Originally marketed as “natural,” “safe,” and “legal” alternatives to cannabis, synthetic cannabinoid receptor agonists or synthetic cannabinoids (SCs) are one of the most widespread groups of New Psychoactive Substances (NPS). The class includes 224 compounds monitored, by the end of 2021, by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and 6,300 seizes amounting to 236 kg across Europe (1). International and national legislations strive to include these novel compounds within the lists of scheduled substances, but the process is limited by the dynamicity of the market (with approximately 15 SCs newly introduced only in 2021 (1)) as well as by several analytical challenges. Indeed, SCs are mostly not detected using regular rapid or screening tests and require target chromatographic techniques, which have to be constantly updated (2). The short detection window of many molecules in blood or serum makes it further challenging to detect SCs consumption, unless the presence of metabolites is ascertained. However, metabolites are often unknown and have to be studied in vitro or in vivo or both in order to prove the unequivocal consumption of SCs (3). These limitations are particularly relevant in driving under the influence of drugs (DUID) cases, where on-road screening analysis may not be efficient and the parent SC might have been completely metabolized by the time a driver is submitted to proper toxicological analyses. DUID constitutes an interaction between a driver and one or more psychoactive substances, whether licit or not. Mind-altering substances might affect different psychomotor functions which are relevant for driving, such as perception, attention, memory, judgment and evaluation, reasoning, decision-making, problem solving etc. Ethanol is the most important psychoactive substance detected in DUID cases and “drunk driving,” i.e., driving while being impaired by alcohol, represents a worldwide health issue (4). Acute consumption of cannabis is also associated with an increased risk of a motor vehicle crash, especially of fatal collisions, as shown by meta-analyses (5, 6). Moreover, since 1980, studies demonstrated that the impact of tetrahydrocannabinol (THC, the main psychoactive component of cannabis) on psychomotor function significantly increase in combination with ethanol intake, considering general performances, reaction speed factor, standing steadiness factor, and psychomotor coordination (7). Since THC and SCs both act on the cannabinoid receptor 1 and 2 (CB1 and CB2) located in the central nervous system (CNS), consumption of SCs can lead to performance deficits similar to or worse than those observed with cannabis use (8). As recently shown by a comparative analysis of animal and human data (9), psychomotor effects associated with the use of SCs have alarming implications for driving, including effects on attention, memory, response time, motor abilities, and interpretation of visual and auditory stimuli, as well as on behavior. However, scientific evidence on the topic is still limited, and data about DUID prevalence, traffic injuries, and fatal car accidents involving SCs is lacking. Moreover, it has to be considered that SCs usually show higher potency and possibly less predictable effects compared to THC, and this might be relevant for driving abilities, especially in combination with ethanol. We postulated that the combined intake of SCs and ethanol might affect the psychomotor performances to a greater extent than the drugs alone. The present study aims to provide a systematic scientific review of evidence focused on the effects, and particularly psychomotor function impairment, related to SCs and ethanol co-consumption.

The literature search led to the identification of 473 hints, 447 duplicates excluded. After the selection process (Prisma flow chart, Figure 1 (10)) a total number of 20 (8, 12–30) were included. Studies were composed of n = 5 epidemiological studies (25%), n = 4 mixed epidemiological/case series (20%), n = 7 case series (35%), and n = 4 case reports (20%). Epidemiological studies were retrospective in three cases, prospective in two cases, cross-sectional in two cases, involved a retrospective analysis of prospectively acquired data in one case, while in one case it was not possible to establish this data. Articles were published from 2011 to 2022, with the oldest presented data pertaining to 2008–2011 and the newest approximately to 2020. The countries or places of study were: Australia, Germany, Hungary, Italy, Norway, Poland, Scotland (United Kingdom), Sweden, Turkey, and United States. United States and Germany provided the highest number of articles (6 and 4, respectively). A wide variety of sample size was seen, depending on the article type. In Table 1, detailed information extracted from articles, together with the calculated prevalence of ethanol and SCs co-consumption are shown.

The lowest prevalence of co-consumption was calculated as 3.45% in a case series of 29 intoxications (12), while the highest one, 90.9% was reported among adolescent users of SCs (14). Considering case reports/series involving SCs and ethanol presenting extractable data, 31 cases were included in the present systematic review and are shown in Table 2. Subjects were predominantly male (n = 29, 93.5%) with only n = 2 cases involving females (6.4%). The mean age was 29.8 years (standard deviation or SD = 10.4), ranging from 16 to 50 years. The type of population/case consisted of 20 acute intoxications, of which two were coupled to death cases, four criminal offenses, and seven DUID, one of which was coupled to a minor drug offense. Toxicological analyses consisted mostly of validated liquid chromatography (LC), high performance (HP), or ultra-high performance (UHP) LC, coupled to tandem mass spectrometry methods (MS/MS) with or without multiple reaction monitoring methods. In one case, the method was not reported (20) and in one case the results of the validation study were not shown (19). The latency between consumption of SCs (or offense) and toxicological analysis was the least reported information. Indeed, in 15 out of 31 cases (48.4%), this data was lacking. When reported, the latency spanned from slightly more than 30 min to a maximum of 8 h. The following synthetic cannabinoids were detected in combination with ethanol: JWH-122 (three cases), JWH-015, JWH-016, JWH-250, JWH-018 (three cases), JWH-201, JWH-307, AM-694, MDMB-CHMICA (six cases), 5F-AKB-48, MAB-CHMINACA, 5F-MDMB-PINACA (three cases), 5F-MDMB-PICA (nine cases), cumyl-CH-MEGACLONE, 4F-MDMB-BINACA (two cases), 5F-MDMB-P7AICA. Multiple SCs and co-consumption of ethanol were detected in 4 out of 31 cases (12.9%). In some cases, SCs were not quantified in blood/plasma/serum, but only qualitatively assessed (#2, #14, #15, #18, #26, and #30) or were identified in urine samples (cases #8, #12). Co-consumption of other drugs, besides SCs, and ethanol, was described in 13 cases (41.9%) and co-consumed drugs more frequently consisted of tetrahydrocannabinol (THC) or metabolites (8 out of 13). BAC ranged from 0.001 to 2.29 g/L. In two cases the alcohol consumption was reported by the subject but ethanol was not confirmed or quantified in blood (cases #9, #18). The impairment of psychomotor functions varied widely across cases, including the absence of abnormalities, nystagmus, light reaction delay, mood alterations until aggressiveness, increased/decreased vigilance, impaired motor coordination, impaired balance and gait, slurred speech, confusion, dissociative state, bradypsychia until unresponsiveness and coma. More details, including SCs concentrations, are shown in Table 2.

Five of the retrieved studies received funding (12, 17), and none disclosed a conflict of interest. Considering the risk of driving impairment after co-consumption of SCs and ethanol as the numerical result assessed, some biases were found in the selected publications. The tolerance of subjects to the effects of SCs and ethanol could not be evaluated in the included articles, and this could act as a confounding factor. Similarly, other factors, e.g., the type of consumption (whether occasional or repeated, the administration way), the consumption of additional drugs, food intake, individual metabolic phenotype etc. could not be always evaluated. Regarding measurement errors in exposure, a risk of bias might arise from the delayed time between SCs and ethanol co-consumption (or offense) and toxicological analysis, as well from the absence of standardized sampling for SCs and of routine drug testing. Moreover, although the employed methodologies were mostly validated, some limitations have to be considered for analytical methods (13). It cannot be excluded that, due to novel substances being released on the market or due to active metabolites not detectable by the method, the measurement of the exposure was biased (26). As already reported, the selection of participants was different from one study to another, not only geographically but also regarding the type of consumption (e.g., naïve vs. SCs users, age groups etc.). As an example, cases from the emergency departments might lead to an overestimation of the risks (12). For cross-sectional studies, a bias connected to the possibility of participants taking the survey more than once from the same computer could not be excluded (17). Surveys and studies at poison centers (15) could be affected by a bias of recall and selective reporting (17, 18), which can alter both selection and outcome measurement (18). Finally, the measurement of the outcome might be biased by the use of proxy for driving disability, such as psychomotor impairment and acute intoxications.

In drivers involved in accidents, toxicological analyses often reveal the presence of alcohol, cannabis as well as a combination of the two drugs. Despite the similarities in effects between cannabis and SCs, data regarding the prevalence of SCs in DUID cases and traffic accident is still scarce. As reported in past studies, the prevalence of diversion of SCs alone (not combined with other drugs) might range from 0.2 to 14%. The study of Jaenicke et al. (13) reported a prevalence of 2.8% of SCs in cases of traffic offenses, similar to what reported for Norwegian drivers (19). A much higher prevalence, approximately 30%, was reported among samples already suspected for SCs use by the police (21). The low availability of epidemiological studies limits the possibility of ascertaining the SCs-mediated risks of traffic accidents, which is not straightforward in the absence of controlled clinical studies and real-driving simulations (19). The prevalence of co-consumption of SCs and alcohol/drugs in this specific setting would be of paramount importance to establish which drugs and tests should be part of a standard drug analysis. Particularly, since SCs are not efficiently detected by immunological and screening methods and require target analyses, it would be beneficial to understand whether DUID cases involving SCs might be intercepted among drivers positive for alcohol or positive for other drugs usually detected at screenings. Furthermore, this data might allow comprehending whether the reason for using SCs resides in the low detectability at screening tests or whether it is based only or partially on other factors, e.g., low prices, easy availability, etc.

In order to understand the risk of traffic accidents resulting from a co-consumption of drugs, both pharmacokinetic and pharmacodynamic interactions should be taken into consideration. It is known that in the presence of ethanol, oral cocaine might be subjected to transesterification via carboxylesterases enzymes (CES) to form a new active metabolite, cocaethylene. A similar transesterification process has been recently described for several SCs by in vitro studies and confirmed in a single case (31–33). The generation of ethyl ester metabolites, although these compounds have shown low pharmacological activities compared to the parent SCs (31), might result in enhanced psychoactive effects (32) and this possibility has yet to be extensively explored in vivo. From a pharmacodynamic point of view, the high density of cannabinoid receptors located on the axons and terminals of the γ-aminobutyric acid (GABA)-ergic striatal neurons of the basal ganglia and the glutamatergic granule cells of the cerebellum suggests that SCs may play a modulatory role in the control of movements and motor functions. GABA receptors occupy a prominent role in the CNS effects mediated also by ethanol. The similarities in pharmacodynamics might represent some physiological basis to hypothesize an increased effect on CNS function when ethanol and SCs are co-ingested or co-consumed. Also, a possible interaction between SCs metabolites and the enzymes necessary for ethanol metabolism, i.e., alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), has been postulated. Indeed, it has been shown that a mono-hydroxylated metabolite of JWH-018, but not the parent compound, could act as a substrate for the two nicotinamide adenine dinucleotide (NAD(+))-dependent enzymes, competing for ethanol (34). To the best of the authors’ knowledge, only one study on animal evaluated the effects on motor impairment and glutamate neurotransmission of the combination of ethanol and SCs (JWH-018 and AB-CHMINACA) compared to ethanol or SCs alone. JWH-018 (0.05 and 0.1 mg/kg) and AB-CHMINACA (0.005 and 0.01 mg/kg) injected intraperitoneally 10 min before the administration of ethanol (2 g/kg) significantly enhanced ethanol-induced motor impairment, as shown by the latency to fall from an accelerating rotarod (35). Results were similar to the administration of tetrahydrocannabinol (THC), with a peak of effects 15 min after administration and a duration of 75 min. The effects were antagonized by CB₁ selective antagonists, showing the relevance of the role of these receptors (35). Furthermore, the glutamate release in the cerebellum was studied, to check whether the neurotransmission in the cerebellum might play a role in motor impairment. Glutamate release was unaffected by the injection of SCs, but a decrease was noted after the co-administration of JWH-018 and ethanol, and this reduction was more marked when compared to the administration of ethanol alone (35). These results appear interesting, especially considering that BAC concentrations were not affected by treatment with SCs, so the impairment detected is likely not a result of a change in ethanol distribution. As in all kinds of animal studies and repeatedly mention by our group, caution must be paid not to directly suppose that the results on mice might be translated easily to humans (9, 36).

The co-consumption of multiple drugs poses several challenges in forensic toxicology, not only in terms of analytical determination, but also of interpretation. It might be difficult, especially when dealing with NPS, to assess the contribution of the drug to a detected impairment (19). Subsequently, this review was focused on the co-consumption of SCs, which have been recently shown to pose a risk to driving abilities, and ethanol, extensively studied in terms of driving impairment.

The present review has shed some light on the challenges connected to the evaluation of psychomotor performances in cases of co-consumption of new psychoactive substances, particularly focusing on synthetic cannabinoids and ethanol. Although certain dose-relationship effect is known for BAC levels and driving performance, this could not be confirmed in case series involving synthetic cannabinoids. Their effects, together with the true prevalence among DUID cases, remain partially obscure. Based on the limited evidence so far reported in literature, an association between co-consumption and increased risk for road accidents was found and it seems likely that co-consumption might play a synergistic effect on the central nervous system depression, as well as on aggressiveness and mood alterations. The lack of data regarding proper sampling methods, tolerance of the involved subjects, pharmacology of compounds and their metabolites, as well as issues in detecting synthetic cannabinoids represent a challenge for a better knowledge of the risks arising from the co-consumption and for demonstrating a causality between co-consumption and driving disability.

AG and RG contributed to conception and design of the study. VO organized the database. AG and VO wrote the first draft of the manuscript. FB made the critical revision of the paper. All authors contributed to manuscript revision, read, and approved the submitted version.

This work was supported by the Department for Drug Policies, in Italy, under the project’s name “Identificazione e studio degli effetti delle NPS: Sviluppo di una multicentrica di ricerca per il potenziamento informativo dello SNAP e della base dati dell’Osservatorio nazionale sulle tossicodipendenze.”

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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