The NNRTI efavirenz has long been one of the most frequently employed antiretroviral drugs in the multidrug regimens used to treat HIV infection, in accordance with its well-demonstrated antiretroviral efficacy and favourable pharmacokinetics. However, growing concern about its adverse effects has sometimes led to efavirenz being replaced by other drugs in the initial treatment selection or to switching of therapy to efavirenz-free regimens in experienced patients. Neurological and neuropsychiatric reactions are the manifestations most frequently experienced by efavirenz-treated patients and range from transitory effects, such as nightmares, dizziness, insomnia, nervousness and lack of concentration, to more severe symptoms including depression, suicidal ideation or even psychosis. In addition, efavirenz has recently been associated with mild/moderate neurocognitive impairment, which is of specific relevance given that half of the patients receiving ART eventually suffer some form of HIVassociated neurocognitive disorder. The mechanisms responsible for efavirenz-induced neurotoxicity are unclear, although growing evidence points to disturbances in brain mitochondrial function and bioenergetics. This review offers a comprehensive overview of the current evidence on the interaction that efavirenz displays with the CNS, including the penetration and concentration of the drug in the brain. We discuss the prevalence, types and specificities of its side effects and recently uncovered cellular mechanisms that may be involved in their development. Funding: grants PI14/00312 and CIBER CB06/04/0071 (both from Instituto de Salud Carlos III, Ministerio de Economía y Competitividad), PROMETEOII/2014/035 and GV/2014/118 (both from Generalitat Valenciana), and P1.1B-2014/15 (Universitat Jaume I). A. B.-G. is a recipient of a Juan de la Cierva contract (JCI-2012-15124, Ministerio de Economía y Competitividad). H. A. F. is the recipient of Predoctoral Trainee Research Grant from Fundación Juan Esplugues.
