¹Fujita Health University, Center for Medical Science, Toyoake, Japan

Background: Alcohol use disorder (AUD) not only severely diminishes patients' quality of life but also imposes substantial social burdens, with its prevalence growing worldwide in recent years. This underscores the urgent need to elucidate its underlying neural mechanisms. Brain metabolic alterations leading to decreased pH has been consistently reported in several neuropsychiatric disorders that share clinical manifestations with AUD, such as cognitive impairments.

Aims & Objectives: In this study, we investigated whether a similar phenomenon occurs in AUD and how it may relate to its molecular pathology through a systematic review and meta-analysis.

Method: Leveraging brain pH data typically reported as demographic information in postmortem studies but previously not treated as a primary outcome, we conducted quantitative meta-analyses comparing postmortem brain pH between patients with AUD and non-AUD controls. Raw pH data were collected from studies in the NCBI GEO and PubMed databases. Transcriptome data from AUD brain samples were comprehensively queried in the BaseSpace database that contains over 260,000 omics datasets and analyzed through pathway meta-analysis in combination with gene sets associated with brain pH change.

Results: A random-effects model applied to 28 studies revealed a significantly decreased brain pH in AUD. This decrease remained significant after considering postmortem interval, age at death, and sex. Subgroup analyses showed that decreased brain pH is not associated with blood alcohol concentration at death or comorbid liver cirrhosis, suggesting that these factors were not major confounds. Furthermore, meta-analysis integrating 27 AUD- and pH-associated transcriptomic datasets highlighted links between pH changes and altered energy metabolism, synaptic organization, and maturational processes, underlined by neural hyperexcitation.

Discussion & Conclusions: These findings suggest that decreased brain pH may be associated with the chronic pathophysiology of AUD rather than the acute effects of alcohol consumption or secondary effects of alcohol-induced liver disease. The observed brain acidification may represent a novel neural basis of chronic AUD, orchestrating its molecular manifestations.