Comparison of the Safety and Efficacy of Oral L-arginine for the Treatment of Cognitive Impairment in Older Adults: A Prospective, Randomized, Placebo-Controlled Pilot Study.

Background Cognitive impairment (mild cognitive impairment and early dementia) is a growing concern with limited therapeutic options. L-arginine, a semi-essential amino acid and precursor of nitric oxide, has shown neuroprotective effects in animal studies, but human trials, particularly in India, are lacking. This pilot study aimed to assess the safety and efficacy of oral L-arginine in elderly patients with cognitive impairment. Methodology This was a prospective, double-blind, randomized, placebo-controlled pilot study conducted at a tertiary care hospital in North India. Sixty-six subjects aged ≥60 years with subjective cognitive complaints were screened using the Hindi version of Addenbrooke's Cognitive Examination III (ACE-III); those scoring ≤82 were included after excluding reversible causes, including low vitamin B12 levels and abnormal thyroid-stimulating hormone (TSH) levels, coronary artery disease (CAD), and substance use. Thirty-eight participants were randomized to receive either oral L-arginine 6.4 g/day or a matching placebo for 30 days. Cognitive function was reassessed post-intervention using ACE-III. Adverse effects and tolerability were recorded. Results Thirty-five subjects completed the study (16 L-arginine and 19 placebo). Baseline characteristics were comparable between groups. After 30 days, the L-arginine group showed statistically significant within-group improvements in attention (p=0.018), memory (p<0.001), and language (p=0.017) domains, while the placebo group improved only in memory (p=0.003). Between-group comparison showed that significantly more patients in the L-arginine group achieved normal ACE-III scores (>82) compared to placebo (37.5% vs. 5.3%, p=0.032). Adverse effects leading to withdrawal in the L-arginine group included thyroid dysfunction (one participant), nausea/diarrhea (one participant), and bitter taste (one participant); no withdrawals occurred in the placebo group (p=0.353). Conclusions Oral L-arginine (6.4 g/day for 30 days) appears safe and improves attention, memory, and language domains in elderly patients with cognitive impairment. Larger, longer-term trials are warranted to confirm these findings and assess progression to dementia.