Brain exposure to efavirenz is high following a single peripherally administered dose; it rapidly accumulates in the CNS. Data adapted and replotted from studies in humans (Gutierrez et al., 2005) and in rats (Dirson et al., 2006). Data are plotted as means ± S.D. (A) Patients that take a standard dose (600 mg) of efavirenz for a long period (average 18 months) and experience CNS adverse events have significantly higher plasma levels of efavirenz. Furthermore, patients having efavirenz plasma concentrations >2.74 µg/ml are over five and half times more likely to experience CNS adverse events (Gutierrez et al., 2005). Mean values and statistics are those reported in the original paper (Gutierrez et al., 2005). (B) Efavirenz at a dose within the range that has behavioral effects in rats (Gatch et al., 2013), rapidly accumulated in rat brain to levels that exceed four and half times the plasma levels (Dirson et al., 2006). The brain tissue exposure data are from a study assessing efavirenz uptake into rat brain tissue in the presence of ABCB1 transport blockers or vehicle (designated placebo in the original report) (Dirson et al., 2006). Replotted here is the efavirenz plus vehicle data (a combination of data for both types of vehicles designated Placebo V and Placebo S/Q). Note that similar high levels of brain accumulation (not shown here) occurs in mice [brain]/[plasma] = 2.9 ± 0.56 as well (Dirson et al., 2006).