Essentials of Complementary and Alternative Medicine (June 1999)

CHAPTER 7. T
HE
 S
AFETY OF
 N
ONHERBAL
 C
OMPLEMENTARY
 P
RODUCTS
Peter A.G.M. De Smet
General Introduction
Animal Preparations
Toxic Metals
 
Germanium
Diets
Vitamins and Trace Elements
Amino Acids
Other Products
Chapter References
GENERAL INTRODUCTION
Many general concerns reviewed in the previous chapter on the safety of herbal products also apply to nonherbal complementary products. For instance, product 
quality is an important issue of nonherbal products because the risk of contamination with a toxic substance is not always limited to herbal products. There have been 
reports about unacceptably high levels of lead in propolis capsules (
1
) and in dietary calcium supplements (
2
). A human case of lead poisoning has been published, 
in which the source of lead was a dietary calcium supplement made from horse bone (
3
). The possibility also exists that animal products transmit an infectious disease 
due to the presence of a pathogenic microbe (
4
, 
5
) or another pathogenic organism (
6
).
The risk of adverse reactions to nonherbal products can also depend on consumer-bound parameters, such as concomitant diseases or concurrent drug use. Acute 
hepatitis B was reported to induce acute hypervitaminosis A in a 42-year-old man who had taken 25,000 IU of vitamin A without ill effects for 10 years (
7
). Vitamin E 
may increase cyclosporin toxicity by improving its absorption (
8
), and it can also enhance the action of oral anticoagulants by increasing vitamin K requirements (
9
, 
10
).
Finally, situational risks should also be taken into consideration when it comes to nonherbal complementary products. For instance, the recreational substance 
gamma-hydroxybutyrate can make its consumers less fit for driving (
11
).
This chapter reviews information on the adverse effects of animal preparations, toxic metals, diets, vitamins and trace elements, amino acids, and various other 
products.
ANIMAL PREPARATIONS
Substances of animal origin can produce anaphylactic or anaphylactoid reactions, particularly after parenteral administration (
12
).
The following is a summary of the known and reported adverse effects of some animal preparations and products. When faced with a patient using these products, 
find the summary of known adverse effects of those products. This will provide an indication of the adverse effects known for that animal substance and help guide the 
practitioner in monitoring for possible adverse effects in that patient. It will also help the practitioner inform the patient about possible risks.

Arumalon
Chondroprotective agent containing an extract of cartilage and of red bone marrow of calves. Parenteral use has been associated with local reactions at the site of 
the injection and with allergic symptoms (e.g., fever, malaise, symptoms of pronounced inflammation, nephrotic syndrome). Allegedly, polymyositis and fatal 
dermatomyositis are also possible (
13
).
Arteparon
Chondroprotective agent prepared from bovine lung and tracheal cartilage. Mucopolysaccharide polysulfuric acid ester (also known as glycosaminoglycan 
polysulfate) is declared its major principle. This substance resembles heparin in its molecular structure and can have the same increasing effect on platelet 
aggregation. Cross-reactivity with heparin is possible. The use of arteparon has been associated with life-threatening thromboembolic complications (e.g., 
myocardial infarction, pulmonary embolus, hemiplegic apoplexia, cerebral hemorrhage, death). Other reported side effects include local reactions at the site of the 
injection, serious allergic symptoms, arthropathy, subcutaneous fat necrosis, and reversible alopecia (
13
).
Bee-sting therapy
The development of persistent nodular lesions from bee-sting therapy has been reported (
14
). Anaphylaxis in allergic individuals is, of course, of concern.
Bile preparations
The raw bile of the grass carp (Ctenopharyngodon idellus) is believed in Asia to be good for health. However, eating this substance can result in hepatic failure and 
renal toxicity. The former reaction may resolve within a few days, but the latter is more serious, culminating in acute renal failure within 2 to 3 days after ingestion. 
The toxic component of the bile is probably 5-a-cyprinol (
15
, 
16
). Likewise, the ingestion of sheep bile as a traditional remedy for diabetes mellitus is associated with 
hepatic and renal toxicity (
17
).
Cell therapy
Cell therapy consists of the parenteral or enteral administration of cells or cell parts obtained from animal organs and/or tissues of bovine donors, sheep, pigs, or 
rabbits. Two different types of cell preparations are in use: fresh cells, which are administered in fresh form, and dried cells or so-called sicca cells, which are 
worked up for later use. The most prevailing risk of cell therapy seems local and generalized allergic reactions (e.g., fever, nausea, vomiting, urticaria, and 
anaphylactic shock). Other untoward consequences include fatal and nonfatal encephalomyelitis, polyneuritis, Landry-Guillain-Barré syndrome, fatal serum 
sickness, perivenous leucoencephalitis, and immune-complex vasculitis (
18
, 
19
 and 
20
).
Fish oil
Fish oil supplements rich in long chain polyunsaturated omega-3 fatty acids (eicosapentaenoic acid, docosahexaenoic acid) can reduce plasma levels of 
triglycerides and very low-density lipoproteins, decrease platelet aggregation, prolong bleeding time, and affect leukotriene production. Reported side effects include 
fullness and epigastric discomfort, diarrhea, and a fishy taste after burping. In addition, some more serious problems have been identified (
18
):
There is a potential risk that the favorable changes in plasma lipids could be offset by a deleterious increase in low-density lipoprotein (LDL) cholesterol or 
LDL apoprotein B.
The capacity to increase bleeding time and to reduce platelet aggregation could have untoward consequences, especially in patients with preexisting bleeding 
and platelet abnormalities, and in those taking other antithrombotic agents.
Preliminary evidence suggests that a deteriorating effect on patients with aspirin-sensitive asthma is possible.
There is also the risk that the metabolic control of patients with type 2 diabetes mellitus may be adversely affected when these patients are not being treated 
with a sulfonylurea derivative (
21
).
Gangliosides
Gangliosides extracted from bovine brain tissue have been widely used in Western Europe and South America for several neurological disorders. In addition to 
discomfort at the injection site, reported side effects include motoneuron diseaselike illness, cutaneous erythema (with or without fever and nausea), and 
anaphylaxis. After evaluating reported associations between the use of gangliosides and Guillain-Barré syndrome (
22
, 
23
), the Committee for Proprietary Medicinal 
Products (CPMP) of the European Commission recommended in 1994 that marketing authorizations for mixtures of gangliosides for the treatment of peripheral 
neuropathies should be withdrawn (
24
).
Ghee
Ghee is the clarified butter from the milk of water buffaloes or cows. Although the butter is heated enough to eliminate nonsporulating organisms, the process is 
unlikely to kill Clostridium tetani spores. This may explain why its traditional use as an umbilical cord dressing is sometimes identified as a risk factor for the 
development of neonatal tetanus (
25
).
Green-lipped mussel
An extract of the New Zealand green-lipped mussel (Perna canaliculus) is advocated for the treatment of arthritic symptoms. Reported side effects include flare-up of 
the disease, epigastric discomfort, flatulence, and nausea (
26
). A case of jaundice appearing weeks after starting treatment has been reported (
27
).
Imedeen
Imedeen is the trade name of an oral health food product containing freeze-dried proteins from the cartilage of deep-sea fish, which is advocated as an antiwrinkling 
agent. Its use has been associated with generalized skin reaction and extensive Quincke's edema (
28
).
Liver extracts
Products derived from animal liver may contain levels of vitamin A that are far greater than nutritional levels (e.g., up to 48,000 IU per tablet). As a result, 
indiscriminate use of such products carries a risk of hypervitaminosis A and birth defects (
29
). Anaphylactic reactions to parenteral forms of liver extracts have been 
rarely reported (
30
, 
31
).
Orgotein
Orgotein (also known as Cu Zn superoxide dismutase) is obtained from bovine liver. It has been advocated as an antiinflammatory agent. Parenteral administration 
has been associated with anaphylactic reactions (
32
, 
33
).
Oyster extract
A food supplement consisting of oyster extract, ginseng, taurine, and zinc has been associated with a case of Quincke's facial edema. The reaction developed 
immediately after intake of the food supplement, and the oyster extract was considered its most likely cause (
34
).
Propolis
Propolis, or bee-glue, is a resinous material used by bees to seal hive walls and to strengthen the borders of the combs as well as the hive entrance. It is 

A food supplement consisting of oyster extract, ginseng, taurine, and zinc has been associated with a case of Quincke s facial edema. The reaction developed 
immediately after intake of the food supplement, and the oyster extract was considered its most likely cause (
34
).
Propolis
Propolis, or bee-glue, is a resinous material used by bees to seal hive walls and to strengthen the borders of the combs as well as the hive entrance. It is 
increasingly associated with cases of allergy following use of the substance in biocosmetics and in self-treatment of various diseases. Although most cases involve 
allergic contact dermatitis arising from topical application, a few reports describe an allergic reaction to oral ingestion (
35
). The poplar bud constituent 
1,1-dimethylallyl caffeic acid ester has been identified as its main contact allergen (
36
).
Rattlesnake meat
Dried rattlesnake meat is a well-known Mexican folk remedy that can be purchased without prescription in Mexico, El Salvador, and the southwestern part of the 
United States. It is available as such and in the form of powder, capsules, or pills, which may be labeled in Spanish as  víbora de cascabel, pulvo de víbora,  or carne 
de víbora. Because the rattlesnake is a well-established reservoir for  Salmonella arizona, such products can cause serious systemic infections. Typically, victims are 
Hispanic patients with a medical illness undermining their immunological integrity (e.g., systemic lupus erythematosus, AIDS). Although most patients respond well 
to intravenous therapy with ampicillin or cotrimoxazole, fatalities have been observed (
13
, 
37
, 
38
).
Royal jelly
Royal jelly is a viscous secretion produced by the pharyngeal glands of the worker bee,  Apis mellifera, and is widely used in alternative medicine as a health tonic. 
Its internal use by atopic individuals can induce severe, sometimes even fatal, asthma and anaphylaxis (
39
, 
40
). Topical application can lead to contact dermatitis 
(
41
).
Shark cartilage
The use of shark cartilage is promoted as a potential treatment for malignant disease, although there is no conclusive evidence of efficacy (
42
). A case of hepatitis, 
which was possibly caused by this form of therapy, has been reported (
43
).
Spanish fly
Spanish fly (also known as cantharides) is the dried blistering beetle ( Cantharis vesicatoria and related species), which contains cantharidin as the major active 
constituent. A related drug, which serves as an alternative cantharidin source in the East, is the Chinese blistering beetle ( Mylabris species). Spanish fly has gained 
a considerable reputation as an aphrodisiac agent after it was observed that nearly toxic doses could cause priapism in men and pelvic congestion with occasional 
uterine bleeding in women. These effects are caused by an irritant effect on the genitourinary tract, which can be misinterpreted as increased sensuality. Cantharidin 
was formerly used medicinally as a counterirritant and vesicant, but this use has been abandoned because of its high toxicity. Manifestations of cantharidin 
poisoning range from local vesicobullous formation to gross hematuria, hepatotoxicity, myocardial damage, denudation of the gastrointestinal tract, and, 
occasionally, death. The lethal dose is not well established. One patient died after the ingestion of only 10 mg, while another patient survived the intake of 50 mg 
(
44
, 
45
 and 
46
).
Squalene
Squalene is a popular over-the-counter Asian folk remedy derived from shark liver oil. Oral capsules are readily available in Asian health food stores, and the 
substance is also widely used in cosmetics. Ingestion of squalene capsules has been associated with a case of severe lipoid pneumonia due to aspiration; the 
patient also had abnormal liver function, which raised the possibility of hepatotoxicity (
47
).
Thyroid hormones
Thyroid hormones continue to be found in unconventional medicines for weight reduction (
47
, 
48
) and in health food capsules (
49
). Although it is well recognized 
that these hormones can help reduce weight, primarily by increasing metabolic rate, they have no place in the therapy of obese euthyroid patients. When dietary 
intake of protein and calcium is inadequate, use of these hormones may induce worrisome catabolic losses of these muscular and skeletal components, and the 
weight loss is not sustained after termination of therapy. Furthermore, the large doses needed for weight reduction may suppress endogenous thyroid function and 
have potentially dangerous effects on the heart, such as tachyarrhythmias and cardiomegaly (
50
, 
51
).
Toad venom
The dried venom of the Chinese toad ( Bufo bufo gargarizans) is a traditional ingredient (Ch'an Su) of Chinese medicine. It contains bufalin and cinobufaginal, which 
are structurally related to digoxin. Deliberate and accidental overdosing with preparations containing Ch'an Su has been associated with serious, sometimes fatal, 
cardiotoxicity (
52
, 
53
, 
54
 and 
55
). Interference with digoxin immunoassays is also possible. By a cross-reaction with the digoxin antibodies, a false impression of 
high plasma digoxin levels is created (
56
). A digoxin immunoassay that avoids cross-reactivity with Chinese medicine has been developed (
57
).
TOXIC METALS
Toxic metals, such as arsenic, cadmium, lead, and mercury, can occur in herbal medicines and in other traditional preparations, not only as accidental contaminants, 
but also as intentional ingredients (
58
). In a given case, the potential intake of the toxic metal can be calculated based on its level in the product and the 
recommended or estimated dosage of the product. This potential exposure can then be put into a toxicological perspective by comparison with the so-called 
Provisional Tolerable Weekly Intake values for toxic metals, which have been established by the Food and Agriculture Organization of the United Nations (FAO) and 
the World Health Organization (WHO) (
Table 7.1
).
Table 7.1. Provisional Tolerable Weekly Intake (PTWI) Values for Toxic Metals, as Established by FAO and WHO
In various parts of the world, toxic metal salts or oxides are also deliberately put in medicines and cosmetics (
Table 7.2
). Of particular concern is the intentional 
presence of toxic metals in traditional medicines from India and Pakistan, which have been associated with a risk of serious poisoning (
Table 7.3
). In the case of 
traditional Chinese medicines, it is often difficult to find out whether the metals are there by accident or on purpose (see 
Chapter 6
). The latter possibility is illustrated 
in 
Table 7.4

Table 7.2. Ethnic Medicines and Cosmetics Known or Suspected to Contain Intoxicating Metal Compounds as Intentional Ingredients*
Table 7.3. Occurrence of Arsenic and Mercury Salts in Chinese Herbal Formulas [69]
Table 7.4. Metal Poisoning by Traditional Preparations of Asian Origin
Toxic metal salts or oxides are also found among the ingredients used for homeopathic medicines, and they may be present in these medicines in potentially unsafe 
levels (
59
). For instance, normal doses of cadmium sulfuricum D3 drops (i.e., 0.1% of cadmium sulfate) will provide a daily amount of 160 to 320 µg cadmium (
60
). 
This exposure exceeds the tolerable limit of 1 µg/kg of cadmium per day, which has been provisionally set by the Joint FAO/WHO Expert Committee on Food 
Additives.
Germanium
The daily intake of germanium through foodstuffs is estimated to be between 0.4 and 3.5 mg. In past years, germanium preparations supplying much larger amounts 
have hit the health food markets of Japan and Europe. Various case reports have shown that a daily intake of 30 to 700 mg of germanium for months or years 
(corresponding to a cumulative dose varying from 8.5 g to more than 300 g of germanium) can lead to serious renal failure, which is not always reversible. 
Neuropathy, myopathy, and hepatic damage may also occur. Some patients ultimately died of gastrointestinal bleeding, cardiogenic shock, or multiple organ failure. 
Most cases involved the use of inorganic germanium dioxide or an unidentified germanium compound. However, carboxyethylgermanium sesquioxide and 
germanium-lactate-citrate have also been incriminated (
70
, 
71
).
DIETS
Strict, injudicious adherence to certain dietary restrictions may result in nutritional deficiencies of protein, vitamins, electrolytes, and/or trace elements. For example, 
an injudicious vegetarian diet can result in vitamin B
12
 deficiency. Infants seem to be at particular risk of developing dietary deficiencies (
72
, 
73
, 
74
, 
75
 and 
76
). 
Unbalanced diets can also lead to an excessive intake of certain nutrients, which can cause adverse reactions, interference with conventional treatment, or both. For 
example, there was a case of myocardial infarction in a patient on warfarin therapy. The patient's special diet provided excessive amounts of vitamin K and had 
apparently induced resistance to the warfarin treatment (
77
). In addition to a risk of pharmacodynamic problems, there is also the possibility that a dietary change 
induces pharmacokinetic changes (
78
). For example, a balanced diet with adequate pro tein causes an acidic urine, whereas a low protein diet or a strict vegetarian 
diet may cause an alkaline urine. Consequently, diet-induced shifts in urinary pH may alter the rate of excretion of both weakly acidic and basic drugs (
92
, 
93
).
VITAMINS AND TRACE ELEMENTS
Vitamins and minerals are not harmful in nutritional doses (
Table 7.5
) (
94
, 
95
), but it is well established that some vitamins and minerals can cause serious adverse 
effects when taken in megadoses. Although regulations for vitamin preparations are increasing, minerals seem to be regulated less commonly, despite the fact that 
such regulations would be just as relevant as they are for vitamin preparations.

Table 7.5. United States Recommended Dietary Allowances (RDA) for Vitamins
The following is a summary of the known and reported adverse effects of vitamins and trace elements.
When faced with a patient using these products, find the summary of known adverse effects of those products. This will provide an indication of the adverse effects 
known for that substance and help guide the practitioner in monitoring for possible adverse effects in that patient. It will also help the practitioner inform the patient 
about possible risks.
Vitamin A (retinol) and Provitamin A (beta carotene)
Acute toxic reactions to vitamin A have become rare after megadose supplementation (0.5–4 million IU) to infants has been abandoned. Chronic toxicity occurs more 
often but is rare at doses below 100,000 IU/day. The risk is increased by low body weight, protein malnutrition, liver disease, renal disease, hyperlipoproteinemia, 
alcohol consumption, and vitamin C deficiency. For an adult, the mean time to intoxication is estimated to be 7.5 months at doses of 300,000 IU/day and 3.5 months 
for 500,000 IU/day. Reported symptoms include skin changes (e.g., dryness, fissures, depigmentation, and pruritus), hair loss, bone and joint pain with marked 
tenderness, hepatotoxicity, neurological complaints (e.g., benign intracranial hypertension), and psychiatric symptoms (
96
, 
97
, 
98
 and 
99
).
Of particular concern are the teratogenic effects of vitamin A (e.g., craniofacial, central nervous system, heart, neural tube, musculoskeletal, and urogenital). In one 
study, an increased frequency of defects was concentrated among babies born to women who had consumed high levels of vitamin A before the seventh week of 
gestation. The apparent threshold for this effect was near 10,000 IU/day of supplemental vitamin A. About 1 in 57 babies born to mothers exceeding this threshold 
had a malformation attributable to vitamin A supplementation (
100
). Women of reproductive age should not take supplements providing more than 8,000 IU/day of 
vitamin A (
101
).
Unlike vitamin A, beta carotene (provitamin A) is generally considered devoid of serious adverse effects. Except for yellowing of the skin after prolonged 
consumption of more than 30 mg/day, only questionable cases of adverse reactions have been reported (
96
, 
99
). Although its teratogenicity in humans has not been 
specifically studied, animal experiments do not indicate that it is teratogenic (
100
). A question about this impeccable safety record was raised when two clinical trials 
showed that beta carotene supplementation (20 or 30 mg/day) was associated with an increased relative risk of lung cancer in Finnish male smokers (
102
) and in 
American smokers, former smokers, and workers exposed to asbestos (
103
). The estimated excess risks observed were small, however, and it could not be 
concluded with certainty that beta carotene was truly harmful (
104
).