Effects of Sativex(Registered Trademark) and Oral THC on Attention, Affect, Working Memory, Reversal Learning, Physiology and Brain Activation

Background: Cannabis sativa contains over sixty cannabinoids, including
delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD lacks psychoactivity and may
attenuate the subjective effects produced by THC. The ratio of THC:CBD in illicit cannabis
in the US is approximately 20:1. Sativex(Registered Trademark), a whole-plant cannabinoid
extract oromucosal spray, contains THC and CBD in a ratio of nearly 1:1. It was approved by
Health Canada in 2005 as a prescription medication for neuropathic pain in multiple
sclerosis (MS) and will be evaluated in Phase III trials in the U.S. in patients with
advanced cancer for the treatment of pain refractory to opiates. No studies have examined
changes in regional brain activity with functional magnetic resonance imaging (fMRI) during
completion of cognitive tasks or affective measures after administration of
Sativex(Registered Trademark).

Objective: 1) To characterize physiological and affective condition, subjective state,
cognitive performance, and concomitant changes in activation of specific brain regions
(blood oxygen level-dependent [BOLD] signal) with fMRI after oromucosal administration of
Sativex(Registered Trademark) and oral administration of THC. 2) To characterize the
pharmacokinetics of THC and CBD and metabolites in plasma, urine, and oral fluid.

Subject Population: 18 healthy controls and 18 healthy cannabis users, 18 - 45 years old,
with no current major psychiatric disorders except nicotine or caffeine dependence.
Non-dependent substance use is allowed for cannabis users. Cannabis using participants must
have used cannabis with an average frequency of at least once in the last 90 days and
maximum frequency of less than daily during the three months prior to study entry.
Enrollment target, based on national population of adult current cannabis users and the
Baltimore City Department of Planning 2000 census, is 65% male, 35% female; 64% African
American, 32% Caucasian, 4% other; and 9% Hispanic and 91% non-Hispanic.

Experimental Design and Methods: This randomized, double blind, double-dummy,
placebo-controlled, within- and between-subject study evaluates the effects of oral THC and
oromucosal administration of Sativex(Registered Trademark) on brain activation and
subjective, affective, cognitive, and physiologic measures. Cannabis users undergo a
thorough medical, psychiatric (including structured diagnostic interview), and psychosocial
(including Addiction Severity Index) evaluation. They enter the research unit the morning of
the dosing/scanning session. Each cannabis-using participant receives, in random order,
synthetic THC 5 mg, synthetic THC 15 mg, two actuations of Sativex(Registered Trademark)
(5.4 mg THC and 5.0 mg cannabidiol), six actuations of Sativex(Registered Trademark) (16.2
mg THC and 15.0 mg cannabidiol), and placebo. There is an interval of at least five days
between dosing sessions. Physiological, psychological, and behavioral measures are
monitored throughout the study to determine onset, magnitude, and duration of effects and to
correlate with THC and cannabidiol pharmacokinetics. Changes in BOLD signal in multiple
brain areas are determined with five fMRI scans during the completion of cognitive tasks and
affective measures after cannabinoid and placebo administration. Eighteen controls undergo
neuroimaging, psychological, and behavioral monitoring as do cannabis users to control for
practice effects. Primary outcome measures include changes in physiologic effects,
subjective effects, BOLD signal, affect, and cognitive task performance in relation to THC,
CBD, and metabolites plasma concentrations. Secondary objectives are to monitor the
disposition of THC, CBD, and metabolites in plasma, urine, and oral fluid. Primary
statistical analysis for changes in affect, cognitive performance, and physiologic and
subjective effects is a within-subject analysis of variance (ANOVA) (or equivalent
analysis). Changes in BOLD signal determined by fMRI are compared between groups and dosing
conditions using repeated-measures ANOVA. Based upon power analyses, we estimate needing 18
cannabis users and 18 controls to complete the experiment.

Risks and Benefits: Potential risks are those associated with administration of
cannabinoids, but proposed doses have proven safe and well tolerated in other studies. The
most common side effects from the oromucosal administration of Sativex(Registered Trademark)
include dry mouth, dizziness, application site discomfort, fatigue, somnolence, nausea, and
diarrhea. Side effects resulting from oral THC administration include sedation, cognitive
impairment, euphoria, poor coordination, tachycardia and hypotension. There are no clinical
benefits to participants. Likely scientific benefits are greater understanding of the role
of cannabidiol in modifying the impact of THC on cognitive performance, affective condition,
subjective state, physiological condition, and brain activation.