From Analgesia to Synaptic Remodeling: A Systematic Review of Acetaminophen's Neuromodulatory Effects

INTRODUCTION: Neuro-related disorders will be rising globally. Current treatments have numerous limitations that can impair patients' quality of life. One of the key therapeutic approaches is promoting neuroplasticity. Neuroplasticity plays a vital role in memory, learning, and recovery of function after neural damage. Acetaminophen (Paracetamol; APAP) has been suggested as a neuroprotective treatment through modulation of neuroplasticity dose-duration dependently. METHODS: This systematic review was conducted across major databases such as PubMed/MEDLINE, Google Scholar, Scopus, and Web of Science, between 2002 and October 2025, and from an initial pool of 537 articles, we selected only English-language studies with complete methodology and full results reporting the effects of acetaminophen on neuroplasticity. RESULTS: Preclinical evidence suggests that short-term, low-dose acetaminophen can have neuroprotective effects. Acetaminophen is metabolized in the brain to AM404, which activates TRPV1, inhibit COX-1/COX-2, and modulates the endocannabinoid system, reducing inflammation and oxidative stress. They also engage BDNF neurotrophic signalling, creating a mechanistic basis for potential neuroplasticity modulation. DISCUSSION: While low-dose, short-term acetaminophen shows neuroprotective effects in preclinical models, long-term or high-dose use may lead to neurotoxicity. CONCLUSION: Although preclinical evidence suggests that acetaminophen may influence neuroplasticity in a dose- and time-dependent manner, substantial heterogeneity in dosing protocols limits definitive conclusions. Therefore, further standardized preclinical and clinical studies with larger sample sizes and longer follow-up are required to define safe and effective exposure windows in humans.