Estimating M value using a gas challenge is an essential component of calibrated fMRI. M is the maximal possible BOLD response and reflects baseline physiology such as CBF, CBV and CMRO2. Despite its common use, it is unknown how caffeine ingestion affects M. Here it is demonstrated that caffeine increases M regionally, with frontal brain regions including the paracingulate and anterior cingulate gyrus particularly affected. M increases were found in the context of decreased baseline CBF. These results indicate that caffeine may be implicated in regional uncoupling between CBF and CMRO2 which causes an increase in M.