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From the Townsend Letter for Doctors & Patients
October 2004

Literature Review and Comment
by Alan R. Gaby, M.D.
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Caffeine: a common cause of anxiety
In this review article, the author points out that high intake of caffeine can produce symptoms that are indistinguishable from those of anxiety neurosis, such as nervousness, irritability, tremulousness, occasional muscle twitching, insomnia, sensory disturbances, rapid breathing, palpitations, flushing, arrhythmias, diuresis, and gastrointestinal disturbances. Heavy coffee drinkers have described a typical set of symptoms that occur if they omit their morning coffee; these include irritability, inability to work effectively, nervousness, lethargy, and restlessness.

Comment: In this 1974 article, the author pointed out that physicians often overlook caffeine intake as a cause of anxiety. Even today, doctors frequently fail to ask about caffeine consumption in their medical history, and many patients overlook caffeine as a factor contributing to their anxiety.

I am reminded of a pharmaceutical ad for Valium that appeared in medical journals about 20 years ago. The ad depicted an elderly, anxious-looking woman holding a cup of coffee in her hand. The ad read: "The strength to overcome excessive anxiety in the elderly cardiac patient." In other words, take a Valium with your coffee, and you will be fine. The ad's in-your-face invitation to doctors to practice "ignore-the-cause-and-just-treat-the-symptoms" medicine was compounded by the presence of what looked like a goiter in the woman's neck. Her anxiety may, therefore, have been due to hyperthyroidism, rather than to Valium deficiency. Thus, the ad carried another subliminal message: don't diagnose, just treat (with Valium).

Greden JF. Anxiety or caffeinism: a diagnostic dilemma. Am J Psychiatry 1974;131:1089–1092.

Inositol for panic disorder
Twenty-five patients with panic disorder with or without agoraphobia were randomly assigned to receive, in double-blind fashion, 6 g of inositol twice a day or placebo (mannitol or glucose) for four weeks, and then the alternate treatment for an additional four weeks. Twenty-one patients (mean age, 35.8 years) completed the trial. The frequency and severity of panic attacks and the severity of agoraphobia declined significantly more with inositol than with placebo. The number of attacks per week fell from about 10 to about 6 with placebo and to about 3.5 with inositol. Two patients complained of sleepiness while taking inositol; otherwise, the treatment was well tolerated.

Comment: This study suggests that inositol, a member of the vitamin B complex, is an effective treatment for panic disorder. Although it is not fully understood how inositol works, it is a component of phosphatidyl inositol, which functions as a second messenger for some noradrenergic and serotonin receptors. Foods high in inositol include fruits, beans, whole grains, and nuts (including peanuts). Even a high-inositol diet, however, is unlikely to provide more than about 2,000 mg per day. Consequently, effective treatment of panic disorder is likely to require an inositol supplement.

Benjamin J, et al. Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder.
Am J Psychiatry 1995;152:1084–1086.

Atkins diet for epilepsy
Six patients (aged 7–52 years) with focal or multifocal epilepsy who had failed to respond to therapy with 2 to 18 anticonvulsant medications (median, 6.5) were started on the Atkins diet. Five patients maintained moderate-to-large ketosis for periods of 6 weeks to 24 months. Three patients had a significant reduction in seizure activity during that time and were able to reduce their anticonvulsant medications. Complete elimination of seizures occurred in a 7-year-old female and a 10-year-old male. An 18-year-old female had a 90% reduction in seizures. A 12-year-old female had a 20% reduction in seizures. A 42-year-old male and a 52-year-old male had no improvement. These results suggest that the Atkins diet may be beneficial for patients with treatment-resistant epilepsy, particularly younger patients.

Comment: Like the ketogenic diet, which has been found to be of great benefit for some people with epilepsy, the Atkins diet can induce a ketotic state. Compared with the very restrictive ketogenic diet, however, the Atkins diet has fewer protein and calorie restrictions and has been used with apparent safety by millions of people for weight reduction. There is some concern that long-term use of the Atkins diet can promote the development of osteoporosis, kidney stones and other problems. Presumably, some of these potential adverse effects can be prevented by appropriate supplementation with vitamins and minerals, as recommended by Dr. Atkins in his writings.

Kossoff EH, et al. Efficacy of the Atkins diet as therapy for intractable epilepsy.
Neurology 2003;61:1789–1791.

Lycopene prevents preeclampsia
Two hundred fifty-one women in New Delhi, India, in their first pregnancy were randomly assigned to receive, in double-blind fashion, lycopene (from a tomato extract), 2 mg twice a day, or placebo, beginning at 16–20 weeks' gestation and continuing until delivery. The incidence of preeclampsia (8.6% vs. 17.7%; 51.4% reduction; p < 005) and the mean diastolic blood pressure (86.7 vs. 92.2 mm Hg; p = 0.012), were significantly lower in the lycopene group than in the placebo group. The incidence of intrauterine growth retardation (12% vs. 23.7%; p = 0.033) was also significantly lower in the lycopene group.

Comment: This study demonstrated that supplementation with a tomato extract can prevent preeclampsia and intrauterine growth retardation in primigravida women in New Delhi. Whether the same benefits would be seen in people consuming Western diets is not known. In earlier studies, placental and maternal serum concentrations of beta-carotene and lycopene were significantly lower in women with preeclampsia than in healthy pregnant women. Although the function of these antioxidant carotenoids in pregnancy is not clear, preeclampsia is associated with increased oxidative stress, and supplementation with other antioxidants (e.g., vitamins C and E) has been shown to reduce the incidence of preeclampsia in women living in England.

While the results seen in the present study may be due solely to lycopene, there are other compounds in tomato extracts, including phytoene, phytofluene, beta-carotene, and tocopherols. Until further research is done, pregnant women who want to prevent preeclampsia should eat tomato products or take a supplement made from tomatoes, rather than taking synthetic lycopene. The amount of lycopene used in the present study can be obtained by daily ingestion of approximately 1.5 ounces of tomato juice or 1 tablespoonful of tomato sauce.

Sharma JB, et al. Effect of lycopene on pre-eclampsia and intra-uterine growth retardation in primigravidas.
Int J Gynaecol Obstet 2003;81:257–262.

Aloe vera for ulcerative colitis
Forty-four patients (aged 18–80 years) with mildly to moderately active ulcerative colitis were randomly assigned in a 2:1 ratio to receive, in double-blind fashion, aloe vera gel (100 ml twice a day) or placebo for four weeks. Patients were advised to start with 25–50 ml twice a day for up to three days, to insure tolerability. Clinical remission (defined as Simple Clinical Colitis Activity Index of 2 or less) occurred in 30% of patients taking aloe vera and 7% of those taking placebo (p = 0.09). Clinical response (defined as remission or improvement) occurred in 47% of patients taking aloe vera and 14% of those taking placebo (p < 0.05). Sigmoidoscopic scores and laboratory paremeters (sedimentation rate, C-reactive protein, and others) did not differ significantly between groups. Adverse events were minor and were similar in the two groups.

Comment: Up to 50% of people with inflammatory bowel disease seek "alternative" treatments; in one survey, aloe vera was the most widely used herbal therapy by patients with this disease. Although previous studies have shown that aloe vera extracts have antiinflammatory activity, this is the first study to provide scientific support for aloe vera as a treatment for ulcerative colitis. Oral aloe vera appears to be safe, and this treatment should be considered as part of a comprehensive approach to the treatment of ulcerative colitis.

Langmead L, et al. Randomized, double-blind, placebo-controlled trial of oral aloe vera gel for active ulcerative colitis.
Aliment Pharmacol Ther 2004;19:739–747.

DHEA: an alternative to estrogen-replacement therapy?
Twenty postmenopausal women (aged 50–65 years) received 25 mg/day of dehydroepiandrosterone (DHEA) orally for 12 months. The mean serum concentrations of testosterone, estrone, and estradiol increased significantly and progressively, each reaching a 3- to 4-fold increase after 12 months. The mean serum concentration of progesterone increased significantly after 6 months, reaching a maximum increase of approximately 2.5-fold after 12 months. The mean concentration of growth hormone also increased significantly and progressively, reaching a maximum increase of more than 2-fold after 12 months. Plasma levels of luteinizing hormone and follicle-stimulating hormone decreased progressively, with the decrease becoming significant after 3 months for FSH and 6 months for LH. The mean Kupperman score (a measure of the severity of climacteric symptoms) showed progressive improvement, with the improvement becoming statistically significant after 3 months; after 12 months the degree of improvement was 76% in women who were 2 to 3 years postmenopausal and 67% in women who were 5 or more years postmenopausal. No side effects or uterine bleeding occurred. Ultrasound evaluation showed no significant increase in endometrial thickness in any of the patients after 6 and 12 months of therapy.

Comment: The results of this study demonstrate that administration of 25 mg/day of DHEA to postmenopausal women modulated a wide range of endocrine parameters and relieved climacteric symptoms, without causing uterine bleeding or endometrial hyperplasia. Although the clinical significance of raising the serum levels of estrogen, progesterone, testosterone, and growth hormone is not entirely clear, the levels of these hormones tend to decline with advancing age, and each of these hormones has been used to prevent or treat menopausal symptoms or various manifestations of aging.

Considering the multitude of adverse effects that are now known to occur with conventional hormone-replacement therapy, DHEA may turn out to be a safe and effective alternative to such therapy. Additional studies are needed to determine the long-term safety of DHEA, which some scientists believe might increase the risk of certain cancers. The safest and most effective hormone-replacement therapy for postmenopausal women will probably turn out to be small doses of various combinations of the four hormones produced by the human ovary (e.g., estrogen, progesterone, DHEA, and testosterone), with the doses individualized according to the needs of each particular patient.

Genazzani AD, et al. Long-term low-dose dehydroepiandrosterone oral supplementation in early and late postmenopausal women modulates endocrine parameters and synthesis of neuroactive steroids.
Fertil Steril 2003;80:1495–1501.

Flaxseed and the prostate
Fifteen men (mean age, 61.5 years) recently diagnosed with prostatic intraepithelial neoplasia (PIN) and/or atypia, who were scheduled for a repeat biopsy after six months, consumed a low-fat diet (< 20% of energy) supplemented with 30 g/day (approximately 3 tablespoons/day) of ground flaxseeds. After six months, a statistically significant decrease in the mean level of prostate-specific antigen (PSA; 5.72 vs. 8.47 ng/ml; 32.5% reduction; p = 0.0002) was seen. The mean serum testosterone concentration did not change significantly. Repeat biopsy was not performed in 2 patients because the PSA level had become normal. Among the 13 men who underwent repeat biopsy, the mean proliferation rate in the benign epithelium decreased significantly by 68% at six months (p = 0.0168). The clinical pathology reports indicated PIN and/or atypia in all cases at baseline; however, when re-reviewed by the reference pathologist, only 7 of 15 patients had PIN and/or atypia at baseline, and 1 of 13 at follow-up.

Comment: The results of this study suggest that supplementation with flaxseeds, when used in conjunction with a low-fat diet, can reduce the proliferation rate of benign prostatic tissue, and may also reverse precancerous changes in prostate tissue. Eating ground flaxseeds may, therefore, be helpful for preventing the development or progression of benign prostatic hyperplasia (BPH) and may also help prevent prostate cancer. These effects may be due to the lignans in flaxseeds, which can reduce testosterone levels and inhibit the conversion of testosterone to dihydrotestosterone.

Several recent epidemiological studies have shown an association between increasing intake of alpha-linolenic acid (ALA) and increased risk of prostate cancer. As flaxseed oil is one of the most potent sources of ALA, some physicians are now reluctant to prescribe flaxseed oil for men, despite anecdotal reports of its value as a treatment for BPH. Whether or not these epidemiological studies reflect cause-and-effect or whether the findings are due to unidentified confounding factors is not known. The results of the present study, however, suggest that ingestion of ground flaxseeds is beneficial, not harmful, to the prostate. The lignans in flaxseeds tend to be concentrated in the non-fat portion, as opposed to oil; even so-called "high-lignan" flaxseed oil does not appear to contain a large amount of lignans. Until further information is available, ground flaxseeds may be considered as potentially safer and more beneficial than flaxseed oil.

One potential negative effect of consuming flaxseeds is the development of vitamin B6 deficiency. Flaxseeds contain a substance called linatine, which interferes with the utilization of vitamin B6. Pigs fed a diet containing 30% by weight of flaxseed had impaired growth and laboratory evidence of vitamin B6 deficiency. Although the effect of eating smaller amounts of flaxseed on vitamin B6 status has not been investigated, it would be prudent for people who habitually consume flaxseed to take a multivitamin that contains vitamin B6.

Demark-Wahnefried W, et al. Pilot study to explore effects of low-fat, flaxseed-supplemented diet on proliferation of benign prostatic epithelium and prostate-specific antigen.
Urology 2004;63:900–904.

Preventing neural-tube defects: more than just folic acid
The association between dietary intakes of choline and its metabolite betaine (as determined by a food-frequency questionnaires) and the risk of neural-tube defects (NTDs) was assessed in a case-control study in California that included 424 cases and 440 control infants without birth defects. After adjustment for intake of dietary and supplemental folic acid, dietary methionine, and other potential confounding variables, the odds ratios for NTD in the 3 increasing quartiles of choline intake relative to the lowest quartile were 0.63 (95% CI, 0.42–0.99), 0.65 (0.39–1.07), and 0.51 (0.25–1.07), respectively. The risk of NTDs also decreased with increasing intake of betaine. NTD risk was lowest for women whose diets were rich in choline, betaine, and methionine. For women whose intake was above the 75th percentile compared with below the 25th percentile for all 3 nutrients, the odds ratio was 0.17 (95% CI, 0.04–0.76).

Comment: These results suggest that choline and betaine play a role in the development of the neural tube, and that inadequate intake of these nutrients may increase the risk of NTDs. The recommended Adequate Intake for choline is 425 mg/day for adult females and 550 mg/day for lactating females (because human milk contains large amounts of choline). Pregnant women are being advised to consume 425 mg/day, but that amount may be suboptimal, considering the increased nutritional needs associated with pregnancy. In contrast, more than half of the women in the present study consumed less than 372 mg of choline per day, suggesting that marginal choline status is prevalent among pregnant American women.

Foods rich in choline include eggs, wheat germ, whole grains, liver, and fish. Foods high in betaine include whole grains, spinach, and beets. Of note, white bread contains substantially less choline and betaine than do whole grains. At some future time, the processed-food industry will probably consider fortifying white flour with choline and betaine, as they did a few years ago with folic acid, and with pyridoxine before that, and with thiamine, riboflavin, niacin, and iron before that. Then, all we'd need to do would be to add back the magnesium, potassium, calcium, manganese, zinc, copper, selenium, molybdenum, chromium, pantothenic acid, vitamin E, essential fatty acids, fiber, and all of the as-yet undiscovered nutrients, and we will have created a perfect food.

Shaw GM, et al. Periconceptional dietary intake of choline and betaine and neural tube defects in offspring.
Am J Epidemiol 2004;160:102–109.


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