Within the case series/reports here considered, authors reported five cases of traffic offenses in which a combination of SCs (of the JWH type) and ethanol was detected, describing effects from none to a severe coordination impairment (12, 13). In one criminal offense case (case #2), JWH-015 in concentrations below 0.2 ng/ml, coupled with a BAC of 0.87 g/L, did not produce any abnormality of psychomotor functions (13). JWH-015, however, is a rather “old” SC, which shows greater affinity to CB₂ rather than to CB₁ receptors. However, the latter is the most abundant in the CNS (41, 42). The role of the SC was also likely mild in case #4 where JWH-016, another naphthoylindole characterized by scarce pharmacological data (43), was detected in combination with high levels of ethanol and multiple co-consumed compounds (13). Indeed, the BAC of 1.93 g/L could well explain the coordination deficits and the cognitive impairment described, though a synergistic effect of low doses of SCs cannot be excluded. Similarly, in one case of erratic driving (case #10) with fast driving and running off the road reported by Musshoff, ethanol was assumed to be the main cause of unsafe driving, despite the detection of 1.1 ng/ml of JWH-307 (8). This compound has a high affinity (43) and acts like a full agonist at CB receptors in mice, leading to antinociception, hypothermia, catalepsy and suppression of locomotory activity (44). Among the 29 SCs-related intoxications reported by Hermanns-Clausen et al., one tested positive for JWH-122 and alcohol (case #1). The subject displayed mild symptoms, which are consistent with the effect of ethanol alone (1.03 g/L). In one DUID case (case #3) of co-consumption of JWH-122, amphetamines and ethanol (1.13 g/L), the resultant psychomotor effect, i.e., inconspicuous mood, could not be associated with certainty to ethanol or SCs and the authors concluded that the amphetamines likely played a role (13).This might be due to the low concentration and relatively low potency of JWH-122 (EC₅₀ values twice compared to that of JWH-018 (45, 46)), or to a developed tolerance to the SCs effects. JWH-122 was also found in slightly higher concentrations in a case of traffic accident (case #7), coupled with very low BAC, low concentrations of THC and of LSD (19). In this case, contrarily to the previous one, the influence of other substances was likely low, given the low levels in blood. However, these concentration were approximately in the same range, so that some confounding factors (considering the same compound potency) likely have to be additionally considered, e.g., delay, synergic effect, tolerance, etc. In case #5, the low BAC (0.63 g/L) appears inadequate to produce the depressive mood and the impairment of coordination, most likely attributable to a relatively high concentration of JWH-250 in combination with tramadol and bromazepam, which are CNS depressants (13). JWH-018 is one of the most studied SCs, which was originally characterized due to its higher potency compared to THC (45). In the present study, it is interesting to note that it was associated to the development of generalized seizures (16, 20) in two cases (case #6 and case #8), in which no quantitation in blood was achieved. It is known that drinking acutely raises the threshold of seizures by acting as a CNS depressant, while reducing it after its cessation/withdrawal. In case #6, ethanol concentration was very low and a past consumption can be hypothesized, although the seizure started soon after the consumption of JWH-018. In case #8, BAC was high and should have theoretically protected the person from seizure. Generalized tonic–clonic seizures have been reported after the consumption of Spice products and this effect seems to be mediated by CB1-receptors (47–49). People affected by epilepsy are usually granted the driving license only after a seizure-free period and, depending on the legislation, they are evaluated by specific commissions (50). In the case of SCs consumption and especially of SCs and ethanol co-consumption, the risk for an unpredicted seizure in a previously seizure-free person has to be considered, especially when alcohol consumption precedes SCs intake.

Interestingly, JWH-018 was also detected in a case (case #9) of severe intoxication, in which the patient experienced periods of unconsciousness (21). The relatively high concentration detected (11 ng/g) is likely due to the low latency between consumption and sampling (only 37 min). Since latency is not reported in many other cases in the literature, although JWH-018 has been repeatedly detected in DUID cases, it is hard to compare this case to others (9). The severity of the clinical picture, however, was most likely connected to the SC, given the absence of confirmed BAC. It is well known that, by increasing the latency between consumption or traffic offense and toxicological analysis, the opportunity of detecting a co-consumption is reduced, especially when dealing with SCs, which usually display a small detection window in blood. The presence of cases in which one or both drugs were only reported or only found in urine further confirms the importance of a rapid sample collection (20, 21, 23). Urinary methods, based on the detection of SCs metabolites, might allow a greater detection window but would not allow to ascertain a psychoactive effect at the time of driving. Interestingly, in the literature collected, latency or delay of toxicological analysis was frequently not reported, and this represents a challenge for the assessment of the effect of drugs on psychomotor performances relevant for driving. The drug stability is another factor which should be considered when evaluating the latency between a driving offense and the toxicological analysis. Among the studies included in the present revision, a stability of SCs at 20°C for 4 days was proven by Jaenicke et al. (13). However, data on stability, even in the freezer, for very long periods is lacking and this appears as a limitation of those studies involving the re-analysis of samples stored for years (13).