Literature Review and Commentary

by Alan R. Gaby, MD

Beta-Carotene and Cancer: Not All Bad News

A prospective study nested within the Physicians’ Health Study was conducted to determine whether supplementation with beta-carotene during radiation therapy for prostate cancer is associated with an increased risk of prostate cancer death or metastases. Three hundred eighty-three participants who had been randomly assigned to receive beta-carotene (50 mg every other day) or placebo underwent radiation therapy for prostate cancer while they were taking their assigned supplement. During a median follow-up period of 10.5 years, the incidence of the composite end point of prostate cancer death or bone metastases was nonsignificantly lower by 28% in the beta-carotene group than in the placebo group (p = 0.24). The 10-year freedom from the composite end point was 92% in the beta-carotene group and 89% in the placebo group.

Comment : Two previous double-blind trials have found that supplementation of cigarette smokers with beta-carotene increased the risk of developing lung cancer. In contrast, there is no evidence that beta-carotene increases cancer risk among nonsmokers.

Many oncologists are concerned about the possibility that beta-carotene or other antioxidants might interfere with the anticancer effects of chemotherapy or radiation therapy. As a result, cancer patients are frequently advised not to take nutrients such as selenium, vitamin C, or beta-carotene while they are receiving conventional cancer treatment. However, most research conducted to date has not found a deleterious effect of these nutrients, and in some studies the addition of antioxidants to chemotherapy or radiation therapy was associated with better outcomes. The results of the present study indicate that beta-carotene does not interfere with radiation therapy in men with prostate cancer, and may even increase survival and help prevent metastases.

Margalit DN et al. Beta-carotene antioxidant use during radiation therapy and prostate cancer outcome in the Physicians’ Health Study. Int J Radiat Oncol Biol Phys. 2012;83:28–32.

Alpha-Linolenic Acid and Prostate Cancer

In the Alpha Omega Trial, 1622 patients (aged 60–80 years) who had a history of myocardial infarction and whose prostate-specific antigen (PSA) level was below 4 ng/ml were randomly assigned to receive, in double-blind fashion, 2 g per day of alpha-linolenic acid (ALA) or placebo in margarine for 40 months. The mean PSA level increased to a nonsignificantly greater extent with ALA than with placebo (0.52 vs. 0.42 ng/ml; p = 0.12). The probability that the PSA level would rise above 4 ng/ml was nonsignificantly higher by 15% in the ALA group than in the placebo group.

Comment : ALA is an essential fatty acid of the omega-3 class. It is present in high concentrations in flaxseed oil, canola oil, soybean oil, and some nuts, and in lesser amounts in a wide range of other plant and animal foods. Most, but not all, observational studies have found that higher intake of ALA is associated with an increased risk of developing prostate cancer. However, there is no clear evidence that ALA per se is responsible for this association. ALA at a physiological concentration has been reported to inhibit the enzyme 5alpha-reductase in vitro. This enzyme catalyzes the conversion of testosterone to dihydrotestosterone, which is believed to play a role in the pathogenesis of prostate cancer. A substance that inhibits 5alpha-reductase would be expected to prevent, rather than promote, prostate cancer. If the association between ALA intake and prostate cancer is causal, it may be due to the fact that ALA is a highly unsaturated molecule that is especially prone to becoming oxidized, either spontaneously or in the presence of heat. Most foods rich in ALA (e.g., cooking oils and roasted nuts) are heated before they are consumed. Heating ALA or oils high in ALA has been shown to produce a number of potential or probable carcinogens, including 1,3-butadiene, benzene, and acrolein.

In the present study, there was a trend toward an increase in PSA levels in men given ALA. However, the ALA-containing margarine used in the study was distributed only once every 12 weeks. It was not stated whether the tubs were airtight, or whether patients were advised to refrigerate after opening and to put the top back on immediately after use. Since ALA is unstable, it may have oxidized during storage, leading to the formation of potentially deleterious compounds.

The available evidence does not suggest that men should avoid foods such as raw nuts or non-rancid flaxseed oil in order to prevent prostate cancer. Many Western diets may already be marginally deficient in ALA, as a result of partial hydrogenation of edible oils and less grazing by farm animals on ALA-rich grasses. However, oils rich in ALA should not be used for high-temperature cooking. It would also seem preferable to consume nuts raw, as opposed to roasted. In addition, ALA-rich foods and oils should be refrigerated and stored in airtight containers, in order to prevent them from becoming rancid.

Brouwer IA et al. Effect of alpha linolenic acid supplementation on serum prostate specific antigen (PSA): results from the alpha omega trial. PLoS One. 2013;8:e81519.

Probiotic for Nonalcoholic Fatty Liver Disease

Forty-eight children (median age, 10.5 years) with biopsy-proven moderate or severe nonalcoholic fatty liver disease (NAFLD) were randomly assigned to receive, in double-blind fashion, the probiotic product VSL#3 or placebo for 4 months. The dosage was 1 sachet per day (450 billion organisms per sachet) for those aged less than 10 years, and 2 sachets per day for older children. The main outcome measure was the change in fatty liver severity at 4 months, as determined by ultrasonography. Compared with placebo, the probiotic significantly decreased the severity of NAFLD (p < 0.001). At the end of the study, the proportion of patients who had none or mild fatty liver was 91% in the VSL#3 group and 7% in the placebo group (p < 0.001).

Comment : NAFLD is a common condition among obese people and individuals with type 2 diabetes. It is characterized by fatty infiltration of hepatocytes. NAFLD appears to be an independent risk factor for cardiovascular disease, and in some cases it can progress to cirrhosis or hepatocellular carcinoma. Nutritional treatments that may be beneficial for this condition include weight loss if overweight, avoidance of dietary fructose, and supplementation with vitamin E and betaine. VSL#3 is a proprietary multistrain probiotic preparation that has been shown to be of value in the treatment of irritable bowel syndrome, inflammatory bowel disease, and minimal hepatic encephalopathy secondary to cirrhosis. The results of the present study demonstrate that this probiotic is also effective against NAFLD.

Alisi A et al. Randomised clinical trial: the beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2014;39:1276–1285.

Green Tea Extract for Xerostomia (Dry Mouth)

Sixty patients with xerostomia, including 10 with Sjögren’s syndrome (7 in the active-treatment group, 3 in the placebo group) were randomly assigned to receive, in double-blind fashion, lozenges containing a proprietary preparation of green tea catechins (MighTeaFlow; Nomax Inc., St. Louis, MO) every 4 hours (maximum of 6 lozenges per day) or placebo for 8 weeks. All lozenges contained 500 mg of xylitol; the amount of green tea catechins in the lozenges was not stated. In the active-treatment group, compared with baseline, there was a significant 3.8-fold increase in unstimulated saliva output and a significant 2.1-fold increase in stimulated saliva output (stimulated by chewing neutral wax). Stimulated and unstimulated saliva output did not change significantly in the placebo group. No separate analysis was reported for the patients with Sjögren’s syndrome. However, in a personal communication from one of the authors (Hsu S; December 10, 2014), in the subset of patients with Sjögren’s syndrome, mean unstimulated saliva output increased significantly by 11.5-fold in the active-treatment group.

Comment : Xerostomia is dryness of the mouth resulting from insufficient saliva production. Consequences of xerostomia may include halitosis, impaired speech and taste sensation, altered dietary habits, and an increased incidence of dental caries (saliva contains factors that prevent caries). More than 400 medications can cause xerostomia, and medication use is the most common cause of this disorder. Other causes include Sjögren’s syndrome and certain other autoimmune diseases, diabetes, mouth-breathing, excessive alcohol intake, nutritional deficiencies, and radiation therapy. Commercially available artificial saliva preparations are often prescribed, but no treatment has been shown to increase natural saliva production. This study provides new hope for people who suffer from dry mouth, including those with Sjögren’s syndrome.

De Rossi SS et al. A phase II clinical trial of a natural formulation containing tea catechins for xerostomia. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;118:447-454.e3.

Iron Supplementation for Restless Legs Syndrome

Thirty patients (aged 20–80 years; mean age, 56 years) with restless legs syndrome and a low-normal serum ferritin level (15–50 ng/ml; suggestive of low or borderline-low iron status) were randomly assigned to receive ferrous sulfate (325 mg twice a day) or pramipexole (0.25 mg at bedtime, with the dosage adjusted at 2, 4, and 8 weeks according to response and tolerance) for 12 weeks. Symptom severity was assessed using the International Restless Legs Syndrome Study Group rating scale for severity (IRLS). Treatment response was defined as a decrease in IRLS score of at least 50% from baseline. At baseline, IRLS scores and serum ferritin levels were similar between groups. Both groups improved significantly; the mean improvement was 41.6% with iron and 39.7% with pramipexole (difference between groups not significant). The response rate was 46.7% in each group.

Comment : Previous research has demonstrated that iron deficiency is a common cause of restless legs syndrome. Iron supplementation has been shown to be beneficial both in patients with overt iron deficiency and in those with low-normal iron status. Pramipexole is a dopamine agonist that has been approved by the FDA for the treatment of restless legs syndrome. It can cause a wide range of side effects, including headache, edema, sedation, and abnormal movements. The results of the present study demonstrate that iron supplementation is as effective as pramiprexole in patients with restless legs syndrome and a low-normal serum ferritin level.

Lee CS et al. Comparison of the efficacies of oral iron and pramipexole for the treatment of restless legs syndrome patients with low serum ferritin. Eur J Neurol. 2014;21:260–266.

Fish Oil for Epilepsy

Twenty-four patients (aged 18–56 years) with drug-resistant epilepsy were randomly assigned to receive, in double-blind fashion, high-dose fish oil (3 capsules twice a day; 2,160 mg per day of eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]), low-dose fish oil (3 capsules per day; 1,080 mg per day of EPA + DHA), or placebo (corn oil) for 10 weeks. Each patient then received each of the other 2 treatments for 10 weeks, with a 6-week washout period between treatments. Compared with placebo, low-dose fish oil significantly decreased mean seizure frequency by 33.6% (p = 0.02) and high-dose fish oil nonsignificantly decreased seizure frequency by 3.7%.

Comment : Omega-3 fatty acids inhibit neuronal excitability and reduce seizures in animal models. High-dose fish oil has been studied in 2 randomized trials in patients with drug-resistant epilepsy, with negative results (Yuen AW et al. Omega-3 fatty acid supplementation in patients with chronic epilepsy: a randomized trial. Epilepsy Behav. 2005;7:253–258; Bromfield E et al. A randomized trial of polyunsaturated fatty acids for refractory epilepsy. Epilepsy Behav. 2008;12:187–190.). The results of the present study suggest that the efficacy of fish oil is dose related: a lower dose (equivalent to about 3 g per day of fish oil) was effective, whereas a higher dose was not. In this study, the magnitude of the effect of low-dose fish oil was similar to that seen in recent clinical trials of antiepileptic drugs in patients with drug-resistant epilepsy. It is not clear why increasing the dose of fish oil might abolish its beneficial effect. However, there are other examples in nutritional medicine of a “therapeutic window,” where both higher and lower doses are less effective than the optimal dose.

DeGiorgio CM et al. Fish oil (n-3 fatty acids) in drug resistant epilepsy: a randomised placebo-controlled crossover study. J Neurol Neurosurg Psychiatry. 2015;86:65–70.

N-Acetylcysteine for Methamphetamine Addiction

Thirty-two methamphetamine-dependent individuals seeking treatment were randomly assigned to receive, in double-blind fashion, 1200 mg per day of N-acetylcysteine (NAC) or placebo for 4 weeks. After a 3-day washout period, each person received the alternate treatment for an additional 4 weeks. Methamphetamine craving was assessed weekly, using the Cocaine Craving Questionnaire-Brief (CCQ-Brief). In the 23 subjects who completed the study, the mean CCQ-Brief score decreased (improved) progressively with NAC treatment. The mean scores in the NAC and placebo groups were 3.38 and 5.96, respectively, at the end of first session, and 4.57 and 3.2, respectively, at the end of the second session (p < 0.001 for the difference between NAC and placebo). Compared with placebo, NAC reduced methamphetamine craving by 43% in the first session and by 30% in the second session.

Comment : The presence of a subnormal concentration of glutamate in the nucleus accumbens region of the brain may increase compulsive or addictive behaviors and heighten cravings. Treatment with NAC has been shown to increase glutamate concentrations in the nucleus accumbens. In previous studies, NAC has shown potential as a treatment for cocaine addiction, nicotine addiction, and pathological gambling. The results of the present study suggest that NAC can also decrease methamphetamine craving. The lesser efficacy of NAC after the participants were crossed over to the alternate treatment may have been due to a carryover effect, since the score in the placebo group was lower in the second session than in the first session. That possibility is supported by a precious study, in which the beneficial effect of NAC in pathological gamblers persisted for 3 months after treatment was discontinued

Mousavi SG et al. The efficacy of N-acetylcysteine in the treatment of methamphetamine dependence: a double-blind controlled, crossover study. Arch Iran Med. 2015;18:28–33.

Vitamin D: Could Toxicity Sneak Up on You?

Twenty-nine individuals (mean age, 62.5 years) with impaired glucose tolerance were randomly assigned to receive 20,000 IU of vitamin D3 or placebo once a week for 3 to 5 years. At the end of the treatment period, abdominal subcutaneous fat tissue was obtained by needle biopsy for measurement of vitamin D3 and 25-hydroxyvitamin D3 (25[OH]D) concentrations. In the group receiving vitamin D, median concentrations of serum 25(OH)D, fat-tissue vitamin D, and fat-tissue 25(OH)D were 99  nmol/L, 209  ng/g, and 3.8  ng/g, respectively. In the placebo group, these values were 62  nmol/L, 32  ng/g, and 2.5  ng/g, respectively. Assuming that an equal amount of vitamin D was stored in all adipose tissue in the body, the median body store in people given vitamin D supplements was 6.6 mg (264,000 IU) of vitamin D and 0.12  mg of 25(OH)D.

Comment : In this study, long-term supplementation with the equivalent of about 3,000 IU of vitamin D per day increased serum 25(OH)D levels by 60%. In contrast, the mean concentration of vitamin D in fat tissue increased by 553%. The study did not investigate whether fat-tissue vitamin D levels plateau or continue to rise with continued supplementation. If the levels do continue to rise, vitamin D toxicity could develop after many years of supplementation with doses that are known to be safe in the short term. Vitamin D toxicity might be accompanied by an abrupt rise in the serum 25(OH)D level, but in the pretoxic phase, the serum 25(OH)D level might not accurately reflect the amount of vitamin D that has accumulated in the body. If toxicity does occur, it could take a long time to resolve, considering the large amount of vitamin D that has accumulated in fat tissue.

Didriksen A et al. Vitamin D3 increases in abdominal subcutaneous fat tissue after supplementation with vitamin D3. Eur J Endocrinol. 2015;172:235–241.