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Research ArticleSpecial Report

Cannabis Edibles: Blood and Oral Fluid Cannabinoid Pharmacokinetics and Evaluation of Oral Fluid Screening Devices for Predicting Δ9-Tetrahydrocannabinol in Blood and Oral Fluid following Cannabis Brownie Administration

Matthew N. Newmeyer, Madeleine J. Swortwood, Maria Andersson, Osama A. Abulseoud, Karl B. Scheidweiler, Marilyn A. Huestis
DOI: 10.1373/clinchem.2016.265371 Published February 2017
Matthew N. Newmeyer
Chemistry and Drug Metabolism Section, Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD; Program in Toxicology, University of Maryland Baltimore, Baltimore, MD;
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Madeleine J. Swortwood
Chemistry and Drug Metabolism Section, Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD; Department of Forensic Science, College of Criminal Justice, Sam Houston State University, Huntsville, TX;
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Maria Andersson
Chemistry and Drug Metabolism Section, Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD; Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institute and University Hospital, Stockholm, Sweden;
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Osama A. Abulseoud
Chemistry and Drug Metabolism Section, Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD;
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Karl B. Scheidweiler
Chemistry and Drug Metabolism Section, Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD;
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Marilyn A. Huestis
Chemistry and Drug Metabolism Section, Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD; University of Maryland School of Medicine, Baltimore, MD.
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  • For correspondence: marilyn.huestis@gmail.com
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Abstract

BACKGROUND: Roadside oral fluid (OF) Δ9-tetrahydrocannabinol (THC) detection indicates recent cannabis intake. OF and blood THC pharmacokinetic data are limited and there are no on-site OF screening performance evaluations after controlled edible cannabis.

CONTENT: We reviewed OF and blood cannabinoid pharmacokinetics and performance evaluations of the Draeger DrugTest®5000 (DT5000) and Alere™ DDS®2 (DDS2) on-site OF screening devices. We also present data from a controlled oral cannabis administration session.

SUMMARY: OF THC maximum concentrations (Cmax) were similar in frequent as compared to occasional smokers, while blood THC Cmax were higher in frequent [mean (range) 17.7 (8.0–36.1) μg/L] smokers compared to occasional [8.2 (3.2–14.3) μg/L] smokers. Minor cannabinoids Δ9-tetrahydrocannabivarin and cannabigerol were never detected in blood, and not in OF by 5 or 8 h, respectively, with 0.3 μg/L cutoffs. Recommended performance (analytical sensitivity, specificity, and efficiency) criteria for screening devices of ≥80% are difficult to meet when maximizing true positive (TP) results with confirmation cutoffs below the screening cutoff. TPs were greatest with OF confirmation cutoffs of THC ≥1 and ≥2 μg/L, but analytical sensitivities were <80% due to false negative tests arising from confirmation cutoffs below the DT5000 and DDS2 screening cutoffs; all criteria were >80% with an OF THC ≥5 μg/L cutoff. Performance criteria also were >80% with a blood THC ≥5 μg/L confirmation cutoff; however, positive OF screening results might not confirm due to the time required to collect blood after a crash or police stop. OF confirmation is recommended for roadside OF screening.

ClinicalTrials.gov identification number: NCT02177513

Blood and/or oral fluid (OF)6 Δ9-tetrahydrocannabinol (THC) showed the largest increase in prevalence among US weekend nighttime drivers from 8.6% in 2007 to 12.6% in 2013–2014 (1). Increasing cannabis use among drivers poses a public health and safety risk due to increased crash risk associated with cannabis intake (2–5). In US adults of ≥18 years of age, who had ever consumed cannabis, 29.8% had consumed cannabis via “edibles or drinks” within the previous 30 days (6). Few data are available for blood (7–10) and OF (10, 11) cannabinoid pharmacokinetics, and there are no data for on-site OF screening devices following edible cannabis administration. Here, we review blood and OF cannabinoid pharmacokinetics and their relationship following cannabis edible ingestion, and Draeger DrugTest®5000 (DT5000) and AlereTM DDS®2 (DDS2) on-site OF screening performance. We also present results from an original edible cannabis administration study addressing identified knowledge gaps.

Blood Cannabinoid Pharmacokinetics after Oral Dosing

Following ingestion of a 20 mg THC cookie, maximum plasma THC concentrations (Cmax) were 4.4–11 μg/L at 60–300 min, demonstrating slow and erratic absorption after oral dosing; the mean (SD) (range) THC bioavailability was 6% (3%) (4%–12%) (7). After eating brownies containing 8.4 mg or 16.9 mg cannabis extract or placebo cannabis laced with equivalent THC, mean plasma THC Cmax were approximately 4–5 μg/L and approximately 7–9 μg/L, respectively (equal doses combined) (8). Following ingestion of milk decoctions containing 16.5 mg or 45.7 mg THC, blood Cmax were 3.8 (1.5–8.3) and 8.4 (3.9–13.1) μg/L for THC, 4.7 (2.7–7.0) and 12.8 (3.4–24.7) μg/L for 11-hydroxy-THC (11-OH-THC), and 27.8 (14.1–42.4) and 66.2 (31.1–99.9) μg/L for 11-nor-9-carboxy-THC (THCCOOH), respectively (9). Finally, after eating brownies containing approximately 10, 25, or 50 mg THC, blood Cmax were 1.0 (0.0–3.0), 3.5 (3.0–4.0), and 3.3 (1.0–5.0) μg/L for THC, 1.0 (0.0–2.0), 3.3 (2.0–5.0), and 3.2 (2.0–4.0) μg/L for 11-OH-THC, and 7.2 (5.0–14.0), 21.3 (12.0–39.0), and 29.3 (16.0–44.0) μg/L for THCCOOH, respectively; cannabinoid detection times were 0–22, 0–12, and 3–94 h, respectively (10).

Minor cannabinoids [THC-glucuronide, cannabidiol (CBD), and cannabinol (CBN)] in blood were evaluated as recent cannabis use markers (12, 13) after smoking a 6.8% THC cigarette. Detection in frequent smokers' blood was up to 0.6, 0.5, and 2.1 h, respectively (13). Other minor cannabinoids [cannabigerol (CBG), Δ9-tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-THCV (THCVCOOH)] may also serve as recent use markers; however, their blood pharmacokinetics have not been characterized, with previous identification only in cannabis smokers' urine (14–16).

OF Cannabinoid Pharmacokinetics after Oral Dosing

OF is an attractive matrix for workplace, clinical, drug treatment, and driving under the influence of drugs (DUID) settings due to advantages over blood or urine, including noninvasive direct observation during sample collection, thus deterring adulteration. OF drug detection indicates recent intake but administration route, extent of plasma protein binding, drug pKa, and drug use frequency influence results and complicate interpretation (17, 18). Disadvantages include small sample volume and analyte dilution in buffer, necessitating sensitive analytical techniques, and reduced salivation after stimulant intake.

Cannabinoid OF pharmacokinetics were investigated following smoked (11, 19–26) and vaporized (27) cannabis. Oromucosal deposition during cannabis inhalation is primarily responsible for observed OF THC, with little contribution initially from blood. OF THC peaks during or shortly after inhalation (28), followed by rapid concentration decreases. OF THCCOOH is primarily detected after chronic frequent intake (24–26), with peak concentrations ≤763 ng/L following smoking of a 6.8% THC cigarette (22). CBD and CBN also were detected in OF following cannabis smoking, with observed peak concentrations ≤588 and ≤1558 μg/L, respectively, and last detection times of 2–6 h (22), potentially indicating recent cannabis intake. Recently, we investigated the utility of THCV and CBG as recent-use OF markers (28). The THCV Cmax and the time of last positive sample detection (tlast) were ≤146, ≤159, and ≤14.5 μg/L and ≤12, ≤8, and ≤5 h, respectively, following smoked, vaporized, and oral cannabis, and for CBG were ≤602, ≤394, and ≤60.6 μg/L and ≤26, ≤20, and ≤10 h, respectively. The 11-OH-THC is rarely detected in OF; previous Cmax were 1.3 μg/L in expectorated OF from a chronic frequent smoker (23) and 4.4 and 5.5 μg/L in frequent and occasional smokers' OF after smoked cannabis (28).

Previous OF oral investigations administered Marinol® (synthetic encapsulated THC that does not contaminate the oral mucosa) (29–31) or Sativex, an oromucosal spray with equivalent THC and CBD doses (31). Following 20–25 mg THC brownie administration, observed OF THC Cmax were 1.2–7.1 μg/L 1–2 h postdose (1 h first collection), with 2 of 3 participants' OF THC-negative by 16 h [0.2 μg/L limit of quantification (LOQ)] and the third participant positive at 72 h (11). In a separate study with brownies containing approximately 10, 25, or 50 mg THC, observed mean (range) OF Cmax were 192 (47.0–412), 478 (70.0–1128), and 598 (350–1010) μg/L for THC and 50.8 (0.0–231), 140 (23.0–251), and 314 (0.0–822) ng/L for THCCOOH, respectively (10).

Relationship between Blood and OF Cannabinoid Pharmacokinetics

High intersubject variability in OF/serum or plasma THC ratios is typically observed, precluding blood cannabinoid concentration estimations from OF data. Following smoking a 3.55% (33.8 mg) THC cigarette, the mean (SD, range) OF/plasma THC ratio from 0.33–4.0 h postdose in a single participant was 1.2 (0.6, 0.5–2.2) (19). Larger OF/serum THC ratios were observed after smoked 13.8–22.3 mg THC [mean (SD) of 46.2 (27.0), range 11.6–105] and 27.5–44.5 mg THC [35.8 (20.3), 11.3–63.9] doses from 0.25–6 h (20). The median (range) OF/serum THC ratio over 8 h in frequent and occasional smokers was 16.5 (0.3–425) after smoking 22.5–47.5 mg THC (21). The OF/plasma THC ratios in a separate group from 1.0–17.1 h after smoking a 5.9% (53.1 mg) THC cigarette were 0.04–47.7 (32). Median (range) OF/blood [9.4 (0.3–887)] and OF/plasma [7.3 (0.2–585)] THC ratios were similarly variable following vaporized low (14.5 mg THC) and high (33.5 mg THC) cannabis, with and without ethanol (33). Wide median (range) OF/blood THC ratios also were observed for drivers in epidemiological investigations stopped at random [14 (1.0–190)] (34) or for suspected DUID [15 (0.01–569)] (35).

In chronic frequent cannabis users at baseline, median (range) OF/plasma THC ratio was 0.5 (0.03–12.0) prior to around-the-clock oral 40–120 mg dronabinol daily doses; over 8 days, OF THC concentrations decreased but significant increases in plasma THC concentrations occurred (36). Similarly, during 5-day dronabinol maintenance (0–120 mg THC/day), OF/plasma THC ratios in daily cannabis smokers decreased from 2.6–7.8 to 0.9–2.0 over 5 h, and after 5 dosing days the ratios were 0.02–0.2; only 6.0% of samples were THC-positive versus 98.9% of plasma samples on day 5 (32). There was no oromucosal contamination by dronabinol due to encapsulation.

On-Site OF Screening Devices

Rapid and sensitive on-site OF devices offer advantages for roadside drug screening, allowing trained officers to presumptively identify drug use, without lengthy delays associated with blood collection. The European Union Driving under the Influence of Drugs, Alcohol and Medicines (DRUID) program suggested an 80% target for analytical sensitivity, specificity, and efficiency when evaluating devices (37). The Substance Abuse and Mental Health Services Administration (SAMHSA) requires a 2 μg/L OF THC confirmatory cutoff for workplace drug testing settings (38), while DRUID implemented a 1 μg/L OF THC confirmatory cutoff (39). Analytical sensitivities, specificities, and efficiencies of the DT5000 (5 μg/L THC cutoff) were 53.0%–80.8%, 95.5%–99.0%, and 84.0%–92.0%, respectively, in drug addiction centers (40, 41) or DUID (42) OF samples with OF THC 1–10 μg/L confirmatory cutoffs. Others reported an improved 92.3% analytical sensitivity for drivers stopped during roadside patrols (43). Performance of the DT5000 also was evaluated in controlled research settings following smoked (44–46) and vaporized (27) cannabis; at least 1 performance criterion was < 80% in these studies.

OF THC concentrations cannot be accurately converted to blood concentrations; however, it would be useful if OF could predict THC presence in blood. Utilizing residual OF from the swab of a first-generation DrugTest device (≥10 μg/L chromatographic cutoff), roadside sensitivity, specificity, and efficiency of predicting THC in serum (≥0.5 μg/L cutoff) was 91.8%, 91.3%, and 91.5%, respectively, among suspected DUID drivers; median (range) serum collection was 1 (0.1–3.3) h later (47). DrugTest roadside sensitivity, specificity, and efficiency (20 μg/L cutoff) for predicting plasma THC (≥0.5 μg/L) in police controls were 50.9%, 92.9%, and 55.7%, respectively. When raising the THC plasma cutoff to ≥2.0 μg/L (Belgian limit), performance was 57.8%, 87.5%, and 65.6%, respectively (48). Other suspected impaired driver evaluations confirmed results for the newer DT5000 with plasma (49) or serum (45, 50), finding 84.8%–93.0% roadside sensitivity, 47.0%–71.4% specificity, and 79.6%–90.0% efficiency. Among research participants administered 19.6–32.8 mg smoked THC, DT5000 roadside sensitivity at any time point 0.25–4 h after smoking was 82%–100% with a serum THC ≥5 μg/L cutoff (51). Differences in device performance may be due to different populations, confirmatory matrices, OF collection devices, and cutoffs.

In the only published data available, the DDS2 OF screening device (25 μg/L cutoff) had 100% analytical sensitivity from 5 THC-positive drivers with a 2 μg/L confirmatory OF cutoff (52).

Neither the DT5000 nor DDS2 on-site devices were evaluated following edible cannabis. Additional characterization of the relationship between blood and OF cannabinoid pharmacokinetics following ingestion of cannabis-containing edibles is required.

Edible Cannabis Administration Study

MATERIALS AND METHODS

Participants.

Adults 18–50 years old were recruited for this Institutional Review Board-, Federal Drug Administration-, and Drug Enforcement Administration-approved study. Inclusion criteria were self-reported cannabis intake frequency ≥2×/month but <3×/week (occasional smokers), or ≥5×/week (frequent smokers) for the previous 3 months, and a positive urine cannabinoid screen (frequent smokers). Exclusion criteria were systolic blood pressure >140 mmHg, diastolic blood pressure >90 mmHg, or heart rate >100 bpm; clinically significant electrocardiogram abnormality; inability to discontinue contraindicated medication; physical dependence on any drug other than cannabis, caffeine, or nicotine; medicinal cannabis use; medical condition or history of neurological illness; history of clinically significant adverse cannabis event; donating >450 mL blood within 8 weeks; pregnant or nursing women; interest or participation in a drug abuse treatment program within 90 days; and food allergy or sensitivity to gluten, dairy, egg, soy, and/or chocolate. Individuals provided written, informed consent.

Study design.

We describe results of an optional dosing session of a larger clinical protocol (ClinicalTrials.gov identification number: NCT02177513) investigating cannabis pharmacodynamics and pharmacokinetics following multiple administration routes over 4 sessions (28, 53). Frequent smokers remained on the clinical unit from the fourth visit and were dosed the following weekday, ≥96 h after the previous cannabis dose, to ensure low blood and OF baseline cannabinoid concentrations. Occasional smokers could not remain on the unit if a dosing frequency greater than their self-reported intake frequency would occur.

Participants consumed an entire oral cannabis dose (approximately 50.6 mg THC, 1.5 mg CBD, and 3.3 mg CBN baked in a brownie) within 10 min, and resided on the research unit for 48 h. Details of brownie preparation are presented elsewhere (28, 53).

Venous blood was collected into potassium oxalate (8 mg)/sodium fluoride (10 mg) Vacutainer® tubes (BD, part #367922), aliquoted into 3.6-mL Nunc® cryotubes (Thomas Scientific), and stored at −20°C until analysis. OF samples collected with the Quantisal™ device (Immunalysis) were followed by the DT5000 or DDS2 on-site screening device (randomly assigned per participant). The OF was collected until volume-adequacy indicators turned blue or 5 min elapsed. Oral intake was prohibited 10 min prior to OF collection. Samples were collected on admission, at baseline (−1 h), and 0.33 (OF only), 0.5 (blood only), 1, 1.5, 3.5, 5, 6 (blood only), 8, 10, 14, 20, 26, 32, 38, 44, and 48 h after dosing.

Blood analysis.

Blood cannabinoids were quantified via a previously published LC-MS/MS method (54). Briefly, 0.2 mL blood was deproteinized with acetonitrile and the cannabinoids extracted from supernatants with disposable pipette extraction (DPX) WAX-S tips (DPX Labs). A diluted aliquot of the resulting organic phase was injected onto a 5500 QTRAP® (Sciex) mass spectrometer. Linear ranges were 0.5–100 μg/L for THC and THCCOOH, 0.5–50 μg/L for 11-OH-THC, CBD, CBN, and THC-glucuronide, 1–100 μg/L for CBG, THCV, and THCVCOOH, and 5–500 μg/L for THCCOOH-glucuronide. Interassay accuracy was 88.9%–115% and imprecision was ≤8.5% CV.

OF analysis.

DT5000 and DDS2 samples were analyzed immediately after collection, with qualitative “positive” or “negative” results at 5 or 25 μg/L THC cutoffs, respectively. Quantisal OF cannabinoids were quantified for THC, THCCOOH, 11-OH-THC, THCV, CBD, and CBG by a previously published LC-MS/MS method (55). Briefly, samples (1 mL elution buffer OF mixture containing 0.25 mL OF) were mixed with 0.3 mL of 1 mol/L ammonium acetate buffer (pH 4) and hydrolyzed with β-glucuronidase, acidified and extracted with cation exchange solid-phase columns. Cannabinoids were analyzed on a 6500 QTRAP® (Sciex) mass spectrometer employing atmospheric pressure chemical ionization with 0.2 μg/L LOQ (except 15 ng/L THCCOOH). Interassay accuracy was 88.1%–106% and imprecision was ≤8.2% CV.

Data analysis.

Demographic data differences between groups were evaluated with independent samples t-tests with SPSS® Statistics 20 for Windows (IBM). Noncompartmental pharmacokinetic analyses were performed with Phoenix® WinNonlin® 6.4 for Windows (Pharsight Software). Analysis of Cmax, baseline-adjusted Cmax (baseline concentrations subtracted from postdose Cmax), time to Cmax (tmax), and tlast differences between smoking groups were evaluated by independent samples t-tests. The OF/blood THC ratios were calculated when analytes were ≥LOQ in both paired samples. Time and smoking group effects on OF/blood THC ratios were evaluated by repeated-measures ANOVA; posthoc tests were conducted with a Bonferroni correction. Only ratios from 0.5–5 h postdose were evaluated to maximize samples included in the analysis. The OF collected at 0.33 h and blood collected at 0.5 h were paired as 0.5 h postdose. Qualitative DT5000 and DDS2 results were compared to quantitative OF and blood results. Statistical significance was attributed to a P < 0.05. A true positive (TP) sample screened positive and confirmed positive for THC; a true negative (TN) screened and confirmed negative. A false positive (FP) sample screened positive but THC was < the evaluated cutoff; a false negative (FN) screened negative but THC was ≥ the evaluated cutoff. Sensitivity (%) = TP/(TP + FN) × 100; specificity (%) = TN/(TN + FP) × 100; and efficiency (%) = (TP + TN)/total × 100. Analytical performance compared OF THC screening results to OF THC confirmation results, and roadside performance compared OF THC screening results to blood THC confirmation results. These parameters were evaluated with OF THC cutoffs 0.2 μg/L (LOQ), 1 μg/L (DRUID), 2 μg/L (SAMHSA), 5 μg/L, and 10 and 25 μg/L (DDS2 only), and blood cutoffs 1, 2, 5, and 10 μg/L.

RESULTS

Participants.

Table 1 summarizes 9 frequent and 7 occasional cannabis smokers' demographic information (ages 19–46 years, 87.5% male, 75% African American). Participant K originally self-reported occasional cannabis intake, but was reclassified as a frequent smoker because baseline and postdose THC and metabolite concentrations were consistent with published frequent smoker data (12, 13); all other participants' cannabinoid pharmacokinetics were consistent with self-report. Occasional smokers began smoking at a significantly older age (P = 0.033), smoked on a significantly fewer number of days out of the previous 14 (P < 0.001), and smoked significantly less per smoking occasion (P = 0.049).

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Table 1.

Demographic data and cannabis smoking histories for 9 frequent and 7 occasional smokers.

Blood pharmacokinetics.

Blood concentration–time plots are presented in Fig. 1, and cannabinoid pharmacokinetic parameters—including statistical comparisons—are summarized in Table 2. Overall, 255 blood (143 frequent, 112 occasional) samples were collected. CBD, CBN, THCV, and CBG were not detected.

Fig. 1.
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Fig. 1. Mean + SD blood cannabinoid concentrations from 9 frequent and 7 occasional cannabis smokers following administration of an oral cannabis dose containing approximately 50.6 mg THC.

Dotted line is LOQ. Data presented on a log scale.

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Table 2.

Summary of observed and baseline-adjusted Cmax, tmax, and tlast in frequent and occasional cannabis smokers after an oral cannabis dose containing approximately 50.6 mg THC.a

All frequent smokers' blood samples were positive for THC (0.7–2.7 μg/L), THCCOOH (3.9–104 μg/L), and THCCOOH-glucuronide (9.2–113 μg/L) at baseline. Among occasional smokers at baseline, only THCCOOH was detected (57.1%, 0.6–1.5 μg/L). Mean (range) observed THC Cmax was significantly greater in frequent [17.7 (8.0–36.1) μg/L] than in occasional [8.2 (3.2–14.3) μg/L; P = 0.040] smokers. After subtracting baseline concentrations, frequent smokers' THC Cmax were minimally reduced [16.2 (5.3–34.6) μg/L], but no longer significantly different from occasional smokers (P = 0.079). At the final collection time (48 h), THC was detected in all frequent smokers' samples (0.6–2.0 μg/L), while no occasional smokers' sample was positive; occasional smokers' mean blood THC tlast was 17 (8.0–38) h, significantly shorter than frequent smokers' (>48 h; P < 0.001). The 11-OH-THC was not observed at baseline in any participant; time courses were similar between groups, but frequent smokers' mean blood Cmax [8.2 (4.7–11.4) μg/L] was significantly higher than occasional smokers' [5.6 (4.1–8.6) μg/L; P = 0.043].

With a blood THC ≥1 μg/L cutoff, 33% of frequent smokers were positive at 48 h; with THC ≥2 or 5 μg/L cutoffs, no frequent smoker was positive by 48 h or 14 h, respectively. No occasional smoker was positive with a THC ≥1, 2, or 5 μg/L cutoff by 26, 14, or 6 h, respectively.

No significant differences in any blood pharmacokinetic parameter for THCCOOH or THCCOOH-glucuronide between groups were observed (Table 2), although frequent smokers' mean concentrations for both analytes trended higher. At 48 h, THCCOOH was present in all frequent (7.2–75.8 μg/L) and occasional (1.7–9.9 μg/L) smokers' samples, while THCCOOH-glucuronide (with a higher LOQ) was present in all frequent (16.3–87.0 μg/L) and 85.7% of occasional (11.0–27.0 μg/L) smokers' samples.

The THCVCOOH was detected at least once in all participants, with low Cmax (≤3.9 μg/L), and mean tlast of 9.2 (1.5–26) and 8.7 (1.8–15) h in frequent and occasional smokers, respectively. Finally, THC-glucuronide was detected at least once in 44.4% and 14.3% of frequent and occasional smokers, respectively, with Cmax (0.6–0.8 μg/L) 0–3.5 h postdose.

OF pharmacokinetics.

Participants' OF concentration–time plots are presented in Fig. 2 and, cannabinoid pharmacokinetic parameters—including statistical comparisons—in Table 2. Overall, 240 OF (135 frequent, 105 occasional) samples were collected. The THC was detected in 5 (55.6%) frequent smokers' (0.2–9.6 μg/L, ≤1.7% THC Cmax) and no occasional smokers' OF at baseline. Peak OF THC concentrations were observed at the first collection (0.33 h) with no significant difference (P = 0.401) in mean Cmax between frequent [573 (39.3–2111) μg/L] and occasional [362 (115–696) μg/L] smokers. THC was detected in frequent smokers' OF significantly longer [39 (20 – >48) h] than in occasional smokers' [23 (20–26) h; P = 0.003]. At discharge (48 h), 44.4% of frequent smokers were THC-positive (0.3–2.6 μg/L), while no occasional smoker was THC-positive beyond 26 h.

Fig. 2.
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Fig. 2. Mean + SD OF cannabinoid concentrations from 9 frequent and 7 occasional cannabis smokers following administration of an oral cannabis dose containing approximately 50.6 mg THC.

Dotted line is LOQ. Data presented on a log scale.

With 1 and 2 μg/L cutoffs, 100% of frequent smokers were THC-positive at 0.33 h postdose, decreasing to 66.7% and 22.2% at 20 h, and 11.1% (both cutoffs) at 48 h, respectively; no occasional smoker was positive by 26 h. With a 5 μg/L cutoff, no frequent or occasional smoker was positive by 20 or 5 h, respectively.

Differences between groups in THCCOOH pharmacokinetics were not observed. Five frequent (55.6%, 24.9–159 ng/L) and 1 occasional (16.7%, 18.5 ng/L) smoker were OF THCCOOH-positive at baseline. Concentrations remained ≥15 ng/L throughout 48 h, with all frequent (23.5–643 ng/L) and 42.9% of occasional (16.4–77.9 ng/L) smokers positive at 48 h. THCCOOH tmax was highly variable across groups [frequent, 12 (3.5–48) h; occasional, 10 (0.33–20) h].

No participants' OF was positive for 11-OH-THC, THCV, CBD, or CBG at baseline and, in most participants, tlast were early, indicating recent use. 11-OH-THC was detected at least once (≤1.2 μg/L) in 77.8% and 85.7% of frequent and occasional smokers' OF, respectively, with tlast ≤5 h. All participants' OF were positive at least once for THCV, CBD, and CBG, all with a 0.33 h tmax. CBG Cmax in frequent and occasional smokers were 31.2 (3.5–90.1) and 21.2 (7.5–33.9) μg/L, respectively. At 0.2 μg/L, THCV, and CBD tlast were ≤3.5 and ≤5 h, respectively, while CBG tlast was ≤14 h, with no differences between groups.

OF/blood THC ratios.

Supplemental Table 1 (in the Data Supplement that accompanies the online version of this report at http://www.clinchem.org/content/vol63/issue3) summarizes OF/blood THC ratios at all times with measurable THC in both matrices. All frequent and occasional smokers had measurable ratios from 1–20 and 1–5 h, respectively. At 48 h, 44.4% of frequent smokers had measurable ratios while no occasional smokers had measurable ratios by 32 h. Mean ratios were 0.2–1.0 in frequent smokers from 3.5–48 h and 1.0–3.1 in occasional smokers from 3.5–20 h.

All participants had measurable OF/blood THC ratios through 5 h, except 1 frequent and 1 occasional smoker without measurable ratios at 0.5 h; only data within 5 h were statistically compared. There was a significant time effect (P = 0.002), with significantly larger ratios at 0.5 h than at 1 (P = 0.033), 1.5 (P = 0.024), 3.5 (P = 0.022), or 5 (P = 0.022) h postdose. The OF and blood THC concentrations were not significantly correlated when all participants' data were analyzed together (P = 0.6380), split by group (frequent, P = 0.713; occasional, P = 0.067), or when data from only 1–5 h were included (P = 0.422).

On-site OF device performance.

Overall, 103 DT5000 (60 samples from 4 frequent and 43 samples from 3 occasional smokers) and 134 DDS2 (72 samples from 5 frequent and 62 samples from 4 occasional smokers) results were obtained. Performance characteristics at various OF and blood confirmation cutoffs are summarized in Table 3. The only OF cutoff that achieved analytical sensitivity, specificity, and efficiency ≥80% for the DT5000 was THC ≥5 μg/L overall and for each smoking group. Additionally, the only blood confirmation cutoff that demonstrated acceptable performance was THC ≥5 μg/L in only occasional smokers; analytical sensitivity and efficiency were 64.3% and 78.3% for frequent smokers. This difference is due to 5 FN results observed only in frequent smokers.

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Table 3.

Performance characteristics for the Draeger DT5000 (5 μg/L THC cutoff) and Alere DDS2 (25 μg/L THC cutoff) on-site OF screening devices with various OF and blood confirmation cutoffs over 48 h following administration of an oral cannabis dose containing approximately 50.6 mg THC.a

The DDS2 performance criteria were ≥80% at OF THC ≥10 and 5 μg/L overall. For frequent smokers, criteria were ≥80% at OF THC ≥25, 10, and 5 μg/L, but not for occasional smokers. In the OF THC cutoff range 5–25 μg/L, analytical sensitivity, specificity, and efficiency were 90.0%–92.9%, 71.2%–77.1%, and 74.2%–80.6%, respectively for occasional smokers. Between 3–8 FP results were observed in frequent smokers with OF THC ≥5–25 μg/L cutoffs (4.2%–11.1% of frequent smokers' total DDS2 tests), while 11–15 FP results were observed in occasional smokers in the same OF THC cutoff range (17.7%–24.2% of occasional smokers' total DDS2 tests). One occasional smoker had 9 FP results with a 5 μg/L OF THC cutoff, representing 81.8% of all occasional smokers' FP results; OF THC concentrations were <LOQ–1.2 μg/L for these FP results. The only other analyte present in the participants' OF when FP were observed was THCCOOH at <LOQ–28 ng/L. Similarly, a blood THC ≥5 μg/L cutoff produced performance criteria ≥80% only in frequent smokers due to high FP results in 1 occasional smoker.

Device performances within shorter time courses also are summarized in Table 3; for ease of comparison, only performance among all participants with OF cutoffs was considered. In general, performance at a cutoff is improved when monitoring over a shorter time course compared to the entire 48 h session. This is particularly true when confirming with a cutoff below the screening cutoff. For example, when considering performance of a THC ≥2 μg/L cutoff for the DT5000, the proportion of tests that were FN decreased from 27.2% to 19.0% when analyzing across a 48 h to a 5 h time course, respectively. As a result, performance characteristics across 5 h were improved compared to across 48 h. For the DDS2, this improvement was such that all performance criteria for the THC ≥1 and ≥2 μg/L cutoffs were ≥80%. One benefit of confirming at a cutoff below the screening cutoff is TP results are maximized; as shown in Table 3, the greatest number of TP results are observed with the lower confirmation cutoffs, regardless of the time course. However, as the time postdose increases, the chance of observing an FN result increases when confirming below the screening cutoff.

Overall participant TP and TN detection rates with various OF and blood THC confirmatory cutoffs are presented in Fig. 3. The TP detection rates at 1 and 2 μg/L cutoffs were identical, with no TP observed by 10 and 26 h with the DT5000 and DDS2, respectively. With a confirmatory OF THC ≥5 μg/L cutoff, detection rates with both devices were similar at each time point, with no TP observed in either device by 8 h. A blood THC ≥2 μg/L cutoff produced no TP by 10 and 14 h with DT5000 and DDS2 respectively, while raising the cutoff to ≥5 μg/L reduced TP detection to <8 and <10 h, respectively. For DT5000, no TN was observed ≤5 and ≤3.5 h postdose with OF cutoffs ≥2 and ≥5 μg/L, respectively; at the same cutoffs for DDS2, no TN was observed ≤3.5 and ≤1.5 h postdose. The TN increased more rapidly with OF THC ≥5 μg/L compared to ≥2 μg/L. Similar trends were observed with blood THC cutoffs.

Fig. 3.
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Fig. 3. Percent TP and TN results from the Draeger DT5000 (4 frequent, 3 occasional cannabis smokers) and Alere DDS2 (5 frequent, 4 occasional cannabis smokers) on-site OF screening devices with OF and blood THC ≥5 and ≥2 μg/L confirmatory cutoffs.

SAMHSA (2 μg/L THC OF cutoff) data were identical to the DRUID (1 μg/L THC cutoff).

DISCUSSION

Differences in blood cannabinoid pharmacokinetics between smoking groups were minimal and some differences observed in previous sessions (53) were not observed here, such as differences in blood THCCOOH and THCCOOH-glucuronide Cmax or 11-OH-THC tlast. Those differences were not observed likely because of frequent smokers' lower baseline concentrations compared to other sessions due to remaining on the closed research unit (≥96 h between cannabis doses). Other blood cannabinoid pharmacokinetic data were comparable to the previous oral administration session. The only significant group difference in OF pharmacokinetics was frequent smokers' later THC tlast compared to occasional smokers', consistent with the previous oral dosing session (28). Unlike for blood, OF THC Cmax were not significantly different between groups because an oral dose is not amenable to titration that can occur during smoking or vaporization, and which contribute to group differences between frequent and occasional users (28). The OF THC concentrations are primarily due to extensive oral mucosa contamination.

These data represent total (free + hydrolyzed) OF THCCOOH results. THCCOOH-glucuronide was previously detected in a frequent smoker's OF before and up to 48 h after cannabis smoking, with THCCOOH concentrations increasing following hydrolysis; in the same participant THC concentrations did not increase following base or enzymatic hydrolysis (56). There may not be THC-glucuronide in OF, it may be present in negligible concentrations, or the hydrolysis methods may not have been efficient at cleaving THC-glucuronide; no data on the hydrolysis efficiencies are presented, making interpreting the data difficult. No OF 11-OH-THC-glucuronide data exist, so it is unclear if the increase in prevalence of positive 11-OH-THC results observed compared to other investigations is due to glucuronide hydrolysis, or the administration route, and/or a more sensitive LOQ (0.2 versus 0.5μg/L).

Limitations of the study include small participant populations for each device, limiting statistical comparisons when stratifying by device, smoking group, or both; and inclusion of a single cannabis potency. Strengths of the study included frequent and occasional cannabis smoker groups, continuous residence on a closed research unit throughout the study sessions, characterization of minor cannabinoid pharmacokinetics following oral cannabis dosing, and evaluation of the relationship between OF and blood THC concentrations. For the first time, we compared performance of on-site OF devices following controlled edible cannabis administration. Since each participant was assigned to only 1 device, direct within-subject comparisons were not possible.

One of the strongest advantages of OF sample collection is the ability to screen roadside for the presence of impairing drugs. OF and blood THC concentrations were significantly correlated from 0.8–8.3 h after cannabis vaporization (33), with THC concentrations in both matrices peaking during or shortly after vaporization followed by rapid decreases. In contrast, observed OF THC Cmax after oral brownie intake occurred at or before the first OF collection (0.33 h), while blood THC Cmax occurred 1.0–5.0 h later. However, following dronabinol or synthetic THC capsule intake, there is no oral mucosa contamination (29, 31). These different pharmacokinetic time courses explain the lack of correlation between OF and blood concentrations during the first 5 h after edible cannabis. Route of administration and THC formulation greatly effect OF/blood THC ratios.

In some countries, such as Germany, blood rather than OF is used to confirm positive OF THC screening results. DT5000 performance in drivers suspected of DUID (45, 49, 50) and in research volunteers following controlled smoked cannabis with and without ethanol (51) demonstrated good roadside sensitivity (80.8%–93.0%) and efficiency (79.6%–90%), but poor-to-moderate roadside specificity (47.0%–71.4%) with plasma/serum confirmatory cutoffs ≥1–5 μg/L THC. The DT5000 and DDS2 had reduced roadside sensitivity (≤66.7%) with a blood THC cutoff ≤2 μg/L in our study, except for DDS2 testing of occasional smokers. Performance was acceptable with a confirmatory blood THC ≥5 μg/L cutoff for occasional smokers only with the DT5000 and frequent smokers only with the DDS2. Blood THC concentrations decreased >73% within 30 min and >90% in 1.4 h after a vaporized cannabis dose (57), making confirmation of positive roadside OF screening results for cannabinoids problematic when blood collection times are highly variable and generally >1.4 h after a police stop or crash (58, 59). For these reasons, we recommend that on-site OF THC tests be confirmed with OF THC confirmation tests.

Increasing the OF confirmation cutoff to match the manufacturer's screening cutoff improved analytical performance above the minimum recommended limits, but TP results were not maximized. Lowering the OF confirmation cutoff to 1 or 2 μg/L maximized TP results but reduced analytical sensitivity for the on-site devices. If the acute THC impairment window is considered to be 6–8 h after intake, an OF confirmation cutoff could be selected to match this time frame. There were no TP OF results ≥8 h with either device when the OF THC confirmation cutoff was ≥5 μg/L, a useful testing protocol for roadside testing. For other drug testing programs, such as drug treatment, a lower OF THC confirmation cutoff of ≥1 or 2 μg/L, produced TP results for 10 and 26 h with the DT5000 and DDS2, respectively, increasing the window of drug detection and potentially meeting the goals of drug testing in treatment settings (Fig. 3).

A reliable conversion between blood and OF THC concentrations does not exist as concentrations between matrices were not correlated. Therefore, we recommend OF screening utilizing either the DT5000 or DDS2 followed by OF confirmation. Recommended performance criteria for on-site OF screening devices of ≥80% are difficult to meet when maximizing TP results with confirmation cutoffs below screening cutoffs. Confirming with OF THC ≥5 μg/L is recommended for DUID settings to restrict the detection window to a similar impairment window, while confirming with ≥1 or 2 μg/L was suitable for drug treatment programs. These recommendations are optimized for cannabis edibles; different recommendations may result following smoked or vaporized cannabis administrations. Since the administration route is generally unknown at the roadside, screening and confirmation data should be interpreted in tandem with observable impairment signs, such as driving behavior or performance on standardized field sobriety tests.

Acknowledgments

The authors thank Dr. Sandrine Pirard for her contribution to study design and the contributions of the clinical staffs of the Intramural Research Program, National Institute on Drug Abuse, and the Clinical Research Unit, Johns Hopkins Bayview Medical Center. Quantisal, DT5000, and DDS2 devices were provided by the manufacturer to NIH through a Materials Transfer Agreement. This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH. M.N. Newmeyer acknowledges the Graduate Partnership Program, NIH.

Footnotes

  • ↵6 Nonstandard abbreviations:

    OF,
    oral fluid;
    THC,
    Δ9-tetrahydrocannabinol;
    DT5000,
    DrugTest 5000;
    Cmax,
    maximum concentration(s);
    11-OH-THC,
    11-hydroxy-THC;
    THCCOOH,
    11-nor-9-carboxy-THC;
    CBD,
    cannabidiol;
    CBN,
    cannabinol;
    CBG,
    cannabigerol;
    THCV,
    Δ9-tetrahydrocannabivarin;
    THCVCOOH,
    11-nor-9-carboxy-THCV;
    DUID,
    driving under the influence of drugs;
    tlast,
    time of last positive sample detection;
    LOQ,
    limit of quantification;
    DRUID,
    Driving under the Influence of Drugs, Alcohol and Medicines program;
    SAMHSA,
    Substance Abuse and Mental Health Services Administration;
    tmax,
    time of Cmax;
    TP,
    true positive;
    TN,
    true negative;
    FP,
    false positive;
    FN,
    false negative.

  • (see editorial on page 629)

  • Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

  • Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

  • Employment or Leadership: M.A. Huestis, Intramural Research Program, National Institute on Drug Abuse, NIH.

  • Consultant or Advisory Role: None declared.

  • Stock Ownership: None declared.

  • Honoraria: None declared.

  • Research Funding: M.N. Newmeyer, Intramural Research Program, National Institute on Drug Abuse, NIH (to the institution); and Graduate Partnership Program, NIH; M.A. Huestis, Quantisal, DT5000, and DDS2 devices provided by the manufacturer to NIH through a Materials Transfer Agreement; and Intramural Research Program, National Institute on Drug Abuse, NIH (to the institution).

  • Expert Testimony: None declared.

  • Patents: None declared.

  • Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, and final approval of manuscript.

  • Received for publication August 12, 2016.
  • Accepted for publication November 21, 2016.
  • © 2016 American Association for Clinical Chemistry

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Clinical Chemistry: 63 (3)
Vol. 63, Issue 3
March 2017
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Cannabis Edibles: Blood and Oral Fluid Cannabinoid Pharmacokinetics and Evaluation of Oral Fluid Screening Devices for Predicting Δ9-Tetrahydrocannabinol in Blood and Oral Fluid following Cannabis Brownie Administration
Matthew N. Newmeyer, Madeleine J. Swortwood, Maria Andersson, Osama A. Abulseoud, Karl B. Scheidweiler, Marilyn A. Huestis
Clinical Chemistry Mar 2017, 63 (3) 647-662; DOI: 10.1373/clinchem.2016.265371
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Cannabis Edibles: Blood and Oral Fluid Cannabinoid Pharmacokinetics and Evaluation of Oral Fluid Screening Devices for Predicting Δ9-Tetrahydrocannabinol in Blood and Oral Fluid following Cannabis Brownie Administration
Matthew N. Newmeyer, Madeleine J. Swortwood, Maria Andersson, Osama A. Abulseoud, Karl B. Scheidweiler, Marilyn A. Huestis
Clinical Chemistry Mar 2017, 63 (3) 647-662; DOI: 10.1373/clinchem.2016.265371

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    • Blood Cannabinoid Pharmacokinetics after Oral Dosing
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