Abstract
As cannabis has become more accessible, use of alternative methods for cannabis administration such as vaporizers has become more prevalent. Most prior controlled pharmacokinetic evaluations have examined smoked cannabis in frequent (often daily) cannabis users. This study characterized the urinary excretion profile of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH), the primary analytical outcome for detection of cannabis use, among infrequent cannabis users following controlled administration of both smoked and vaporized cannabis. Healthy adults (N = 17), with a mean of 398 (range 30–1,825) days since last cannabis use, smoked and vaporized cannabis containing 0, 10, and 25 mg of Δ9-tetrahydrocannabinol (THC) across six outpatient sessions. Urinary concentrations of THCCOOH were measured at baseline and for 8 h after cannabis administration. Sensitivity, specificity, and agreement between three immunoassays (IA) for THCCOOH (with cutoffs of 20, 50, and 100 ng/mL) and gas chromatography-mass spectrometry (GC/MS) results (confirmatory concentration of 15 ng/mL) were assessed. THCCOOH concentrations peaked 4–6 h after cannabis administration. Median maximum concentrations (Cmax) for THCCOOH were qualitatively higher after administration of vaporized cannabis compared to equal doses of smoked cannabis. Urine THCCOOH concentrations were substantially lower in this study relative to prior examinations of experienced cannabis users. The highest agreement between IA and GC/MS was observed at the 50 ng/mL IA cutoff while sensitivity and specificity were highest at the 20 and 100 ng/mL IA cutoffs, respectively. Using federal workplace drug-testing criteria (IA cutoff of 50 ng/mL and GC/MS concentration ≥15 ng/mL) urine specimens tested positive in 47% of vaporized sessions and 21% of smoked sessions with active THC doses (N = 68). Urinary concentrations of THCCOOH are dissimilar after administration of smoked and vaporized cannabis, with qualitatively higher concentrations observed after vaporization. Infrequent users of cannabis may excrete relatively low concentrations of THCCOOH following acute inhalation of smoked or vaporized cannabis.
Introduction
National and international laws regulating cannabis have changed substantially in recent years. As of April 29th, 2019 33 U.S. states and the District of Columbia (D.C.) have legalized cannabis use for medicinal purposes, 10 of which have also legalized cannabis use for non-medicinal (“recreational”) purposes. These legislative changes have made cannabis available to an unprecedented number of people and spawned the creation of an expansive, largely unregulated, retail cannabis market.
Retail cannabis dispensaries, located in states that permit legal cannabis use, typically contain a variety of cannabis products and formulations. Diversity with respect to methods of cannabis self-administration, beyond traditional smoked preparations, are also now commonplace. Cannabis vaporizers, analogous to electronic cigarettes (e-cigs), have become a popular alternative method for cannabis inhalation (1, 2). Generally, vaporizer products use an internal heating mechanism to aerosolize (or “vaporize”) the contents of the device, which are then inhaled by the user. Cannabis vaporizers, however, can vary widely. Some are pre-filled with cannabinoid-containing liquids or resins while others require the user to insert dried cannabis or cannabis concentrates into the device. Cannabis vaporizers emit fewer toxicants compared with smoked methods (3) and the perception of reduced harm, compared with smoking, makes vaporization appealing to cannabis users (1, 2).
The legalization of cannabis and emergence of new cannabis products and methods of administration pose many unique challenges for drug-testing programs in workplace, treatment, research, criminal justice, and other settings (4, 5). 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) is a metabolite of Δ9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, and is the analyte in urine samples (the most common biological matrix for drug testing) tested to detect cannabis use. Prior controlled pharmacokinetic evaluations of cannabis use have informed the current regulatory standards (i.e., cannabinoid concentration cutoffs) for urine drug testing. Most of these studies have evaluated urinary THCCOOH excretion profiles in moderate (at least monthly) to heavy (daily or nearly daily) cannabis users, either following an abrupt period of cessation from cannabis (6–10), or after administering cannabis in a smoked or oral form (11–15). Notably, experienced, frequent cannabis users can extract more cannabinoids in a single smoking session through more effective smoking techniques (16, 17), and tend to have higher cumulative cannabinoid levels from repeated exposure compared with moderate users; both of these factors can prolong the detection time for THCCOOH in urine (6, 7, 10, 15). In addition, cannabis vaporizers can deliver cannabinoids more efficiently than smoked instruments under some conditions (3, 18), though other studies have found comparable cannabinoid levels in blood and urine after administration of the same dose of smoked and vaporized cannabis (16, 19). Thus, overall, additional studies are needed to characterize the urinary pharmacokinetic profile of cannabis when it is used by infrequent users and with alternative methods of administration (e.g., vaporizers).
The primary purpose of the present study was to evaluate urinary excretion profile of THCCOOH following administration of smoked and vaporized cannabis (0, 10, and 25 mg THC) by infrequent cannabis users (no cannabis use in the month prior to enrollment). Because most prior studies of THCCOOH included males predominantly, the present study attempted to balance the number of male and female participants to provide data on sex differences. This report provides detailed urinary pharmacokinetics of THCCOOH, including maximum concentrations (Cmax) and time to maximum concentrations (Tmax). Sensitivity, specificity, and agreement between immunoassay (IA) and gas chromatography-mass spectrometry (GC/MS) are also presented.
Method
Study design and procedure
Volunteers were recruited by print and online media advertisements and word-of-mouth. Interested individuals first completed a brief telephone interview and those who appeared eligible were invited to complete a screening visit at the Johns Hopkins Behavioral Pharmacology Research Unit (BPRU). During the screening visit, written informed consent was obtained from all participants. This study was approved by the Institutional Review Board (IRB) of Johns Hopkins University School of Medicine and was conducted in accordance with ethical standards established in the Helsinki Declaration. Participants were compensated (up to $2,130 USD) for their time.
In order to be eligible, participants had to: be healthy (as assessed using medical history, a 12-lead electrocardiogram (EKG), blood chemistry, hematology, and serology analysis, and a physical examination); have experience using cannabis but report no use in the month prior to the first experimental session; and provide a urine specimen negative for cannabis and other illicit drugs (i.e., amphetamines, benzodiazepines, cocaine, MDMA, opioids, and PCP) at screening and prior to each experimental session. For females, a positive pregnancy test (serum test conducted at screening; urine test conducted prior to each study session) was exclusionary. At the initial screening visit, and prior to each experimental session, participants’ use of cannabis, alcohol, tobacco, and illicit drugs for the prior 90 days was assessed with the Timeline Follow-Back Method (20).
Each participant completed six, approximately 8.5 h, outpatient sessions that differed only by inhalation method (smoked or vaporized) and THC dose (0, 10, or 25 mg). Experimental sessions, including all study procedures, were conducted at BPRU. Sessions were clustered by inhalation method (i.e., participants completed the three smoked cannabis sessions first then the three vaporized sessions second, or vice versa). THC dose order was randomized within each cluster. Sessions were separated by ≥ 1 week to facilitate satisfactory drug washout between conditions. The study was double-blinded with respect to THC dose, but participants and research staff were not blinded to the inhalation method.
Participants arrived at approximately 07:30 h for each experimental session. At the onset of each session, participants completed a urine drug test, an alcohol breathalyzer, and females took a urine pregnancy test (participation was contingent on negative results for all tests). All participants consumed a standard low-fat breakfast. Following baseline assessments, participants inhaled the given smoked or vaporized THC dose ad libitum (i.e., at their own pace) within 10 min. Participants inhaled vaporized cannabis doses produced by the Volcano Medic® (Storz and Bickel, Oakland, CA). This device heated cannabis at 204°C (400°F), and the resulting aerosol was trapped in a balloon that contained a one-way valve for user inhalation. This temperature setting was suggested by the manufacturer via personal communication. Participants were instructed to inhale three full balloons (until empty) within the allocated 10 min. In the pre-testing phase for this study, we ensured that this procedure would fully aerosolize each THC dose. A new balloon was used in each session to prevent contamination from previous THC doses. Preliminary testing revealed that placebo cannabis produced less visible aerosol than cannabis containing THC. In order to minimize aerosol visibility and preserve the double-blind, an opaque bag was placed over each balloon to prevent participants and staff from seeing the aerosol produced in each session. In smoked cannabis sessions, participants ignited cannabis contained in a small hand-held pipe with a lighter and inhaled the resulting smoke. Non-blinded pharmacy staff verified that all plant material had turned to ash, thus ensuring that participants administered the maximal THC dose in each session. The pipe contained a metal top that obstructed participants’ and blinded study staff members’ view of the plant material. This metal top also minimized side-stream smoke and reduced the loss of THC. For sterilization, the pipe and metal top were submerged in ethanol for ~24 h after each session. Unlike the metal top, a new pipe screen was used for each session to prevent contamination from previous doses of THC.
All cannabis used in this study was obtained from the National Institute on Drug Abuse (NIDA) Drug Supply Program and dispensed by the Johns Hopkins BPRU Pharmacy. Two batches of cannabis were used. The first batch (active cannabis) contained 13.4% THC, 0.08% Δ-8-THC, 0.03% Cannabidiol (CBD), and 0.8% Cannabinol (CBN). The second batch (placebo cannabis) contained <0.01% THC and did not contain detectable levels of Δ-8-THC, CBD, or CBN. Participants were provided the same quantity of plant material (186.6 mg) in each session; plant material was weighed by pharmacy staff before sessions. 186.6 mg of placebo and active cannabis were dispensed in the 0 mg and 25 mg THC conditions, respectively. For the 10 mg THC smoked and vaporized conditions, 74.6 mg of active cannabis and 112 mg of placebo cannabis were mixed together.
Outcome measures
Individual urine specimen collections occurred at baseline and exactly 1, 2, 3, and 4 h after the end of each drug administration period. After the 4 h collection time point, urine voids were pooled between 4–6 h and between 6–8 h post cannabis administration during each experimental session. That is, during these time windows, participants voided ad libitum into a single container and these collective urine voids were mixed together before being aliquoted. Participants were also asked to void at the end of each pooled time period (i.e., 6 and 8 h after drug administration) and these specimens were added to the pooled sample for that respective time window. For each urine specimen, two 30 mL aliquots of urine (designated samples A and B) were transferred into polypropylene bottles and wrapped with parafilm. All samples were stored at −20°C until they were shipped overnight (on dry ice) to the Clinical Reference Laboratory (CRL; Lenexa, KS). Additional outcome measures assessed in this study included whole blood and oral fluid cannabinoid concentrations, subjective drug effects, cardiovascular effects, and cognitive/psychomotor performance. These results have been previously published elsewhere (18, 21).
GC/MS analysis was used to test all urine samples for concentrations of THCCOOH using methods described elsewhere (13, 22). The limit of quantitation (LOQ) for these analyses was 0.75 ng/mL and the upper limit of linearity (ULOL) was 600 ng/mL. Specimens with concentrations that exceeded the ULOL were diluted to increase the accuracy of quantitation. Prior to analysis, samples were hydrolyzed with 5N KOH (200 μL). Acceptance criteria included: retention times of analyte and internal standard within ±2% of the calibrator; ion ratios within ± 20% of the calibrator; and positive controls within ±20% of established concentrations. Creatinine was measured using Siemens modified Jaffe reagent. The DRI Cannabinoid Assay® (Thermo Scientific, Waltham, MA) was used for all IA analyses and all urine specimens were tested at three different IA cutoffs 20, 50, and 100 ng/mL.
Data presentation and analysis
Participant demographics and test results for urinary specimens are presented using descriptive statistics. Urinary THCCOOH concentrations are presented both in absolute form and normalized by creatinine. That is, THCCOOH concentrations for each specimen were divided by the specimen’s corresponding creatinine concentration as in Huestis & Cone, 1998 (23). Creatinine normalization was conducted to reduce variability in THCCOOH concentrations attributable to differences in the degree of dilution between urine samples (23). Planned contrasts were conducted to compare absolute (non-creatinine normalized) THCCOOH Cmax values between smoked and vaporized cannabis (at both the 10 and 25 mg doses) and also to compare Cmax values between each THC dose within each route of administration. Additional planned contrasts were conducted to compare mean THCCOOH concentrations between smoked and vaporized cannabis (at both the 10 and 25 mg doses) at each urine collection point (i.e., baseline, and 1, 2, 3, 4, 4–6, and 6–8 h post cannabis administration). Statistical significance for these analyses was defined as an alpha error probability level of p < 0.05. All analyses were performed using GraphPad Prism (version 8) and descriptive statistics were generated using SPSS (version 25).
Sensitivity, specificity, and agreement between IA and GC/MS results were conducted for urinary THCCOOH for the active (i.e., 10 and 25 mg THC) smoked and vaporized doses. Three separate IA screening cutoffs were used for these analyses: 20, 50, and 100 ng/mL. A confirmatory GC/MS cutoff of 15 ng/mL was used for all analyses, as this cutoff corresponds with the mandatory guidelines for federal workplace drug testing set forth by the Substance Abuse and Mental Health Services Administration (SAMHSA) (24). Urinary THCCOOH test results were categorized as either: true positive (TP; IA response ≥ cutoff concentration and GC/MS positive, i.e., ≥15 ng/mL), true negative (TN; IA response < cutoff concentration and GC/MS negative i.e., <15 ng/mL), false positive (FP; IA response ≥ cutoff concentration and GC/MS negative i.e., <15 ng/mL), or false negative (FN; IA response < cutoff concentration and GC/MS positive, i.e., ≥15 ng/mL). Sensitivity, specificity, and agreement were calculated as follows: sensitivity (100 × [TP/(TP + FN)]), specificity (100 × [TN/(TN + FP)]), and agreement (100 × [(TP + TN)/(TP + TN + FP + FN)]).
Results
Participants
Demographic characteristics for study completers are shown in Table I. On average, participants had last used cannabis 398 days (SD = 437 days; range 30–1,825) prior to study entry. At screening and prior to each experimental session, all participants provided a negative urine sample (assessed via rapid enzyme IA test kits), suggesting participants were compliant with pre-session abstinence requirements for this study. Detailed descriptions of adverse events that occurred in this study can be found elsewhere (21, 25).
Table I.
Participant characteristics (N = 17)
| Number or mean (SD) | |||
|---|---|---|---|
| Total (N = 17) | Males (N = 9) | Females (N = 8) | |
| Race (# Caucasian) | 11 | 6 | 5 |
| Age (years) | 27.3 (5.7) | 28.0 (6.6) | 26.5 (4.8) |
| Weight (kg) | 77.9 (15.5) | 85.2 (14.5) | 69.8 (12.9) |
| Body mass index (BMI; kg/m2) | 26.2 (3.3) | 26.8 (2.4) | 25.4 (4.1) |
| Days since last cannabis use | 397.6 (436.8) | 546.1 (561.8) | 230.6 (123.3) |
| Age of first cannabis use (years) | 17.9 (2.0) | 18.6 (1.9) | 17.2 (1.8) |
| Tobacco cigarettes smoked per day | 0 (0) | 0 (0) | 0 (0) |
GC/MS results
Full IA and GC/MS results for each individual participant and time point are presented in Table II. Figure 1 presents mean urinary concentrations of THCCOOH before and after inhalation of smoked and vaporized cannabis. For smoked cannabis, mean Cmax THCCOOH concentration at the 25 mg dose was significantly higher than concentrations observed in the placebo and 10 mg conditions (ps < 0.05; Table III). For vaporized cannabis, THCCOOH concentrations did not differ significantly between the 10 and 25 mg conditions, though THCCOOH concentrations for both active dose conditions were significantly greater than placebo (ps < 0.05). Mean THCCOOH Cmax concentrations did not differ significantly between smoked and vaporized cannabis at either the 10 or 25 mg THC doses (ps > 0.05 for planned contrasts). However, at the 10 mg THC dose, inhalation of vaporized cannabis resulted in qualitatively higher mean and median Cmax THCCOOH concentrations compared with smoked cannabis (Table III). Further, at the 25 mg THC dose, median Cmax THCCOOH concentrations were also qualitatively higher after vaporized, as opposed to smoked cannabis inhalation (Table III); mean Cmax concentrations at the 25 mg dose did not follow this trend due to several extreme outliers in the 25 mg smoked condition. Specifically, at the 25 mg smoked dose, participant #15 had a Cmax concentration of 334.1 ng/mL and participant #38 had a Cmax concentration of 272.6 ng/mL (Table II). These values were over 100 ng/mL greater than the next highest Cmax value observed across all participants and experimental sessions. When normalized by creatinine, THCCOOH median values were also qualitatively higher after vaporized cannabis inhalation compared with the same dose of smoked cannabis (mean values were again similar between smoked and vaporized conditions at 25 mg THC due to outliers in the smoked condition). Additional planned contrasts compared mean THCCOOH concentrations for smoked and vaporized conditions at each individual time point. At the 10 mg dose, THCCOOH concentrations were significantly higher for vaporized, compared to smoked cannabis, at the 4–6 and 6–8 h post-drug administration time points (ps < 0.05); there were no statistically significant differences between smoked and vaporized conditions for any time point at the 25 mg dose.
Table II.
Analyses of urine specimens following inhalation of smoked and vaporized cannabis
| Smoked | Vaporized | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Subject# | Time (h) | THC dose (mg) | THC-COOH (GC-MS; ng/mL) | Creatinine (mg/dL) | THC-COOH Creatinine normalized (ng/mg) | 20 IA THC-COOH | 50 IA THC-COOH | 100 IA THC-COOH | THC-COOH (GC-MS; ng/mL) | Creatinine (mg/dL) | THC-COOH Creatinine normalized (ng/mg) | 20 IA THC-COOH | 50 IA THC-COOH | 100 IA THC-COOH |
| 15 M | BL | 10 | 0.0 | 255 | 0.000 | NEG | NEG | NEG | 0.0 | 211 | 0.000 | NEG | NEG | NEG |
| 15 | 1 | 10 | 1.8 | 40.3 | 0.045 | NEG | NEG | NEG | 8.0 | 164 | 0.049 | POS | POS | NEG |
| 15 | 2 | 10 | 6.9 | 49.7 | 0.139 | POS | NEG | NEG | 54.1 | 287 | 0.189 | POS | POS | POS |
| 15 | 3 | 10 | 10.6 | 49.4 | 0.215 | POS | NEG | NEG | 55.1 | 195 | 0.283 | POS | POS | POS |
| 15 | 4 | 10 | 5.4 | 27.6 | 0.196 | NEG | NEG | NEG | 7.9 | 18.8 | 0.420 | POS | NEG | NEG |
| 15 | 4–6 | 10 | 18.2 | 128 | 0.142 | POS | NEG | NEG | 37.9 | 111.5 | 0.340 | POS | POS | NEG |
| 15 | 6–8 | 10 | 21.0 | 162 | 0.130 | POS | NEG | NEG | 30.5 | 99.2 | 0.307 | POS | POS | NEG |
| 15 | BL | 25 | 0.0 | 297 | 0.000 | NEG | NEG | NEG | 0.0 | 213 | 0.000 | NEG | NEG | NEG |
| 15 | 1 | 25 | NS | NS | N/A | NS | NS | NS | 9.4 | 286 | 0.033 | POS | POS | NEG |
| 15 | 2 | 25 | NS | NS | N/A | NS | NS | NS | NS | NS | N/A | NS | NS | NS |
| 15 | 3 | 25 | NS | NS | N/A | NS | NS | NS | 92.8 | 277 | 0.335 | POS | POS | POS |
| 15 | 4 | 25 | NS | NS | N/A | NS | NS | NS | 15.4 | 36.7 | 0.420 | POS | NEG | NEG |
| 15 | 4–6 | 25 | 334.1 | 503 | 0.664 | POS | POS | POS | 27.2 | 59.9 | 0.454 | POS | POS | NEG |
| 15 | 6–8 | 25 | 155.2 | 204 | 0.761 | POS | POS | POS | 24.4 | 64.9 | 0.376 | POS | POS | NEG |
| 20 M | BL | 10 | 0.0 | 34.3 | 0.000 | NEG | NEG | NEG | 0.0 | 35 | 0.000 | NEG | NEG | NEG |
| 20 | 1 | 10 | 0.0 | 12.8 | 0.000 | NEG | NEG | NEG | 1.8 | 21.3 | 0.085 | POS | POS | NEG |
| 20 | 2 | 10 | 0.0 | 26 | 0.000 | NEG | NEG | NEG | 42.0 | 157.4 | 0.267 | POS | POS | POS |
| 20 | 3 | 10 | 0.0 | 11.1 | 0.000 | NEG | NEG | NEG | 5.3 | 12.8 | 0.414 | POS | NEG | NEG |
| 20 | 4 | 10 | 0.0 | 16.4 | 0.000 | NEG | NEG | NEG | 4.0 | 7.5 | 0.533 | NEG | NEG | NEG |
| 20 | 4–6 | 10 | 1.5 | 30.6 | 0.049 | NEG | NEG | NEG | 10.2 | 22.6 | 0.451 | POS | NEG | NEG |
| 20 | 6–8 | 10 | 1.1 | 31.7 | 0.035 | NEG | NEG | NEG | 20.4 | 48.3 | 0.422 | POS | NEG | NEG |
| 20 | BL | 25 | 0.0 | 190.3 | 0.000 | NEG | NEG | NEG | 0.0 | 271 | 0.000 | NEG | NEG | NEG |
| 20 | 1 | 25 | 0.0 | 13.5 | 0.000 | NEG | NEG | NEG | 9.1 | 245 | 0.037 | POS | POS | NEG |
| 20 | 2 | 25 | 1.2 | 8.1 | 0.148 | NEG | NEG | NEG | 9.6 | 35.3 | 0.272 | POS | POS | NEG |
| 20 | 3 | 25 | 2.9 | 24.6 | 0.118 | POS | NEG | NEG | 3.9 | 10.8 | 0.361 | NEG | NEG | NEG |
| 20 | 4 | 25 | 3.8 | 16.1 | 0.236 | POS | NEG | NEG | 4.0 | 9.7 | 0.412 | NEG | NEG | NEG |
| 20 | 4–6 | 25 | 7.1 | 28 | 0.254 | POS | NEG | NEG | 7.3 | 20.8 | 0.351 | POS | NEG | NEG |
| 20 | 6–8 | 25 | 6.4 | 26 | 0.246 | NEG | NEG | NEG | 21.1 | 70.3 | 0.300 | POS | NEG | NEG |
| 36 M | BL | 10 | 0.0 | 55.7 | 0.000 | NEG | NEG | NEG | 0.0 | 91.4 | 0.000 | NEG | NEG | NEG |
| 36 | 1 | 10 | 8.9 | 102 | 0.087 | POS | POS | NEG | 0.0 | 20 | 0.000 | NEG | NEG | NEG |
| 36 | 2 | 10 | 5.6 | 20 | 0.280 | POS | NEG | NEG | 84.1 | 405.3 | 0.208 | POS | POS | POS |
| 36 | 3 | 10 | 7.3 | 22.3 | 0.327 | POS | NEG | NEG | 17.2 | 46.6 | 0.369 | POS | NEG | NEG |
| 36 | 4 | 10 | 15.0 | 42.8 | 0.350 | POS | NEG | NEG | 9.5 | 28.1 | 0.338 | POS | NEG | NEG |
| 36 | 4–6 | 10 | 13.2 | 43.9 | 0.301 | POS | NEG | NEG | 9.5 | 29.5 | 0.322 | POS | NEG | NEG |
| 36 | 6–8 | 10 | 7.4 | 29.1 | 0.254 | POS | NEG | NEG | 37.1 | 100.3 | 0.370 | POS | POS | NEG |
| 36 | BL | 25 | 0.0 | 210 | 0.000 | NEG | NEG | NEG | 0.0 | 115 | 0.000 | NEG | NEG | NEG |
| 36 | 1 | 25 | 3.7 | 71.2 | 0.052 | POS | NEG | NEG | 4.9 | 99.9 | 0.049 | POS | NEG | NEG |
| 36 | 2 | 25 | 101.4 | 320 | 0.317 | POS | POS | POS | 6.5 | 29.6 | 0.220 | POS | NEG | NEG |
| 36 | 3 | 25 | 66.3 | 147 | 0.451 | POS | POS | POS | 5.2 | 14.3 | 0.364 | POS | NEG | NEG |
| 36 | 4 | 25 | 11.0 | 23.6 | 0.466 | POS | NEG | NEG | 12.5 | 39.3 | 0.318 | POS | NEG | NEG |
| 36 | 4–6 | 25 | 16.3 | 37.2 | 0.438 | POS | NEG | NEG | 6.5 | 24.4 | 0.266 | POS | NEG | NEG |
| 36 | 6–8 | 25 | 47.5 | 129 | 0.368 | POS | POS | NEG | 19.0 | 71.3 | 0.266 | POS | NEG | NEG |
| 38 M | BL | 10 | 0.0 | 42.4 | 0.000 | NEG | NEG | NEG | 0.0 | 46.6 | 0.000 | NEG | NEG | NEG |
| 38 | 1 | 10 | 0.0 | 20.6 | 0.000 | NEG | NEG | NEG | 0.0 | 9.7 | 0.000 | NEG | NEG | NEG |
| 38 | 2 | 10 | 12.1 | 36.5 | 0.332 | POS | NEG | NEG | 6.6 | 16.6 | 0.398 | POS | NEG | NEG |
| 38 | 3 | 10 | 18.6 | 44.6 | 0.417 | POS | NEG | NEG | 31.6 | 58.8 | 0.537 | POS | NEG | NEG |
| 38 | 4 | 10 | 7.9 | 17.6 | 0.449 | POS | NEG | NEG | 37.3 | 64.4 | 0.579 | POS | POS | NEG |
| 38 | 4–6 | 10 | 18.4 | 45.9 | 0.401 | POS | NEG | NEG | 46.0 | 85 | 0.541 | POS | POS | NEG |
| 38 | 6–8 | 10 | 6.7 | 21.6 | 0.310 | NEG | NEG | NEG | 14.8 | 28.5 | 0.519 | POS | NEG | NEG |
| 38 | BL | 25 | 0.0 | 24.5 | 0.000 | NEG | NEG | NEG | 0.0 | 22.9 | 0.000 | NEG | NEG | NEG |
| 38 | 1 | 25 | 11.7 | 15.6 | 0.750 | POS | NEG | NEG | 5.6 | 16.5 | 0.339 | POS | NEG | NEG |
| 38 | 2 | 25 | 30.9 | 12.5 | 2.472 | POS | NEG | NEG | 15.9 | 15.4 | 1.032 | POS | NEG | NEG |
| 38 | 3 | 25 | 122.9 | 42.8 | 2.871 | POS | POS | POS | 68.9 | 49.8 | 1.384 | POS | POS | POS |
| 38 | 4 | 25 | 272.6 | 104 | 2.621 | POS | POS | POS | 63.1 | 43.8 | 1.441 | POS | POS | POS |
| 38 | 4–6 | 25 | NS | NS | N/A | NS | NS | NS | 105.9 | 74.2 | 1.427 | POS | POS | POS |
| 38 | 6–8 | 25 | 183.4 | 68 | 2.697 | POS | POS | POS | 36.6 | 26.5 | 1.381 | POS | POS | NEG |
| 50 M | BL | 10 | 0.0 | 270 | 0.000 | NEG | NEG | NEG | 0.0 | 103.1 | 0.000 | NEG | NEG | NEG |
| 50 | 1 | 10 | 0.0 | 24 | 0.000 | NEG | NEG | NEG | 0.0 | 15.3 | 0.000 | NEG | NEG | NEG |
| 50 | 2 | 10 | 0.0 | 34.2 | 0.000 | NEG | NEG | NEG | 0.0 | 43 | 0.000 | NEG | NEG | NEG |
| 50 | 3 | 10 | 1.4 | 84.5 | 0.017 | NEG | NEG | NEG | 3.6 | 96.1 | 0.037 | NEG | NEG | NEG |
| 50 | 4 | 10 | 0.0 | 37.2 | 0.000 | NEG | NEG | NEG | 0.0 | 13.4 | 0.000 | NEG | NEG | NEG |
| 50 | 4–6 | 10 | 0.0 | 46.6 | 0.000 | NEG | NEG | NEG | 0.0 | 45 | 0.000 | NEG | NEG | NEG |
| 50 | 6–8 | 10 | 1.6 | 81.9 | 0.020 | NEG | NEG | NEG | 2.0 | 42.4 | 0.047 | NEG | NEG | NEG |
| 50 | BL | 25 | 0.0 | 251 | 0.000 | NEG | NEG | NEG | 0.0 | 69.1 | 0.000 | NEG | NEG | NEG |
| 50 | 1 | 25 | 0.0 | 173 | 0.000 | NEG | NEG | NEG | 0.0 | 27.1 | 0.000 | NEG | NEG | NEG |
| 50 | 2 | 25 | 0.0 | 19.5 | 0.000 | NEG | NEG | NEG | 4.5 | 29.5 | 0.153 | POS | NEG | NEG |
| 50 | 3 | 25 | 0.0 | 17.5 | 0.000 | NEG | NEG | NEG | 7.5 | 43.4 | 0.173 | POS | NEG | NEG |
| 50 | 4 | 25 | 0.0 | 72.5 | 0.000 | NEG | NEG | NEG | 16.9 | 82.6 | 0.205 | POS | NEG | NEG |
| 50 | 4–6 | 25 | 3.2 | 113 | 0.028 | NEG | NEG | NEG | 7.6 | 52.4 | 0.145 | POS | NEG | NEG |
| 50 | 6–8 | 25 | 1.8 | 109 | 0.017 | NEG | NEG | NEG | 8.2 | 61.7 | 0.133 | POS | NEG | NEG |
| 55 M | BL | 10 | 0.0 | 340 | 0.000 | NEG | NEG | NEG | 0.0 | 59.6 | 0.000 | NEG | NEG | NEG |
| 55 | 1 | 10 | 0.0 | 20.8 | 0.000 | NEG | NEG | NEG | 0.0 | 17 | 0.000 | NEG | NEG | NEG |
| 55 | 2 | 10 | 0.0 | 13.2 | 0.000 | NEG | NEG | NEG | 1.7 | 13.1 | 0.130 | NEG | NEG | NEG |
| 55 | 3 | 10 | 1.8 | 25.6 | 0.070 | NEG | NEG | NEG | 10.7 | 95.4 | 0.112 | POS | NEG | NEG |
| 55 | 4 | 10 | 2.8 | 60.6 | 0.046 | NEG | NEG | NEG | 5.7 | 45.3 | 0.126 | NEG | NEG | NEG |
| 55 | 4–6 | 10 | 4.6 | 104 | 0.044 | NEG | NEG | NEG | 12.9 | 134 | 0.096 | POS | NEG | NEG |
| 55 | 6–8 | 10 | 3.2 | 121 | 0.026 | NEG | NEG | NEG | 4.8 | 57 | 0.084 | NEG | NEG | NEG |
| 55 | BL | 25 | 0.0 | 230 | 0.000 | NEG | NEG | NEG | 0.0 | 174 | 0.000 | NEG | NEG | NEG |
| 55 | 1 | 25 | 0.0 | 19.8 | 0.000 | NEG | NEG | NEG | 0.0 | 19.1 | 0.000 | NEG | NEG | NEG |
| 55 | 2 | 25 | 1.0 | 13 | 0.077 | NEG | NEG | NEG | 3.8 | 15.1 | 0.252 | NEG | NEG | NEG |
| 55 | 3 | 25 | 3.3 | 29.5 | 0.112 | NEG | NEG | NEG | 7.8 | 30.4 | 0.257 | POS | NEG | NEG |
| 55 | 4 | 25 | 4.5 | 39.3 | 0.115 | NEG | NEG | NEG | 13.9 | 54.6 | 0.255 | POS | NEG | NEG |
| 55 | 4–6 | 25 | 9.9 | 104 | 0.095 | NEG | NEG | NEG | 24.5 | 115 | 0.213 | POS | NEG | NEG |
| 55 | 6–8 | 25 | 6.4 | 87.1 | 0.073 | NEG | NEG | NEG | 18.4 | 90 | 0.204 | POS | NEG | NEG |
| 58 M | BL | 10 | 0.0 | 144 | 0.000 | NEG | NEG | NEG | 0.0 | 126 | 0.000 | NEG | NEG | NEG |
| 58 | 1 | 10 | 1.4 | 14 0 | N/A | NEG | NEG | NEG | 0.0 | 132 | 0.000 | NEG | NEG | NEG |
| 58 | 2 | 10 | 1.9 | 34.2 | 0.056 | NEG | NEG | NEG | 2.7 | 50.1 | 0.054 | POS | NEG | NEG |
| 58 | 3 | 10 | 2.2 | 27.4 | 0.080 | NEG | NEG | NEG | 1.7 | 13.3 | 0.128 | NEG | NEG | NEG |
| 58 | 4 | 10 | 3.7 | 38.6 | 0.096 | NEG | NEG | NEG | 2.9 | 28.9 | 0.100 | NEG | NEG | NEG |
| 58 | 4–6 | 10 | 3.8 | 42 | 0.090 | NEG | NEG | NEG | 10.5 | 100.7 | 0.104 | POS | NEG | NEG |
| 58 | 6–8 | 10 | 2.9 | 50 | 0.058 | NEG | NEG | NEG | 10.2 | 101.8 | 0.100 | POS | NEG | NEG |
| 58 | BL | 25 | 0.0 | 179.9 | 0.000 | NEG | NEG | NEG | 0.0 | 403 | 0.000 | NEG | NEG | NEG |
| 58 | 1 | 25 | 4.4 | 166 | 0.027 | POS | POS | NEG | 6.7 | 366 | 0.018 | POS | POS | NEG |
| 58 | 2 | 25 | 12.6 | 103 | 0.122 | POS | POS | NEG | 12.6 | 123 | 0.102 | POS | POS | NEG |
| 58 | 3 | 25 | 6.2 | 29 | 0.214 | POS | NEG | NEG | 14.7 | 102 | 0.144 | POS | NEG | NEG |
| 58 | 4 | 25 | 4.3 | 19.1 | 0.225 | NEG | NEG | NEG | 14.4 | 92.4 | 0.156 | POS | NEG | NEG |
| 58 | 4–6 | 25 | 23.6 | 102 | 0.231 | POS | NEG | NEG | 6.8 | 47.7 | 0.143 | NEG | NEG | NEG |
| 58 | 6–8 | 25 | 11.1 | 50.5 | 0.220 | POS | NEG | NEG | 16.6 | 119 | 0.139 | POS | NEG | NEG |
| 59 M | BL | 10 | 0.0 | 6.8 | 0.000 | NEG | NEG | NEG | 0.0 | 147 | 0.000 | NEG | NEG | NEG |
| 59 | 1 | 10 | 2.3 | 22.7 | 0.101 | NEG | NEG | NEG | 0.0 | 24.8 | 0.000 | NEG | NEG | NEG |
| 59 | 2 | 10 | 7.1 | 20.8 | 0.341 | NEG | NEG | NEG | 5.8 | 36.5 | 0.159 | NEG | NEG | NEG |
| 59 | 3 | 10 | 5.5 | 16.8 | 0.327 | NEG | NEG | NEG | 1.3 | 6.9 | 0.188 | NEG | NEG | NEG |
| 59 | 4 | 10 | 8.2 | 24.9 | 0.329 | NEG | NEG | NEG | 1.6 | 9 | 0.178 | NEG | NEG | NEG |
| 59 | 4–6 | 10 | 12.2 | 50.3 | 0.243 | NEG | NEG | NEG | 4.8 | 34.1 | 0.141 | NEG | NEG | NEG |
| 59 | 6–8 | 10 | 3.0 | 14.7 | 0.204 | NEG | NEG | NEG | 7.5 | 66.4 | 0.113 | NEG | NEG | NEG |
| 59 | BL | 25 | 0.0 | 156 | 0.000 | NEG | NEG | NEG | 0.0 | 205 | 0.000 | NEG | NEG | NEG |
| 59 | 1 | 25 | 21.2 | 110 | 0.193 | POS | NEG | NEG | 27.0 | 258 | 0.105 | POS | POS | NEG |
| 59 | 2 | 25 | 19.2 | 28.5 | 0.674 | POS | NEG | NEG | 114.6 | 263 | 0.436 | POS | POS | POS |
| 59 | 3 | 25 | 29.5 | 31.3 | 0.942 | POS | NEG | NEG | 131.1 | 221 | 0.593 | POS | POS | POS |
| 59 | 4 | 25 | 9.6 | 12.1 | 0.793 | NEG | NEG | NEG | 146.0 | 173 | 0.844 | POS | POS | POS |
| 59 | 4–6 | 25 | 3.8 | 8.9 | 0.427 | NEG | NEG | NEG | NS | NS | N/A | NS | NS | NS |
| 59 | 6–8 | 25 | 9.7 | 25.1 | 0.386 | NEG | NEG | NEG | 4.9 | 7.1 | 0.690 | NEG | NEG | NEG |
| 60 M | BL | 10 | 0.0 | 162 | 0.000 | NEG | NEG | NEG | 0.0 | 120 | 0.000 | NEG | NEG | NEG |
| 60 | 1 | 10 | 0.0 | 15.7 | 0.000 | NEG | NEG | NEG | 2.9 | 14.5 | 0.200 | NEG | NEG | NEG |
| 60 | 2 | 10 | 0.0 | 11.9 | 0.000 | NEG | NEG | NEG | 7.7 | 17 | 0.453 | NEG | NEG | NEG |
| 60 | 3 | 10 | 0.0 | 14.1 | 0.000 | NEG | NEG | NEG | 22.0 | 50.2 | 0.438 | POS | NEG | NEG |
| 60 | 4 | 10 | 0.0 | 19.4 | 0.000 | NEG | NEG | NEG | 12.0 | 26.5 | 0.453 | POS | NEG | NEG |
| 60 | 4–6 | 10 | 0.0 | 41.9 | 0.000 | NEG | NEG | NEG | 8.2 | 16.5 | 0.497 | POS | NEG | NEG |
| 60 | 6–8 | 10 | 0.0 | 41.1 | 0.000 | NEG | NEG | NEG | 16.4 | 48.9 | 0.335 | POS | NEG | NEG |
| 60 | BL | 25 | 0.0 | 227 | 0.000 | NEG | NEG | NEG | 0.0 | 224 | 0.000 | NEG | NEG | NEG |
| 60 | 1 | 25 | 0.0 | 54.8 | 0.000 | NEG | NEG | NEG | 5.8 | 89.2 | 0.065 | POS | NEG | NEG |
| 60 | 2 | 25 | 0.0 | 31.2 | 0.000 | NEG | NEG | NEG | 7.7 | 29.2 | 0.264 | POS | NEG | NEG |
| 60 | 3 | 25 | 0.0 | 25.4 | 0.000 | NEG | NEG | NEG | 7.0 | 22.6 | 0.310 | POS | NEG | NEG |
| 60 | 4 | 25 | 0.0 | 21 | 0.000 | NEG | NEG | NEG | 11.7 | 42.9 | 0.273 | POS | NEG | NEG |
| 60 | 4–6 | 25 | 0.0 | 24.9 | 0.000 | NEG | NEG | NEG | 8.0 | 33.9 | 0.236 | POS | NEG | NEG |
| 60 | 6–8 | 25 | 0.0 | 23.1 | 0.000 | NEG | NEG | NEG | 28.9 | 145 | 0.199 | POS | POS | NEG |
| 4 F | BL | 10 | 0.0 | 20.4 | 0.000 | NEG | NEG | NEG | 0.0 | 20.9 | 0.000 | NEG | NEG | NEG |
| 4 | 1 | 10 | 0.0 | 10.2 | 0.000 | NEG | NEG | NEG | 1.0 | 11 | 0.091 | NEG | NEG | NEG |
| 4 | 2 | 10 | 0.0 | 1 0. 4 | N/A | NEG | NEG | NEG | 7.5 | 21.4 | 0.350 | POS | NEG | NEG |
| 4 | 3 | 10 | 0.0 | 12.4 | 0.000 | NEG | NEG | NEG | 6.0 | 10.7 | 0.561 | POS | NEG | NEG |
| 4 | 4 | 10 | 0.0 | 10.7 | 0.000 | NEG | NEG | NEG | 11.1 | 8.5 | 1.306 | POS | NEG | NEG |
| 4 | 4–6 | 10 | 0.0 | 13.6 | 0.000 | NEG | NEG | NEG | 40.1 | 75 | 0.535 | POS | POS | NEG |
| 4 | 6–8 | 10 | 0.0 | 13.1 | 0.000 | NEG | NEG | NEG | 33.4 | 63.4 | 0.527 | POS | POS | NEG |
| 4 | BL | 25 | 0.0 | 29.4 | 0.000 | NEG | NEG | NEG | 0.0 | 14.7 | 0.000 | NEG | NEG | NEG |
| 4 | 1 | 25 | 0.0 | 10.6 | 0.000 | NEG | NEG | NEG | 0.0 | 12.9 | 0.000 | NEG | NEG | NEG |
| 4 | 2 | 25 | 1.8 | 18.5 | 0.097 | NEG | NEG | NEG | 2.8 | 11.6 | 0.241 | NEG | NEG | NEG |
| 4 | 3 | 25 | 3.5 | 23.5 | 0.149 | NEG | NEG | NEG | 13.7 | 45.7 | 0.300 | POS | NEG | NEG |
| 4 | 4 | 25 | 6.1 | 35.3 | 0.173 | POS | NEG | NEG | 22.7 | 69.2 | 0.328 | POS | NEG | NEG |
| 4 | 4–6 | 25 | 3.6 | 28.9 | 0.125 | NEG | NEG | NEG | 15.8 | 54.7 | 0.289 | POS | NEG | NEG |
| 4 | 6–8 | 25 | 3.3 | 28.1 | 0.117 | NEG | NEG | NEG | 5.9 | 32.9 | 0.179 | NEG | NEG | NEG |
| 25 F | BL | 10 | 0.0 | 23.5 | 0.000 | NEG | NEG | NEG | 0.0 | 21.8 | 0.000 | NEG | NEG | NEG |
| 25 | 1 | 10 | 0.0 | 19.1 | 0.000 | NEG | NEG | NEG | 7.6 | 34.4 | 0.221 | POS | NEG | NEG |
| 25 | 2 | 10 | 0.0 | 164 | 0.000 | NEG | NEG | NEG | 9.4 | 13.9 | 0.676 | POS | NEG | NEG |
| 25 | 3 | 10 | 0.0 | 32.6 | 0.000 | NEG | NEG | NEG | 24.0 | 31.5 | 0.762 | POS | NEG | NEG |
| 25 | 4 | 10 | 0.0 | 17.6 | 0.000 | NEG | NEG | NEG | 114.4 | 313 | 0.365 | POS | POS | POS |
| 25 | 4–6 | 10 | 1.6 | 16 | 0.100 | NEG | NEG | NEG | 49.1 | 89.2 | 0.550 | POS | POS | NEG |
| 25 | 6–8 | 10 | 3.0 | 24.3 | 0.123 | NEG | NEG | NEG | 15.1 | 30.4 | 0.497 | NEG | NEG | NEG |
| 25 | BL | 25 | 0.0 | 157.2 | 0.000 | NEG | NEG | NEG | 0.0 | 26.9 | 0.000 | NEG | NEG | NEG |
| 25 | 1 | 25 | 0.0 | 14.2 | 0.000 | NEG | NEG | NEG | 1.4 | 11.9 | 0.118 | POS | NEG | NEG |
| 25 | 2 | 25 | 1.0 | 16.4 | 0.061 | NEG | NEG | NEG | 9.7 | 17.7 | 0.548 | POS | NEG | NEG |
| 25 | 3 | 25 | 4.3 | 47.1 | 0.091 | NEG | NEG | NEG | 5.3 | 9.2 | 0.576 | POS | NEG | NEG |
| 25 | 4 | 25 | NS | NS | N/A | NS | NS | NS | 7.8 | 12.3 | 0.634 | POS | NEG | NEG |
| 25 | 4–6 | 25 | NS | NS | N/A | NS | NS | NS | 28.8 | 50.6 | 0.569 | POS | NEG | NEG |
| 25 | 6–8 | 25 | 4.3 | 49.6 | 0.087 | NEG | NEG | NEG | 8.3 | 21.2 | 0.392 | POS | NEG | NEG |
| 29 F | BL | 10 | 4.6 | 43.2 | 0.106 | NEG | NEG | NEG | 0.0 | 397.2 | 0.000 | NEG | NEG | NEG |
| 29 | 1 | 10 | 2.6 | 27.4 | 0.095 | NEG | NEG | NEG | 1.5 | 34.5 | 0.043 | POS | NEG | NEG |
| 29 | 2 | 10 | 0.0 | 15.4 | 0.000 | NEG | NEG | NEG | 3.0 | 12.8 | 0.234 | POS | NEG | NEG |
| 29 | 3 | 10 | 8.3 | 32.2 | 0.258 | POS | NEG | NEG | 7.7 | 25 | 0.308 | POS | NEG | NEG |
| 29 | 4 | 10 | 5.4 | 13.8 | 0.391 | POS | NEG | NEG | 15.0 | 35.5 | 0.423 | POS | NEG | NEG |
| 29 | 4–6 | 10 | 7.3 | 18 | 0.406 | POS | NEG | NEG | 39.0 | 130.2 | 0.300 | POS | POS | NEG |
| 29 | 6–8 | 10 | 11.5 | 23.1 | 0.498 | POS | NEG | NEG | 10.9 | 39.4 | 0.277 | POS | NEG | NEG |
| 29 | BL | 25 | 0.0 | 182.5 | 0.000 | NEG | NEG | NEG | 0.0 | 56.9 | 0.000 | NEG | NEG | NEG |
| 29 | 1 | 25 | 0.0 | 17.7 | 0.000 | NEG | NEG | NEG | 0.0 | 10.4 | 0.000 | NEG | NEG | NEG |
| 29 | 2 | 25 | 3.8 | 22.3 | 0.170 | NEG | NEG | NEG | 5.9 | 11.2 | 0.527 | POS | NEG | NEG |
| 29 | 3 | 25 | 2.6 | 12.6 | 0.206 | NEG | NEG | NEG | NS | NS | N/A | NS | NS | NS |
| 29 | 4 | 25 | 2.9 | 11.8 | 0.246 | NEG | NEG | NEG | 56.8 | 83.1 | 0.684 | POS | POS | POS |
| 29 | 4–6 | 25 | 10.0 | 62.6 | 0.160 | POS | NEG | NEG | 25.4 | 36.3 | 0.700 | POS | NEG | NEG |
| 29 | 6–8 | 25 | 2.3 | 13.1 | 0.176 | NEG | NEG | NEG | 14.7 | 24.6 | 0.598 | POS | NEG | NEG |
| 53 F | BL | 10 | 0.0 | 135 | 0.000 | NEG | NEG | NEG | 0.0 | 201 | 0.000 | NEG | NEG | NEG |
| 53 | 1 | 10 | 0.0 | 19.9 | 0.000 | NEG | NEG | NEG | 6.7 | 167 | 0.040 | POS | POS | NEG |
| 53 | 2 | 10 | 1.2 | 25 | 0.048 | NEG | NEG | NEG | 3.0 | 10.5 | 0.286 | NEG | NEG | NEG |
| 53 | 3 | 10 | 2.1 | 31.5 | 0.067 | NEG | NEG | NEG | 2.6 | 8.9 | 0.292 | NEG | NEG | NEG |
| 53 | 4 | 10 | 3.6 | 40 | 0.090 | NEG | NEG | NEG | 3.1 | 9.8 | 0.316 | NEG | NEG | NEG |
| 53 | 4–6 | 10 | 5.9 | 86.2 | 0.068 | NEG | NEG | NEG | 5.3 | 14.1 | 0.376 | NEG | NEG | NEG |
| 53 | 6–8 | 10 | 1.4 | 23.6 | 0.059 | NEG | NEG | NEG | 6.8 | 28.8 | 0.236 | NEG | NEG | NEG |
| 53 | BL | 25 | 0 | 185 | 0.000 | NEG | NEG | NEG | 0.0 | 167.5 | 0.000 | NEG | NEG | NEG |
| 53 | 1 | 25 | 0 | 16.6 | 0.000 | NEG | NEG | NEG | NS | NS | NS | NS | NS | NS |
| 53 | 2 | 25 | 2.1 | 18.5 | 0.114 | NEG | NEG | NEG | NS | NS | NS | NS | NS | NS |
| 53 | 3 | 25 | 4.3 | 32 | 0.134 | NEG | NEG | NEG | 8.4 | 26.2 | 0.321 | POS | NEG | NEG |
| 53 | 4 | 25 | NS | NS | NS | NS | NS | NS | 3.8 | 4.6 | 0.826 | NEG | NEG | NEG |
| 53 | 4–6 | 25 | 3.7 | 20.4 | 0.181 | NEG | NEG | NEG | 7.6 | 13.6 | 0.559 | POS | NEG | NEG |
| 53 | 6–8 | 25 | 2.6 | 14.3 | 0.182 | NEG | NEG | NEG | 34.2 | 75.1 | 0.455 | POS | POS | NEG |
| 54 F | BL | 10 | 0.0 | 275 | 0.000 | NEG | NEG | NEG | 0.0 | 76 | 0.000 | NEG | NEG | NEG |
| 54 | 1 | 10 | 0.0 | 16.4 | 0.000 | NEG | NEG | NEG | 0.0 | 15.1 | 0.000 | NEG | NEG | NEG |
| 54 | 2 | 10 | 1.0 | 13.8 | 0.072 | NEG | NEG | NEG | 0.0 | 6.8 | 0.000 | NEG | NEG | NEG |
| 54 | 3 | 10 | 4.4 | 44.6 | 0.099 | POS | NEG | NEG | 0.0 | 13.3 | 0.000 | NEG | NEG | NEG |
| 54 | 4 | 10 | 3.1 | 37 | 0.084 | NEG | NEG | NEG | 0.0 | 10.4 | 0.000 | NEG | NEG | NEG |
| 54 | 4–6 | 10 | 9.7 | 148 | 0.066 | POS | NEG | NEG | 3.4 | 22.6 | 0.150 | NEG | NEG | NEG |
| 54 | 6–8 | 10 | 9.8 | 153 | 0.064 | POS | NEG | NEG | 3.6 | 25.5 | 0.141 | NEG | NEG | NEG |
| 54 | BL | 25 | 0.0 | 86 | 0.000 | NEG | NEG | NEG | 0.0 | 34.5 | 0.000 | NEG | NEG | NEG |
| 54 | 1 | 25 | 1.1 | 20.5 | 0.054 | NEG | NEG | NEG | 0.0 | 22.9 | 0.000 | NEG | NEG | NEG |
| 54 | 2 | 25 | 2.4 | 14.8 | 0.162 | NEG | NEG | NEG | 1.2 | 12.5 | 0.096 | NEG | NEG | NEG |
| 54 | 3 | 25 | 5.0 | 26.1 | 0.192 | POS | NEG | NEG | 2.7 | 13.6 | 0.199 | NEG | NEG | NEG |
| 54 | 4 | 25 | 12.2 | 67.4 | 0.181 | POS | NEG | NEG | 10.0 | 49.4 | 0.202 | POS | NEG | NEG |
| 54 | 4–6 | 25 | 20.4 | 128.5 | 0.159 | POS | POS | NEG | 15.0 | 63.5 | 0.236 | POS | NEG | NEG |
| 54 | 6–8 | 25 | 20.8 | 140 | 0.149 | POS | POS | NEG | 28.6 | 143.5 | 0.199 | POS | POS | NEG |
| 63 F | BL | 10 | 0.0 | 66.5 | 0.000 | NEG | NEG | NEG | 0.0 | 126 | 0.000 | NEG | NEG | NEG |
| 63 | 1 | 10 | 3.5 | 48.6 | 0.072 | POS | NEG | NEG | 0.0 | 17.9 | 0.000 | NEG | NEG | NEG |
| 63 | 2 | 10 | 35.6 | 95.4 | 0.373 | POS | POS | POS | 3.4 | 10.4 | 0.327 | NEG | NEG | NEG |
| 63 | 3 | 10 | 58.7 | 130 | 0.452 | POS | POS | POS | 3.9 | 12.9 | 0.302 | NEG | NEG | NEG |
| 63 | 4 | 10 | 6.4 | 11.4 | 0.561 | POS | NEG | NEG | 8.0 | 26.9 | 0.297 | POS | NEG | NEG |
| 63 | 4–6 | 10 | 2.8 | 6.7 | 0.418 | NEG | NEG | NEG | 31.0 | 143 | 0.217 | POS | POS | NEG |
| 63 | 6–8 | 10 | 5.5 | 19.3 | 0.285 | NEG | NEG | NEG | 4.5 | 29.3 | 0.154 | NEG | NEG | NEG |
| 63 | BL | 25 | 0.0 | 38 | 0.000 | NEG | NEG | NEG | 0.0 | 90.8 | 0.000 | NEG | NEG | NEG |
| 63 | 1 | 25 | 1.7 | 18 | 0.094 | POS | NEG | NEG | 1.6 | 23 | 0.070 | NEG | NEG | NEG |
| 63 | 2 | 25 | 91.5 | 159 | 0.575 | POS | POS | NEG | 5.1 | 14.5 | 0.352 | POS | NEG | NEG |
| 63 | 3 | 25 | 14.8 | 16.2 | 0.914 | POS | NEG | NEG | 5.2 | 8.2 | 0.634 | NEG | NEG | NEG |
| 63 | 4 | 25 | 6.1 | 6.3 | 0.968 | POS | NEG | NEG | 5.5 | 10.6 | 0.519 | POS | NEG | NEG |
| 63 | 4–6 | 25 | 6.6 | 6.5 | 1.015 | NEG | NEG | NEG | 23.6 | 57.6 | 0.410 | POS | NEG | NEG |
| 63 | 6–8 | 25 | 14.5 | 23.6 | 0.614 | POS | NEG | NEG | 25.7 | 79.6 | 0.323 | POS | NEG | NEG |
| 64 F | BL | 10 | 0.0 | 164 | 0.000 | NEG | NEG | NEG | 0.0 | 19.3 | 0.000 | NEG | NEG | NEG |
| 64 | 1 | 10 | 0.0 | 27.6 | 0.000 | NEG | NEG | NEG | 0.0 | 21.7 | 0.000 | NEG | NEG | NEG |
| 64 | 2 | 10 | 0.0 | 8.8 | 0.000 | NEG | NEG | NEG | 31.4 | 209 | 0.150 | POS | POS | POS |
| 64 | 3 | 10 | 0.0 | 8.2 | 0.000 | NEG | NEG | NEG | 44.4 | 157 | 0.283 | POS | POS | POS |
| 64 | 4 | 10 | 1.1 | 9.9 | 0.111 | NEG | NEG | NEG | 3.3 | 9.7 | 0.340 | NEG | NEG | NEG |
| 64 | 4–6 | 10 | 2.8 | 37 | 0.076 | NEG | NEG | NEG | 2.3 | 7.5 | 0.307 | NEG | NEG | NEG |
| 64 | 6–8 | 10 | 6.4 | 118 | 0.054 | POS | NEG | NEG | 5.3 | 24.5 | 0.216 | NEG | NEG | NEG |
| 64 | BL | 25 | 0.0 | 138 | 0.000 | NEG | NEG | NEG | 0.0 | 197.8 | 0.000 | NEG | NEG | NEG |
| 64 | 1 | 25 | 3.5 | 1,289 | 0.003 | POS | NEG | NEG | 0.0 | 46.5 | 0.000 | NEG | NEG | NEG |
| 64 | 2 | 25 | 2.3 | 14.7 | 0.156 | NEG | NEG | NEG | 0.0 | 7.2 | 0.000 | NEG | NEG | NEG |
| 64 | 3 | 25 | 1.1 | 7.4 | 0.149 | NEG | NEG | NEG | 1.1 | 7.1 | 0.155 | NEG | NEG | NEG |
| 64 | 4 | 25 | 1.7 | 9.4 | 0.181 | NEG | NEG | NEG | 2.3 | 17.5 | 0.131 | NEG | NEG | NEG |
| 64 | 4–6 | 25 | 7.8 | 40.8 | 0.191 | POS | NEG | NEG | 4.9 | 28.9 | 0.170 | NEG | NEG | NEG |
| 64 | 6–8 | 25 | 8.0 | 49 | 0.163 | POS | NEG | NEG | 4.9 | 30.4 | 0.161 | NEG | NEG | NEG |
| 65 F | BL | 10 | 0.0 | 40.9 | 0.000 | NEG | NEG | NEG | 0.0 | 24.3 | 0.000 | NEG | NEG | NEG |
| 65 | 1 | 10 | 0.0 | 13.8 | 0.000 | NEG | NEG | NEG | 0.0 | 8.1 | 0.000 | NEG | NEG | NEG |
| 65 | 2 | 10 | 0.0 | 9.2 | 0.000 | NEG | NEG | NEG | 0.0 | 9.3 | 0.000 | NEG | NEG | NEG |
| 65 | 3 | 10 | 2.5 | 26.9 | 0.093 | NEG | NEG | NEG | 0.0 | 16.8 | 0.000 | NEG | NEG | NEG |
| 65 | 4 | 10 | 2.6 | 33.9 | 0.077 | NEG | NEG | NEG | 5.7 | 88.3 | 0.065 | POS | NEG | NEG |
| 65 | 4–6 | 10 | 1.1 | 17.6 | 0.063 | NEG | NEG | NEG | 0.0 | 16.7 | 0.000 | NEG | NEG | NEG |
| 65 | 6–8 | 10 | 0.0 | 17.1 | 0.000 | NEG | NEG | NEG | 0.0 | 23.1 | 0.000 | NEG | NEG | NEG |
| 65 | BL | 25 | 0.0 | 79.4 | 0.000 | NEG | NEG | NEG | 0.0 | 15 | 0.000 | NEG | NEG | NEG |
| 65 | 1 | 25 | 2.9 | 74.2 | 0.039 | POS | NEG | NEG | 0.0 | 12.5 | 0.000 | NEG | NEG | NEG |
| 65 | 2 | 25 | 30.7 | 161 | 0.191 | POS | POS | NEG | 2.8 | 15.2 | 0.184 | POS | NEG | NEG |
| 65 | 3 | 25 | 4.1 | 12.4 | 0.331 | POS | NEG | NEG | 3.4 | 12.7 | 0.268 | NEG | NEG | NEG |
| 65 | 4 | 25 | 3.0 | 8 | 0.375 | NEG | NEG | NEG | 2.9 | 9.8 | 0.296 | NEG | NEG | NEG |
| 65 | 4–6 | 25 | 2.8 | 10.3 | 0.272 | NEG | NEG | NEG | 2.7 | 10.6 | 0.255 | NEG | NEG | NEG |
| 65 | 6–8 | 25 | 2.4 | NS | N/A | NS | NS | NS | 2.5 | 13.8 | 0.181 | NEG | NEG | NEG |
Note: IA = Immunoassay response; NS = no sample; N/A = not applicable; M = Male participant; F = female participant.
Figure 1.
Quantitative mean THCCOOH (+SEM) urine concentrations before and for 8 h after inhalation of smoked and vaporized cannabis (0, 10, and 25 mg THC) for 17 infrequent cannabis users. Data are presented in both absolute form (top panel) and normalized by creatinine (bottom panel).
Table III.
Mean and median THCCOOH maximum concentration (Cmax), mean time to maximum concentration (Tmax), and individual ranges following smoked and vaporized cannabis inhalation
| Dose (mg) | THCCOOH Mean Cmax (ng/mL; range) | THCCOOH Median Cmax (ng/mL) | THCCOOH Tmax (h; range) | Creatinine Normalized THCCOOH Mean Cmax (ng/mg; range) | Creatinine Normalized Median THCCOOH Cmax (ng/mg) | Creatinine Normalized THCCOOH Tmax (h; range) |
|---|---|---|---|---|---|---|
| Smoked | ||||||
| 10 | 10.4 (0–58.7) | 5.9 | 4.8 (0–7) | 0.19 (0–0.56) | 0.10 | 3.8 (0–7) |
| 25 | 56.3 (0–334.1) | 10.0 | 3.9 (0–7) | 0.48 (0–2.88) | 0.23 | 4.1 (0–7) |
| Vaporized | ||||||
| 10 | 33.5 (3.6–114.4) | 31.0 | 4.4 (2–7) | 0.39 (0.05–1.31) | 0.37 | 4.1 (2–7) |
| 25 | 39.8 (3.4–146.0) | 25.7 | 5.4 (3–7) | 0.49 (0.16–1.44) | 0.36 | 4.1 (3–5) |
Note. The midpoint of the collection time period was used to quantify the time point for pooled specimen for Tmax calculations.
Mean detection time windows and individual ranges to first and last positive for THCCOOH in urine (cutoff = 15 ng/mL) are displayed in Table IV. On average, urinary THCCOOH concentrations peaked between 4 to 6 h after the end of the smoked and vaporized cannabis administration periods and began to decrease gradually thereafter. Positive THCCOOH specimens (i.e., ≥15 ng/mL) were observed for slightly longer in the 25 mg conditions compared with the 10 mg conditions. Specimens also tested positive (i.e., ≥15 ng/mL) for THCCOOH for longer after vaporized cannabis administration compared with the same dose of smoked cannabis (Table IV). Positive specimens (i.e., ≥15 ng/mL) were observed in 35% (12/34) of smoked sessions (10 mg: N = 4; 25 mg: N = 8) and 74% (25/34) of vaporized sessions (10 mg: N = 10; 25 mg: N = 15). Using federal workplace drug-testing criteria established by SAMHSA (IA cutoff of 50 ng/mL and GC/MS concentration ≥15 ng/mL), urine specimens tested positive for THCCOOH in 47% (16/34) of vaporized sessions and 21% (7/34) of smoked sessions with active THC doses. In the 0 mg THC smoked and vaporized conditions, no samples contained THCCOOH concentrations that exceeded 15 ng/mL.
Table IV.
Mean detection times and ranges of positive THCCOOH (≥15 ng/mL) urine specimens following inhalation of smoked and vaporized cannabis
| Dose (mg) | Time (h) | N |
|---|---|---|
| Smoked: Detection Time (h) to First Positive | ||
| 10 | 3.5 (2–5) | 4 |
| 25 | 3.0 (1–5) | 8 |
| Smoked: Detection Time (h) to Last Positive | ||
| 10 | 4.8 (3–7) | 4 |
| 25 | 5.0 (2–7) | 8 |
| Vaporized: Detection Time (h) to First Positive | ||
| 10 | 3.1 (2–5) | 10 |
| 25 | 4.9 (1–7) | 15 |
| Vaporized: Detection Time (h) to Last Positive | ||
| 10 | 5.5 (2–7) | 10 |
| 25 | 6.2 (4–7) | 15 |
Note: Positive THCCOOH concentration: ≥15 ng/mL. Sessions in which participants could not void after cannabis self-administration were not included in time to first detection analyses (see Table II). The midpoint of the collection time period was used to quantify the time point for pooled specimens.
As demonstrated in Figure 2, male participants exhibited qualitatively higher mean THCCOOH concentrations compared with females at both 25 mg THC doses. However, when normalized by creatinine, THCCOOH concentrations were only discordant across sex in smoked conditions (see Figure 2). There were no systematic sex differences observed in regards to THCCOOH urinary concentrations between smoked and vaporized cannabis.
Figure 2.
Quantitative mean THCCOOH (+SEM) urine concentrations before and for 8 h after inhalation of smoked and vaporized cannabis (25 mg THC) for nine male and eight female infrequent cannabis users. Data are presented in both absolute form (top panel) and normalized by creatinine (bottom panel).
Sensitivity, specificity, and agreement
Results of sensitivity, specificity, and agreement analyses between IA and GC/MS for THCCOOH in urine are summarized in Table V. Three separate IA values (20, 50 and 100 ng/mL) were compared to the GC/MS results (confirmation of positive test was always: ≥15 ng/mL). For both smoked and vaporized cannabis, sensitivity was highest at the 20 ng/mL cutoff and decreased substantially at the 50 and 100 ng/mL cutoffs while the opposite trend was observed for specificity results (i.e., highest specificity observed at the 100 ng/mL cutoff). For smoked conditions, agreement was similar at the 50 and 100 ng/mL cutoff, but for vaporized conditions, the highest agreement was observed at the 50 ng/mL cutoff. At the 100 ng/mL cutoff, higher sensitivity was observed in smoked, compared with vaporized, sessions. At the 20 ng/mL cutoff, higher specificity was also observed in smoked conditions compared to vaporized conditions. Agreement was generally higher in smoked conditions at each cutoff concentration. Agreement was higher for smoked cannabis conditions because there were more false positives in vaporized conditions at the 20 ng/mL IA cutoff, and because there were more false negatives in vaporized conditions at the 50 and 100 ng/mL cutoffs.
Table V.
Comparisons of immunoassay responses to confirmation analyses (GC/MS) in urine specimens following inhalation of smoked and vaporized cannabis containing 10 and 25 mg THC
| Urine THCCOOH IA (cutoff = 20 ng/mL) vs THCCOOH GC/MS (confirmation = 15 ng/mL) | Urine THCCOOH IA (cutoff = 50 ng/mL) vs THCCOOH GC/MS (confirmation = 15 ng/mL) | Urine THCCOOH IA (cutoff = 100 ng/mL) vs THCCOOH GC/MS (confirmation = 15 ng/mL) | |
|---|---|---|---|
| Smoked | |||
| #True Positive (%) | 25 (10.9) | 15 (6.5) | 11 (4.8) |
| #True Negative (%) | 162 (71.1) | 200 (87.7) | 203 (89.0) |
| #False Positive (%) | 41 (18.0) | 3 (1.3) | 0 (0.0) |
| #False Negative (%) | 0 (0.0) | 10 (4.3) | 14 (6.1) |
| N | 228 | 228 | 228 |
| % Sensitivity | 100.0 | 60.0 | 44.0 |
| % Specificity | 79.8 | 98.5 | 100.0 |
| % Agreement | 82.0 | 94.0 | 93.8 |
| Vaporized | |||
| #True Positive (%) | 54 (23.2) | 32 (13.7) | 15 (6.4) |
| #True Negative (%) | 111 (47.6) | 172 (73.8) | 178 (76.4) |
| #False Positive (%) | 67 (28.8) | 6 (2.6) | 0 (0.0) |
| #False Negative (%) | 1 (0.4) | 23 (9.9) | 40 (17.2) |
| N | 233 | 233 | 233 |
| % Sensitivity | 98.2 | 58.2 | 27.2 |
| % Specificity | 62.4 | 96.7 | 100.0 |
| % Agreement | 70.8 | 87.5 | 82.8 |
Note: 0 mg smoked and vaporized conditions were not included in sensitivity and specificity analyses.
Discussion
Urinary quantification of THCCOOH remains the primary means for detection of cannabis use in a variety of settings in which drug testing is performed. Prior controlled research on the pharmacokinetics of cannabis has focused predominantly on male frequent cannabis users who administer cannabis in a smoked form. Further characterization of the urinary excretion profile of THCCOOH across different types of cannabis users and methods of administration is important because accessibility to cannabis has increased substantially and alternative methods of cannabis administration such as vaporizers have become popular. The present study evaluated the urinary excretion profile of THCCOOH following smoked and vaporized cannabis administration among individuals who were infrequent cannabis users (i.e., no use for ≥ one month prior to participation).
In our prior report describing detailed whole blood and oral fluid results from this study, we described that vaporized cannabis produced higher blood cannabinoid concentrations compared to equivalent doses of smoked cannabis (21). Urinary excretion of THCCOOH followed the same trend, as qualitatively higher concentrations were generally observed following vaporized cannabis administration. For example, at the 25 mg THC dose, median Cmax concentrations in urine after inhalation of smoked and vaporized cannabis were 10.0 and 25.7 ng/mL, respectively. Though there were few statistically significant differences between smoked and vaporized cannabis conditions, the qualitatively higher THCCOOH concentrations observed following cannabis vaporization are clinically relevant and have important implications for drug testing outcomes. Notably, a much higher proportion of urine specimens collected during vaporized conditions had THCCOOH concentrations that exceeded 15 ng/mL, the confirmation cutoff widely used to identify cannabis exposure in various drug testing programs. Indeed, in 74% of vaporized sessions with an active dose of THC, THCCOOH concentrations for at least one specimen were ≥15 ng/mL in contrast to only 35% of smoked sessions. Additionally, each of the three IA screening tests used (i.e., cutoffs of 20, 50, and 100 ng/mL) detected more positive specimens during vaporized, as opposed to smoked, conditions. On average, THCCOOH was also detected for longer (i.e., remained ≥15 ng/mL) during vaporized conditions. Collectively, these findings suggest that individuals who use vaporizers to self-administer cannabis may be more likely to test positive for cannabis use compared with individuals who administer cannabis in a smoked form. However, additional controlled studies with larger sample sizes are needed to confirm this assertion, particularly given that other studies have failed to detect differences in blood and/or urine cannabinoid concentrations following smoked and vaporized cannabis administration (16, 19).
There are noteworthy differences between results from this study and prior studies that examined urinary excretion of THCCOOH after smoked cannabis administration with regular cannabis users. Although Tmax values for THCCOOH reported here were in accordance with prior controlled examinations of smoked cannabis (i.e., ~4–6 h after administration) (12), Cmax concentrations of THCCOOH were much lower in the present study. As depicted in Table III, mean Cmax THCCOOH concentrations ranged from 10.4 to 56.3 ng/mL in this study. Conversely, in other studies that administered similar doses of smoked cannabis (e.g., 16 mg and 27 mg THC) to frequent cannabis users, mean Cmax THCCOOH concentrations ranged from 90 to 179 ng/mL (11, 12). In addition, using current SAMHSA guidelines for workplace drug testing (i.e., positive IA response for 50 ng/mL cutoff with GC/MS concentration ≥15 ng/mL for THCCOOH), prior research has demonstrated that chronic cannabis users can produce positive urine samples for several weeks following abstinence from cannabis (6, 7). Conversely, in this study, using the same criteria, positive samples were only detected in 12% (4/34) of smoked sessions and 21% (7/34) of vaporized sessions at the 8 h post-cannabis administration urine collection point. In a study conducted by Brenneisen and colleagues (26), urinary excretion of THCCOOH was evaluated in 12 infrequent cannabis users (≤1 use in prior month) after administration of ~25 mg of smoked cannabis. Mean Cmax THCCOOH concentrations in that study were 15.3 ng/mL (range: 3.9–38.2 ng/mL) and peak concentrations were generally observed 4 to 8 h after cannabis administration, both of which are in line with findings from the present study. Additionally, 24 hours after cannabis administration, only one participant provided a urine specimen with a THCCOOH concentration ≥ 15 ng/mL (26). These collective findings suggest that, using current drug-testing guidelines, the window for detection of cannabis use for infrequent cannabis users is limited to 24 hours in most cases, and cannabis use may not be detected at all in some individuals.
Sensitivity, specificity, and agreement analyses were conducted between three THCCOOH IA tests (with cutoffs of 20, 50, and 100 ng/mL) and a confirmatory GC/MS cutoff of 15 ng/mL. Overall, these results are in accordance with findings from prior studies. For both smoked and vaporized conditions, sensitivity (i.e., the ability to detect true positive results) was highest at the 20 IA cutoff and lowest at the 100 IA cutoff, while specificity (i.e., the ability to detect true negative results) was highest at the 100 IA cutoff and lowest at the 20 IA cutoff. The 100 ng/mL IA cutoff had the worst sensitivity because it resulted in the highest number of false negatives, while the 20 ng/mL cutoff had the worst specificity because it resulted in the highest number of false positives. The IA cutoff of 50 ng/mL resulted in the highest agreement with confirmatory GC/MS results for both smoked and vaporized cannabis, supporting the continued use of these cutoff concentrations for workplace drug testing. Interestingly, there was better agreement between IA and GC/MS during smoked conditions due to a higher false positive rate at the 20 ng/mL IA cutoff and higher false negative rates at the 50 and 100 ng/mL cutoffs in vaporized cannabis conditions.
Notably, as with other studies (10–12, 16), urinary excretion of THCCOOH was extremely variable across participants. Despite all participants receiving the same THC doses, THCCOOH was not detected at all for several participants while for others, concentrations were commensurate with that of experienced cannabis users after administration of higher doses (e.g., 34 mg THC) (11). Windows of detection for positive urine specimens also varied considerably between participants. Future research should attempt to identify factors that may drive such inter-individual variability in cannabis pharmacokinetics including age, sex, BMI, genetics, and puffing behaviors such as inhalation depth and puff duration.
This study had several limitations. First, the collection window for urine in this study (i.e., 8 h) was much shorter than other studies that have measured urinary excretion of THCCOOH. Indeed, as mentioned above, positive specimens were provided at the last collection time point in 16% (11/68) of non-placebo sessions. Future studies should compare the urinary pharmacokinetics of smoked and vaporized cannabis over longer periods of time in order to fully characterize the excretion profile of THCCOOH. The use of only one chemovar of cannabis (high in THC and low in CBD), one type of vaporizer, and the limited sample size (e.g., only non-smokers) further limit the generality of the results of this study.
Conclusion
THCCOOH urinary concentrations were generally lower, with shorter detection windows, following acute administration of both smoked and vaporized cannabis for these infrequent cannabis users than in prior studies that enrolled frequent cannabis users. THCCOOH concentrations were qualitatively higher after administration of vaporized cannabis compared with equal doses of smoked cannabis. The highest agreement between IA and GC/MS was observed at the 50 ng/mL IA cutoff while sensitivity and specificity were highest at the 20 and 100 ng/mL IA cutoffs, respectively. Using federal workplace drug-testing criteria (IA cutoff of 50 ng/mL and GC/MS concentration ≥15 ng/mL) urine specimens tested positive in 47% (16/34) of vaporized sessions and 21% (7/34) of smoked sessions. As more individuals obtain legal access to cannabis and cannabis products and administration methods continue to proliferate, additional pharmacokinetic characterizations of cannabis will be necessary to inform and refine procedures for detection of cannabis use.
Acknowledgments
We thank the support staff of the Johns Hopkins University Behavioral Pharmacology Research Unit for outstanding contributions to the implementation of this study. We also thank the many individuals involved with the NIDA Drug Supply Program for providing their services and cannabis for the conduct of this study. We also thank David Kuntz from the Clinical Reference Laboratory (CRL) for performing analytical testing for this study.
Funding
This research was supported by the Substance Abuse and Mental Health Services Administration (SAMHSA) and the National Institute on Drug Abuse (NIDA; T32DA07209).
Conflict of interest
Dr. Vandrey has served as a consultant or received honoraria from Zynerba Pharmaceuticals, Insys Therapeutics, Battelle Memorial Institute, and Canopy Health Innovations Inc. The remaining authors have no other conflicts of interest to declare.
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