Defining recent cannabis use analytically

Two articles [1,2] published in this Issue of Clinical Toxicology explore ways to establish the recent use of cannabis analytically. The work of Kosnett et al. [1] has several advantages over the preceding work by Heustis et al. [3], who used Δ9-tetrahydrocannabinol and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol concentrations to derive complex equations to estimate the time interval since the last use of cannabis.

By comparison, Kosnett et al. [1] propose a simple and intuitive ratio. They calculated two blood cannabinoid molar metabolite ratios: [Δ9-tetrahydrocannabinol] to [11-nor-9-carboxy-Δ9-tetrahydrocannabinol] and ([Δ9-tetrahydrocannabinol] + [11-hydroxy-Δ9-tetrahydrocannabinol]) to [11-nor-9-carboxy-Δ9-tetrahydrocannabinol]. In occasional and daily users, the blood cannabinoid molar metabolite ratios were superior to whole blood Δ9-tetrahydrocannabinol as indicators of recent cannabis smoking, with 98% specificity, 91–93% sensitivity, and 95–96% accuracy for identifying recent cannabis smoking. In contrast, the optimum cutoff value for Δ9-tetrahydrocannabinol concentrations of 5.3 µg/L only showed 88% specificity, 73% sensitivity, and 80% accuracy for defining recent use. Kosnett et al. [1] recommend measurement and reporting of Δ9-tetrahydrocannabinol, 11-hydroxy-Δ9-tetrahydrocannabinol, and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol, and their molar metabolite ratios in forensic and safety investigations.

The second article from Rague et al. [2] concerns cannabigerol (a less familiar, minor metabolite of Δ9-tetrahydrocannabinol) as an indicator of the recent use of cannabis within the previous 30 min. In this cohort, the detection threshold cannabigerol concentration of 0.2 µg/L appears very specific (96%) but only about 50% sensitive for cannabis smoked within the previous 30 min. Nonetheless, the authors claim that whole blood cannabigerol may have forensic utility as a highly specific albeit insensitive biomarker of recent cannabis smoking. In reality, the extremely rapid clearance of cannabigerol makes it unlikely to be useful as a primary analyte in assessing motorists stopped by police for traffic violations or involved in vehicular crashes. Whether hospital and forensic laboratories will add cannabigerol to their testing is unclear. If they do, then future research may bring a better understanding of the laboratory detection and diagnosis of cannabis exposure.

The legal status of cannabis and related products, such as edibles, has rapidly changed in the past two decades in the United States (US). As of the end of 2022, possession and personal use of cannabis is legal in 21 US states, and 37 states and the District of Columbia have legalized cannabis for “medical” purposes [4]. Four states have pending ballot measures for 2023 and 2024.

Legalization of cannabis use is associated with an increase in the proportion of injured drivers with cannabinoids found even though overall vehicular crashes and those involving alcohol remained generally stable in the US [5,6]. This points to the growing need for law enforcement and the judicial system to have access to accurate information on recent cannabis exposure and methods to determine driver impairment.

Six US states, including Colorado, Illinois, Montana, Nevada, Ohio, and Washington, have adopted per se limits for blood concentration of Δ9-tetrahydrocannabinol [7]. Grotenherman et al. [8] found that a Δ9-tetrahydrocannabinol concentration of 6 to 8 µg/L carried an odds ratio of motor vehicle crash comparable to the odds ratio for a blood alcohol concentration of 500 mg/L (10.9 mmol/L). Australian drivers with blood Δ9-tetrahydrocannabinol concentrations greater than 5 µg/L were nearly seven times as likely to be the culpable driver in a crash than drivers with no detectable alcohol or drug [9]. This odds ratio was greater than the corresponding odds ratio for drivers with blood alcohol concentrations in the range of 1,000–1,500 mg/L (21.7–32.6 mmol/L). Di Ciano et al. [10] found that Δ9-tetrahydrocannabinol concentrations greater than 5 µg/L produced a larger standard deviation of lateral position (weaving) in driving simulations.

A majority of US states rely upon the field assessments of law enforcement officers to determine whether a driver is driving under the influence of drugs [7]. The unreliability of standard field sobriety tests to distinguish drivers with and without impairment by cannabis and the current patchwork quilt of varying legal standards in the US illustrate the need for more consistent and objective measures of recent cannabis exposure and of impairment by cannabis.

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