Confirmation of some basic drugs by LC/MSMS is limited by collision induced dissociation (CID) fragmentation producing an insufficient number of product ions. The range of diagnostic product ions can be increased by ionising these basic drugs simultaneously in positive and negative mode. The ionisation of basic drugs in negative mode can be enhanced through the use of 0.2 mM ammonium fluoride in the chromatography mobile phases. This confirmation strategy has been applied to a range of drug targets including lignocaine, mepivacaine, detomidine and medetomidine, together with their metabolites. Negative mode ionisation has also proven effective with O-desmethyltramadol but tramadol itself was not capable of negative ionisation.