Effects of Alprazolam on Driving Ability, Memory Functioning and Psychomotor Performance: A Randomized, Placebo-controlled Study Joris C. Verster, M.S., Edmund R. Volkerts, Ph.D., and Marinus N. Verbaten, Ph.D. Alprazolam is prescribed for the treatment of anxiety and performed 2.5 h after treatment administration, comprising panic disorder. Most users are presumably involved in daily the Sternberg Memory Scanning Test, a Continuous activities such as driving. However, the effects of Tracking Test, and a Divided Attention Test. Relative to alprazolam on driving ability have never been investigated. placebo, alprazolam caused serious driving impairment, as ϭ This study was conducted to determine the effects of expressed by a significantly increased SDLP (F1,19 97.3, Ͻ ϭ Ͻ alprazolam (1 mg) on driving ability, memory and p .0001) and SDS (F1,19 30.4, p .0001). This was psychomotor performance. Twenty healthy volunteers confirmed by subjective assessments showing significantly ϭ Ͻ participated in a randomized, double-blind, placebo- impaired driving quality (F1,19 16.4, p .001), decreased ϭ Ͻ controlled crossover study. One hour after oral alertness (F1,19 43.4, p .0001), decreased mental ϭ Ͻ administration, subjects performed a standardized driving activation (F1,19 5.7, p .03) and increased mental effort ϭ Ͻ test on a primary highway during normal traffic. They were during driving (F1,19 26.4, p .0001). Furthermore, instructed to drive with a constant speed (90 km/h) while alprazolam significantly impaired performance on the maintaining a steady lateral position within the right traffic laboratory tests. In conclusion, alprazolam users must be lane. Primary performance measures were the Standard warned not to drive an automobile or operate potentially Deviation of Lateral Position (SDLP) and the Standard dangerous machinery. Deviation of Speed (SDS). After the driving test, subjective [Neuropsychopharmacology 27:260–269, 2002] driving quality, mental effort, and mental activation during © 2002 American College of Neuropsychopharmacology. driving were assessed. A laboratory test battery was Published by Elsevier Science Inc. KEY WORDS: Alprazolam; Driving; Memory; Psychomotor; Alprazolam is the most frequently used drug of the Performance benzodiazepine family and is one of the 10 most pre- scribed drugs in the USA (RxList 2000). Alprazolam, a From the Utrecht Institute for Pharmaceutical Sciences, Depart- 1,4-triazolobenzodiazepine analog, has a relatively ment of Psychopharmacology, University of Utrecht, The Nether- lands. short half-life, is free from active metabolites and is Address correspondence to: Joris C. Verster, University of Utrecht, usually prescribed for the treatment of generalized anx- Utrecht Institute for Pharmaceutical Sciences, Department of Psy- iety and panic disorder. Clinical dosages of alprazolam, chopharmacology, P.O. Box 80082, 3508 TB Utrecht, The Nether- lands. Tel.: ϩ31 30 253 69 09; Fax: ϩ31 30 253 73 87; E-mail: administrated in divided doses, range from 0.5 mg to 4 [email protected] mg/day for the treatment of anxiety disorder and from Received October 1, 2001; revised February 5, 2002; accepted Feb- 6 to 10 mg/day for the treatment of panic disorder. ruary 11, 2002. Online publication: 2/14/02 at www.acnp.org/citations/ Alprazolam has also anticonvulsant and antidepres- Npp021402246. sant properties (Jonas and Cohon 1993; Petty et al. 1995; NEUROPSYCHOPHARMACOLOGY 2002–VOL. 27, NO. 2 © 2002 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/02/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(02)00310-X NEUROPSYCHOPHARMACOLOGY 2002–VOL. 27, NO. 2 Alprazolam and Driving Ability 261 Casacalenda and Boulenger 1998). Since anxiety is often short half life (Ͻ24 h), such as alprazolam (mean half accompanied by depression it is suggested that alpra- life is approximately 11 h). Some epidemiological zolam is a more powerful anxiolytic in comparison to studies, however, did specifically investigate alpra- other benzodiazepines that lack these antidepressant zolam’s effects, and an association between alpra- properties (Petty et al. 1995). The drug has a fast onset zolam use and increased risk of falling down has been to anxiety relief (less than one week) when compared shown (Mendelson 1996). with anxiety treatment with buspirone or SSRIs (two to The popularity and clinical efficacy of alprazolam four weeks). has resulted in a large number of studies concerning Besides the benefits of alprazolam’s therapeutic ef- its effects on various aspects of human performance fects, commonly reported adverse central nervous sys- and memory functioning. These studies consistently tem (CNS) effects are sedation, reduced alertness, reported significant performance impairment after drowsiness, confusion, sleepiness, dizziness and head- acute dosages (1.0 mg and higher) of alprazolam in ache. These adverse effects seem to diminish during tests measuring skills related to driving, such as track- treatment; however, they do not disappear completely ing (Ellinwood et al. 1985, 1987; Linnoila et al. 1990; (O’Sullivan et al. 1994). In addition, long-term alpra- Nikaido et al. 1990; Ellinwood et al. 1993; Vermeeren zolam treatment raised concerns about abuse potential, et al. 1995; Kroboth et al. 1998), vigilance performance drug dependency, and withdrawal phenomena. (Kožená et al. 1995; Suzuki et al. 1995) and reaction The effects of alprazolam can be explained by its speed (Hindmarch 1983; Block and Berchou 1984; Lin- pharmacological actions in the brain, where it binds noila et al. 1990; Bond et al. 1991; Danjou et al. 1992; with high affinity to the GABAA benzodiazepine recep- Saletu et al. 1994; Kroboth et al. 1998). There is, how- tor complex. Alprazolam facilitates the binding of ever, a lively debate concerning the predictive validity GABA resulting in an increased influx of chloride ions. of laboratory tests to actual on-the-road driving per- In turn, the presence of GABA inhibits the action of formance. In this context, it has been shown that labo- connected brain structures by interacting with several ratory simulation tests are not sensitive when com- other neurotransmitter systems, including noradrener- pared with actual on-the-road driving tests during gic, serotonergic, cholinergic and opioidergic systems normal traffic (Volkerts et al. 1992). (Julien 1998). The GABAA benzodiazepine receptor The effects of alprazolam on driving during normal complex comprises several subunits, of which ␣ and ␥ traffic have not yet been investigated. Referring to the subunits are able to bind benzodiazepines. Recent evi- CNS effects of alprazolam and taking its wide use into dence (Rudolph et al. 2001; Weinberger 2001) has account, the purpose of the present study was to deter- shown that these subunits can be further divided into mine the acute effects of alprazolam (1 mg) on driving ␣ ␣ ␥ ␥ numerically labeled isoforms ( 1- 6, 1- 3). It has been ability during normal traffic. In addition, driving-related ␣ shown that activation of 1 subunits mediates sedation, skills were investigated under controlled laboratory con- anterograde amnesia, and hypnotic effects of benzodi- ditions. During driving, motor control is essential to ␣ azepines, whereas activation of 2 subunits causes anti- manage safe driving. For example, the driver has to keep ␣ anxiety effects. It is therefore not surprising that 2 the car in a steady position within the traffic lane. To ex- subunits are abundantly present in the amygdala, hip- amine motor control, a tracking test was included, com- pocampus and cerebral cortex: brain structures that are prising an easy and a hard version. Also, continuous de- involved in mediating anxiety processes. mands on working memory are necessary to interact Unfortunately, the effects of alprazolam are not safely with the traffic environment. For example, the ␣ limited to ‘therapeutic meaningful’ sites of action ( 2 driver has to be aware of the approaching vehicles in the effects), since alprazolam enhances the inhibitory ef- adjacent traffic lane in order to take decisions for per- fects of GABA which causes a general slowing of brain forming overtaking maneuvers and to respond to road activity, resulting in sedation and reduced alertness signaling. Therefore, the Sternberg memory scanning ␣ ( 1 effects). test was included in the laboratory test battery. Finally, a Taking into account the large number of alprazolam divided attention test was included, since the driver has prescriptions, its ambulatory use, and adverse CNS ef- to attend to a number of traffic circumstances during fects, it is evident that the effects of alprazolam on driving that occur simultaneously. daily activities such as driving a car are of major con- cern to society. In this context, epidemiological evi- dence showed increased risk of hip fractures (Ray et HYPOTHESES al. 1987, 1989) and traffic accidents (Neutel 1995; Hem- melgarn et al. 1997; Barbone et al. 1998) after anxi- It is hypothesized that alprazolam will impair driving olytic benzodiazepine use. However, these effects ability, resulting in significantly increased SDLP and were significant only for benzodiazepines with a long SDS. It is also hypothesized that alprazolam will signif- elimination half life (Ͼ24 h), and not for those with a icantly impair laboratory test performance. 262 J.C. Verster et al. NEUROPSYCHOPHARMACOLOGY 2002–VOL. 27, NO. 2 METHODS For safety reasons, a licensed driving instructor pro-