Replica exchange with solute tempering (REST2) is an enhanced sampling method that involves "heating" a highly localised part of the solute and exchanging information across concurrent simulations being performed at different intermediate points along the alchemical path and which have different "effective temperatures". It has been claimed that REST2 accelerates local sampling around the alchemical region and should either improve the results or leave them unchanged. However, we have previously reported that the blind application of this method can degrade the quality of free energy predictions. In the present study, we report a systematic and statistically robust assessment of REST2 that establishes beyond doubt the general validity of our findings.