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 GABAA and 5-HT2A receptors. In rodents, interaction with the 5-HT2A 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-HT2A receptor. Similar to LSD, efavirenz induces head-twitch responses in wild-type, but not in 5-HT2A-knockout, mice. Despite having GABAA-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-HT2A 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.
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Acknowledgements
We thank Dr Michael Oglesby for critical reading of early versions of the manuscript, Dr Kathyrn Cunningham for insightful discussions related to this work, and Brian Weiss, Shahnawaz Amdani, Marshayla McPhaul, Terrell Holloway and Fatima Sahyouni for technical assistance. We also thank Dr David Lynch (University of Pennsylvania) for providing the cDNAs encoding rat NR1a, NR2A, and NR2B, Dr Eldo Kuzhikandathil (UMDNJ-New Jersey Medical School) for providing an Att20 cell line stably expressing the human D3 receptor, and Dr David B Bylund (University of Nebraska Medical Center) for providing the HEK293 cell line stably expressing the human α2C adrenergic receptor. This work was supported, in part, by the National Institutes of Health (Grant R01-MH063162 (JAS); K05DA17918 (CPF); R01 MH084894 (JGM); R01-DA022370 (GHD, MJF); N01DA-7-8872 (HHSN271200700014C) (MJF)), UNTHSC Intramural Grant RI-6015 (JAS, MG, and MJF), and institutional funds (JAS, MJF, and GHD). A portion of this work was also supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism (KCR).
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Gatch, M., Kozlenkov, A., Huang, RQ. et al. The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties. Neuropsychopharmacol 38, 2373–2384 (2013). https://doi.org/10.1038/npp.2013.135
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DOI: https://doi.org/10.1038/npp.2013.135
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