The HIV antiretroviral drug efavirenz has LSD-like properties

Michael B. Gatch, Alexey Kozlenkov, Ren Qi Huang, Wenjuan Yang, Jacques D. Nguyen, Javier González-Maeso, Kenner C. Rice, Charles P. France, Glenn H. Dillon, Michael J. Forster, John A. Schetz

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

Anecdotal reports have surfaced concerning misuse of the HIV antiretroviral medication efavirenz ((4S)-6-chloro-4-(2-cyclopropylethynyl)-4- (trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one) by HIV patients and non-infected teens who crush the pills and smoke the powder for its psychoactive effects. Molecular profiling of the receptor pharmacology of efavirenz pinpointed interactions with multiple established sites of action for other known drugs of abuse including catecholamine and indolamine transporters, and GABA A and 5-HT 2A receptors. In rodents, interaction with the 5-HT 2A receptor, a primary site of action of lysergic acid diethylamine (LSD), appears to dominate efavirenz's behavioral profile. Both LSD and efavirenz reduce ambulation in a novel open-field environment. Efavirenz occasions drug-lever responding in rats discriminating LSD from saline, and this effect is abolished by selective blockade of the 5-HT 2A receptor. Similar to LSD, efavirenz induces head-twitch responses in wild-type, but not in 5-HT 2A-knockout, mice. Despite having GABA A-potentiating effects (like benzodiazepines and barbiturates), and interactions with dopamine transporter, serotonin transporter, and vesicular monoamine transporter 2 (like cocaine and methamphetamine), efavirenz fails to maintain responding in rats that self-administer cocaine, and it fails to produce a conditioned place preference. Although its molecular pharmacology is multifarious, efavirenz's prevailing behavioral effect in rodents is consistent with LSD-like activity mediated via the 5-HT 2A receptor. This finding correlates, in part, with the subjective experiences in humans who abuse efavirenz and with specific dose-dependent adverse neuropsychiatric events, such as hallucinations and night terrors, reported by HIV patients taking it as a medication.

Original languageEnglish
Pages (from-to)2373-2384
Number of pages12
JournalNeuropsychopharmacology
Volume38
Issue number12
DOIs
StatePublished - Nov 2013

Keywords

  • AIDS
  • adverse neuropsychiatric events
  • hallucinogen
  • side effects

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    Gatch, M. B., Kozlenkov, A., Huang, R. Q., Yang, W., Nguyen, J. D., González-Maeso, J., Rice, K. C., France, C. P., Dillon, G. H., Forster, M. J., & Schetz, J. A. (2013). The HIV antiretroviral drug efavirenz has LSD-like properties. Neuropsychopharmacology, 38(12), 2373-2384. https://doi.org/10.1038/npp.2013.135