Assessing cannabis consumption frequency: Is the combined use of free and glucuronidated THCCOOH blood levels of diagnostic utility?

Abstract

Heavy cannabis consumption is considered incompatible with safe driving. In Swiss traffic policy, drivers suspected of regular cannabis use are therefore required to undergo medical assessment of their long-term fitness to drive. A whole blood concentration of the cannabis metabolite 11-nor-9-carboxy-Δ 9 -tetrahydrocannabinol (THCCOOH) of 40 μg/L is currently used by Swiss forensic experts as decision limit for regular cannabis consumption. The present study aimed to investigate the suitability of THCCOOH-glucuronide blood levels as an additional and/or better marker for the frequency of cannabis use. Whole blood samples collected from 23 heavy (≥ 10 joints/month) and 25 occasional smokers (≥ 1 joint/month, but ≤ 1 joint/week) enrolled in a placebo-controlled cannabis smoking study were analyzed for THCCOOH and THCCOOH-glucuronide. Based on ROC curve analysis concentration thresholds could be established for distinguishing between these two groups. Proposed thresholds for heavy use were THCCOOH-glucuronide > 52 μg/L (100% specificity; 41% sensitivity) and/or total THCCOOH > 58 μg/L (100% specificity; 43% sensitivity). Optimum thresholds for occasional use were THCCOOH-glucuronide < 5 μg/L (73% specificity; 97% sensitivity) and/or total THCCOOH < 5 μg/L (62% specificity; 98% sensitivity). Our results indicate that the THCCOOH-glucuronide whole blood concentration is a useful parameter that complements the free THCCOOH level to assess the frequency of cannabis consumption. The consideration of the blood concentrations of both free and glucuronidated THCCOOH improves the identification of heavy users whose fitness to drive has to be carefully assessed.

Quantitative determination of five cannabinoids in blood and urine by gas chromatography tandem mass spectrometry applying automated on‐line solid phase extraction

“…30 The ratio of glucuronidated to free THC-COOH in blood is highly variable and ranges from approximately 0.5 to 5 and is dependent on consumption frequency and time difference between intake and blood sampling. [31][32][33] Cut-off concentrations of free THC-COOH and/or its glucuronide in blood have been proposed as a marker for frequent THC-consumption. 33,34 Based on the work by Fabritius et al, 34 the Swiss Society of Legal Medicine (SGRM) has implemented a cut-off concentration of 40 ng/mL for free THC-COOH in whole blood, above which a frequent consumption (i.e., twice or more per week) is presumed.…”

“…[31][32][33] Cut-off concentrations of free THC-COOH and/or its glucuronide in blood have been proposed as a marker for frequent THC-consumption. 33,34 Based on the work by Fabritius et al, 34 the Swiss Society of Legal Medicine (SGRM) has implemented a cut-off concentration of 40 ng/mL for free THC-COOH in whole blood, above which a frequent consumption (i.e., twice or more per week) is presumed. In cases involving driving under the influence of drugs (DUID), a concentration of ≥40 ng/mL of THC-COOH can result in an evaluation of general driving fitness.…”

“…The major THC‐metabolite THC‐COOH is glucuronidated by several UDP‐glucuronyltransferases 30 . The ratio of glucuronidated to free THC‐COOH in blood is highly variable and ranges from approximately 0.5 to 5 and is dependent on consumption frequency and time difference between intake and blood sampling 31–33 . Cut‐off concentrations of free THC‐COOH and/or its glucuronide in blood have been proposed as a marker for frequent THC‐consumption 33,34 .…”

Can a threshold for 11‐nor‐9‐carboxy‐Δ9 ‐tetrahydrocannabinol in hair be derived when its respective concentration in blood serum indicates regular use?

“…At present, several recommendations on blood concentrations of THC‐COOH exist to differentiate “light” from “heavy” use. A THC‐COOH concentration of ≥100 μg/L serum has widely been accepted as an important indicator of persistent cannabis use . which is an arbitrary classification, such as, for example “≥10 joints/month.”…”

Cytosolic Enzymes Generate Cannabinoid Metabolites 7-Carboxycannabidiol and 11-Nor-9-carboxytetrahydrocannabinol

“… ,, The major circulating metabolites of CBD and THC in vivo are 7-carboxy-CBD (7-COOH-CBD) and 11-nor-9-carboxy-tetrahydro­cannabinol (abbreviated as 11-carboxy-THC or 11-COOH-THC) formed from the pharmacologically active metabolites 7-hydroxy-CBD (7-OH-CBD) and 11-hydroxy-THC (11-OH-THC), respectively. Glucuronide metabolites of these carboxylic acids make up the majority of drug-related material recovered in urine. − The plasma area under the concentration versus time curve (AUC) of 7-COOH-CBD is up to 40-fold higher than that of CBD following repeated administration of CBD to children. , A similar AUC ratio of 11-COOH-THC to THC was measured following single-dose oral administration of THC to healthy adult volunteers, and 11-COOH-THC has been proposed as a biomarker for level of cannabis use. − Additionally, the major glucuronide metabolite of 11-COOH-THC has been shown to inhibit multiple major P450 enzymes, including CYP2B6, CYP2C9, and CYP2D6 in vitro. Factors affecting downstream 7-COOH-CBD and 11-COOH-THC formation may therefore impact the systemic exposure of the active metabolites of CBD and THC and hence the pharmacological effects of CBD and THC.…”