Table 4.

Description of the papers assessing the impacts of legal drugs against anxiety on driving performances.

Study	Country	Participants			Control group	Legal Drugs (anxiolytics)	Driving task/Survey	Impact Behaviour (BEH) Impact Cognition (COG) Risk of crash (RISK)
		N Sample	age rang (mean ± SD)	Gender Female/Male
Boucard et al. (2007) [41]	France	36 Licensed drivers	18 to 35	52.8% F 47.2% M	yes	-Benzodiazepine (0.1 mg/kg) (0.3 mg/kg)	Streams of 15 real-world scenes displaying a road were presented for 50 m s each	COG: Diazepam at a therapeutic dosage affects attentional shifting in the temporal domain and impairs dual-task performance
Brown et al. (2018) [42]	USA	8 Licensed drivers	21 to 40 (30)	50% F 50% M	no (own control)	-Alprazolam (1 mg) -Hydrocodone/acetaminophen (10 mg/325 mg) -Combination	35-min simulated driving on urban, interstate and rural roadway, night-time conditions	BEH: Detrimental effects of alprazolam on driving measures of lateral control and longitudinal control.
Daurat et al. (2013) [43]	France	14 Licensed drivers	25 to 35 (29.79 ± 3.5)	100% M	no (own control)	-Benzodiazepine (2 mg lorazepam)	- Simulator 200 km on highway - Real-world 200 km on highway	BEH: Increased the standard deviation of the lateral position (SDLP)
Leufkens et al. (2007) [44]	The Netherlands	18 Licensed drivers	21 to 45 (32.3 ± 2.0)	50% F 50% M	no (own control)	-Benzodiazepine (1 mg of XR or IR alprazolam)	-Real-world 100 km on highway	BEH: Increased SDLP COG: Impact on Divided Attention Task/tracking performance/go reaction time
Mercier-Guyon & Choay, (1999) [45]	France	16 Licensed drivers (>5 years & >15,000 km)	29 to 44 (40)	100% M	no (own control)	-Lorazepam for 7 days (0.5 mg morning and lunchtime, 1 mg at bedtime) -Captodiamine for 7 days (50 mg, 3 times/day).	Closed circuit 900 m (15min) -2 passages between beacons to choose to go through or to avoid -Braking in a designated area -Slalom	BEH: Increased driving errors due to clumsiness and disinhibition with lorazepam and decreased with captodiamine COG: Reduction in reaction time to auditory stimuli in favour of captodiamine (marginally significant)
O'Hanlon et al. (1995) [46]	The Netherlands	Study 1 - 16 Study 2 - 9 Study 3 56 anxious Licensed drivers (>3 years & >8000 km/year)	St. 1 25 to 43 (34 ± 4) St. 2 22 to 34 (25 ± 4) St. 3 24 to 64 (43 ± 0.9)	St. 1 50% F 50% M St. 2 100% F St. 3 64.3% F 35.7% M	no	St. 1: 8 days ondasentron (1 mg/4 mg) or diazepam (5 mg) 3 times/day. St. 2: 8 days suriclone (0.2 mg) or lorazepam (0.5 mg). St. 3: 15 days alpidem (50 mg) or lorazepam (2 mg)	Standard Driving test: 100 km highway	BEH: Diazepam increased SDLP after one 5 mg dose and even more after repeated dosing. Suriclone and lorazepam produced a marked rise in SDLP at the beginning of the dosing series and a lesser though still significant rise at the end. Lorazepam also affected the reaction time and suriclone nearly so from the first test day.
Okamura et al. (2018) [47]	Japan	1424 Licensed drivers (>20 years & driving frequency > once per week & medication)	22 to 79 (52.2 ± 11.3)	25% F 75% M	no	-Antianxiety drugs and antidepressants (including benzodiazepines) -Sleeping pills -Cold medicines, sinus medicines, etc (variable dosages)	Occupational Driver Behaviour Scale (ODBS) concerning speeding, rules violations, inattentionn and tiredness	BEH: People taking psychotropic show more favourable or careful driving attitudes (scored lower in ODBS) compared with cold/sinus medicines group, but they drive less frequently
Takahashi et al. (2010) [48]	Japan	18 Licensed drivers (>10 years & >5000 km/year)	32 to 44 (37.1 ± 3.3)	100% M	no (own control)	-Benzodiazepine (5 mg diazepam) -Tadospirone (20 mg)	-Car-following test to maintain a constant distance with a lead car -Harsh-braking test to maintain a constant speed and to avoid crashing into humanoid models on the road	BEH: Diazepam impaired the harsh-braking performance in acute dosing. Tandospirone does not impair it. No differences in standard deviation of lateral position (SDLP). COG: No differences in cognitive functions measured by cognitive tests (Wisconsin Card Sorting Test, WCST)
Touliou et al. (2013) [49]	Greece	51 15 treated 18 untreated 18 healthy control	Treated (42.4 ± 13.9) Untreated (36.9 ± 8.9) Control (35.4 ± 8.8)	51% F 49% M	yes	-Benzodiazepine (0.5 mg alprazolam)	-Lane tracking (20 min) in a highway environment maintaining a constant speed -Car-following (20 min) in a highway environment maintaining a safe distance from the lead vehicle	BEH: Increased weaving (SDLP) in treated and untreated anxiety patients after alprazolam intake, present even in small concentrations. Increase in brake reaction time in treated and untreated patients but not in the control group. COG: Decrease in alertness only in the control group after alprazolam intake. Untreated patients felt less vigilant in the alprazolam condition. Similarly, healthy participants felt significantly less vigilant after alprazolam intake
van der Sluiszen et al. (2019) [50]	The Netherlands	44 12 + 32 (benzodiazepine + hypnotic) 65 healthy control Licensed drivers (>3 years & >500 km/year)	Benzodiazep. (55.2 ± 9.6) Hypnotic. (55.6 ± 12.3) Control (57.9 ± 10.5)	Patients 59.1% F 40.9% M Control 43.1% F 56.9% M	yes	-Benzodiazepines -Hypnotics (variable dosages)	Standard Driving test: 100 km highway (1 h)	BEH: SDLP of hypnotics users exceeded 2.5 cm from controls, indicating clinically relevant impairment. SDLP of users of anxiolytics did not differ COG: Users of hypnotics and anxiolytics showed longer reaction times than control on neurocognitive tasks. Results, mostly inconclusive for users of anxiolytics, showed clinically relevant impairment in users of hypnotics for Psychomotor Vigilance Test, Digit Symbol Substitution Test and Determination Test. Mitigation of the effects at long term
Verster et al. (2002) [51]	The Netherlands	20 Licensed drivers (>3 years & >8000 km/year)	(25.1 ± 2.0)	60% F 40% M	no (own control)	-Benzodiazepine: (1 mg alprazolam)	Standard Driving test: 100 km highway	BEH: Increased SDLP, Speed and number of excursions out of the lane after alprazolam COG: Alertness decreased. Tracking ability was impaired, increased reaction times for both Stenberg Memory Scanning Test and Divided Attention test and increased number of errors too.