sign in sign up
<<
Home , Efavirenz, Whoonga

European Review for Medical and Pharmacological Sciences 2020; 24: 10729-10735 as a psychotropic

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 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 , 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 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 5-HT2A immunodeficiency virus (HIV) infection are gen- receptor antagonist, a serotonin- 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 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 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 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 , 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 with other drugs tentiates GABA-A currents and acts as a serotonin of abuse14,15. Efavirenz does not have significant and dopamine reuptake inhibitor by inhibiting pharmacokinetic interactions with drugs of abuse the synaptical monoamine transporters (DAT and (unlike protease inhibitors which may potentiate SERT) and the vesicular drugs of abuse via CYP3A4 inhibition16), so its (VMAT). In the behavioral study it depressed open abuse potential is likely due to a direct effect of field locomotor activity and induced a head twitch the drug in the central nervous system. response in a dose dependent manner similar to the The psychotropic properties of the drug were psychedelic hallucinogen lysergic acid diethylam- evident even during its clinical trials, as psy- ide (LSD). It could also partially substitute for LSD chiatric disturbances were noted to be the most and methylenedioxymethamphetamine (MDMA) common reason for discontinuation. Observa- in rats trained to discriminate these substances tional studies focusing on the neuropsychiatric from saline, but it could not substitute for effects of efavirenz have been conducted, but or (a GABAergic sedative similar to such studies were designed to evaluate the side ). Its abuse potential was found to be effect burden of the drug and provide insight limited, as it was not reliably self-administered, into possible measures to increase treatment tol- nor could it induce place preference in a manner erability17. Sleep disturbances (abnormal dreams similar to cocaine. Based upon these results the and nightmares) and appear to be the authors concluded that the psychotropic effects of most common adverse effects of prolonged use efavirenz may be similar to psychedelic drugs like of efavirenz, with hallucinations and feelings LSD. A subsequent in vitro study27 (in transfect- of depersonalization typically presenting upon ed HEK293 cells) by the same group found that the initiation of treatment18,19. The psychotropic efavirenz also functions as a MAO-A inhibitor, a effects of efavirenz appear to be dose dependent 5-HT2B antagonist, a 5-HT6 inverse agonist and and are more pronounced the first few days of an antagonist at muscarinic acetylcholine recep- therapy, suggesting that tolerance may devel- tors M1 and M3. In the 5-HT2 receptor family efa- op to a certain degree20,2199/279 (78% African virenz functioned as an antagonist, preventing Gq American, 88% male. The findings of such stud- activation the subsequent increase in intracellular ies have been reviewed at length elsewhere22,23. concentrations of inositol triphosphate and ionized The acute effects of efavirenz on perception and calcium, competing for the same binding site as mood (in comparison with other psychotropic the endogenous ligand serotonin, LSD and the drugs) remain unclear. Efavirenz also (in cases of hallucinogen 2,5-dimethoxy-4-iodoamphetamine both acute and chronic exposure) seems to exert (DOI). The same team in a study with a similar detrimental effects on cognitive function22,24,25. design28 demonstrated that efavirenz interacts with No discontinuation syndrome (a constellation of GABA-A receptors with 2 distinct mechanisms: as symptoms which present upon abrupt cessation a positive allosteric modulator in all receptor com- of treatment) has been described for efavirenz. To plexes containing a subunits other than a3, a5 and our knowledge, prospective studies which evalu- as a non-competitive antagonist (chloride channel ate efavirenz as a psychotropic drug directly have blocker) at the picrotoxin site. 3 amino acid resi- not been conducted yet. dues which are conserved at all GABA-A receptor a subunits apart from a3, a5 seem to be necessary Psychopharmacology of Efavirenz for the potentiating effect of efavirenz: arginine The clinical observations on the neuropsychi- 84, methionine 89 and isoleucine 120. This site atric effects of efavirenz led to investigation into is distinct from the binding sites of other depres- the possible mechanisms of its psychotropic prop- sant GABA-A modulators, including benzodiaze- erties. Research was conducted in a single center pines29, barbiturates, , carisoprodol30 and in North America and published in 3 different methaqualone31 (Figure 1). articles. The first study26 included an in vitro com- Sleep disturbances and nightmares are among ponent of molecular assays for the activity of efa- the most common side effects of treatment with virenz on a variety of CNS molecular targets and efavirenz and are most pronounced upon initia- an in vivo component to evaluate the behavioral tion of treatment. Sleep studies have found that effects of the drug and its abuse potential in rats. efavirenz prolongs stage 4 NREM and REM The authors reported that efavirenz has low mi- sleep32, while also increasing the amplitude cromolar affinity for serotonin 5-HT2A, 5-HT2C of sleep spindles observed in stage 2 NREM

10731 N. Zareifopoulos, M. Lagadinou, A. Karela, F. Pouliasi, I. Economou, A. Tsigkou, D. Velissaris

of 5-HT2A receptors coupled with phospholipase C and preferentially activating the phospholipase A2 second messenger system38,39. It may also activate 5-HT2A/metabotropic glutamate type 2 (mGluR2) receptor dimers preferentially, while acting as an antagonist at monomeric 5-HT2A re- ceptors40,41. It would be worth examining whether efavirenz exhibits a similar degree of selectivity in vivo, which would explain why it can partially substitute for LSD in preconditioned rats. If it functions as a pure antagonist, its interaction with 5-HT2A receptors would not explain its psycho- tropic properties, as pure 5-HT2A antagonists are relatively well tolerated38,42. Another interesting finding by Gatch et al26 was that efavirenz could also partially substitute MDMA. The 2 drugs have many molecular targets in common, includ- ing SERT, MAO-A and VMAT, so it would be worth examining whether efavirenz functions as a serotonin releasing agent in vivo (Figure 2). Figure 1. Efavirenz has a unique interaction with GABA-A It should however be noted that whereas MD- receptors, acting as a positive allosteric modulator at a MA and most are trace amine specific site in the α subunits, while also binding to the associated receptor 1 (TAAR1) agonists, it is not picrotoxin site where it acts as a channel blocker. Efavirenz yet known whether efavirenz interacts with this does not bind to the same sites as GABA, receptor. or barbiturates. The behavioral effects of its interaction with the GABA-A receptors are unclear. sleep33. This is in contrast to the effects of most sedatives, (including SSRIs and MAOIs) and , which suppress REM sleep and decrease the amount of time spent in deep sleep (NREM phase 4)34,35. is an example of a drug which has a similar effect on sleep and is also notorious for producing vivid and sometimes unpleasant dreams36. Mir- tazapine functions as an antagonist at 5-HT2A and 5-HT2C receptors, similar to efavirenz, but it is also an antagonist of a2 adrenergic and H1 histamine receptors37. The findings of the in vitro and animal stud- ies mentioned above shed some light into the mechanisms underlying the CNS activity of efa- virenz but many questions remain unanswered. Figure 2. Efavirenz acts as an inhibitor of SERT, MAO, Dalwaldi et al27 indicated that efavirenz acts as VMAT, while it is also a ligand of 5-HT2A receptors. The an antagonist at the 5-HT2A receptors whereas psychedelic effects of LSD are thought to be mediated by selective activation of the PLA2 signal transduction pathway LSD and DOI act as full agonists in the same at 5-HT2A receptors, in contrast to the Gq-PLC pathway model. However, past literature indicates that the activated by the endogenous ligand serotonin. It is however psychotropic properties of psychedelic drugs are unclear whether efavirenz does the same. Efavirenz has mediated by partial agonism of 5-HT2A recep- many molecular targets in common with MDMA, which also tors and can be prevented by coadministration of functions as an agonist of the TAAR1 receptors. TAAR1 agonism is thought to be necessary for MDMA and other both antagonists and full agonists of the receptor. amphetamines to induce monoamine release. Efavirenz LSD in particular may display a certain degree may partially substitute for MDMA, but it remains unclear of functional selectivity, acting as an antagonist whether the mechanism of action is similar.

10732 Efavirenz as a psychotropic drug

The contribution of muscarinic receptor an- prohibition47. Furthermore, it is still unclear tagonism to the psychotropic effects of efavirenz whether prolonged exposure to efavirenz could is also unclear. drugs are con- be associated with adverse effects that would sidered as in overdose they can induce not be readily reversible upon discontinuation. perceptive distortions that cannot be differen- Long term use of psychotropic drugs is not a tiated from reality along with profound cogni- controversial issue due to the risk of mental and tive dysfunction, anterograde amnesia and ste- neurological side effects which may persist even reotypical behavioral patterns. Anticholinergic after discontinuation of the offending agent. intoxication induces a mental state similar to that The most typical example of this is tardive observed in advanced dementia or in the deliri- dyskinesia associated with prolonged exposure um that is observed in critically ill patients, but to . Other antimicrobial agents it is directly dose dependent and reversible, with (specifically mefloquine) have been associated symptoms gradually improving as the drug is with persistent neuropsychiatric adverse effects3 cleared43. Anticholinergic drugs suppress REM so further investigation is warranted to deter- sleep, an effect associated with reduced frequen- mine whether efavirenz could induce similar cy and intensity of dreams34; this is not however persistent effects, and whether the risk for such observed with efavirenz, as it is notorious for events increases with cumulative exposure. In causing nightmares with nightly dosing. Sensitiv- the case of antiretroviral drugs, daily exposure ity to the psychotropic effects of anticholinergic for many years is the norm as HAART must be drugs increases greatly with advanced age, and continued indefinitely. For this reason, pharma- even substances with subclinical anticholinergic covigilance studies to identify adverse effects effects in young, otherwise, healthy individuals with a delayed onset are recommended for efa- can lead to significant cognitive impairment and virenz as well as other antiretroviral drugs. perceptive disturbances in the elderly44. Based on these observations we suggest that the antimus- carinic effects of efavirenz could have a minor Conflict of Interest contribution to its overall psychotropic effect, The Authors declare that they have no conflict of interests. which could be of greater clinical significance in elderly, demented or otherwise frail individuals45. Funding Statement There is no funding to report for this review. Conclusions

The observations from the past two decades References indicate beyond reasonable doubt that efavirenz Zareifopoulos N, Panayiotakopoulos G. is a potent psychotropic drug, whose mechanism 1) Neuropsy- chiatric effects of antimicrobial agents. Clin Drug of action remains unclear. Further research is Investig 2017; 37: 423-437. warranted into the psychopharmacology of efa- 2) Ueda N, Umetsu R, Abe J, Kato Y, Nakayama Y, Ka- virenz, including preclinical studies to evaluate to Z, Kinosada Y, Nakamura M. Analysis of neuro- its performance in animal models of psychiatric adverse events in patients treated with and psychosis in comparison to approved anti- oseltamivir in spontaneous adverse event re- and drugs (to examine ports. Biol Pharm Bull 2015; 38: 1638-1644. whether drugs with a similar profile could be 3) Thomas KH, Martin RM, Potokar J, Pirmohamed M, Gunnell D useful in psychiatry) and studies to evaluate . Reporting of drug induced depression and fatal and non-fatal suicidal behaviour in the its psychotropic action in healthy volunteers in UK from 1998 to 2011. BMC Pharmacol Toxicol comparison to drugs of abuse, such as MDMA 2014; 15: 54. 46 and LSD . The ethical and legal ramifications 4) Nevin RL, Leoutsakos J-M. Identification of a syn- of such research cannot be overstated, as mil- drome class of neuropsychiatric adverse reac- lions of people throughout the world (many of tions to mefloquine from latent class modeling of whom were asymptomatic when treatment was FDA adverse event reporting system data. Drugs R D 2017; 17: 199-210. initiated) have been exposed to a potent psy- 5) Gulick RM. Choosing initial antiretroviral therapy: chotropic drug which bears similarities to sub- current recommendations for initial therapy and stances considered to have no clinically useful newer or investigational agents. Top Antivir Med effects and abuse potential so great as to warrant 2015; 23: 128-131.

10733 N. Zareifopoulos, M. Lagadinou, A. Karela, F. Pouliasi, I. Economou, A. Tsigkou, D. Velissaris

6) Ford N, Shubber Z, Pozniak A, Vitoria M, Doherty RM. Impact of efavirenz on neuropsychological M, Kirby C, Calmy A. Comparative safety and neu- performance and symptoms in HIV-infected indi- ropsychiatric adverse events associated with efa- viduals. Ann Intern Med 2005; 143: 714-721. virenz use in first-line antiretroviral therapy: a 18) Birbal S, Dheda M, Ojewole E, Oosthuizen F. Ad- systematic review and meta-analysis of random- verse drug reactions associated with antiretrovi- ized trials. J Acquir Immune Defic Syndr 2015; 69: ral therapy in South Africa. Afr J AIDS Res 2016; 422-429. 15: 243-248. Cavalcante GIT, Capistrano VLM, Cavalcante FSD, 7) 19) Drury A, Gleadow-Ware S, Gilfillan S, Ahrens J. HIV Vasconcelos SMM, Macedo DS, Sousa FCF, Woods and mental illness in Malawi and the neuropsychi- DJ, Fonteles MMF . Implications of efavirenz for atric sequelae of efavirenz. Malawi Med J 2018; neuropsychiatry: a review. Int J Neurosci 2010; 30: 40-45. 120: 739-745. 20) Juethner SN, Seyfried W, Aberg JA. Tolerance of Cavalcante GIT, Chaves Filho AJM, Linhares MI, de 8) efavirenz-induced central nervous system side Carvalho Lima CN, Venancio ET, Rios ERV, de Sou- effects in HIV-infected individuals with a history za FCF, Vasconcelos SMM, Macedo D, de Franca of . HIV Clin Trials 2003; 4: 145- Fonteles MM . HIV antiretroviral drug Efavirenz in- 149. duces anxiety-like and depression-like behavior Kontorinis N, Dieterich DT in rats: evaluation of neurotransmitter alterations 21) . Toxicity of non-nucle- in the striatum. Eur J Pharmacol 2017; 799: 7-15. oside analogue inhibitors. Semin Dis 2003; 23: 173-182. 9) Abers MS, Shandera WX, Kass JS. Neurological and Decloedt EH, Maartens G psychiatric adverse effects of antiretroviral drugs. 22) . Neuronal toxicity of efa- CNS Drugs 2014; 28: 131-145. virenz: a systematic review. Expert Opin Drug Saf 2013; 12: 841-846. 10) Dabaghzadeh F, Khalili H, Ghaeli P, Dashti-Khav- Gaida R, Truter I, Grobler C, Kotze T, Godman B. idaki S. Potential benefits of in 23) HIV-positive patients under treatment with an- A review of trials investigating efavirenz-induced tiretroviral drugs including efavirenz. Expert Opin neuropsychiatric side effects and the implica- Pharmacother 2012; 13: 2613-2624. tions. Expert Rev Anti Infect Ther 2016; 14: 377- 388. 11) Dabaghzadeh F, Ghaeli P, Khalili H, Alimadadi A, Ja- Treisman GJ, Soudry O. fari S, Akhondzadeh S, Khazaeipour Z. Cyprohepta- 24) Neuropsychiatric effects dine for prevention of neuropsychiatric adverse of HIV antiviral medications. Drug Saf 2016; 39: effects of efavirenz: a randomized . 945 -957. AIDS Patient Care STDS 2013; 27: 146-154. 25) Decloedt EH, Rosenkranz B, Maartens G, Joska J. 12) Decloedt EH, Sinxadi PZ, van Zyl GU, Wiesner L, Central nervous system penetration of antiretro- Khoo S, Joska JA, Haas DW, Maartens G. Pharma- viral drugs: pharmacokinetic, pharmacodynamic cogenetics and of CNS pene- and pharmacogenomic considerations. Clin Phar- tration of efavirenz and its metabolites. J Antimi- macokinet 2015; 54: 581-598. crob Chemother 2019; 74: 699-709. 26) Gatch MB, Kozlenkov A, Huang R-Q, Yang W, Nguy- en JD, Gonzalez-Maeso J, Rice KC, France CP, Dil- 13) Srinivas N, Rosen EP, Gilliland Jr WM, Kovarova M, lon orster chetz Remling-Mulder L, De La Cruz G, White N, Adamson GH, F MJ, S JA. The HIV antiretro- L, Schauer AP, Sykes C, Luciw P, Garcia JV, Akkina R, viral drug efavirenz has LSD-like properties. Neu- Kashuba ADM. Antiretroviral concentrations and ropsychopharmacology 2013; 38: 2373-2384. surrogate measures of efficacy in the brain tissue 27) Dalwadi DA, Kim S, Amdani SM, Chen Z, Huang RQ, and CSF of preclinical species. Xenobiotica 2019; Schetz JA. Molecular mechanisms of 49: 1192-1201. action of the HIV-1 antiretroviral efavirenz. Phar- 14) Rough K, Dietrich J, Essien T, Grelotti DJ, Bansberg macol Res 2016; 110: 10-24. DR, Gray G, Katz IT. and the abuse and 28) Huang R, Chen Z, Dolan S, Schetz JA, Dillon GH. diversion of antiretrovirals in Soweto, South Afri- The dual modulatory effects of efavirenz on GAB- ca. AIDS Behav 2014; 18: 1378-1380. AA receptors are mediated via two distinct sites. 15) Grelotti DJ, Closson EF, Smit JA, Mabude Z, Mat- Neuropharmacology 2017; 121: 167-178. thews LT, Safren SA, Bangsberg DR, Mimiaga MJ. 29) Horsfall JT, Sprague JE. The pharmacology and Whoonga: potential recreational use of HIV an- toxicology of the “Holy Trinity”. Basic Clin Phar- tiretroviral medication in South Africa. AIDS Be- macol Toxicol 2017; 120: 115-119. hav 2014; 18: 511-518. 30) Kumar M, Gonzalez LA, Dillon GH. Assessment 16) Tossonian HK, Raffa JD, Grebely J, Trotter B, Viljo- of subunit-dependent direct gating and allosteric en M, Mead A, Khara M, McLean M, Duncan F, Fra- modulatory effects of carisoprodol at GABA(A) ser C, DeVlaming S, Conway B. dosing receptors. Neuropharmacology 2015; 97: 414- strategies in HIV-infected injection drug users en- 425. rolled in a directly observed therapy program. J 31) Hammer H, Bader BM, Ehnert C, Bundgaard C, Acquir Immune Defic Syndr 2007; 45: 324-327. Bunch L, Hoestgaard-Jensen K, Schroeder OH-U, 17) Clifford DB, Evans S, Yang Y, Acosta EP, Goodkin K, Bastlund JF, Gramowski-Voss A, Jensen AA. A Mul- Tashima K, Simpson D, Dorfman D, Ribaudo H, Gulick tifaceted GABAA : functional

10734 Efavirenz as a psychotropic drug

properties and mechanism of action of the sed- 40) Moreno JL, Holloway T, Albizu L, Sealfon SC, ative-hypnotic and recreational drug methaqua- González-Maeso J. Metabotropic glutamate mG- lone (Quaalude). Mol Pharmacol 2015; 88: 401- lu2 receptor is necessary for the pharmacological 420. and behavioral effects induced by hallucinogen- 32) Moyle G, Fletcher C, Brown H, Mandalia S, Gazzard ic 5-HT2A receptor agonists. Neurosci Lett 2011; B. Changes in sleep quality and brain wave pat- 493: 76-79. terns following initiation of an efavirenz-contain- 41) Urban JD, Clarke WP, von Zastrow M, Nichols DE, ing triple antiretroviral regimen. HIV Med 2006; 7: Kobilka B, Weinstein H, Javitch JA, Roth BL, Chris- 243-247. topoulos A, Sexton PM, Miller KJ, Spedding M, Mail- man RB 33) Simen AA, Ma J, Svetnik V, Mayleben D, Maynard J, . Functional selectivity and classical con- Roth A, Mixson L, Mogg R, Shera D, George L, Mast cepts of quantitative pharmacology. J Pharmacol TC, Beals C, Stoch A, Struyk A, Shire N, Fraser I. Exp Ther 2007; 320: 1-13. Efavirenz modulation of sleep spindles and sleep 42) Corena-McLeod M. Comparative pharmacology of spectral profile. J Sleep Res 2015; 24: 66-73. and . Drugs R D 2015; 34) Wichniak A, Wierzbicka A, Walęcka M, Jernajczyk W. 15: 163-174. Effects of antidepressants on sleep. Curr Psychi- 43) Volgin AD, Yakovlev OA, Demin KA, Alekseeva PA, atry Rep 2017; 19: 63. Kyzar EJ, Collins C, Nichols DE, Kalueff AV. Under- 35) Wichniak A, Wierzbicka A, Jernajczyk W. Sleep and standing central nervous system effects of treatment. Curr Pharm Des 2012; hallucinogenic drugs through experimental animal 18: 5802-5817. models. ACS Chem Neurosci 2019; 10: 143-154. Salahudeen MS, Duffull SB, Nishtala PS 36) Dolder CR, Nelson MH, Iler CA. The effects of mir- 44) . Anticho- tazapine on sleep in patients with major depres- linergic burden quantified by anticholinergic risk sive disorder. Ann Clin Psychiatry 2012; 24: 215- scales and adverse outcomes in older people: a 224. systematic review. BMC Geriatr 2015; 15: 31. Ali S, Peterson GM, Bereznicki LR, Salahudeen MS 37) Carvalho AF, Sharma MS, Brunoni AR, Vieta E, Fa- 45) . va GA. The safety, tolerability and risks associat- Association between anticholinergic drug burden ed with the use of newer generation antidepres- and mortality in older people: a systematic re- sant drugs: a critical review of the literature. Psy- view. Eur J Clin Pharmacol 2020; 76: 319-335. chother Psychosom 2016; 85: 270-288. 46) Family N, Maillet EL, Williams LTJ, Krediet E, Car- hart-Harris RL, Williams TM, Nichols CD, Goble 38) Berg KA, Maayani S, Goldfarb J, Scaramellini C, Leff DJ, Raz S. P, Clarke WP. Effector pathway-dependent rela- Safety, tolerability, pharmacokinetics, tive efficacy at serotonin type 2A and recep- and of low dose lysergic ac- tors: evidence for agonist-directed trafficking of id diethylamide (LSD) in healthy older volunteers. receptor stimulus. Mol Pharmacol 1998; 54: 94- Psychopharmacology (Berl) 2020; 237: 841-853. 104. 47) Nutt D. Psychedelic drugs-a new era inpsychia- 39) Wacker D, Wang C, Katritch V, Han GW, Huang X-P, try?. Dialogues Clin Neurosci 2019; 21: 139-147. Vardy E, McCorvy JD, Jiang Y, Chu M, Siu FY, Liu W, 48) Correll CU, Kane JM, Citrome LL. Epidemiology, Xu HE, Cherezov V, Roth BL, Stevens RC. Structural prevention, and assessment of tardive dyskine- features for functional selectivity at serotonin re- sia and advances in treatment. J Clin Psychiatry ceptors. Science 2013; 340: 615-619. 2017; 78: 1136-1147.

10735