European Review for Medical and Pharmacological Sciences 2020; 24: 10729-10735 Efavirenz as a psychotropic drug N. ZAREIFOPOULOS1, M. LAGADINOU1, A. KARELA1, F. POULIASI1, I. ECONOMOU1, A. TSIGKOU2, D. VELISSARIS1,3 1Emergency Department, University Hospital of Patras, Patras, Greece 2Department of Architecture, University of Patras, Patras, Greece 3Department of Internal Medicine, University of Patras School of Medicine, Patras, Greece Abstract. – OBJECTIVE: Antiretroviral drugs Introduction are the mainstay of treatment for human immu- nodeficiency virus (HIV) infection. Lifelong high- Neuropsychiatric adverse effects are a common ly active antiretroviral therapy (HAART) is in- occurrence in daily clinical practice, and they are dicated to prevent disease progression to ac- quired immunodeficiency syndrome (AIDS). Efa- frequently observed even during treatment with virenz was a first-line component of HAART drugs that would not be expected to affect the ner- across the world for many years. The purpose vous system. Antimicrobial agents have been asso- of this article is to review the psychotropic prop- ciated with neuropsychiatric adverse effects which erties of efavirenz, which are the most import- may be severe, but this rarely affects prescribing ant adverse events associated with the drug and practices and guidelines1. This is to be expected as commonly result in treatment discontinuation. MATERIALS AND METHODS: A PubMed infectious diseases are life-threatening, whereas search was conducted using efavirenz as a the typically reversible psychotropic side effects search term, which returned 4655 results. Titles of antimicrobial agents are not; and the drugs in- and abstracts of articles were screened for rele- dicated are extremely effective, perhaps more so vance, and all relevant articles published in En- than any other class of drugs for its specific indi- glish were included in the narrative review. cations. In rare cases the risks associated with the RESULTS: Acute exposure to efavirenz may cause profound perceptual disturbances (de- neuropsychiatric adverse effects of treatment may lusions and hallucinations) whereas chron- outweigh the benefits leading to a specific practice ic exposure may be associated with abnormal becoming a subject of controversy, such as the use dreams and other sleep disturbances, anxi- of neuraminidase inhibitors for the treatment of ety, depressed mood and suicidality. It may al- influenza in children which is outright contrain- so be abused as a hallucinogen, especially 2 in individuals with a history of poly-substance dicated due to the risk of behavioral disturbances abuse. Recent research indicates that efavirenz and the use of mefloquine (which has been associ- directly affects monoaminergic neurotransmis- ated with irreversible psychiatric disturbances) for sion and may partially substitute for psyche- malaria prophylaxis3,4. delic drugs, such as lysergic acid diethylam- Drugs indicated for the treatment of human ide (LSD). Efavirenz acts as a serotonin 5-HT2A immunodeficiency virus (HIV) infection are gen- receptor antagonist, a serotonin-dopamine re- uptake inhibitor, an inhibitor of monoamine ox- erally not well tolerated with most patients expe- idase (MAO) and a vesicular monoamine trans- riencing adverse effects which may limit treat- porter 2 (VMAT2) inhibitor, which are mecha- ment adherence or lead to discontinuation. The nisms common with many psychotropic drugs. mainstay of treatment for HIV infection is the use Efavirenz interacts with many of the same mo- of highly active antiretroviral therapy (HAART), lecular targets as the empathogen methylendi- which consists of a combination of at least 3 dif- oxymethamphetamine (MDMA), but the effects of the 2 drugs may differ. ferent antiretroviral drugs of at least 2 different 5 CONCLUSIONS: The exact mechanism of ac- classes . It is recommended that treatment should tion of efavirenz as a psychotropic drug remains be continued indefinitely once initiated, as inter- unclear and future studies should focus on eval- mittent exposure to antiretroviral drugs increases uating whether prolonged exposure could lead the risk of resistance. As HIV infections is in- to irreversible side effects. variably fatal without treatment, neuropsychiatric Key Words: effects of antiretroviral drugs would be cause Efavirenz, HIV, HAART, Serotonin, MDMA. for alarm as they may lead to reduced treatment Corresponding Author: Nicholas Zareifopoulos, MD; e-mail: [email protected] 10729 N. Zareifopoulos, M. Lagadinou, A. Karela, F. Pouliasi, I. Economou, A. Tsigkou, D. Velissaris adherence, but there is no question as to whether which arise as a result of prolonged exposure. the benefits of therapy outweigh the risks. Efa- Efavirenz use has been associated with delusions, virenz, however, was a first line component of hallucinations and other symptoms of psycho- HAART throughout the world due to its efficacy sis, whereas sleep disturbances and alteration in and relatively low risk of life-threatening adverse mood are common complaints after prolonged reactions, and for this reason most HIV positive use6-8. The neuropsychiatric adverse effects of individuals have been exposed to it. The most efavirenz are extremely common, being observed common adverse effects of efavirenz are related in up to 50% of patients on an efavirenz-contain- to its psychotropic properties, the mechanism ing HAART regimen, although these are rarely for which is not clear yet, though it may bear serious enough to warrant emergency medical similarities to the mechanism of action of known attention or discontinuation of treatment. Though drugs of abuse. Apart from the substantial risk of efavirenz may be associated with increased sui- non-adherence and treatment discontinuation as- cidality due to its psychotropic effects, the use sociated with these effects, the fact that efavirenz of efavirenz containing HAART regimens is not is a psychotropic drug may have substantial eth- linked to an increased risk of suicide compared to ical implications, as prolonged exposure to it the use of antiretroviral therapy regimens which could lead to psychiatric disturbances which may do not contain the drug. Abnormal, vivid dreams not be reversible immediately upon treatment are a common side effect of efavirenz and may discontinuation. Furthermore, as efavirenz may be due to the recommendation to take the drug at be abused due to its hallucinogenic properties and night9. Individuals who experience nightmares as may be trafficked alongside other drugs of abuse, a result of treatment may benefit by taking their any insight into its mechanism of action may dose during the day. The side effects of efavirenz have forensic implications as well. The objective may be attenuated by concurrent use of cy- of this study is to evaluate the data regarding the proheptadine10,11, a first-generation antihistamine psychotropic properties of efavirenz and review which also functions as a non-selective serotonin its clinical implications. antagonist, an option which may be in some cases preferable to discontinuation. It should be noted that efavirenz is highly protein bound and crosses Materials and Methods the blood brain barrier readily, attaining cerebro- spinal fluid concentrations similar to its plasma This study was conceived as a narrative re- concentrations. The absolute concentrations are view, with the intention of summarizing what however misleading as the protein content of the is known regarding the psychotropic properties CSF is several orders of magnitude lower than of efavirenz and the clinical implications of this that of blood plasma, so the free efavirenz con- information. A PubMed search for the term efa- centration of the CSF may be much greater than virenz was conducted, which revealed the entire- the plasma concentration (100-1000 times greater ty of the literature on the drug (4655 articles). in fact)12. Furthermore, in animal experiments13 it An abstract and title screen was conducted to has been found to accumulate in brain tissue, as identify articles relevant to the subject of this measured post mortem in whole brain dialysate. review, which were subsequently studied in their For these reasons it is among the drugs of choice entirety. All relevant reviews and original in- for AIDS with prominent CNS manifestations, vestigations were to be included in the narrative and it would make sense to attribute its psycho- review, in order to enable a qualitative synthesis tropic properties to a direct effect on the CNS. of the available data and to investigate its clinical Recreational use of efavirenz has been report- implications. ed in South Africa, where drug users smoke efa- virenz in combination with marijuana and other drugs, in a concoction known as whoonga14. The Results intended effect of this practice is unclear, but it suggests that the neuropsychiatric effects of Clinical Observations on the efavirenz are not necessarily unpleasant and they Neuropsychiatric Effects of Efavirenz may even be desirable for certain individuals Efavirenz has been associated with numerous in the right setting. Efavirenz may have hallu- psychiatric adverse effects, some of which occur cinogenic properties which are sought by drug immediately upon treatment initiation and others users, but it is unclear whether it is used for this 10730 Efavirenz as a psychotropic drug purpose as a sole drug or if its recreational value receptors, and at similar concentrations also po- manifests only in combination