Essentials of Complementary and Alternative Medicine (June 1999)

Vitamin D (cholecalciferol)
Excessive intake (e.g., 50,000–60,000 IU or more daily) of vitamin D for months or years can lead to hypercalcemia and its associated symptoms and complications, 
such as nausea, vomiting, weakness, headache, bone pain, hypercalciuria, renal calcinosis, metastatic calcification, and hypertension (
94
, 
97
, 
98
, 
105
, 
106
, and 
107
).
Vitamin E (tocopherols)
Case reports are few at dosages less than 3,200 mg/day (
96
). In large doses, vitamin E increases the vitamin K requirement severalfold. Although this increase does 
not lead to bleeding diathesis in otherwise healthy individuals who are taking sufficient dietary amounts of vitamin K, coagulopathy can be produced in vitamin 
K–deficient patients. Therefore, it seems prudent to avoid substantial vitamin E supplementation in patients taking oral anticoagulants (
96
, 
99
and 
108
). Intravenous 
administration of vitamin E to neonates has been associated with hepatotoxicity in necrotizing enterocolitis (
99
).
Provitamin B
3
 (niacin = nicotinic acid)
Niacin is transformed into nicotinamide (vitamin B
3
) by the liver. Because of its vasodilator properties, niacin can produce flushing and hypotension headaches when 
taken in substantial doses. Other reported effects of high doses include pruritus, abdominal pain, diarrhea, peptic ulcer, skin rash, hepatotoxicity, hyperuricemia, 
hyperglycemia, and arrhythmias (
100
, 
101
). There is evidence to suggest that users of sustained-release products are more prone to hepatotoxic reactions than are 
consumers of unmodified products (
109
, 
110
).
Vitamin B
6
 (pyridoxine)
Prolonged administration can lead to severe peripheral sensory neuropathy and ataxia. Although this risk is primarily associated with large doses (2–6 g/day), it has 
also been observed following 500 mg/day (
94
, 
97
, 
111
, 
112
 and 
113
). Pyridoxine reduces the effects of levodopa, but this does not occur if a dopa decarboxylase 
inhibitor is also given (
94
).
Vitamin B
11
 (folic acid)
The principal risk of folic acid supplementation is the masking or precipitation of clinical symptoms related to vitamin B
12
 deficiency; strict vegetarians need to be 
informed that they are at risk of this deficiency (
114
, 
115
).
Vitamin C (ascorbic acid)
Adverse reactions to vitamin C are rare at dosages less than 4 g/day. Gastrointestinal symptoms (e.g., diarrhea, esophagitis) have been observed, and vitamin C 
has also been associated with the formation of renal oxalate stones. Although this latter problem was reportedly caused by high oral doses, most reports involved 
either intravenous administration or chronic renal failure. Vitamin C can alter the results of various laboratory tests because it is a reducing agent and can thus 
interfere with colorimetric redox assays (
96
).
Chromium
No adverse effects were seen in 30 patients with type 2 diabetes mellitus who received 200 µg of chromium picolinate for 2 months (
116
). However, there have been 
reports on dichromate toxicity among urbanized South African blacks who have started to replace the herbal ingredients of their traditional purgative enemas with 
sodium or potassium dichromate. This replacement can result in serious poisoning, characterized by acute renal failure, gastrointestinal hemorrhage, and 
hepatocellular dysfunction (
117
, 
118
).
Copper
One case described a patient who developed acute liver failure and cirrhosis resembling Wilson's disease due to chronic overdosing of a dietary copper supplement 
(10–20 times the maximum recommended dose of 3 mg/day for years) (
119
).
Selenium
No cases of selenium toxicity were observed in a clinical trial that involved oral treatment of hundreds of patients with a history of basal or squamous cell carcinoma 
with 200 µg/day of selenium for several years (
120
). A level of 0.5–0.6 mg of selenium has been repeatedly proposed as the maximum acceptable daily intake level 
(
121
, 
122
 and 
123
). Some reports have described toxicity due to health food tablets that contained many times more selenium (5–31 mg per tablet) than was stated 
on their label. Among the observed symptoms were nausea and vomiting, abdominal cramps, watery diarrhea, nail changes, alopecia, dryness of hair, fatigue, 
irritability, and paraesthesias (
124
, 
125
 and 
126
).

No cases of selenium toxicity were observed in a clinical trial that involved oral treatment of hundreds of patients with a history of basal or squamous cell carcinoma 
with 200 µg/day of selenium for several years (
120
). A level of 0.5–0.6 mg of selenium has been repeatedly proposed as the maximum acceptable daily intake level 
(
121
, 
122
 and 
123
). Some reports have described toxicity due to health food tablets that contained many times more selenium (5–31 mg per tablet) than was stated 
on their label. Among the observed symptoms were nausea and vomiting, abdominal cramps, watery diarrhea, nail changes, alopecia, dryness of hair, fatigue, 
irritability, and paraesthesias (
124
, 
125
 and 
126
).
Zinc
The risk of copper deficiency and anemia due to prolonged use of excessive doses has been occasionally reported (
127
, 
128
, 
129
 and 
130
). Treatment of 11 
healthy men with 150 mg of elemental zinc twice a day for 6 weeks was associated with a reduction in lymphocyte stimulation response to phytohemagglutinin as 
well as chemotaxis and phagocytosis of bacteria by polymorphonuclear leukocytes (
131
). However, the clinical relevance of these findings remains to be 
established. Because of concern for possible toxicity, it is recommended that chronic use of zinc supplements exceeding 15 mg/day should be undertaken only 
under medical supervision (
94
).
AMINO ACIDS
Amino acids are not devoid of adverse effects when consumed in excessive amounts (
132
). The following is a summary of the known and reported adverse effects of 
some amino acids. When faced with a patient using these products, the practitioner should find the summary of known adverse effects of those products. This will 
provide an indication of the adverse effects known for that amino acid 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.
Carnitine
The natural amino acid L-carnitine functions in the transport of fatty acids into mitochondria, and its therapeutic value in the treatment of primary carnitine 
deficiencies (and some secondary deficiencies) is well established. Its direct toxicity seems negligible, and only minor adverse effects (e.g., gastrointestinal 
discomfort) have been observed in its consumers (
133
, 
134
). According to one case report, the addition of L-carnitine (1 g/day orally) to long-term acenocoumarol 
therapy may result in marked potentiation of this anticoagulant (
135
).
DL-Carnitine has been advocated in health food stores as a means to improve athletic performance. It competitively inhibits L-carnitine and can thus cause 
symptoms of carnitine deficiency. An exemplary case involved an athlete who took 500 mg of DL-carnitine for 2 days before running a long-distance race. No 
problems were encountered during the race, but later he developed muscle weakness and urinary discoloration suggestive of myoglobinuria (
136
).
Tryptophan
L-tryptophan (LT) is a naturally-occurring essential amino acid that has been advocated as an innocuous health food for the treatment of depression, insomnia, 
stress, behavioral disorders, premenstrual syndrome, and so on. At the end of 1989, LT-containing health food products were associated with an epidemic in the 
United States of the so-called eosinophilia-myalgia syndrome (EMS). This syndrome was characterized by an eosinophil count of ³10
9
/l and intense generalized 
myalgia. Other relatively frequent signs and symptoms were reports of fatigue, arthralgia, skin rash, cough and dyspnea, edema of the extremities, fever, 
sclerodermalike skin abnormalities, increased hair loss, xerostomia, pneumonia or pneumonitis with or without pulmonary vasculitis, and neuropathy. About one third 
of the cases required hospitalization, and a substantial number of patients died. Although there is good evidence that the epidemic was triggered by a contaminant, 
the responsible substance has not been identified (
137
).
In 1994, LT was reintroduced on the United Kingdom market under the strict condition that it should only be prescribed by hospital specialists for patients with 
long-standing resistant depression (
138
).
OTHER PRODUCTS
The following is a summary of the known and reported adverse effects of various other complementary products. When faced with a patient using these products, the 
practitioner should find the summary of known adverse effects of those products. This will provide an indication of the adverse effects known for that product 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.

Baking soda
Life-threatening complications developed following the use of baking soda (sodium bicarbonate) as a home remedy intended to help a 6-week-old infant burp (
139
).
Edetate
The parenteral administration of edetate disodium is advocated as chelation therapy for cardiovascular diseases. Serious adverse effects have been reported, such 
as renal tubular necrosis, acute renal failure, and death. Rapid infusions have been associated with acute hypocalcemia, tetany, and cardiac arrhythmias. Less 
commonly, vasculitis, bone marrow depression, and exfoliative dermatitis have occurred in association with chelation therapy. Few adverse effects have been 
reported when a protocol using 50 mg/kg per infusion was followed as recommended (
140
, 
141
 and 
142
).
Fumaric acid esters
Monoethyl and dimethyl fumarate are being used in some countries to treat psoriasis. The major risk is nephrotoxicity. This effect can take the form of an acute renal 
failure, which is only partially reversible (
143
); osteomalacia due to renal tubular toxicity has been reported (
144
). Other side effects include gastrointestinal 
disturbances, skin reactions, flushing, reversible elevation of transaminases, reversible lymphopenia, and eosinophilia (
145
, 
146
). Consequently, the use of fumaric 
acid esters requires regular hematological control as well as periodic renal and hepatic function determinations.
Gamma-hydroxybutyrate
Gamma-hydroxybutyrate (GHB, or sodium oxybate) has been illicitly promoted for body building, weight control, treatment of insomnia, and recreational use as a 
euphoric agent (“liquid ecstasy”). Ingestion of 0.5–3 teaspoons can produce vomiting, drowsiness, hypotonia and/or vertigo, loss of consciousness, irregular 
respiration, tremors, or myoclonus. Seizure-like activity, bradycardia, hypotension, and/or respiratory arrest have also been reported. Severity and duration of 
symptoms depend on the dose of GHB and on the presence of other CNS depressants, such as alcohol (
147
, 
148
, 
149
 and 
150
). A recent case suggests that GHB 
may cause impairment of the psychomotor skills required for safe operation of a motor vehicle (
151
). Prolonged use of high doses may lead to a withdrawal 
syndrome (e.g., insomnia, anxiety, and tremor), which takes 3 to 12 days to resolve (
152
).
D-Glucosamin
Parenteral administration of this chondroprotective agent may produce a local reaction at the injection site as well as serious allergic reactions. Other reported side 
effects include nausea, vomiting, stupor, and isolated cases of blood disorders. It is likely that these reactions are partly due to the presence of lidocaine in the 
injection fluid (
153
).
Hydrogen peroxide
Intravenous injection of hydrogen peroxide as an unconventional therapy for cancer or AIDS has resulted in acute hemolytic ane mia, which can be followed by fatal 
complications, such as cardiopulmonary arrest (
154
) or progressive renal impairment (
155
).
Lorenzo's Oil
This oil (20% erucic acid and 80% oleic acid) has been advocated as a miracle cure for adrenoleukodystrophy. Prolonged treatment has been associated with 
thrombocytopenia (
156
).
Ozone
Ozone therapy involves the foaming up of citrated autologous blood with oxygen, subsequent treatment of the blood in a quartz-glass container with UV-B radiation, 
and, finally, reinjection of the ozone-enriched blood. This treatment has been repeatedly associated with transmission of viral hepatitis (
157
, 
158
). A possible case of 
pancytopenia has also been reported (
159
).
Ubidecarenone
Ubidecarenone (coenzyme Q
10
) not only is an investigational cardiovascular drug, but it is also widely available as an unconventional over-the-counter product. 
Several cases have been described in which a reduced effect of warfarin was observed after adding nonorthodox ubidecarenone to the patients' warfarin regimens. 
Ubidecarenone is chemically closely related to menaquinone (vitamin K
2
), but the exact mechanism of this interaction remains to be identified (
160
, 
161
).
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HAPTER
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CHAPTER 8. T
HE
 S
AFETY OF
 H
OMEOPATHY
Essentials of Complementary and Alternative Medicine