Abstract
Background and Objectives
Ketamine is a psychoactive substance used for its stimulant and hallucinogenic properties. As the use of ketamine may lead to impaired driving, we aimed to assess the occurrence of ketamine in the driving population tested positive for narcotics in roadside checks using oral fluid analysis. Oral fluid concentrations of ketamine and norketamine were examined to determine the percentage of drivers susceptible to ketamine impairment.
Methods
A retrospective descriptive study was conducted over a 32‐month period in 2020–2023 on drivers who tested positive to the DrugWipe®5S saliva test in our region of northeastern France. Mass spectrometry was used to confirm the DrugWipe®5S result and to determine oral fluid concentrations of ketamine and norketamine.
Results
During the entire study period, 3364 drivers were tested positive at the roadside using the DrugWipe®5S rapid test. After mass spectrometry, 3043 drivers were finally confirmed as true positives. Ketamine was detected in 88 drivers who were 80.7% male, 95.4% polydrug users and were 27.5 ± 7.1 years old, representing 2.6% of the total driver population. Ketamine concentrations were 821 ± 2264 and 7.8 ± 12.3 ng/mL in the presence and absence of norketamine, respectively. Finally, 26.1% of the ketamine‐positive drivers had a ketamine oral fluid concentration potentially associated with impaired driving.
Conclusion
Ketamine and norketamine should be added to the list of drugs to be tested in oral fluid for driving under the influence of drugs. Besides blood or urine, oral fluid could be an interesting alternative biological matrix for addiction medicine.
Keywords: addiction, drug abuse, drug testing, ketamine, oral fluid
Abbreviations
- 6‐AM
6‐acetylmorphine
- AMP
amphetamines
- BZE
benzoylecgonine
- COC
cocaine
- DUID
driving under the influence of drugs
- MDA
methylenedioxyamphetamine
- MDEA
3,4‐methylenedioxyethylamphetamine
- MDMA
3,4‐methylenedioxy‐N‐methylamphetamine
- OPI
opiates
- THC
tetrahydrocannabinol
1. INTRODUCTION
Ketamine or ketamine hydrochloride (2‐[2‐chlorophenyl]‐2‐methylamino‐cyclohexan‐1‐one) is a non‐barbiturate dissociative anaesthetic derived from phencyclidine synthetized in 1962 by the Parke‐Davis Pharmaceutical Company US [1]. Patented in 1966 as Ketalar®, ketamine was finally approved by the Food and Drug Administration (FDA) in 1970 and was widely used to induce and maintain anaesthesia in humans and in veterinary medicine for over 40 years [2]. The psychoactive properties of ketamine were also quickly responsible for the emergence of its misuse as a recreational drug since the 1970s. Often used as a sniffing powder or injected in its liquid form by young people, particularly at raves and in electronic music circles [3], ketamine acts as a stimulant at low doses and as a hallucinogen at high doses [4]. Despite its widespread misuse [5, 6], ketamine is currently not subject to international control. In fact, due to its low cost and ease of use, ketamine is listed among essential medicines by World Health Organization (WHO) and is considered as difficult to replace in developing countries [7]. Nevertheless, its misuse has led some countries to build a policy for controlling ketamine at the national level, including its import and export. In France, for example, the first cases of ketamine abuse were described from 1992, and ketamine was finally listed as a narcotic in 1997. However, ketamine was included for the first time in the national survey on representations, opinions and perceptions of psychotropic drugs (EROPP) in 2023, mainly because of increasing concerns about ketamine since 2021 [4, 8]. In France, a study conducted by the French Addictovigilance Network clearly showed a 2.5‐fold increase in the number of ketamine users among people with substance use disorders between 2012 and 2021 [9]. This finding is even more alarming given that the number of daily users, users with distress at discontinuation and users with addiction were also found to be increasing. In 2023, it was estimated that 2.6% of adults aged 18–64 in France had experience with ketamine [8].
Among other regulatory measures, ketamine is also tested for driving under the influence of drugs (DUID) in several countries and in various biological matrices [10]. In France, the use of oral fluid in roadside drug testing was introduced in 2016 with the strengthening of the French DUID law [11]. As in many countries, oral fluid collection has attracted interest because it is a non‐invasive and easy to collect sampling method with a very low risk of adulteration [12, 13]. The usefulness of oral fluid in the context of DUID is further reinforced by the fact that several studies reported the detection of ketamine in this biological matrix. Cheng et al. found ketamine in the oral fluid of 39 out of 62 Chinese volunteers leaving discos between January 2004 and December 2004 [14]. In Norway, Brazil and France, Gjerde et al., da Cunha et al. and Gish et al., found ketamine in the oral fluid of two out of 651, 136 out of 462 and one out of 265 music festival attendees in June/August 2016, 2018–2020 and June 2019, respectively [15, 16, 17]. In the driver population, Chu et al. and Wille et al. detected ketamine in 15 of 853 and two of 199 oral fluid samples, respectively, between June 2009 and August 2010 in Australia and between January and August 2015 in Belgium [18, 19]. In addition, it is interesting to note that ketamine was not found in the studies by Institóris et al. in Hungary and Zancanaro et al. in Brazil, which were conducted in 2738 and 2235 oral fluid samples collected from drivers between January 2008 and December 2009 and between August 2008 and September 2009, respectively [20, 21]. Prevalence reported in the previous studies was highly heterogeneous across countries, ranging from 63% and 29% in China and Brazil, to 0.4% and 1.5% in France and Australia and 0% in Hungary. In line with these previous studies and given the scarcity of data on ketamine use in the driver population in France and more globally in Europe, we carried out a retrospective study to search for ketamine users among drivers tested positive for opiates (OPI), cocaine (COC), amphetamines (AMP) or cannabis (THC) by oral fluid roadside rapid test in our region of northeastern France. In addition, we described the population of ketamine‐positive drivers and simultaneously measured oral fluid concentrations of ketamine and its metabolite norketamine to assess the percentage of ketamine‐positive drivers potentially impaired by its use.
2. MATERIALS AND METHODS
We conducted a retrospective descriptive study over a 32‐month period between 22 May 2020 and 28 February 2023 among drivers who tested positive at the roadside to the DrugWipe®5S saliva test—used to detect AMP, OPI, COC and THC—in our region located in northeastern France.
2.1. Study design and data collection
Data were collected from DUID cases positive on the DrugWipe®5S saliva test and sent to the Clinical Pharmacology and Toxicology Laboratory of our University Hospital for confirmation by mass spectrometry. Cases were considered ketamine‐positive if ketamine and/or its metabolite, norketamine, was detected by mass spectrometry in the driver's oral fluid sample. Data collected included age, gender, qualitative results of a roadside rapid drug test for oral fluid performed by law enforcement, concentrations of ketamine and norketamine detected in oral fluid samples by mass spectrometry and time elapsed between last reported drug use and oral fluid collection. This study was performed in accordance with the authorization of the Courts of Justice in our region, and all data collected were anonymized.
2.2. Chemicals, reagents and equipment
Qualitative analysis of oral fluid was performed at the roadside by law enforcement authorities using a DrugWipe®5S saliva test (Securetec Detektions‐Systeme AG, Neubiberg, Germany). This rapid test complied with French legislation and has minimum detection limits of 10 ng/mL for COC, benzoylecgonine (BZE), morphine (MOR) and 6‐acetymorphine (6‐AM), 15 ng/mL for THC and 50 ng/mL for amphetamine, methamphetamine and MDMA [11]. Quantitative analysis of oral fluid collected on a buffer‐free FLOQSwab® (Copan Diagnostics, Murrieta, USA) performed in our laboratory using a Nexera X2 ultra‐high performance liquid chromatography system (Shimadzu, Japan) coupled to a 6500+ QTRAP triple quadrupole mass spectrometer (Sciex, Framingham, USA). Briefly, analysis of ketamine (K), norketamine (NK) and 31 other psychoactive molecules in oral fluid was performed by in‐line solid‐phase extraction, consistent with a previous work published by Mercier et al. [12] The limits of quantification for ketamine and norketamine were set at 0.1 and 0.2 ng/mL in saliva, respectively. In accordance with the French law requiring specific testing for amphetamine, methamphetamine, MDMA, MDA, MDEA, COC, BZE, MOR, 6‐AM and THC, the limits of quantification in oral fluid were 1 ng/mL for THC and 10 ng/mL for all other substances.
2.3. Statistical analysis
Descriptive statistics assessed the characteristics of the included drivers, the concentrations of ketamine and norketamine found in oral fluid and the time course of ketamine‐positive cases. Continuous variables are presented as median, means and standard deviations (SD), and categorical variables are presented as percentages. Mann–Whitney test was conducted to test for significant differences between the years 2020, 2021 and 2022 in the number of ketamine‐positive cases per month (p < 0.05). Mann–Whitney test was also used to compare oral fluid concentrations between drivers using ketamine with and without its metabolite norketamine (p < 0.01). Comparison of time from last self‐reported drug intake of the substances to oral fluid collection in the population of ketamine‐ and norketamine‐positive drivers and in the population of ketamine‐positive drivers only was assessed by Student's t test (p‐value <0.05) after demonstration of equality of variance performed by F test (p‐value <0.05). The comparison of categorical variables between the characteristics of the male and female populations was evaluated by the Z‐test (p‐value <0.01). Statistical analysis was performed using R version 4.2.3 for Windows® (https://www.r-project.org/, accessed on 14 December 2024).
3. RESULTS
During the entire 32‐month study period, a total of 3364 drivers tested positive for drugs of abuse using the DrugWipe®5S oral fluid roadside rapid test. After mass spectrometry confirmation, 3043 were finally confirmed as truly positive (Table 1).
TABLE 1.
Characteristics of drivers with a roadside oral fluid (OF) sample detected as positive by the qualitative DrugWipe®5S in the total population, in males and females, respectively.
| Population characteristics | Total population | Males | Females |
|---|---|---|---|
| Number of drivers | 3364 (100.0%) | 3097(100.0%) | 267 (100.0%) |
| Male | 3097(92.1%) | ||
| Female | 267 (7.9%) | ‐ | ‐ |
| Mean age ± sd (y.o) | 31.3 ± 9.4 | 31.4 ± 9.4 | 30.3 ± 8.2 |
| Median age(y.o) | 30.0 | 30.0 | 29.0 |
| Repeat offender | 266 (7.9%) | 244 (7.9%) | 22 (8.2%) |
| Polyconsumer of illicit drugs a | 882 (26.2%) | 800 (25.8%) | 82 (30.7%) |
| Confirmed positive Illicit drugs a | 3043 (90,5%) | 2802 (90.5%) | 241 (90.3%) |
| 9‐Tetrahydrocannabinol | 2561 (76.1%) | 2375 (76.7%) | 186 (69.7%) |
| Cocaine | 877 (26.1%) | 797 (25.7%) | 80 (29.9%) |
| Opiates | 577 (17.1%) | 515 (16.6%) | 62 (23.2%)* |
| Amphetamines | 95 (2.8%) | 82 (2.6%) | 13 (4.9%) |
| Confirmed positive other substances b | 1075 (32.0%) | 966 (31.2%) | 109 (40,8%)* |
| Ketamine/norketamine | 88 (2.6%) | 71 (2.3%) | 17 (6.3%)* |
Note: * Due to the multiple use of drugs and the fact that a substance may be present in combination, the percentages determined for illicit drugs or other substances do not add up to 100%. Data are given as number of cases. Percentages are given in brackets.
Including at least one of the 10 illicit substances defined by French law: 9‐tetrahydrocannabinol, cocaine, benzoylecgonine, 6‐acetylmorphine, morphine, 3,4‐methylenedioxymethamphetamine, 3,4‐methylenedioxyamphetamine, 3,4‐methylenedioxyethylamphetamine, amphetamine and methamphetamine.
Including at least one of the following substances: cannabidiol, codeine, methadone, tramadol, buprenorphine, oxycodone, mephedrone, ketamine and norketamine.
statistically different in comparison with males (Z‐test, p < 0.01).
3.1. Total population characteristics
The total population included 3097 men and 267 women. The mean and median ages in the total population were 31.3 ± 9.4 and 30.0 years, respectively, and were of the same order in females as in males. The proportions of repeat drivers and polydrug users were 8.2% and 30.7%, respectively, for women and 7.9% and 25.8%, respectively, for men. The presence of THC was confirmed in the oral fluid of 76.1% of drivers, well before COC, OPI or AMP, which were found in 26.1%, 17.1% and 2.8% of drivers, respectively. Other substances such as cannabidiol, codeine, methadone, tramadol, buprenorphine, oxycodone, mephedrone, ketamine or norketamine were present in oral fluid in 32.0% of the drivers. A more frequent presence of these substances, as well as opiates, in the oral fluid of women compared to men was statistically significant (Z‐test, p = 0.0006).
3.2. Ketamine user driver characteristics
Ketamine and norketamine, detected only by mass spectrometry, were found in 88 drivers, 71 males and 17 females, representing 2.6% of the total driver population in our study, a percentage close to that of AMP (2.8%) (Table 2). Two drivers, one male and one female, were found to be repeat offenders. Notably, the proportion of women who tested positive for ketamine in the female population was higher than the same proportion in men, accounting for 6.3% and 2.3% of female and male drivers, respectively (Z‐test, p < 0.0001). The mean and median ages in the ketamine user population were 27.5 ± 7.1 and 25.6 years, respectively. There was no gender difference in mean and median age, and these drivers were younger than those in the total driver population (31.3 ± 9.4 and 30.0 years, respectively). The 20 age group was the most represented (71.6%), regardless of gender (70.4% for men and 76.5% for women). The 31–40 and 41–50 age groups represented 14.8% and 10.2% of the population, respectively. Finally, the 18–20 age group was the least represented with only 3.4% of ketamine users. In the ketamine user population, multiple use of illicit drugs appeared to be the rule, as 95.4% of drivers in this population tested positive for at least one of the 10 illicit substances required by French law to be tested in the driver's oral fluid. The use of ketamine in combination with substances from two of the four traditional narcotic classes (AMP, OPI, COC and THC) was found in 45.4% of ketamine users. Cocaine was the most commonly associated drug (80.7%), just ahead of THC (70.4%) and far ahead of AMP (35.2%) and OPI (9.1%). These observations were similar in both gender groups. Finally, cannabidiol, codeine, methadone and tramadol were also found in the oral fluid of ketamine users in relatively small proportions compared with illicit drugs. Cannabidiol and codeine were the most common substances found in 13.6% and 9.1% of ketamine users, respectively.
TABLE 2.
Characteristics of drivers with a roadside oral fluid (OF) sample detected as positive for ketamine and norketamine by mass spectrometry in the total population, in males and females, respectively.
| Population characteristics | Total population | Males | Females |
|---|---|---|---|
| Number of drivers | 88 (100.0%) | 71 (100.0%) | 17 (100.0%) |
| Male | 71 (80.7%) | ||
| Female | 17 (19.3%) | ‐ | ‐ |
| Mean age ± sd (y.o) | 27.5 ± 7.1 | 27.7 ± 7.3 | 26.7 ± 6.2 |
| Median age(y.o) | 25.6 | 25.6 | 25.5 |
| Repeat offender | 2 (2.3%) | 1 (1.4%) | 1 (5.9%) |
| Ketamine | |||
| Ketamine + norketamine | 36 (40.9%) | 31 (43.7%) | 5 (29.4%) |
| 52 (59.1%) | 40 (56.3%) | 12 (70.6%) | |
| Polyconsumer of illicit drugs a | 84 (95.4%) | 68 (95.8%) | 16 (94.1%) |
| + 1 class of illicit drugs | 21 (23.9%) | 19 (26.8%) | 2 (11.8%) |
| + 2 classes of illicit drugs | 40 (45.4%) | 31 (43.7%) | 9 (52.9%) |
| + 3 classes of illicit drugs | 21 (23.9%) | 17 (23.9%) | 4 (23.5%) |
| + 4 classes of illicit drugs | 2 (2.3%) | 1 (1.4%) | 1 (1.7%) |
| Illicit drugs | |||
| Cocaine | 71 (80.7%) | 57 (80.3%) | 14 (82.3%) |
| Cocaine | 71 (80.7%) | 57 (80.3%) | 14 (82.3%) |
| Benzoylecgonine | 61 (69.3%) | 48 (67.6%) | 13 (76.5%) |
| 9‐tetrahydrocannabinol | 62 (70.4%) | 50 (70.4%) | 12 (70.6%) |
| Amphetamines | 31 (35.2%) | 23 (32.4%) | 8 (47.1%) |
| Ecstasy (MDMA) | 27 (30.7%) | 20 (28.2%) | 7 (41.2%) |
| Amphetamine | 14 (15.9%) | 9 (12.7%) | 5 (29.4%) |
| Methamphetamine | 2 (2.3%) | 1 (1.4%) | 1 (1.7%) |
| Opiates | 8 (9.1%) | 6 (8.4%) | 2 (11.8%) |
| 6‐Acetymorphine | 8 (9.1%) | 6 (8.4%) | 2 (11.8%) |
| Morphine | 8 (9.1%) | 6 (8.4%) | 2 (11.8%) |
| Other substances | 28 (31.8%) | 23 (32.4%) | 5 (29.4%) |
| Cannabidiol | 12 (13.6%) | 9 (12.7%) | 3 (17.6%) |
| Codeine | 8 (9.1%) | 7 (9.9%) | 1 (1.7%) |
| Methadone | 6 (6.8%) | 6 (8.4%) | 0 (0.0%) |
| Tramadol | 2 (2.3%) | 1 (1.4%) | 1 (1.7%) |
Note: * Due to the multiple use of drugs and the fact that a substance and/or its metabolite may be present in combination, the percentages determined for illicit drugs or other substances do not add up to 100%. Data are given as number of cases. Percentages are given in brackets.
Including at least one of the 10 illicit substances defined by French law: 9‐tetrahydrocannabinol, cocaine, benzoylecgonine, 6‐acetylmorphine, morphine, 3,4‐methylenedioxymethamphetamine, 3,4‐methylenedioxyamphetamine, 3,4‐methylenedioxyethylamphetamine, amphetamine and methamphetamine.
3.3. Seasonality in the use of ketamine
Ketamine was found throughout the year, but some seasons seemed to be more favourable for its use (Figure 1). The percentage of positive cases per month ranged from 0.0% to 8.1%. Looking at the full years 2021 and 2022, the two last thirds of the year, between May and August and between September and December, were the periods with the highest number of ketamine‐positive cases. Indeed, in those years, a peak of positive cases was observed in October (5.4%) in 2021 and in July (5.9%) in 2022, respectively.
FIGURE 1.
Percentage of ketamine‐positive drivers out of the total population for each month or for each specific time period. * statistically different (Mann–Whitney test, p < 0.05).
Comparison of similar periods of the year, such as the 7‐month period between June and December in 2020, 2021 and 2022, showed a significantly higher percentage of ketamine‐positive drivers between 2020 and 2021 (1.3% vs. 3.1%) (Mann–Whitney test, p = 0.002). However, no statistical difference was observed between 2020 and 2022 (1.3% vs. 2.6%) and between 2021 and 2022 (3.1% vs. 2.6%). In addition, the annual incidence was similar for 2021 and 2022 (2.6% vs. 2.2%). Finally, in 2023, it should be noted that 8.1% of positive cases was reported in January, a finding coincidental to a huge rave party in our region.
3.4. Ketamine in oral fluid samples
Among all ketamine‐positive samples (n = 88), ketamine was found without norketamine (K + NK−) in 36 drivers (40.9%) and in combination with its metabolite, norketamine (K + NK+) in 52 drivers (59.1%) (Table 1). It should be noted that norketamine was never detected in the absence of ketamine. The concentrations of ketamine and norketamine found in the oral fluid samples ranged from 0.15 to 16 100 ng/mL and from 0.52 to 6100 ng/mL, respectively. In the oral fluid samples of the total population of ketamine user, the mean and median concentrations of ketamine and norketamine were 821 ± 2264 and 33.7 and 282.8 ± 859.3 and 64.9 ng/mL, respectively (Figure 2). However, if these values were highly dispersed, they were particularly different for ketamine concentrations between the K + NK+ and the K + NK− groups. Indeed, the mean and median concentrations of ketamine were 7.8 ± 12.3 and 2.3 and, 1385 ± 2819 and 146 ng/mL for the K + NK and K + NK+ groups, respectively. Therefore, ketamine concentration was significantly higher in the group in which norketamine was detected concomitantly (Mann–Whitney, p < 0.0001). Furthermore, while none of the ketamine concentrations in the K + NK− group exceeded 50 ng/mL, 23 of the 52 drivers (44.2%) in the K + NK + group had a ketamine oral fluid concentration greater than 300 ng/mL, representing 26.1% of the total population.
FIGURE 2.
Semilogarithmic representation of ketamine [K] and norketamine [NK] concentrations in the oral fluid of the subgroup of ketamine‐positive cases with norketamine (K + NK+) (n = 52) (light grey) and the subgroup of ketamine‐positive cases without norketamine (K + NK−) (n = 36) (white). The box plots show the minimum and maximum concentrations of ketamine and norketamine in oral fluid, the interquartile ranges, the mean (black cross) and the median (black line dividing the box into two parts). *: statistically different (Mann–Whitney test, p < 0.01).
Regarding the combination of ketamine with other substances, it is interesting to note that COC, THC and AMP (amphetamine or ecstasy) were the three most commonly associated substances in both the K + NK+ and K + NK− groups. The combination of ketamine with one illicit drug from each of the classes of AMP, OPI, COC and THC was observed only in the K + NK + group and not in the K + NK− group.
Finally, the mean time from last self‐reported drug intake to oral fluid collection was reported by only 46 drivers and was 47.6 ± 78.7 h in the entire study population, ranging from 0.5 to 421.5 h, with a median value of 18.5 h. In the K + NK− and K + NK+ subgroups, the same parameters were 43.6 ± 74.5 h, ranging from 0.5 to 421.5 h, with a median value of 20.6 and 55.9 ± 88.9 h, ranging from 0.6 to 347.0 h, with a median value of 16.5 h, respectively. The time from last self‐reported drug intake to oral fluid collection was not statistically different between the two groups (Figure 3).
FIGURE 3.
Semilogarithmic representation of the time from last self‐reported drug intake to oral fluid collection among all ketamine‐positive samples (all cases, n = 46) (dark grey), the subgroup of ketamine‐positive cases with norketamine (K + NK+) (n = 31) (light grey) and the subgroup of ketamine‐positive cases without norketamine (K + NK−) (n = 15) (white). The box plots show the minimum and maximum delay, the interquartile ranges, the mean (black cross) and the median (black line dividing the box into two parts).
4. DISCUSSION
In the present study, the overall percentage of drivers who tested positive for ketamine in a roadside oral fluid test was 2.6%. This percentage was higher than that described by Gish et al. in samples collected at a music festival in southwest France (1.4% in 2017 and 0.4% in 2019) [17], but also higher than the prevalence previously reported in the driver population of other countries [18, 19, 20, 21] where the highest prevalence was found in Australia in 2012 (1.5%) [18]. While the nature of the musical event may partly explain the difference observed in our study (rave party) with that of Gish et al. (rock festival), regional disparities in illicit drug use may exist. The percentage of ketamine positivity observed in our study during the last 7 months of 2020 was of the same order as those previously described, but cannot be compared to earlier data from our region since ketamine in oral fluid samples was unfortunately not tested in our laboratory before May 2020. However, we report a significant increase in ketamine use in 2021 compared to 2020, which is consistent with the study led by the French Addictovigilance Network, where the number of ketamine users with a substance use disorder in the OPPIDUM programme increased 2.5‐fold between 2012 and 2021 [9]. In this study, we also observed a higher number of ketamine‐positive cases in the summer and autumn. This observation is consistent with the evolution of ketamine use from a confidential one, at high doses in free parties and in the party scene in the 2000s, to a large one, in a ‘techno and electro’ festive context during festivals, in bars or in clubs [22, 23, 24]. It is now more common to consume ketamine in trace amounts, as consumers are no longer looking for hallucinogenic properties, but rather for a more moderate stimulant effect. The higher consumption of ketamine during the summer period reported in the present study is consistent with those reported in Toulouse (southwestern France) since 2017, in relation to a diffusion of this substance from alternative parties to electronic parties. Indeed, the latter are more frequent in the summer period and the larger number of participants in outdoor events is also a source of increased diversity and availability of substances [25]. In addition to summer and autumn, a marginal use of ketamine in winter was observed in our region during a rave party in January 2023. The same situation was observed in Toulouse during techno‐house and industrial techno parties in 2018, underlining the trivialized consumption of ketamine by techno partygoers. In this study, we cannot exclude the possibility that drivers attending supervised events, such as music festivals, which require prior authorization from the prefecture and are associated with more pronounced and systematic control, were included, thus introducing a possible bias. On the contrary, it should be noted that the use of the DrugWipe®5S as a roadside screening test in accordance with French regulations did not allow for the direct detection of ketamine [11]. This may have introduced a potential underestimation and selection bias among drivers tested for drug use, but this may be limited as 95.4% of the ketamine‐positive drivers identified in this study were polydrug users, mainly using COC, THC and AMP. Interestingly, this problem could be easily overcome by using some rapid oral fluid tests such as DrugWipe® 6S, Ora‐Check®, SalivaScreen®, OratectXP®, which are able to detect ketamine at cut‐offs of 5 to 50 ng/mL for ketamine and 30 to 75 ng/mL for norketamine [26, 27]. Finally, among the ketamine users, we do not exclude the possibility of having included depressed persons using the antidepressant esketamine. Indeed, the dextrorotatory isomer of ketamine (s‐ketamine) cannot be differentiated from ketamine by our non‐chiral chromatography method, whereas major depression has been reported to favour drug of abuse consumption [28]. However, the study by Baudot et al. showed that only a small number of patients are treated with esketamine in France [29], limiting the bias introduced by our analytical method.
The characteristics of our ketamine‐positive driver population were similar to those described in other studies, namely, a majority of males in their 20s with polydrug use [30]. In accordance with other studies, ketamine was associated with other drugs such as COC, THC and AMP, in particular MDMA, which are the three most commonly used illicit drugs in Europe and in France, but also the most commonly available and consumed in commercial free parties [31, 32, 33, 34]. The high prevalence of COC in our study may also be related to the spreading, over the past decade, of a new drug mix used in nightclubs in many countries (England, the USA, France, etc.) called Calvin Klein (CK)—also known as ‘CK1’ or ‘cable’—that combines cocaine and ketamine. Mainly consumed by injecting or sniffing and coupled with MDMA, this mixture can produce powerful euphoric and hallucinogenic effects [35, 36]. In addition to the Calvin Klein mix, other combinations with ketamine are also reported by users, such as ‘Kite Surf’, which combines ketamine with ‘speed’—a mixture of AMP and caffeine—‘Trinity’, which consists of MDMA followed by ketamine and then cannabis, or the unnamed mixes, which combine ketamine with MDMA and lysergic acid (LSD) [31, 32, 33]. It should be noted that LSD was not targeted by our multiplex analysis, thus excluding artificially this molecule from the ketamine‐associated drugs list.
Finally, based on the presence of norketamine, the study population of ketamine‐positive drivers was subdivided into drivers found positive for ketamine and norketamine, and the second corresponding to drivers found positive for ketamine without norketamine. From the higher concentration of ketamine found in the first subgroup, and taking into account, the time elapsed between last self‐reported drug use and oral fluid collection and the pharmacokinetic profile of ketamine and norketamine in blood, we suggest that the source of the ketamine was ketamine use and that norketamine may be a good additional indicator of actual ketamine use [37, 38]. This suggests that only relatively recent users of ketamine were included, calling into question the date of last use reported by some drivers beyond 72 h. This point highlights the declarative nature of the self‐reported drug use by the drivers, which cannot be verified and it can sometimes be unreliable. The recent use of ketamine in norketamine‐positive drivers is further supported by the fact that 44.2% of the drivers tested positive for ketamine and norketamine had oral fluid concentrations above 300 ng/mL, the saliva threshold described by Cheng et al. as being associated with clear signs of impairment [14]. In the total population of drivers testing positive for ketamine, this percentage of suspected impairment was 26.1%. Finally, the origin of the ketamine found in low or very low concentrations in the subgroup without norketamine is questionable. Hypotheses such as contamination of companion narcotics by ketamine, environmental contamination or previous use of ketamine could be raised.
5. CONCLUSION
In conclusion, in the present work, ketamine‐positive drivers tested positive to a roadside rapid test for AMP, OPI, COC and THC were 2.6%, a percentage close to that of AMP. Among these drivers, 26.1% had ketamine oral fluid concentrations potentially associated with impairment. The lower percentage of positivity in 2020 compared to 2021 suggests a possible influence of the health restrictions put in place to counter the spread of COVID‐19 on ketamine use among the driver population in our region, more pronounced in late spring and summer. Finally, we have shown that norketamine may be a good indicator for the actual use of ketamine. Ketamine and norketamine should be added to the list of drugs to be tested for in oral fluid in the context of DUID, especially as almost half of the drivers who tested positive for these two substances were likely to have impaired alertness, vigilance and psychomotor performance. This study should be repeated in other regions, in close collaboration with addictovigilance centres, in order to improve the effectiveness of prevention and public health initiatives in France. Finally, oral fluid could be an interesting alternative biological matrix to blood or urine for addiction medicine, especially as it can at least be tested by commercially available rapid immunochromatography tests and ideally confirmed by mass spectrometry.
AUTHOR CONTRIBUTIONS
All authors contributed to the conception, drafting and revision of the work and approved the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Julien Scala‐Bertola and Nicolas Gambier contributed to the study conception and design. Data acquisition, analysis and interpretation were carried out by Laïyna Lilo Aouichi, Elise Pape and Allan Kolodziej. The first draft of the manuscript was written by Laïyna Lilo Aouichi, Julien Scala‐Bertola, Elise Pape and Jean‐Yves Jouzeau and all authors commented on previous versions of the manuscript. Valérie Gibaja, Eyrian Aubin‐Beale, Catherine Feliu and Elodie Marchand revisited it critically for important intellectual content. All authors have read and approved the final manuscript.
CONFLICT OF INTEREST STATEMENT
The authors have no conflicts of interest to declare that are relevant to the content of this article. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non‐financial interest in the subject matter or materials discussed in this manuscript.
ETHICS STATEMENT
Ethical approval is not required for this study since it was performed using routinely collected deidentified data, in line with the French regulations for mandatory reporting by healthcare professionals (article R5132–102 of the Public Health Code) and in accordance with the authorization of the Courts of Justice in our region.
ACKNOWLEDGEMENTS
The authors would like to thank Dr N. Colling and Dr F. Lapicque and the entire technical team (Alycia Bour, Margot Brequel, Virginie Delfosse, Nathalie Meissner, Lydie Renard, Laurence Richard, Christelle Simonot and Sandrine Maury) at our university hospital's clinical pharmacology and toxicology laboratory for their invaluable help in carrying out this work.
Aouichi LL, Pape E, Jouzeau J‐Y, et al. Detection of ketamine in the oral fluid of drivers in northeastern France during the years 2020–2023. Fundam Clin Pharmacol. 2025;39(2):e13060. doi: 10.1111/fcp.13060
Nicolas Gambier and Julien Scala‐Bertola contributed equally to this work.
Funding information None.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. These data are not publicly available as they are the property of the courts in our region.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. These data are not publicly available as they are the property of the courts in our region.