Oral Fluid, Plasma and Whole Pharmacokinetics and Stability Following Smoked Cannabis

Background: Smoking is the most common route of cannabis administration, yet the
pharmacokinetic properties of cannabinoids in oral fluid following cannabis smoking have not
been adequately characterized. Characterization of cannabinoid pharmacokinetics in oral
fluid, correlations between concentrations in different matrices and relationships between
biomarker concentrations and concurrent pharmacodynamic effects are critical for the
appropriate interpretation of cannabinoid tests. Furthermore, the short- and long-term
stability of cannabinoid biomarkers, including glucuronide conjugates, in authentic whole
blood, plasma, and oral fluid specimens following cannabis smoking is poorly defined. The
only stability data available are from fortified samples, rather than authentic specimens.

Objectives: Part A: (1) Characterize cannabinoid ( -9-tetrahydrocannabinol, [THC];
11-hydroxy-THC, [11-OH-THC]; 11-nor-9-carboxy-THC, [THCCOOH]; and their Phase II conjugates)
pharmacokinetics in whole blood, plasma, oral fluid and urine following a single smoked dose
of cannabis. (2) Determine inter-matrix cannabinoid ratios in authentic specimens following
controlled smoked cannabis (3) Correlate cannabinoid concentrations in whole blood, plasma
and oral fluid with impairment and risk-taking behavior as determined through subjective
assessments, risk-behavior trait assessments and neurocognitive tasks. (4) Determine
stability over time of free and conjugated cannabinoids in authentic whole blood, plasma, and
oral fluid from cannabis users following a single smoked dose of cannabis under various
storage conditions. (5) Characterize the sensitivity, specificity, efficiency and duration of
detection of cannabinoids with the Draeger DrugTest 5000 after a single smoked dose of
cannabis.

Part B: Characterize cannabinoid pharmacokinetics in whole blood, plasma, oral fluid, breath,
and urine following a single smoked dose of cannabis. (2) Characterize the sensitivity,
specificity, accuracy and length of detection of cannabinoids with the Draeger DrugTest 5000
after a single smoked dosed of cannabis. (3) Determine inter-matrix cannabinoid ratios in
authentic specimens following controlled smoked cannabis. (4) Correlate cannabinoid
concentrations in whole blood, plasma, breath, and oral fluid with impairment as determined
through subjective assessments and neurocognitive tasks. (5) Determine stability over time of
free and conjugated cannabinoids in urine from cannabis users following a single smoked dose
of cannabis under various storage conditions.

Subject Population: Up to 50 healthy cannabis users aged 18-45 will be recruited for the
study. In Part A, 10 completers with an average frequency of use of at least twice per month
in the three months prior to study are required. In Part B, 10 occasional cannabis smokers
with an average frequency of less than twice per week in the past three months and 10 chronic
frequent cannabis smokers with an average frequency at least four times per week in the past
three months are required.

Experimental Design and Methods: In parts A and B, participants smoke one standardized NIDA
THC cigarette during a single visit. Serial blood and oral fluid collections (part A and B)
and breath collections (part B only), and assessment of neurocognitive, physiological and
subjective effects are performed once prior to and multiple times after smoking.

Outcome Measures: Primary outcome measures for part A include cannabinoid concentrations in
whole blood, plasma, and oral fluid, stability of these concentrations over time, performance
on neurocognitive tasks, and subjective assessments. Primary outcome measures for part B
include cannabinoid concentrations in whole blood, plasma, breath, and oral fluid, evaluation
of the DrugTest 5000 and correlation of cannabinoid breath concentration with performance on
neurocognitive tasks and subjective assessments. An outcome measure for subsequent occasional
smoker participants after the 9th completer is stability over time of cannabinoid
concentrations in whole blood and plasma collected in gray-top Vacutainer tubes containing
sodium fluoride and potassium oxalate.

Benefits: There is no direct benefit to participants, but the study is likely to yield
generalizable knowledge regarding cannabinoid pharmacokinetics, and pharmacodynamics for both
Part A and Part B.

Risks: Participation in this study represents more than minimal risk for both Part A and Part
B because of the administration of smoked cannabis.

- INCLUSION CRITERIA:

1. 18 to 45 years of age;

2. Cannabis use with a minimum frequency of at least twice per month during the
three months prior to study entry for Part A or average frequency of cannabis
smoking of less than twice per week (occasional cannabis smoker) in the past 3
months or at least four times per week (chronic frequent cannabis smoker) in the
past 3 months for Part B;

3. A positive urine cannabinoid screen if in the chronic frequent cannabis smoker
group;

4. Peripheral veins suitable for repeated venipuncture and/or placement of an
intravenous catheter;

5. Blood pressure (BP) and heart rate (HR) at or below the following values while
sitting after five min rest: Systolic BP (SBP) 140 mm Hg, diastolic BP (DBP) 90
mm Hg, heart rate (HR) 100 bpm;

6. ECG and three-minute rhythm strip without clinically relevant abnormalities;

EXCLUSION CRITERIA:

1. History or presence of any clinically significant illness, as detected by history,
physical examination, and/or laboratory tests, that might put the subject at increased
risk of adverse events;

2. History of a clinically significant adverse event associated with cannabis
intoxication;

3. Donation of more than 450 mL of blood within 30 days of study drug administration;

4. If female, pregnant or nursing;

5. Currently interested in or participating in drug abuse treatment, or participated in
drug abuse treatment within 60 days preceding study enrollment.