Efavirenz is highly effective at suppressing HIV-1, and the WHO guidelines list it as a component of the first-line antiretroviral (ARV) therapies for treatment-naïve patients. Though the pharmacological basis is unclear, efavirenz is commonly associated with a risk for neuropsychiatric adverse events (NPAEs) when taken at the prescribed dose. In many patients these NPAEs appear to subside after several weeks of treatment, though long-term studies show that in some patients the NPAEs persist. In a recent study focusing on the abuse potential of efavirenz, its receptor psychopharmacology was reported to include interactions with a number of established molecular targets for known drugs of abuse, and it displayed a prevailing behavioral profile in rodents resembling an LSD-like activity. In this report, we discovered interactions with additional serotonergic targets that may be associated with efavirenz-induced NPAEs. The most robust interactions were with 5-HT_3A and 5-HT₆ receptors, with more modest interactions noted for the 5-HT_2B receptor and monoamine oxidase A. From a molecular mechanistic perspective, efavirenz acts as a 5-HT₆ receptor inverse agonist of G_s-signaling, 5-HT_2A and 5-HT_2C antagonist of G_q-signaling, and a blocker of the 5-HT_3A receptor currents. Efavirenz also completely or partially blocks agonist stimulation of the M₁ and M₃ muscarinic receptors, respectively. Schild analysis suggests that efavirenz competes for the same site on the 5-HT_2A receptor as two known hallucinogenic partial agonists (±)-DOI and LSD. Prolonged exposure to efavirenz reduces 5-HT_2A receptor density and responsiveness to 5-HT. Other ARVs such as zidovudine, nevirapine and emtricitabine did not share the same complex pharmacological profile as efavirenz, though some of them weakly interact with the 5-HT₆ receptor or modestly block GABA_A currents.

Copyright © 2016. Published by Elsevier Ltd.