In this review we first analyzed the general relationship between any crashes in DUIC chronic cannabinoid use, and second, how this relationship changes when potential co-factors are considered. The research on these topics includes five meta-analyses on several study types (case-control, culpability, and cohort studies) (2, 7, 15–17).

All five meta-analyses agreed that cannabinoid use is related to a higher traffic crash risk. However, the OR estimates and 95% CI and statistical significance across studies are variable (Table 1), while the number of included studies unsurprisingly increase over time. The initial meta-analysis (2) analyzed nine studies with n = 51,783 participants, the second meta-analysis from the same year (16) also included nine studies with n = 92,200 individuals. In this second meta-analysis (16), only two studies (9, 31) were previously analyzed (2). The third meta-analysis (7) with 27 studies included eight studies each of the first (2) and second (16) meta-analysis, while 12 studies were added. Rogeberg and Elvik (17) re-analyzed data from the first and second meta-analysis (2, 16) and added a second study with 21 included investigations, of which n = 14 were also analyzed in the previous study of Elvik (7). The most recent analysis (15) included 24 studies, of which 12 were analyzed in the hitherto largest meta-study (7). Thus, there is some, but not complete, overlap of studies included into available meta-analytical research on this topic. Selection criteria also vary across studies. Some include case-control and culpability studies (2, 17) or in addition cohort (16) or laboratory studies (7) and eventually case-control, culpability, survey, and cohort studies (15).

All meta-analyses noted significant heterogeneity across included studies [Asbridge et al. (2): I2: 81; Li et al. (15): heterogeneity: Q = 38.21; P < 0.0001; I2 ¼ 79.1; Elvik (7): test for heterogeneity “positive” for all outcomes; Rogeberg and Elvik (17): “there is heterogeneity across studies;” Hostiuc et al. (15): overall Q = 216,59, p < 0.001; I2 = 90%]. The last study also presented heterogeneity statistics for several outcome criteria [collision subgroup Q = 47,06, p < 0.001, I2 89%; injury subgroup Q = 62.0; p < 0.001, I2 82%; fatal Q = 19.26, p < 0.001, I2 79% (15)].

All these factors may explain why there is some variation in the OR estimates across meta-analyses for the overall statistics. Further, case-control studies reach higher OR estimates than culpability studies and, except for (2), fatal crashes lower OR estimates than other kinds of crashes. Finally, studies based on self-reports have higher ORs than those based on blood or urine results. Culpability studies (2) include drivers involved in collisions, sub-grouped into those responsible for the collision and those not responsible. The premise of these studies is, if cannabis use increases collision risk, then it should more likely be detected in drivers judged to be responsible for their collision. However, OR may be higher in case-control studies, where DUIC subjects are compared to non-DUIC controls. Further, DUIC may impair driving skills and increase crash risk, however, risk of fatal crashes is lower than other types of crashes (collision only, injury). Thus, the increased risk for car crashes is relatively higher for collision and injury and somewhat attenuated but still increased for fatalities.

Self-reports of cannabis use may be subject to recall bias and may be less precise to detect actual cannabis use compared to blood or urine tests. Usually, it is assumed that cannabis use is underestimated in self-reports. As commented in previous analyses (16) different methods of assessing cannabis use (e.g., self-report, urine tests, and blood tests) may have different levels of validity and reliability. The authors of one meta-analysis (17) stated that, to their view, laboratory analyses of blood samples for all subjects included in a study provide the best information on acute intoxication while driving. The second best indicator is saliva. Urine is a less informative indica tor, as inactive metabolites of cannabis can be detected in samples of urine a long time after the substance became inactive.

Most of these screenings determine whether cannabis was used within the past few weeks, whereas acute impairment in driving skills from cannabis use lasts between 3 and 12 h (16, 33). Cannabis being an illicit drug in most countries, drivers in the comparison groups might be less likely than those involved in crashes to submit to testing, which could lead to overestimation of the effect of marijuana use on crash risk.

These meta-analyses have several limitations. The fourth meta-analysis (17) found only five studies that calculated crash risk for drivers with blood THC > 2 ng/ml. Further, all case–control studies had high refusal rates (>15%), potentially resulting in selection bias if drivers who refused participation had different rates of drug use than those who participated. Different methods to detect cannabis exposure in cases vs. controls (e.g., blood THC in cases and saliva THC in controls) were employed in many case-control studies, non-comparable controls (e.g., patients visiting hospital for medical problems) were recruited to estimate THC use in the general driving population (29), and only a fraction of included studies measured THC in blood samples or a combination of blood samples and urine or saliva samples or self-reports [Asbridge et al. 9 of 10 (2), Elvik 20 of 27 (7), Li et al. 2 of 9 (16), and Hostiuc et al. 10 of 24 studies (15)]. All of these limit the generalizability of findings.

In addition, whole blood, plasma, urine, and saliva are body fluids with different characteristics when it comes to assessment of THC levels. Experimental studies could not find a significant correlation between THC concentrations (logarithms) in oral fluid and plasma, while time influences THC concentrations in plasma and oral fluid differently after repeated oral THC doses (33). Cannabinoids in urine have a longer window of detection than blood and oral fluids, and THC's elimination is non-linear so that reverse extrapolation of concentrations to an earlier time is not feasible. When utilizing blood rather than plasma cannabinoid concentrations, concentrations must be approximately doubled because cannabinoids are tightly bound to proteins in plasma (>90%), and there is minimal partitioning into erythrocytes (34).

Also, cannabinoid blood and plasma concentrations were significantly higher in frequent smokers compared with occasional smokers at most time points for THC and 11-OH-THC (35). In oral fluids, THC levels above 2 μg/L were detected in occasional smokers for 26 h while frequent smokers had higher levels for >72 h. Thus, low THC concentrations can be detected for several days in oral fluids of chronic smokers similar to blood and urine (36). Eventually, the authors of the review comment that cannabinoid stability in these measures not only depend on characteristics of the body fluids used and the smoking status of the individuals, it also depends on collection method, buffer composition in commercial collection devices, the analytes, storage containers, and storage temperature and duration.

The third purpose of our analyses on the relationship between THC concentration and car crash risk was addressed by five case-control studies with “high quality (++)” SIGN rating (Table 2). None of the meta-analyses reported statistics on this relationship. However, the association is of importance since there are various legal cut-off values for THC blood levels across European countries for DUIC. While the penalty increases in Norway according to the THC concentration detected (1.3, 3, 9 ng/ml), other countries have cut-off values of 1 ng/ml (Germany, Belgium, Ireland, Luxemburg, Netherlands in the presence of other substances), 2 ng/ml (Czech Republic, United Kingdom), and 3 ng/ml (Netherlands) [EMCDDA Cannabis and Driving (5)]. It is a relevant issue whether studies report evidence using which of the legal cut-off concentrations supported by empirical data.

The Australian study (26) indicated a significantly higher risk for THC ≥ 5 ng/ml with the highest OR estimates across studies (OR 6.6) which is higher than ORs from later studies [Laumon et al. (27) unadjusted OR (uaOR) 4.7, Martin et al. (28) (uaOR) 3.95, and Brubacher et al. (29) (uaOR) 2.29 for the same subgroup of individuals with THC ≥ 5 ng/ml]. However, in the Drummer et al. sample, in 84% of the THC-only cases the THC concentration was ≥5 ng/ml and the median was 12 ng/ml. This rate is higher compared to the French and Canadian samples [Laumon et al. (27): 2.66%, Martin et al. (28): 4.2%, Brubacher et al. (29): 0.9%]. Therefore, based on the high rate of individuals with THC above 5 ng/ml, it was quite likely to see an effect of THC on crash risk in the Australian sample. Further, in the Australian study (26), alcohol was commonly found in THC-positive cases (43%), the effect of THC was also evaluated in the THC plus alcohol cases and significant interaction was found. This interaction could not be replicated in French and Canadian samples. In the first French study (27), no statistical interaction between blood concentrations of THC and alcohol was detected as well as in the later studies (28, 29). Thus, most studies report a significant influence of cannabis and alcohol use on culpability for fatal crashes or injuries, but both substances obviously exert their effects independently (6). Results from the Australian Study (26) also suggested that both alcohol and cannabis showed a biological gradient with higher doses of both substances have a higher OR of culpability in fatal crashes. This significant dose-effect was also reported from the first French (27) and the Canadian Study (29), while in the second French study (28), the ORs show an inverse U-curve trend with a maximum at THC concentrations between >2 and <5 ng/ml, after controlling for alcohol intoxication. All authors across studies consistently argue that their studies yield a marked dose effect and a potential causal role of DUIC in fatal crashes. The latest study of Drummer et al. (30) confirmed the finding that elevated odds of culpability are positively associated with THC, particularly those with higher blood concentrations.

Culpability studies may be well suited to compare risk of fatal and non-fatal crashes, because THC blood levels were measured in all five samples. If THC blood levels are compared regarding fatal (26–28) and non-fatal crashes (29, 30), the odds ratios for any THC blood levels are similar [fatal crashes: 2.7 ng/ml (26), 1.78 ng/ml (27), 1.65 ng/ml (28) vs. non-fatal crashes 1.13 ng/ml (29), 1.9 ng/ml (30)] while the levels in fatal crashes tended to be higher. A previous meta-analysis and systematic review, which excluded low-quality studies, reported cannabis-associated risk for non-fatal crashes (OR = 1.74; 95% CI = 0.88–3.46) and for fatal crashes (OR = 2.1; 95% CI = 1.31–3.36) (2) and confirm the findings for the included five culpability studies in our analysis.

However, case-control and culpability studies have limitations. As several of the authors pointed out, estimating the degree of intoxication for cannabis is a more difficult task than for alcohol (26, 29). As far as cannabis is concerned, after smoking and vaporization, there is a delay in maximal cannabis effects compared to the peak THC blood concentration after consumption, with peak effects after ~30 min depending upon study design and time of testing. Effects on cognition and psychomotor function do not decline as quickly as THC concentration decreases (37–40). When smoking a “joint,” whole blood THC concentrations typically peak at >100 ng/ml during smoking and then drop so rapidly that THC is usually <2 ng/ml within 4 h of a single acute exposure (38). Psychotropic effects typically peak at 20–30 min and resolve by 4 h. Ingesting cannabis delays the onset and extends the duration of these effects. The main THC metabolite, 11-nor-9-carboxy-THC (THC-COOH), is not psychoactive and persists in blood and urine long after impairment resolves. Thus, THC-COOH provides evidence of previous cannabis exposure but does not necessarily indicate impairment or recent use (41). The active ingredient behind most of the effects of cannabis that impair driving ability is THC. Metabolites such as THC-COOH are present and detectable for a significant time after consumption but lack any proven psychoactive effects which impair driving ability.

The results of culpability and case-control studies must be compared with findings from experimental and laboratory studies. Laboratory and simulator studies certainly suffer from the limitation that they are conducted in an artificial environment. Thus, experimental data show that drivers attempt to compensate cannabis intoxication by slower driving after smoking cannabis, but their control deteriorates with increasing task complexity (5, 6). These behaviors limit the generalizability of experimental study results to authentic traffic situations (2). However, as with other cognitive tasks, cannabis smoking (THC-dominant and THC-CBD-equivalent) increases lane weaving after 40–100 min following vaporization (9) and impaired cognitive function consistently as well as critical-tracking tasks, reaction times, divided-attention tasks, and lane-position variability, all of which may increase car crash risk.

In general, however, there is no clear overall relationship with THC blood or serum levels and driving skills or crash risk from experimental studies, even if time of use and duration of consumption are considered. Not surprisingly, there is no unanimous agreement on potential THC legal cut-off levels despite the dose effect with higher THC blood concentrations resulting in higher OR estimates for crashes. However, a relationship does not necessarily provide a clue for a scientifically supported cut-off value. Experts suggest that many drivers with blood THC >3 ng/ml (42) or >3–5 ng/ml (43) have significant impairment and should be prohibited from driving. Based on these reports, many jurisdictions, including many US states and Canada, have set THC per se limits of 2 or 5 ng/ml, while many European countries have a limit of 1 ng/ml. Advocates of these lower THC concentrations argue that THC concentration drops rapidly after smoking, so a driver impaired with high THC concentrations at the time of driving could show concentrations below 5 ng/ml several hours later if there is a delay in obtaining blood samples (44), a fact that supports lower per se limits for THC (30). These concentrations, especially the 1 or 2 ng/ml levels, were criticized because they may not indicate impairment especially in frequent users who develop tolerance to some THC impairing effects (6, 42). Due to the accumulation of cannabinoids in fat, some daily users may have blood THC > 1 ng/ml after a week or more of abstinence (6). Therefore, the various THC concentrations used to define a cannabis-related driving offense in EU countries and some US-states varying between 1 and up to 7 ng/ml alone may not be appropriate to evaluate driving skill impairment comprehensively.

Measures of THC and its non-psychoactive metabolite THC-COOH within hours of an accident suffer from several limitations and may not reflect driving skill impairment. Even higher THC concentrations of >5 ng/ml in recent studies yielded higher risks of injuries and fatal concentrations, however not all studies reported statistically significant relationships. Rather, the assessment of both biological measures and psychomotor characteristics may render evaluation of driving fitness more accurate (more valid to “real” impairment) and is probably applicable in practical traffic control situations. Thus, future experimental and laboratory research on cannabinoid's effects on fitness to drive should consider designs which include measures of psychomotor and cognitive functions like reaction times and decision making after long and monotonous drives and divided attention tasks. These cognitive characteristics may be most impaired by cannabis according to available research (5, 6).

Finally, it is important to recognize that an important compound of cannabis-products used is Cannabidiol (CBD). As for driving skills, it is a substance with sedative effects and therefore may play a role in impairing driving abilities and increase risks for accidents. However, no study investigates the influence of CBD alone on car crash risks. Certainly, since CBD is in increasing demand in sales and consumption, further studies are needed to evaluate the relationship between CBD use, driving ability, and car crash risks.

In summary, there is unanimous agreement across studies that acute cannabis use significantly increases the risk for car crashes and impairs specific driving skills, and confidence in the results from several types of studies (case-control, culpability, and cohorts) is rated “moderate” according to CERQual. In meta-analyses, cannabis user's ORs for car crashes are slightly but significantly increased, when several confounders are considered in multivariate analyses. Further, self-report vs. blood test, case control vs. culpability, and non-fatal crashes had higher OR estimates. High quality culpability studies (SIGN) noted that there is a dose effect of higher THC blood concentrations with increased risk for fatal crashes and those with injuries. However, this biological gradient does not provide a clear legal cut off value. Therefore, these cut off values still range between 1 and 5 ng/ml. While there are various problems related to the measure of THC and its metabolite THC-COOH in blood and other tissues within hours after a crash (different body fluids with different time frames of THC levels), these values may not even reflect actual driving skill impairment. Thus, the biological measures alone may be not appropriate to assess fitness to drive and should be combined with ratings of psychomotor and cognitive skills.