The HIV antiretroviral drug efavirenz has LSD-like properties.

Efavirenz, an HIV antiretroviral, is misused by crushing and smoking the pills for psychoactive effects. Molecular profiling shows it interacts with multiple targets of abused drugs, including catecholamine and indolamine transporters, and GABAA and 5-HT(2A) receptors. In rodents, its behavioral effects resemble LSD, mediated primarily through the 5-HT(2A) receptor: both reduce ambulation in open-field tests, efavirenz occasions drug-lever responding in rats discriminating LSD, and it induces head-twitch responses in wild-type but not 5-HT(2A)-knockout mice. Despite also having GABAA-potentiating effects and interactions with dopamine and serotonin transporters, efavirenz does not maintain self-administration in rats trained on cocaine or produce conditioned place preference. These findings correlate with subjective experiences in humans who abuse efavirenz and with dose-dependent neuropsychiatric side effects like hallucinations and night terrors in HIV patients.

Study at a glance

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-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 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-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.