Can N-acetylcysteine Help with Smoking Cessation?

Ninety male smokers in Indonesia (mean age, 39 years) participating in a smoking cessation program were randomly assigned to receive, in double-blind fashion, 1,200 mg of N-acetylcysteine (NAC) or placebo twice a day for 4 weeks. Smoking cessation was verified by measuring the amount of exhaled carbon monoxide and by self-report from the participants. The abstinence rate at the end of the study was significantly higher in the NAC group than in the placebo group (37.7% vs. 6.6%; p = 0.02). The median score on a scale that measured craving was significantly lower (less craving) (p = 0.004), and withdrawal symptoms were nonsignificantly lower (p = 0.18) in the NAC group than in the placebo group. No serious adverse events were reported, although some patients receiving NAC experienced gastrointestinal discomfort and one patient experienced arthralgia.

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.¹ In the present study, NAC supplementation appeared to be useful for people who were trying to quit smoking.

Harlivasari AD, et al. The role of twice-daily N-acetylcysteine (NAC) 2400 mg in smoking cessation: a randomized, placebo-controlled trial in Indonesia. Cureus. 2024;16(2):e54322.

Benefits of Virgin Olive Oil May Not Occur with Refined Olive Oil

The association between olive oil consumption and all-cause and cause-specific mortality was examined in a prospective cohort study of 12,161 Spanish adults (mean age, 47 years). After a mean follow-up period of 10.7 years, 143 cardiovascular deaths and 146 cancer deaths occurred. The hazard ratio (HR) (95% confidence interval) for all-cause mortality in the highest tertile of consumption was 0.96 (not significant) for refined olive oil and 0.66 (0.49-0.90; p for trend = 0.04) for virgin olive oil. Virgin olive oil consumption was also inversely associated with cardiovascular mortality, with a HR of 0.43 (0.20-0.91; p for trend < 0.02), but no significant trend was seen with refined olive oil (HR = 0.88; p for trend = 0.24). Neither type of olive oil was associated with cancer mortality.

Comment: The beneficial effects of olive oil (both virgin and refined) are thought to be due in part to its high concentration of monounsaturated fatty acids. However, extra-virgin olive oil and, to a lesser extent, virgin olive oil also contain a number of phenolic antioxidants (oleuropein, hydroxytyrosol, vanillic acid, and verbascoside), which may have anti-inflammatory and cardioprotective effects. These phenolic compounds are almost entirely removed during the refining process. In the present observational study, daily consumption of about 1.5 tablespoons of virgin olive oil was associated with a one-third lower risk of all-cause mortality and a 50% lower risk of cardiovascular mortality. The associations with consumption of refined olive oil were much smaller and not statistically significant.

Donat-Vargas C, et al. Only virgin type of olive oil consumption reduces the risk of mortality. Results from a Mediterranean population-based cohort. Eur J Clin Nutr. 2023;77:226-234.

Melatonin for Melasma

Seven patients in India with melasma (disease duration, 6 months to 4 years) that had failed to respond to various topical treatments including the Kligman regimen (hydroquinone, a retinoid, and hydrocortisone) were treated with 3 mg of melatonin once a day for 12 weeks. All patients used a strong topical sunscreen product (SPF 50). The effect of treatment was assessed with the modified Melasma Area and Severity Index (MASI). MASI scores range from 0 to 24, with higher numbers indicating more severe melasma. After 12 weeks, all patients reported a lessening of the hyperpigmentation. The mean score on the modified MASI improved from 7.11 at baseline to 4.10 after 12 weeks (42% improvement).

Comment: Melasma is a brown hyperpigmentation that occurs on the face and other sun-exposed areas. Around 90% of cases occur in women. Hormonal factors appear to be involved, as the condition occurs frequently during pregnancy or as a side effect of oral contraceptives. The present case reports suggest that melatonin is moderately effective as a treatment for melasma. The authors of this study suggested that melatonin may work by modulating the effects of certain hormones involved in the pathogenesis of melasma, including melanocyte-stimulating hormone, estrogen, and progesterone.

As noted above, all of the patients in this study used a strong topical sunscreen product, and it is possible that some or all of the improvement was due to the use of this product. The authors did not state whether the patients had previously been advised to minimize sun exposure, although such advice is generally recognized as a key component of melasma treatment.

Sarkar R, et al. Use of oral melatonin in recalcitrant melasma. Int J Dermatol. 2024;63:1111-1112.

Can Dietary Changes Improve Gastrointestinal Symptoms Associated with Endometriosis?

Thirty-five Australian women (mean age, 31 years) with poorly controlled gastrointestinal symptoms associated with endometriosis (confirmed by laparoscopy and/or ultrasound) were randomly assigned to consume, in single-blind fashion, a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs), containing less than 5 g per day of FODMAPs or a control diet containing 20 g per day of FODMAPs. Both diets contained gluten and were low in lactose. Dietary interventions were started on day 1 of the menstrual cycle and continued for 28 days. After a washout period of at least 28 days (during which participants consumed their usual diet), the women were crossed over to the other diet, beginning on day 1 of the menstrual cycle and continuing for 28 days. A response was defined as a reduction of more than 20 mm on a 100-mm visual analogue scale that assessed irritable bowel syndrome symptoms; or, if the baseline score was 50 or less, a response was defined as a post-intervention score of less than 30. The proportion of responders was 60% on the low-FODMAPs diet and 26% on the control diet (p = 0.008). In the fourth week of the intervention, the median overall symptom score was lower (better) with the low-FODMAPs diet than with the control diet (35 vs. 58; p < 0.001). Abdominal pain, bloating, and stool form were significantly better with the low-FODMAPs diet than with the control diet.

Comment: Most women with endometriosis experience gastrointestinal symptoms. While the cause of these symptoms is not entirely clear, they may result from mechanical obstruction or from inflammation caused by endometriosis lesions. Low-FODMAPs diets have previously been reported to relieve symptoms of irritable bowel syndrome. The results of the present study suggest that this diet may also improve gastrointestinal symptoms associated with endometriosis.

Varney JE, et al. Clinical trial: effect of a 28-day low FODMAP diet on gastrointestinal symptoms associated with endometriosis (EndoFOD) – a randomised, controlled crossover feeding study. Aliment Pharmacol Ther. 2025;61:1889-1903.

Is Intravenous Vitamin C Effective Against Sepsis, or Is This More Fraudulent Research from Egypt?

Fifty full-term neonates in Tanta, Egypt, who had developed sepsis after a surgical procedure and required mechanical ventilation were randomly assigned to receive, in double-blind fashion, intravenous vitamin C or placebo, in addition to standard care. Vitamin C was administered as a loading dose of 500 mg per kg of body weight, followed by 500 mg per kg per hour for 6 hours. This treatment was continued daily for 7 to 10 days. Compared with placebo, vitamin C significantly improved various parameters of respiratory function and significantly decreased the need for mechanical ventilation and inotropic support. The authors concluded that intravenous vitamin C is beneficial in the treatment of sepsis among neonates.

Comment: As readers of the Townsend Letter know, over the past 10 years or so, I have been concerned about the large and growing number of published papers in the field of nutrition that left me wondering whether the research was fabricated; that is, whether people were writing papers about research that had not actually been conducted. Most of the questionable papers have come from Iran, but there have also been concerns about papers from Egypt, China, Japan, India, Italy, and a few other countries.

A careful review of the present study revealed a number of concerns. I outlined these concerns in an email to the European Journal of Pediatrics, and they replied that they would conduct an investigation. My email listed the following concerns:

1. Issue related to funding: The only funding mentioned in the paper was for open-access printing. It does not seem plausible that this randomized controlled trial could have been conducted without additional funding.
2. Unusually large dose of vitamin C: The dosage of intravenous vitamin C (after the loading dose was given) was 500 mg per kg of body weight per hour for 6 hours, repeated every day for 7 to 10 days. That dosage is equivalent to 3 g per kg of body weight per day, which is about 6 times higher than the dosage of intravenous vitamin C used in studies to treat adults with septic shock. There is little or no research demonstrating that the very large amount of vitamin C used in this study (equivalent to 210 g per day for a 70-kg adult) is safe for either infants or adults. In addition, administering 3 g of intravenous vitamin C over 6 hours would require a large amount of fluid, the safety of which is not clear. The patients in the placebo group would also have had to receive a large amount of intravenous fluid, the safety of which is also unclear. For these reasons, it is surprising that the ethics committee would have approved the study. In addition, the “informed consent” document would have had to mention the unknown safety of this large dose of vitamin C. If parents had been aware of the lack of safety data, one wonders whether 50 of the 55 sets of eligible parents would have agreed to allow their baby to participate in the study.
3. Questionable baseline characteristics: The mean gestational age was 4 days longer in the vitamin C group than in the placebo group, but the mean birth weight was 55 g less in the vitamin C group than in the placebo group. Those numbers seem unusual. The mean birth weight in the entire study group was 1,902 g, which seems implausibly low for a group of 50 full-term infants.
4. Missing data: There was no mention of what types of surgery the infants underwent. In addition, there was no mention of the vehicle in which the vitamin C was administered or of the composition of the placebo infusion.
5. Issues related to recruitment: One might question whether it was possible to recruit the number of patients that this paper claimed to have recruited during a 6-month period at a single hospital. To be included in the study, the infant had to develop sepsis after undergoing a surgical procedure. The need for surgery is uncommon in full-term infants (estimated to be 0.6% to 1% of births). When surgery is needed, it is often due to a congenital anomaly, but patients were excluded from the study if they had a major congenital anomaly. The city of Tanta (where the study was conducted) has a population of around 600,000 and an annual birth rate of 15 per 1,000 population. In the 6 months during which the study was conducted, one would have expected around 4,500 births. Since around 12% of births are preterm (another exclusion criterion), there would have been around 3,960 full-term births in Tanta during the study period. It is difficult to believe that 55 of 3,960 full-term infants required surgery for something other than a major congenital anomaly AND developed sepsis AND required mechanical ventilation AND were admitted to Tanta University Hospital (there are multiple neonatal intensive care units in Tanta, Egypt).

Elmesiry AM, Mai Rabie Elsheikh AM, Elshimy LM, Abotaleb AM. Role of vitamin C infusion in postoperative mechanically ventilated neonates with sepsis: a randomized controlled trial. Eur J Pediatr 2025 Nov 29;184(12):806.

Iron Supplementation for Heart Failure: Is the Use of Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors a Contraindication?

A retrospective study was conducted on 16,660 patients with iron deficiency (serum ferritin < 100 ng/L) and systolic heart failure who were receiving a sodium-glucose transport protein 2 (SGLT2) inhibitor. After propensity score matching to balance confounding factors between groups, 3,183 patients who received intravenous iron were compared with 3,183 patients who did not receive intravenous iron. Iron therapy (as compared with no iron therapy) was associated with a 56% increase in the risk of thromboembolic events (p = 0.001), a 51% increase in major adverse cardiovascular events (p = 0.007), a 41% increase in heart failure exacerbations (p = 0.003), and a 55% increase in all-cause mortality (p < 0.001).

Comment: Numerous studies have found that treatment with intravenous iron can decrease hospitalizations, improve functional capacity, and possibly decrease mortality in patients with heart failure and iron deficiency. SGLT2 inhibitors such as empagliflozin (Jardiance), dapagliflozin (Farxiga), and canagliflozin (Invokana) have also been found to have cardioprotective effects, but little is known about their effects when used in combination with iron therapy in patients with heart failure. In the present study of patients with heart failure who were receiving SGLT2 inhibitors, intravenous iron therapy was associated with a significant increase in thromboembolic events, major adverse cardiovascular events, heart failure exacerbations and all-cause mortality. The authors of the study suggested that the mechanism of the adverse interaction was the combined erythropoietic effect of SGLT2 inhibitors and iron therapy, leading to increased serum viscosity and hemoconcentration, which are known to promote venous thrombosis.

Alruwaili W, et al. Clinical outcomes of intravenous iron therapy in systolic heart failure patients receiving SGLT2 inhibitors. Am J Cardiol. 2025;254:5-12.

Can Eating Curry Prevent Cognitive Decline?

Curry consumption was examined at baseline in 2,446 community-dwelling individuals in Singapore (aged 55 years or older; mean age, 65.5 years) who did not have a neurocognitive disorder. During a mean follow-up period of 4.5 years, higher intake of curry was associated with a lower rate of cognitive decline (p for trend < 0.04). The cumulative incidence of mild cognitive impairment/dementia was 13.1% in those who never or rarely consumed curry, as compared with 3.6% in those who consumed curry daily (p for trend < 0.001). The adjusted odds ratio across levels of curry consumption showed a linear trend (p = 0.02), from an odds ratio of 0.61 (p < 0.05) for occasional consumption to an odds ratio of 0.21 (p < 0.001) for daily consumption.

Comment: In this study of elderly community-dwelling individuals in Singapore, higher intake of curry was associated with a lower incidence of cognitive decline and mild cognitive impairment/dementia. Turmeric, one of the main ingredients in curry, contains large amounts of curcumin, a compound that has antioxidant and anti-inflammatory activity. Previous studies have suggested that curcumin may be useful for preventing or treating cardiovascular disease, age-related macular degeneration, inflammatory bowel disease, and some types of arthritis and cancer. The results of the present study suggest that curcumin (the presumed active ingredient in curry) may also help prevent age-related cognitive decline.

Lu Y, et al. Curcumin-rich curry consumption is associated with lower risk of cognitive decline and incidence of mild cognitive impairment or dementia: an Asian population-based study. Nutrients. 2025;17:2488.

Magnesium Improves Sleep

One hundred fifty-five healthy adults (aged 18-65 years) with self-reported poor sleep quality were randomly assigned to receive, in double-blind fashion, 250 mg per day of magnesium (from magnesium bisglycinate) or placebo, taken 30 to 60 minutes before bedtime for 4 weeks. The mean improvement in sleep quality (as determined by the Insomnia Severity Index) was greater in the magnesium group than in the placebo group (p < 0.05). The effect size was small (Cohen’s d = 0.2), indicating a modest benefit. Exploratory analyses suggested that the improvements were greater among participants with lower baseline dietary magnesium intake.

Comment: Insomnia is one of the symptoms of magnesium deficiency. The typical Western diet contains less than the Recommended Dietary Allowance for magnesium. In addition, various types of physical and mental stress can lead to magnesium depletion and an increased magnesium requirement. For these reasons, many otherwise healthy people have suboptimal magnesium status. The results of the present study support previous research demonstrating that magnesium supplementation can improve sleep quality among poor sleepers.

Schuster J, et al. Magnesium bisglycinate supplementation in healthy adults reporting poor sleep: a randomized, placebo-controlled trial. Nat Sci Sleep. 2025;17:2027-2740.

Reference

1. Grant JE, et al. N-Acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study. Biol Psychiatry. 2007;62:652-7.