Pharmacokinetics Clinical Trial
Official title:
Effects of Sativex(Registered Trademark) and Oral THC on Attention, Affect, Working Memory, Reversal Learning, Physiology and Brain Activation
Background:
- The therapeutic modalities of cannabis have received more research attention recently
with the discovery of its ability to stimulate appetite and to provide pain and nausea
relief in patients with AIDS, cancer, and multiple sclerosis, among other diseases.
Sativex(Registered Trademark), an experimental drug derived from the marijuana plant,
contains tetrahydrocannabinol (THC) and cannabidiol (CBD), both of which affect brain
activity. Sativex(Registered Trademark) is being tested to determine how and to what
extent it affects brain activity.
- Functional magnetic resonance imaging (fMRI) uses magnetic waves to study brain
activity. Researchers are interested in using fMRI to study how Sativex(Registered
Trademark) affects regional brain activity, including thinking abilities and behavior.
Objectives:
- To study changes in regional brain activity produced by Sativex(Registered Trademark)
compared with THC and placebo.
- To determine how Sativex(Registered Trademark) is processed by the body.
Eligibility:
- Individuals between 18 and 45 years of age who are either current users of cannabis (less
than daily) or healthy volunteers who do not use cannabis.
Design:
- The study will involve one training session and five testing sessions on separate days.
- At every session, subjects will receive either THC or placebo capsules and either
Sativex(Registered Trademark) or placebo spray.
- Participants will complete a training session in a mock fMRI scanner to adapt to the
fMRI scanning environment. In the training session, participants will practice the tests
that will track thinking ability, attention, working memory, and other cognitive tasks.
- Participants will have five fMRI scanning sessions with the tests they have practiced
previously, and will provide blood, urine, and saliva samples as required by the
researchers. Participants will be discharged approximately 12 hours after they arrive
for the study sessions....
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.
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