this may not occur when the drug is given directly into the system. This argument would not appear to hold good where intraperitoneal administration is concerned, though it may be valid for intramuscular use (see below).
345
Remedies used in non-orthodox medicine
Acute human toxicity Also relevant to the question of enzymatic breakdown is a report by Ortega and Creek on a child with a neuroblastoma which had been treated with cyclophosphamide; the patient, a boy of 3, was lost to follow-up and was subsequently found to be undergoing treatment with Laetrile given both orally and intravenously. Because of difficulties with intravenous injection, the mother began to administer the parenteral product as an enema; following a second daily enema containing 3.5 g Laetrile, the patient developed vomiting and diarrhoea, and after the third enema severe cyanide poisoning developed; the diagnosis was confirmed when cyanide blood concentrations a little below the lethal level were detected. These authors point out that after rectal administration one might expect hydrolysis of amygdalin to occur under the influence of beta-glucosidases, as after oral administration (16Or). A further case of poisoning due to accidental ingestion of Laetrile by a small child has been reported by Braico e t al.; death from cyanide intoxication resulted (17 C). A report by Rubino and Davidoff (18 c) serves as a reminder that, alongside Laetrile and various other brands of amygdalin, plain apricot seeds have acquired something of a reputation as a tonic or remedy, and that these too can cause acute cyanide poisoning. Finally, a report from Morse e t aL (21 c) illustrates the fact that cyanide poisoning can and does occur in patients undergoing treatment in so-called 'Laetrile clinics' such as exist in Mexico. Interaction with ascorbic acid In SEDA-3 the point was made that the dietary rituals sometimes adopted by amygdalin users may themselves prove detrimental. In view of the fact that megadoses of vitamin C are a component of one so-called 'antineoplastic diet', Backer and Herbert (19) performed in vitro studies to determine whether ascorbic acid would increase the hydrolysis of amygdalin and thus increase the risk of cyanide poisoning. Their findings suggest that though such an effect does occur it is not particularly marked, only a small fraction of the total available cyanide being released. Human pharmaeokinetics Ames e t al. (20 Cr) determined amygdalin concentrations in the urine and plasma of two patients taking Laetrile b n their own initiative. Fol-
lowing intramuscular administration to a male patient of a dose which according to the labelling contained 6 g of amygdalin, 4.25 g was recovered in the urine. The amygdalin was found to be excreted primarily as the unchanged molecule, and in view of the fact that in the past the amygdalin content of such products has been found to be considerably below that stated on the label, Ames e t al. consider that urinary recoveries following parenteral (i.m.) administration may approach 100%. In a woman who had taken 500 mg Laetrile orally, 55% of the label dose was recovered in the urine. The most important finding in this study is certainly the fact that amygdalin is after intramuscular administration excreted primarily as the unchanged molecule. The very limited scope of the study, however, and uncertainty as to the true amygdalin content of the products administered leaves some doubt as to the extent of the differences in the fate of intramuscularly and orally administered amygdalin.
Nomenclature It will be noted that in reviewing the literature one encounters some studies in which the products dealt with are designated 'amygdalin', in others 'laetrile' or 'Laetrile'; the terms are not necessarily synonymous and claims are sometimes advanced as to the superiority of products branded 'Laetrile'. In the absence of comprehensive analytical data and the evidence repeatedly advanced as to product variation it is impossible to draw firm conclusions as to the general validity of much of the work done; certainly one must beware of comparing and collating data from various studies as if they all related to the same product.
APHRODISIACS ( S E D A - 3 , 3 9 0 ) Amyl nitrite Though amyl nitrite has receded into the background as a coronary vasodilator it has in recent years acquired some popularity as an 'orgasm expander'; the products illegally traded for this purpose may also contain other volatile nitrites (1R). When used in cardiology the drug is notorious for its unpleasant adverse reactions including headaches, orthostatic symptoms and reflex tachycardia, and it does not appear to confer any pleasurable sensation on the patient. It
346 would seem that persons misusing the volatile nitrites are sometimes inhaling them throughout the day; whether this will be accompanied by harmful long-term sequelae is not known. Lead and other metals Brearley and Forsythe (2 or) have described a case of lead poisoning in a Bangladeshi immigrant to Britain; the manifestations included irritabihty, intestinal ileus and sideroblastic anaemia. Four aphrodisiac powders in his possession, brought from Bangladesh, were analyzed; one was a powder containing 46% of lead w/w; other powders variously contained smaller quantities of lead, silver or stannous sulphide. Traditionally many medicines in the Indian subcontinent which have a reputation as aphrodisiacs are based on silver or gold, but this case suggests that substitution with base metals, including lead, is practised.
SURMA Surma is a fine powder which is applied to the conjunctival surface of the eyelids in Asian countries and by Asian immigrants in Europe. Its name is derived from the Urdu word for antimony, but oriental pharma-
M. N. G. Dukes copoeias contain prescriptions for Surma which include salts of antimony, zinc and lead; lead sulphide seems to be currently employed, often in combination with camphor or menthol to induce lacrimation. Although used primarily as a cosmetic, it is also considered to be a remedy for eyestrain and soreness. As of 1 9 7 9 S u r m a has been prohibited in the United Kingdom, following reports of lead encephalopathy and increased blood lead levels among Asian children in Britain (28R).
MINERAL WATER (SEDA-3, 390) According to press reports, the US Health authorities have altered the labelling of two popular brands of mineral water to include a warning that they may be detrimental to health (3r). The step has been taken because of the arsenic content; that of Apollinaris water is 5 parts per milhon, that of Vichy Celestins 24 per 100 milhon. The Netherlands Health Authorities permit a maximum content of 5 parts per 100 million. In view of the exceptionally small quantities present in these brands of mineral water and the known ability of the body to adapt itself to chronic intake of arsenic it would seem most unlikely that mineral water can in this respect prove harmful.
REFERENCES 1. Cohen, S. (1979): The volatile nitrites. J. Amer. med. Ass., 241, 2077. 2. Brearley, R.L. and Forsythe, A. M. (1979): Lead poisoning from aphrodisiacs: potential hazard in immigrants. Brit. reed. J., 4, 1748. 3. Anonymous (1979): Attic in Amerika tegen mineraalwater. NRC Handelsblad, 28 september. 4. Baenkler, H. W. (1978): Gefahren der Zellulartherapie. Z. allg. Med., 54, 1228. 5. Anonymous (1978): Chrysanthemum Crystals: Gef'abrliche 'Wunderdroge'. Dtsch. Apoth. Ztg, 118, 1809. 6. Forster, P. J. G., Calverley, M., Hubball, S. and McConkey, B. (1979): Chuei-Fong-Tou-Geu-Wan in rheumatoid arthritis. Brit. med. J., 3, 308. 7. Uitdehaag, C. M.J., Hekster, Y.A., van de Putte, L. B. A., Waas, R. J. M., Bertels, B., Huysse, H., Slijkhuis, C. and Smits, H. M. (1979): Chinese pillen, Cushing-syndroom en geneesmiddelenonderzoek. Ned. T. Geneesk., 123, 1009. 8. Martin, V. (1979): 'Herbal' medicines and rheumatoid arthritis. Brit. reed. J., 3, 504. 9. Siegel,R. K. (1979): Ginseng abuse syndrome. J. Amer. med. Ass., 241, 1614.
10. Liberti, L. E. and Marderosian, A. D. (1978): Evaluation of commercial ginseng products. J. Pharm. ScL, 67, 1487. 11. Preissig, R. (1979): Personal communication. 12. National Coordinating Group for Male Contraceptives (1978): A new male contraceptive gossypol. Chin. Med. J. (Peking), 8, 455. 13. de Peyster, A. and Wang, Y. Y. (1979): Gossypol - proposed contraceptive for men passes the Ames test. New Engl. J. Med., 301,275. 14. Cleton, F. J. (1979): Laetrlle en kanker. Ti]dschr. Kanker, 3, 1. 15. Khandekar, J. D. (1979): Studies of amygdalin (Laetrile) toxicity in rodents. J. Amer. med. Ass., 242, 169. 16. Ortega, J. A. and Creek, J. E. (1979): Acute cyanide poisoning following administration of Laetrile enemas. J. Paediat., 93, 1059. 17. Braieo,K.T., Humbert, J. R., Terplan, K. L. and Lehotay, J. M. (1979): Laetrile intoxication. New Engl. J. Meal., 300, 238. 18. Rubino, M. J. and Davidoff, F. (1979): Cyanide poisoning from apricot seeds. J. Amer. reed. Ask, 241,359.
Remedies used in non-orthodox medicine 19. Backer, R.C. and Herbert, V. (1979): Cyanide production from laetrile in the presence of megadoses of ascorbic acid. J. Amer. reed. Ass., 241, 1891. 20. Ames, M. M., Kovach, J. S. and Flora, K. P. (1978): Initial pharmacologic studies of amygdalin (Laetrile) in man. Res. Commun. Chem. Path.
Pharmacol., 22, 1. 21. Morse, D.L., Boros, L. and Findley, P. A. (1979): More on cyanide poisoning with Laetrile.
New Engl. J. Med., 301,892. 22. Fensbo, C. and Harbeck, C. (1979): Datura stramonium anvendt som urtete. Ugeskr. Laeg., 141, 1150. 23. Belton, P. A. and Gibbons, D. O. (1979): Da-
347 tura intoxication in West Cornwall. Brit. med. J.,
1,585. 24. Anonymous (1979): Toxic reactions to plant products sold in health food stores. Med. Letter, 21, 29. 25. Editorial (1979): Liver injury, drugs, and popular poisons. Brit. med. J., 4, 574. 26. Schimmer, O. (1978): Natiirliche Mutagene in h6heren Pflanzen. Dtsch. Apoth. Ztg, 48, 1818. 27. Speer, F. (1979): Allergy to methyl salicylate. Ann. Allergy, 36. 28. Editorial (1979): Surma and lead poisoning. Lancet, L 28. 29. Gunby, P. (1979): Plant known for centuries still causes problems today. J. Amer. med. Ass., 241, 2246.