Literature Review and Commentary

by Alan R. Gaby, MD

Does Pomegranate Juice Improve Cognitive Function?

Two hundred sixty-one non-demented subjects (aged 50-75 years) were randomly assigned to receive, in double-blind fashion, 8 ounces per day of pomegranate juice or placebo for 12 months. Compared with placebo, pomegranate juice significantly improved the ability to learn visual information, although it had no effect on other measures of cognitive function.

Comment: One possible conclusion from this study is that drinking pomegranate juice had a positive effect on a specific measure of cognitive function. However, it is also possible that pomegranate juice had no effect, and that the difference between pomegranate juice and placebo was due to an adverse effect of the placebo. The contents of the placebo were not mentioned in the paper, but a personal communication with the lead author revealed that it contained high-fructose corn syrup, FD&C Red #40, and FD&C Blue #1. High-fructose corn syrup has numerous adverse effects on metabolism, and FD&C Blue #1 is a potent inhibitor of mitochondrial respiration in vitro. FD&C Red #40 might adversely affect brain function, since it appears to exacerbate the symptoms of attention deficit hyperactivity disorder in children. These ingredients were included in the placebo in order to mimic the taste and appearance of pomegranate juice. Similar placebos have been used in previous studies in which the active treatment was blueberry juice. It might be better to use something like apple juice or orange juice as a “placebo,” even though the study would no longer be blind.

Siddarth P, et al. Randomized placebo-controlled study of the memory effects of pomegranate juice in middle-aged and older adults. Am J Clin Nutr. 2020;111:170-177.

Case Report: Food Allergy and Depression

A 34-year-old woman with a long history of major depressive disorder experienced symptomatic improvement on an allergy elimination diet. Individual food challenges implicated dairy products as a cause of symptoms. Improvement was maintained over a two-year period as long as the patient avoided symptom-evoking foods, but symptoms recurred on five occasions when she went off the diet.

Comment: Nutrition-oriented practitioners have long known that hidden food allergy can cause depression, but mainstream medicine remains mostly unaware of this association. This case report should remind us that food allergy should be considered in the differential diagnosis of depression, particularly in patients who have other symptoms that are sometimes due to food allergy, such as migraines, irritable bowel syndrome, asthma, perennial rhinitis, or recurrent infections.

Aucoin M, Bhardwaj S. Major depressive disorder and food hypersensitivity: a case report. Neuropsychobiology. 2019;78:249-255.

Gluten-Free Diet for Schizophrenia

Sixteen patients with schizophrenia or schizoaffective disorder who had elevated IgG anti-gliadin antibodies but a negative test for celiac disease (tissue transglutaminase antibodies) were admitted to an inpatient unit. They were fed a gluten-free diet and were randomly assigned to receive, in double-blind fashion, a daily shake containing 10 g of gluten flour or 10 g of rice flour for five weeks. Fourteen patients completed the trial. Compared with the gluten-containing diet, the gluten-free diet resulted in improvement on the Clinical Global Impressions scale, which is a scale that measures the overall response to treatment. Improvement was also seen on the Scale for the Assessment of Negative Symptoms, which measures the so-called negative symptoms of schizophrenia such as apathy, blunting of the emotions, social withdrawal, and impairment of cognitive function. The gluten-free diet also improved gastrointestinal symptoms, as determined by the Gastrointestinal Symptom Rating Scale. No improvement was seen in positive symptoms.

Comment: About one-third of people with schizophrenia have elevated levels of IgG anti-gliadin antibodies, which is a higher rate than in the healthy population. An elevated anti-gliadin antibody level is not by itself diagnostic of gluten sensitivity, but it has been reported to correlate with a higher likelihood of a positive response to a gluten-free diet in patients with conditions such as psoriasis and recurrent aphthous ulcers. In the present study, the magnitude of the benefit was calculated by dividing the mean difference between the two diets by the standard deviation. This is known as the Cohen effect size, which is frequently used in clinical research. The Cohen effect size for the various improvements ranged from medium to large, which is considered good for most non-pharmaceutical interventions. Especially noteworthy is the improvement in the negative symptoms of schizophrenia, because these symptoms often fail to improve with antipsychotic medication. The study did not examine whether patients who do not have elevated anti-gliadin antibodies could also benefit from a gluten-free diet.

Kelly DL, et al. Randomized controlled trial of a gluten-free diet in patients with schizophrenia positive for antigliadin antibodies (AGA IgG): a pilot feasibility study. J Psychiatry Neurosci. 2019;44:269-276.

Nutrient “Cocktail” Not Effective for Depression

One hundred fifty-eight Australian patients (aged 18-70 years; mean age, 42 years) with major depressive disorder who continued to have moderate-to-severe depression on their current antidepressant medication were randomly assigned to receive, in double-blind fashion, a combination of nutrients or placebo for eight weeks. The nutrient combination provided daily 800 mg of S-adenosylmethionine, 500 µg of folinic acid, 200 µg of vitamin B12, 1,000 mg of eicosapentaenoic acid esters, 656 mg of docosahexaenoic acid esters, 200 mg of 5-hydroxytryptophan, 30 mg of zinc, 100 mg of vitamin B6, 60 mg of vitamin C, 40 mg of magnesium, and 40 IU of vitamin E. Placebo was nonsignificantly more effective than the nutrient combination, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory Rating Scale-II. The number of responders (defined as at least a 50% reduction in the MADRS score) was nonsignificantly higher in the placebo group than in the nutrient combination group (51% vs. 40%).

Comment: In this study, a “shotgun” approach using a combination of nutrients was not more effective than placebo in patients with major depressive disorder who had not responded adequately to antidepressant medication. To the contrary, there was a nonsignificant trend toward the nutrients being less effective than placebo. This finding is surprising, since many of the nutrients used in this study have demonstrated an antidepressant effect when administered individually. The authors suggested that the unusually high placebo response rate seen in this study may have masked a potential benefit of the nutrients. Another possibility is that some nutrients interfered with the positive effects of other nutrients. Over the years, a number of studies that investigated drugs, nutrients, or herbs as a treatment for depression produced surprisingly negative results that did not conform to the larger body of published research. We still have a lot to learn about how to use nutrients most effectively to treat depression. The results of the present study suggest that we should not begin with a “shotgun” approach.

Sarris J, et al. Nutraceuticals for major depressive disorder – more is not merrier: An 8-week double-blind, randomised, controlled trial. J Affect Disord. 2019;245:1007-1015.

Omega-3 Fatty Acids for Epilepsy

Ninety-nine Sudanese patients (85 children, 14 adults) with drug-resistant epilepsy were randomly assigned to receive, in double-blind fashion, two, four, or six capsules per day (based on age) of docosahexaenoic acid (DHA)-based fatty acids, eicosapentaenoic acid (EPA)-based fatty acids, or placebo for one year. Each DHA-based capsule contained 418 mg of DHA and 51 mg EPA. Each EPA-based capsule contained 386 mg of EPA and 81 mg of DHA. The placebo was high-oleic-acid sunflower oil. The mean number of seizures per month was 9.7 with EPA-based capsules, 11.7 with DHA-based capsules, and 16.6 with placebo. After adjustment for age, gender, and seizure type, compared with placebo, the mean number of seizures was significantly lower by 42% with EPA-based capsules (p = 0.008) and by 39% with DHA-based capsules (p = 0.04).

Comment: This study suggests that supplementation with the omega-3 fatty acids present in fish oil can reduce seizure frequency in patients with drug-resistant epilepsy. Previous studies that examined the effect of these fatty acids in the treatment of epilepsy have produced conflicting results. There is no clear explanation why the results differed in different studies, and the mechanism of action of omega-3 fatty acids is not known.

Ibrahim FA, et al. The differential effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on seizure frequency in patients with drug-resistant epilepsy – A randomized, double-blind, placebo-controlled trial. Epilepsy Behav. 2018;87:32-38.

Is Coenzyme Q10 Effective for Sepsis, or Is This More Iranian Research Fraud?

Forty Iranian patients with sepsis received standard treatment for sepsis and were randomly assigned to receive or not to receive (control group) 100 mg of coenzyme Q10 (CoQ10) twice a day for seven days. The primary outcome measures were changes in markers of inflammation and oxidative stress (interleukin-6, tumor necrosis factor-alpha, glutathione peroxidase, and malondialdehyde). Secondary outcome measures included in-hospital mortality. Compared with placebo, significant decreases were seen in mean levels of tumor necrosis factor-alpha and malondialdehyde. In-hospital mortality was significantly lower in the CoQ10 group than in the control group (20% vs. 65%; p = 0.01).

Comment: Readers of the Townsend Letter know that I suspect a large proportion of the nutrition research coming from Iran is fraudulent. Numerous aspects of the present study cause me to question its validity.

1. Inclusion criteria: The patients had to have an APACHE (Acute Physiology and Chronic Health Evaluation) II score of at least 15 to be eligible for the study. However, in Table 1, the mean APACHE II score in the group that received CoQ10 was 15.3, with a standard deviation of 5.2. With that mean and standard deviation, it is mathematically highly implausible that all of the patients had an APACHE II score of at least 15.

2. Sample size: The paper stated that the target sample size was 60, but the registration document on the Iranian Registry of Clinical Trials (IRCT) website stated that the target sample size was 40.

3. CoQ10 dosage: The paper stated that the patients received 100 mg of CoQ10 twice a day, but the IRCT document listed the dosage as 60 mg twice a day.

4. Blinding: The IRCT document stated that the study was double-blind and that the control group received a placebo. However, the paper did not state that the control group received a placebo; it only stated that the control group did not receive CoQ10.

5. Secondary outcome measures: The IRCT document listed length of hospital stay and duration of mechanical ventilation as secondary outcome measures, but neither of these outcome measures was discussed in the paper. In contrast, the paper listed length of ICU stay as an outcome measure, but length of ICU stay was not mentioned in the IRCT document.

6. Exclusion of patients: Twelve patients were excluded from the analysis because blood tests were not obtained at the proper time. However, the researchers presumably had data for these 12 patients regarding mortality and length of ICU stay. These 12 patients should therefore have been included in the analysis of mortality and length of ICU stay.

7. Discrepancies about recruitment dates: The paper stated that patients were recruited between September 2016 and March 2017. However, the IRCT document, which was registered on July 6, 2015, stated that recruitment was complete. The IRCT document also stated, “Registered while recruiting.” It is not possible for both statements in the IRCT document to be true. Moreover, both of the statements in the IRCT document contradict the recruitment dates reported in the paper.

8. Implausibly large effect size: The reduction in mortality seen with CoQ10 was very large; much greater than what would be expected from a single nutrient. There is only one similar randomized controlled trial in the medical literature: a study that examined the effect of ubiquinol (reduced CoQ₁₀; 200 mg per day) in patients with severe sepsis or septic shock. In that trial, the mortality rate was 21% in the ubiquinol group and 11% in the placebo group.¹

Soltani R, et al. Coenzyme Q₁₀ improves the survival and reduces inflammatory markers in septic patients. Bratisl Lek Listy. 2020;121:154-158.

High-dose Vitamin D and Multiple Sclerosis

Mice were fed a vitamin D-deficient diet (less than 5 IU per kg of food), a diet with a standard amount of vitamin D (1,500 IU per kg of food), or a diet with a large amount of vitamin D (75,000 IU kg of food). The standard dose was designed to produce a serum 25-hydroxyvitamin D (25[OH]D) level of 40 ng/ml. The high dose was designed to produce a level of 100 ng/ml, and is roughly equivalent to 30,000 IU per day for a 70-kg human. After eight weeks on the diet, experimental autoimmune encephalomyelitis (EAE) was induced (EAE is an animal model of multiple sclerosis). EAE was the least severe in the animals given the standard dose of vitamin D. Vitamin D deficiency increased the severity of the disease, but the worst outcome was seen in the mice given the highest dose of vitamin D.

Comment: While animal models of multiple sclerosis are not necessarily relevant for humans, the findings from this study are consistent with an earlier double-blind trial in humans. In that study, 23 patients with relapsing-remitting multiple sclerosis received approximately 13,000 IU per day or 1,000 IU per day of vitamin D₂ for six months. The dose in the high-dose group was adjusted to maintain a serum 25(OH)D level of 52-70 ng/ml. After six months, the median amount of disability (as measured by the Expanded Disability Status Scale) was significantly worse in the high-dose group than in the low-dose group. In addition, 36% of the patients in the high-dose group suffered a relapse during the study, whereas no one in the low-dose group had a relapse.² These findings argue against the use of high-dose vitamin D to treat multiple sclerosis.

Hausler D, et al. High dose vitamin D exacerbates central nervous system autoimmunity by raising T-cell excitatory calcium. Brain. 2019;Jul 13:awz190.

Effective Treatment for Hidradenitis Suppurativa

In 2013, the authors described an effective new treatment for hidradenitis suppurativa. Twelve patients with axillary or perineal fistulas due to hidradenitis suppurativa underwent surgical excision or localized treatment. All patients were found to have IgG antibodies to brewer’s yeast and were put on a brewer’s yeast-free diet for 12 months. In every case the skin lesions regressed completely over the 12-month treatment period. All patients had an immediate recurrence of skin lesions after accidental or deliberate ingestion of beer or foods containing brewer’s yeast.³

The present study was a follow-up of the original report and includes a total of 37 patients with hidradenitis suppurativa who followed a yeast-free diet. Twenty-six patients (70%) reported an improvement without any other treatment. In 21 of these 26 patients, improvement occurred in less than 6 months. Of the 37 patients who followed the diet, 32 (87%) had a recurrence after eating a restricted food, often within a few days after eating the food.

Comment: Hidradenitis suppurativa is a chronic painful acneiform condition affecting the axillae, groin, and other areas that contain apocrine glands. It is caused by occlusion of follicles, which leads to inflammation and infection of the surrounding tissue. Results of conventional therapy, which may include antibiotics, glucocorticoids, retinoids, or surgery, are frequently disappointing. The findings from the present study suggest that sensitivity to yeast is an important contributing factor in patients with hidradenitis suppurativa. Consumption of a yeast-free diet results in clinical improvement, and in many cases may obviate the need for surgery.

Aboud C, et al. Treatment of hidradenitis suppurativa: surgery and yeast (Saccharomyces cerevisiae)-exclusion diet. Results after 6 years. Surgery. 2020 Feb 22 [Epub ahead of print].