to brain pH11, and a lower brain pH, indicating a protracted agonal state, has been associated with significant changes in transcriptional profile12, in particular of apoptotic, reactive oxygen stress, mitochondrial, chaperone and proteasome pathways.13 Furthermore, variations in respiratory stress in the acute agonal state during heroin overdose deaths differentially changed brain pH levels, and significantly impacted levels of proenkephalin and dopamine-related genes.14 Brain tissue from smokers appeared to have significantly lower brain pH than non-smokers9, which may skew expression data for transcripts such as mitochondrial genes that appear sensitive to agonal/pH state.13 Other potentially important sets of transcriptional differences are encoded by gender15–16, while the effects of age, ethnicity and postmortem interval are less clear-cut, but should all be addressed in the study design. Identifying potential confounds, and matching control and substance use cases accordingly, helps ensure that the transcriptional differences identified are not artifacts but representative of ante-mortem substance use.
