This paper is a review and exploration of pre-pulse inhibition (PPI) in humans, with comparisons made across species and between human volunteers with and without major mental illnesses. Findings in human pharmacological studies were compared with findings in non-human animals (mostly rodents). While some drugs appeared to have similar effects on PPI in human and non-human animals (dopaminergic drugs, nicotine), there were significant cross-species differences in effects on PPI produced by other drugs (MDMA, ketamine and psilocybin). MDMA reduced PPI in rodents, but facilitated PPI in humans, and this effect was attenuated by pre-treatment with the SSRI citalopram. Findings of inter-species differences in drug effects on PPI suggest that researchers should be cautious when making other cross-species comparisons.