Essentials of Complementary and Alternative Medicine (June 1999)

The Practice of Orthomolecular Medicine
A growing number of physicians in the United States are using meganutrient therapy for the prevention and treatment of a wide range of medical conditions. Some of 
these clinical applications are theoretical, some are supported by anecdotal reports or uncontrolled studies, and other clinical applications have been documented by 
double-blind, placebo-controlled trials. Although the scientific documentation of orthomolecular medicine is increasing, the amount of research in this field is still small 
compared with many areas of orthodox medicine, such as drug therapies. And, although some orthomolecular treatments have not been subjected to rigorous 
controlled trials, many physicians have been impressed with their effectiveness.
It should be noted that orthomolecular physicians often use a combination of nutrients that have each been studied individually but usually not together. For example, 
there is evidence that coenzyme Q
10
 (CoQ
10
), taurine, and magnesium are each valuable in the treatment of congestive heart failure (CHF) (
15
, 
16
 and 
17
). The 
physician might prescribe all three of these nutrients, hoping for an additive or synergistic effect.
PROVIDER-PATIENT INTERACTION
In orthomolecular medicine, history taking, physical examination, and laboratory tests are largely the same as those done in a conventional medical setting. However, 
a physician practicing orthomolecular medicine may also seek additional information. For example, a patient with asthma might be questioned about symptoms of 
carpal tunnel syndrome because both conditions often respond to vitamin B
6
. The physical examination would include observation for signs of nutritional deficiency 
(e.g., white spots on the fingernails, which may indicate zinc deficiency, or follicular hyperkeratosis, which suggests vitamin A deficiency). Certain laboratory tests may 
be used to help guide the treatment plan or to identify adverse effects. For example, whole-blood serotonin measurements can be used to predict which hyperactive 
children will respond to vitamin B
6
, and erythrocyte copper levels may be measured in conjunction with high-dose zinc therapy because zinc supplementation can 
induce copper deficiency (
18
).
Although the classification of diseases in orthomolecular medicine is essentially the same as in conventional medicine, the treatment plans are often different. For 
example, a conventional physician is likely to treat rheumatoid arthritis with nonsteroidal anti-inflammatory drugs, corticosteroids, and antirheumatic drugs. An 
orthomolecular physician is likely to use essential fatty acids, zinc, copper, and dietary modifications, as well as prescription medications if the response is 
unsatisfactory. In most cases, nutrients can be administered concomitantly with conventional therapy. However, in some cases, the dosages of prescription 
medications must be adjusted (e.g., with a diabetic patient whose insulin requirement is reduced by supplementation with chromium and other nutrients). Nutritional 
therapy sometimes produces clinical improvements that are significant enough to obviate the need for conventional drug therapy.
At present, there are no established standards as to which treatments are most appropriate for which conditions. However, there now exists a substantial body of 
scientific research and clinical data from which practitioners can draw. The process of determining appropriate therapy is based largely on scientific research and 
clinical experience, just as it is in conventional medicine. Unlike many areas in conventional medicine, there generally are not data from large multicenter clinical trials 
on combination nutritional therapies as used in practice.
ORTHOMOLECULAR THERAPY AND OUTCOMES
Evaluation of treatment outcomes is also similar to that in conventional medicine. For example, bone densitometry studies would be used to monitor the effectiveness 
of an orthomolecular treatment for osteoporosis. The time period over which changes are expected to occur varies with the nature and severity of the illness, the age 
of the patient, and other well-known factors in conventional medicine. As in conventional medicine, changes in the treatment plan depend mainly on response to 
therapy, side effects, and cost.
USE OF THE SYSTEM FOR TREATMENT
This chapter's scope does not permit a comprehensive review of the field of orthomolecular medicine. Therefore, several medical conditions have been selected to 
illustrate the therapeutic potential of orthomolecular medicine. Practitioners interested in incorporating nutrient therapeutics into their practices should become familiar 
with the biochemical actions of the various nutrients, their clinical indications and toxicity, and their interactions with drugs and other nutrients (
19
).
Congestive Heart Failure
Conventional treatment for congestive heart failure (CHF) focuses primarily on minimizing the consequences of a failing myocardium but does little to improve the 
health and functionality of the heart muscle. Supplementing the patient with nutrients that have been shown to enhance cardiac function may help improve 
conventional therapy.
C
OENZYME
 Q
10
CoQ
10
 is a component of the electron transport chain, which is involved in the production of adenosine triphosphate (ATP). A deficiency of CoQ
10
 would be expected 
to impair energy- dependent processes, including myocardial contractility. The concentrations of CoQ
10
 in both plasma and myocardial tissue are significantly lower in 
patients with ischemic heart disease or dilated cardiomyopathy than in healthy controls (
20
, 
21
). Furthermore, the level of CoQ
10
 has been found to decrease 
progressively with increasing severity of heart disease.
Administration of 100 mg/day of CoQ
10
 to patients with cardiomyopathy resulted in a significant increase in mean left ventricular ejection fraction (from 41 to 59%) and 
a more than fivefold increase in survival time, compared with published survival statistics (
22
). In a double-blind trial, 641 patients with CHF were randomly assigned 
to receive placebo or CoQ
10
 (2 mg/kg/day) for one year. Conventional therapy was continued in both groups. The number of patients requiring hospitalization for heart 
failure was 38% less in the CoQ
10
 group than in the placebo group (p 10
 group than in 
the placebo group (p 23
). CoQ
10
 therapy has also been reported to improve edema, pulmonary rales, dyspnea, and other manifestations of CHF (
15
).
T
AURINE
Taurine constitutes more than 50% of the free amino acid pool in the heart. Taurine has been shown to have a positive inotropic effect and antiarrhythmic activity and 
to regulate the transport of calcium and potassium across myocardial cell membranes. Oral administration of taurine reduced the extent of cardiac lesions in 
genetically cardiomyopathic hamsters (
24
) and reduced the severity of experimentally induced CHF in rabbits (
25
).
In human studies, seven patients with CHF resulting from valvular disease received 2 g of taurine twice daily. Before treatment with taurine, all patients were restricted 
in activity and all had experienced worsening heart failure despite treatment with digitalis and diuretics for at least four weeks. Marked improvement was noted in 5 of 
7 patients within 3 to 21 days after administration of taurine. These patients improved from New York Heart Association functional class III to class II within 4 weeks, 
and improvement was maintained with continued taurine supplementation (up to 12 months) (
26
). In a double-blind study, 58 patients with CHF received taurine (2 g, 
3 times daily) or a placebo for 4 weeks. Administration of taurine resulted in significant improvements in dyspnea, edema, palpitations, cardiothoracic ratio on chest 
x-ray, and New York Heart Association functional class, whereas no significant improvements were seen in the placebo group (
16
).
M
AGNESIUM
Magnesium also plays an important role in cardiac health. It functions as a vasodilator, calcium-channel blocker, and cofactor for the synthesis of ATP. In animal 
studies, magnesium deficiency resulted in focal myocardial necrosis. In humans with cardiomyopathy, myocardial concentrations of magnesium were 65% lower than 

in healthy individuals, although serum levels were normal (
17
).
Although there have been no controlled trials of magnesium therapy for CHF, the author has seen dramatic results using parenteral magnesium. One patient, a 
55-year-old man with a 15-year history of cardiomyopathy, was in the final stages of heart failure, being kept alive only by a continuous infusion of dobutamine in an 
intensive care unit. At the time, his life expectancy was thought to be hours or days. However, after administration of a single intramuscular injection of magnesium 
sulfate (1 g), the patient almost immediately experienced a marked improvement, which became even more pronounced following additional magnesium injections. 
The dobutamine infusion was successfully discontinued and the patient was able to return home, where he lived for two more years. During that time, he would rapidly 
decompensate if he did not receive a magnesium injection every fourth day. Although there are no randomized controlled trials of these three agents in combination 
for CHF, physicians using orthomolecular medicine will use this information from the scientific literature to put together combination therapies for CHF using nutrients 
and endogenous substances.
Osteoarthritis
Another example of how orthomolecular treatments are developed can be seen in arthritis. In the 1940s, William Kaufman, MD, administered niacinamide (900 to 
4000 mg/day) to several hundred patients with osteoarthritis. In most cases, joint range of motion increased (as measured by goniometry) and symptoms, such as 
pain and stiffness, were reduced. Results were usually apparent three to four weeks after the initiation of treatment. Thereafter, progressive improvement occurred 
with continued treatment, but a gradual return of symptoms was noted if treatment was discontinued (
27
, 
28
).
Kaufman's observations recently have been confirmed in a double-blind trial. Seventy-two patients with osteoarthritis were randomly assigned to receive niacinamide 
(500 mg, 6 times daily) or a placebo for 3 months. Compared with the placebo, administration of niacinamide resulted in significant improvements in joint mobility and 
in overall severity of arthritis. Niacinamide-treated patients showed a reduction in erythrocyte sedimentation rate and were able to decrease their anti-inflammatory 
medications (
29
).
The delayed onset of action of niacinamide and the gradual return of symptoms on discontinuation of treatment suggest that niacinamide does more than merely 
relieve the symptoms of osteoarthritis. Apparently, this vitamin somehow controls the disease process. Nonsteroidal anti-inflammatory drugs, however, may actually 
accelerate the progression of osteoarthritis (
30
). At the present time, the mechanism of niacinamide's action is not known.
Niacinamide should be administered in at least three divided doses because it has a rapid half-life. On rare occasions, hepatotoxicity has developed with high-dose 
niacinamide. Therefore, liver enzymes (aminotransferases) should be monitored periodically, and patients should be advised to watch for nausea (an apparent early 
warning sign of niacinamide hepatotoxicity). Note that niacinamide causes liver damage less frequently than does niacin (nicotinic acid). When used appropriately, 
niacinamide is well tolerated and appears to be safer than nonsteroidal anti-inflammatory drugs.
Glucosamine sulfate, a compound that occurs naturally in the body, has also been shown to be effective in the treatment of osteoarthritis. Glucosamine sulfate is a 
precursor for the synthesis of the proteoglycans that make up joint cartilage and has also been shown to inhibit the degradation of proteoglycans (
31
). In one study, 
20 patients with osteoarthritis of the knee received glucosamine sulfate (500 mg, 3 times daily) or a placebo for 6 to 8 weeks. Glucosamine sulfate was significantly 
more effective than placebo in relieving symptoms of pain, joint tenderness, and swelling. The results were rated as excellent in all 10 patients receiving glucosamine 
sulfate, whereas all 10 patients given placebo rated the results as fair or poor (
32
).
In another study, 40 patients with osteoarthritis of the knee received, in double-blind fashion, either glucosamine sulfate (500 mg, 3 times daily) or ibuprofen (1.2 
g/day) for 8 weeks. The rate of improvement was slower in the glucosamine sulfate group, but the degree of improvement increased in that group as the study 
progressed. By the eighth week, glucosamine sulfate was significantly more effective than ibuprofen (
33
). Other studies have confirmed the effectiveness of 
glucosamine sulfate against osteoarthritis (
34
, 
35
). This compound appears to act directly on the disease process, reversing tissue degeneration and stimulating the 
production of healthy joint cartilage (
36
). Glucosamine sulfate is generally well tolerated and has not been reported to cause serious side effects or significant 
changes in standard laboratory parameters. An orthomolecular treatment for osteoarthritis of the knee may involve a combination of the previously mentioned and 
other compounds.
Gingivitis
Three small studies of nutritional therapy in gingivitis combine to provide another useful treatment. Thirty healthy volunteers participated in a double-blind study of the 
effect of folic acid on gingival health. Each participant rinsed his or her mouth twice daily with 5 mL of a 0.1% solution of folic acid or placebo. After 60 days, gingival 
inflammation (as assessed by the gingival index and bleeding index) was significantly less in the folic acid group than in the placebo group (
37
). Similar results were 
obtained after oral administration of folic acid (4 mg/day) (
38
).
CoQ
10
 also appears to play a role in the prevention and treatment of gingivitis. Gingival biopsies have revealed subnormal concentrations of CoQ
10
 in 60 to 96% of 
patients with periodontal disease (
39
, 
40
). Eighteen patients with periodontal disease received either CoQ
10
 (50 mg/day) or a placebo for three weeks in a 
double-blind trial. All 8 patients receiving CoQ
10
 improved, whereas only 3 of 10 patients receiving placebo showed improvement (p < 0.01) (
41
). Orthomolecular 
physicians have found that combining these two approaches is very helpful in treating gingivitis.
Fatigue
Fatigue, which has many causes, is a common and often difficult problem to treat. Vitamin B
12
 has long been used as a general “tonic” to relieve fatigue and to 
enhance well-being. Although vitamin B
12
 injections are widely used, most physicians believe that the benefits are purely a placebo effect. The efficacy of vitamin B
12
 
as a tonic was investigated in a 1973 double-blind study. Twenty-eight individuals complaining of fatigue (all of whom had normal serum levels of vitamin B
12
) 
received intramuscular injections of vitamin B
12
 (hydroxocobalamin; 5 mg twice weekly) or a placebo, each for two weeks. Compared with placebo, vitamin B
12
 
treatment produced significant improvements in general well-being (p = .006) and happiness (p = .032). Improvements in fatigue (p = .09) and appetite (p = .073) were 
of borderline statistical significance (
42
). Other studies have not always shown benefit.
Another compound that has been found to be useful in the treatment of fatigue is potassium magnesium aspartate. It is thought that fatigue may in some cases be a 
result of inefficient mitochondrial energy production and, because of key roles in this process, potassium magnesium aspartate might be expected to improve 
mitochondrial function. Magnesium is involved in the synthesis of ATP and potassium in the stabilization of membranes. Aspartate serves as a substrate for the 
tricarboxylic acid (Krebs) cycle, and there is evidence that aspartate promotes the facilitated transport of potassium and magnesium into mitochondria.
Three double-blind, placebo-controlled studies that included a total of nearly 3000 patients have evaluated the effect of potassium magnesium aspartate (usually 1 g 
twice daily) in the treatment of fatigue. An improvement in symptoms was reported by 75 to 91% of patients receiving active treatment, compared to only 5 to 25% of 
patients given placebo (
43
, 
44
 and 
45
). The author's experience is that a combination of these treatments, along with others, can significantly help many patients who 
have fatigue of unknown etiology.
Kidney Stones
Approximately 75% of the kidney stones that occur among Americans consist wholly or partly of calcium oxalate. Magnesium is known to inhibit the formation of 
calcium oxalate crystals (
46
), and vitamin B
6
 has been reported to reduce urinary oxalate levels, apparently by reducing its endogenous synthesis (
47
). In one study, 
55 patients with recurrent kidney stones received 500 mg/day of magnesium (in the form of magnesium hydroxide) for up to 4 years. Urinary magnesium increased 
and remained elevated during the entire treatment period. The mean number of stone recurrences was reduced by 90%, and 85% of the patients remained stone-free 
(
48
). In another study, 149 patients with recurrent stone formation were given 300 mg of magnesium oxide (equivalent to 180 mg of magnesium) and 10 mg of vitamin 
B
6
 daily for 4.5 to 6 years. During this period, the mean stone formation rate decreased by 92.3%, from 1.3 to 0.1 stones per person per year (
49
). More research is 
needed, but the treatment is inexpensive and safe, warranting use for those with recurrent stones.
Osteoporosis

The effects of calcium, vitamin D, and estrogen on osteoporosis prevention are well known. However, several other nutrients also appear to play an important role in 
osteoporosis prevention. Magnesium, which constitutes up to 1% of bone ash, regulates calcium transport and bone mineralization. In one study, magnesium 
deficiency was demonstrated in 16 of 19 women with osteoporosis (
50
). Thirty-one postmenopausal women with osteoporosis received magnesium (250–750 mg/day) 
for 1 year. During that time, bone density increased in 22 women (71%) and remained stable in another 5 (
51
).
Vitamin K is required for the synthesis of osteocalcin, the bone protein that promotes mineralization of bone. In one study, the mean serum vitamin K concentration 
was significantly lower (by 56%) in patients with a history of vertebral crush fractures than in age-matched controls (
52
). In a clinical trial in Japan, supplementation 
with vitamin K markedly reduced bone loss in postmenopausal women (
53
).
Trace minerals also appear to play a role in osteoporosis prevention. Postmenopausal women treated with calcium plus trace minerals (e.g., zinc, copper, and 
manganese) for 2 years showed a 1.48% increase in mean bone mineral density (BMD), whereas mean BMD decreased by 1.25% in women receiving calcium alone. 
Calcium plus trace minerals, but not calcium alone, was significantly more effective than placebo in preventing bone loss (
54
). In another study, administration of 
copper (3 mg/day) significantly reduced bone loss relative to placebo (
55
). There is evidence that other nutrients (including folic acid, vitamin B
6
, vitamin D, boron, 
silicon, and strontium) may also be important for osteoporosis prevention (
56
, 
57
). Although these studies are small and the nutrients have not yet been evaluated in 
combination, the ability to monitor bone loss allows the physician to determine when the nutrients are effective in individual patients.
Orthomolecular Psychiatry
Nutrient therapy has shown potential in the treatment of schizophrenia, depression, dementia, and other psychiatric disorders.
S
CHIZOPHRENIA
In 1962, Hoffer and Osmond reported that administration of large doses of niacin or niacinamide (usually 3–6 g/day) to schizophrenic patients significantly reduced 
the incidence of re-admission to the hospital (
58
). Follow-up studies by other groups produced equivocal or negative results, and the use of megavitamins for 
schizophrenia has remained controversial. Hoffer later found that ascorbic acid enhanced the effect of niacinamide. More recently, Kanofsky reported that 
administration of large doses of ascorbic acid (up to 6 g/day) resulted in dramatic improvements in some schizophrenics (
59
). After 40 years of experience with 
megavitamin therapy, Dr. Hoffer has stated, “I can confidently tell the family of an acute schizophrenic that there is a 95% chance he or she will be back to normal in 
two years, and if chronic schizophrenic there is a 65% chance of [becoming] normal in ten years” (
60
). Because schizophrenia is a serious condition that is often 
refractory to treatment, controlled clinical trials using the orthomolecular approach are urgently needed, and sedative use in carefully monitored patients seems 
warranted.
D
EPRESSION
Depression is often treated in conventional medicine by drugs designed to increase the concentration or the effect of serotonin, norepinephrine, or other 
neurotransmitters. Supplementation with the precursors of these neurotransmitters may have an effect similar to those of antidepressant drugs. Tryptophan, the 
precursor to serotonin, has been used with some success in the treatment of depression. Administration of niacinamide in combination with tryptophan appears to 
enhance the effectiveness of the latter, possibly by increasing the conversion of tryptophan to serotonin (
61
). Tyrosine, the precursor to norepinephrine, is also 
reportedly effective for some patients with depression (
62
). However, the efficacy of tryptophan and tyrosine has been inconsistent. Buist developed an algorithm to 
help predict which patients are most likely to respond to each of these amino acids (
63
).
D
EMENTIA
Several naturally occurring compounds are being used to treat dementia. In one study, 12 of 16 elderly patients with dementia and polyneuropathy had low levels of 
vitamin B
12
 in the cerebrospinal fluid (CSF). However, only three of these patients had low serum levels of the vitamin. Parenteral administration of vitamin B
12
 was 
associated with clinical improvement (
64
). This study suggests that vitamin B
12
 deficiency (localized to the brain and central nervous system) may play a role in the 
etiology of some cases of dementia. Furthermore, serum vitamin B
12
 measurements may fail to identify this abnormality in many cases. Because obtaining CSF is an 
invasive procedure, and because vitamin B
12
 injections are safe and inexpensive, I recommend a therapeutic trial of intramuscular vitamin B
12
 injections (1000 mcg 
weekly for 6 weeks). If effective, the treatment is continued as needed. Other compounds that are reportedly of value in the treatment of dementia include 
phosphatidylserine (
65
), L-acetylcarnitine (
66
), and nicotinamide adenine dinucleotide (NADH) (
67
). Clearly, much more research is needed before a completely 
rational administration of nutrient therapies is achieved. Currently, there are few documented ways to help identify which patients will benefit from specific nutrient 
therapies. However, an increasing number of functional and serum tests are developing that may aid in a more rational and objective use of orthomolecular medicine 
in the future.