The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties

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 selfadminister 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.

Substance use in older HIV-infected patients

“…An emerging area of prescription drug misuse of particular importance to HIV providers is the report of increased diversion and nonmedical use of antiretroviral medications for their psychoactive properties[67–69]. Efavirenz in particular, may have a distinct hallucinogenic effect similar to LSD, and there are reports of its abuse alone and in combination with other psychoactive substances[67, 70].…”

“…Efavirenz in particular, may have a distinct hallucinogenic effect similar to LSD, and there are reports of its abuse alone and in combination with other psychoactive substances[67, 70]. In addition, ritonavir, an inhibitor of CYP2D6, is reported to heighten the psychoactive effects of methamphetamine and ecstasy[68].…”

Recreational Drugs and Antiretrovirals: Is It Worth the World or Trivial?

“…Çalışmalar efavirenzin halüsinojen bir madde olan LSD ile benzer psikoaktif özelliklere sahip olduğunu göstermektedir [59] . Beraber kullanılmaları farmakodinamik etkileşim sonucu LSD etkisinde ve efavirenz yan etkisinde artmaya neden olabilir.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Also other hallucinogens, such as N,N-dimethyltryptamine and the phenethylamine hallucinogen mescaline have significant affinity mainly to the G q/11 -coupled 5-HT 2A/C receptors (Aghajanian and Marek, 1999;Ray, 2010). Moreover, efavirenz [(4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H,3,1-benoxazin-2-one], a nonnucleoside reverse-transcriptase inhibitor used for treatment of HIV-1 infection, shows a risk for neuropsychiatric adverse effects such as night terrors and hallucinations and is a potent 5-HT 2A agonist (Gatch et al, 2013). MDMA, however, a stimulant with secondary hallucinogenic properties, produces its hallucinogenic effects mainly indirectly, by increasing synaptic 5-HT levels through SERT-mediated 5-HT release (Liechti et al, 2000).…”