Effects of Cannabis Administration Routes on Human Performance and Pharmacokinetics

Objectives

Cannabinoids are most commonly administered via smoking. Oral consumption in medications,
teas, oils, or food also is widely utilized. Additionally, cannabis vaporization followed by
inhalation for medical and illicit administration is common. Differences in cannabis
pharmacodynamics and pharmacokinetics between these three administration routes and in
occasional and frequent cannabis smokers are not thoroughly characterized. This study
evaluates cannabis pharmacodynamics and pharmacokinetics in occasional and frequent smokers
after smoked, vaporized, and oral cannabis administration.



Study Population

Up to 80 healthy cannabis smokers, aged 18-50, without a history of adverse reactions to
cannabis will be recruited. For dosing sessions 1-4, ten occasional smokers (smoking
frequency greater than or equal to 2 times/month but <3 times/week) and ten frequent smokers
(smoking frequency generally greater than or equal to 5times/week) are required. For the
optional 5th session, 8-20 participants (regardless of smoking history) are required.



Study Design

Occasional and frequent cannabis smokers are recruited to participate. Prior to dosing
sessions, there is a training visit for all study procedures. Sessions 1-4 are 3 and 4 days
each for occasional and frequent cannabis smokers, respectively, and the study design is
double blind, double dummy, randomized, crossover, and placebo-controlled. In each session,
participants will consume a placebo or active oral (baked in a brownie) cannabis (6.9%
9-tetrahydrocannabinol [THC]) dose followed by either placebo or active smoked or vaporized
cannabis. Only one active dose will be administered in each dosing session. Whole blood, oral
fluid, urine, dried blood spots, and breath are collected throughout all sessions. Due to the
large THC body burden stored in the tissues, we will collect biological specimens for a
longer period in frequent cannabis smokers than for occasional cannabis smokers. An optional
5th dosing session will be offered in which participants receive a single oral cannabis dose
for pharmacokinetic monitoring. The placebo cannabis plant material has a low THC
concentration. As we are expecting that the active brownie dose might result in low THC oral
fluid contamination, it is necessary to have an active brownie THC dose that is not followed
by placebo vaporizer or smoked cannabis. Occasional smokers may stay or be discharged between
sessions, including between the 4th and optional 5th dosing session, but dosing must not
exceed self-reported intake frequency. Frequent smokers must be discharged for at least 72 h
between dosing sessions 1-4, and must stay on the unit at the end of session 4 for session 5
if they choose to participate. The difference between requirements for occasional and
frequent smokers to participate in the optional 5th dose is due to the potential confound of
low THC concentrations in frequent smokers that might not permit the detection of low THC
concentrations after consumption of a low oral THC dose. Occasional cannabis smokers will
reside on the closed research unit for approximately 72 h for dosing sessions 1-4, and for
approximately 66 h for dosing session 5. Frequent cannabis smokers will reside on the closed
research unit for approximately 90 h for dosing sessions 1-3 (and 4 if not participating in
optional session 5). If a frequent smoker chooses to participate in dosing session 5, they
will remain on the unit for approximately 162 h for sessions 4 and 5. Participants will
complete a battery of subjective, objective, and neurocognitive tests before and after
dosing. Subjective effects are assessed with visual analog scales. Objective measurements
include physiological measurements, expired carbon monoxide, reddening of the conjunctivae
and tests measuring psychomotor skills and cognitive functions.



Outcome Parameters

Primary outcome measures include subjective and objective assessments, performance on
neurocognitive tasks, and cannabinoid concentrations in whole blood, oral fluid, urine, dried
blood spots, and breath. Correlations between cannabinoid concentrations in whole blood,
dried blood spots, oral fluid, and breath will be investigated, the Oral Fluid Working Group
for the Partnership for Clean Competition oral fluid screening algorithm will be evaluated,
and the pharmacokinetic profiles of alternative cannabinoids will be characterized. Secondary
investigations include comparing cannabinoid stability in dried blood spots and whole blood,
evaluating the World Anti-Doping Agency urine 11-nor-9-carboxy-THC decision limit,
characterizing the performance of the Alere DDS2 on-site oral fluid screening device, and
evaluating effects of acute cannabis administration on leptin and other appetitive
peptides.

- INCLUSION CRITERIA:

1. 18 to 50 years of age;

2. Cannabis consumption with a minimum frequency of at least twice per month during
the three months prior to the study and average frequency of cannabis smoking of
less than three times per week (occasional cannabis smoker) in the past 3 months
or at least an average of five times per week (frequent cannabis smoker) in the
past 3 months;

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

4. Peripheral veins suitable for repeated venipuncture and/or placement of an
intravenous catheter, as assessed by a physician s assistant, nurse, or
physician;

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;

7. Women with reproductive potential must use a medically acceptable form of
contraception for the duration of the study. Medically acceptable forms of
contraception include: oral contraceptive, intrauterine device (IUD), depot
hormonal preparation (ring, injection implant), or a barrier method of
contraception such as a diaphragm, sponge with spermicide, or a condom.
Abstinence is an alternative lifestyle and subjects practicing abstinence may be
included in the study.

8. Must be able to safely suspend use of CNS depressant, anticholinergic, and/or
sympathomimetic medications before study dosing. Length of medication suspension
will be equal to 3 half-lives of the medication in use.

EXCLUSION CRITERIA:

1. Current physical dependence on any drug other than cannabis, caffeine, or nicotine;

2. Currently using cannabis for medical purposes under the explicit recommendation of a
physician providing medical care;

3. 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 such as history of psychotic disorder, clinically
significant mood and/or anxiety disorder, diabetes, liver, renal or cardiovascular
disease;

4. Liver enzymes greater than or equal to 2 times upper normal limit and/or clinical
signs/symptoms consistent with liver disease including but not limited to nausea,
vomiting, jaundice, itching, abdominal pain, and swelling;

5. History of clinically significant adverse events associated with cannabis intoxication
such as severe anxiety and panic, paranoia and psychosis, sustained tachycardia, or
severe hypotension;

6. Donation of more than 450 mL blood within 8 weeks of study treatment phase;

7. Hemoglobin less than 12.0 g/dL and/or clinical signs/symptoms consistent with anemia
including but not limited to fatigue, tachycardia, shortness of breath, and dizziness;

8. If female, pregnant or nursing;

9. Currently interested in or participating in drug abuse treatment, or participated in
drug abuse treatment within 90 days preceding study enrollment;

10. History of food allergy or sensitivity to gluten, dairy, egg, soy, and/or chocolate.

11. Any form of color blindness