Only women seemed to reap a cognitive benefit from sodium benzoate, according to exploratory data from researchers in Taiwan.
In a post hoc secondary analysis of a randomized trial, 30 women with later-phase Alzheimer's disease or vascular dementia saw a significant improvement in cognitive scores with six weeks of sodium benzoate treatment, reported Hsien-Yuan Lane, MD, PhD, of China Medical University Hospital in Taichung, and colleagues, in JAMA Network Open.
As measured by the 70-point Alzheimer disease assessment scale-cognitive subscale (ADAS-cog) with higher scores indicating more impairment, this improvement was marked by an average drop of 3.1 points versus no point change for women on placebo (Cohen d=0.56, P=0.04).
However, this therapy didn't evoke a behavioral benefit, as measured by Behavioral Pathology in Alzheimer Disease Rating Scale scores (z=0.18, P=0.86), according to the researchers.
Men saw no cognitive nor behavioral benefit with six weeks of sodium benzoate treatment in the analysis, they noted.
Sodium benzoate acts as an indirect NMDA receptor (NMDAR) enhancer. It is most commonly used as a preservative in packaged and processed foods and beverages. The chemical compound, which appears as a crystalline powder, is made from combining benzoic acid and sodium hydroxide.
The authors reported that there were some slight hormonal changes in women in the study, as benzoate treatment was significantly tied to an increase in estradiol to follicle-stimulating hormone (FSH) ratios in women compared with those on placebo (mean difference between baseline and endpoint 0 versus -0.1 with placebo, P=0.03). Despite this statistically significant change, the researchers pointed out this "minor" difference in ratio was likely too small to hold any clinical relevance.
However, the individual endpoint differences in estradiol (26.3 pg/mL with benzoate vs 23.5 pg/mL with placebo) and FSH (48.0 mIU/mL vs 45.9 mIU/mL, respectively) levels by the close of the trial didn't significantly differ among women.
The original randomized study was a 6-week trial that included a total of 97 patients (average age 75) from three major Taiwanese medical centers; in the original analysis, sodium benzoate appeared ineffective. All participants (n=62 women) were deemed to have probable Alzheimer's disease as defined by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria or probable vascular dementia, according to National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria.
The majority of the men and women included had a Clinical Dementia Rating of 1 at baseline, indicating moderate disease. About a third of the cohort had a score of 2, indicating severe memory loss, and a handful of participants had a score of 3, the most severe stage of disease.
Patients randomized to sodium benzoate started on an initial dose between 250 to 500 mg per day, which was increased in biweekly increments of 250 to 50 mg daily if indicated, to a threshold dose of 1,500 mg per day.
Lane's group said these findings build upon some of their previous research, which suggested a cognitive functional benefit with sodium benzoate in both men and women with early-phase dementia.
They added that because this current post-hoc analysis only found a benefit in females with later-phase dementia, this lends support "to the previous notion that women may be more susceptible to NMDAR modulation than males, which was based upon animal study."
"Sodium benzoate has antibacterial and antifungal activity," the researchers also pointed out, as one possible mechanism of action to this therapy.
"Accumulating evidence shows the role of brain-gut-microbiota axis in neuropsychiatric disorders. It is of interest to investigate the role of gut microbiota before and after treatment of benzoate in the future," they suggested.
A study limitation was the short 6-week duration. Lane's group noted that sodium benzoate has shown some success in prior studies in improving psychotic symptoms in schizophrenia, but those trials also utilized a much higher average dose (either 1,000 or 2,000 mg daily at week 6) than the current study.
"Whether sodium benzoate can help at least a portion of dementia patients, such as women or patients at a younger age and earlier phase of illness, deserves more studies with longer duration and higher doses (and perhaps also lower doses) for confirmation," they concluded.
Disclosures
The study was supported by Taiwan Ministry of Science and Technology, the National Health Research Institutes, Kaohsiung Chang Gung Memorial Hospital, and China Medical University Hospital in Taiwan.
Lin and co-authors disclosed no relevant realtionships with industry.
