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


Phase 1
18 Years
45 Years
Not Enrolling
Both
Cannabis, Dependence, Cannabis Abuse, Pharmacokinetics, fMRI

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Trial Information

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.

Inclusion Criteria


- Eligibility Criteria for Cannabis Users

INCLUSION CRITERIA:

1. 18 to 45 years of age;

2. Cannabis use with a minimum frequency of once in the last 90 days and maximum
frequency of less than daily during the three months prior to study entry;

3. 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;

4. 12-lead standard ECG and three-minute rhythm strip without clinically relevant
abnormalities;

5. Peripheral veins suitable for repeated venipuncture and placement and maintenance of
an IV catheter;

6. Ability to swallow capsules;

7. Ability to communicate well with the investigators and to comply with study
requirements;

8. If female with reproductive potential, must be using a reliable method of birth
control or abstaining from vaginal sexual intercourse;

9. Estimated IQ greater than or equal to 85 determined by the Wechsler Abbreviated Scale
of Intelligence;

10. Right-handed.

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 or that might interfere with the absorption,
distribution, metabolism, or excretion of study drugs. Clinically significant is
defined as being likely to affect the safety of the subject during his/her
participation in this trial, or preclude achievement of the protocol objectives.

2. Current tolerance to any substance other than nicotine or caffeine;

3. Positive serological tests for syphilis or HIV infection;

4. Positive purified protein derivative (PPD) test in the absence of a negative chest
X-ray;

5. History of a clinically significant adverse event associated with cannabis
intoxication or withdrawal;

6. History of epileptic seizures or head trauma with loss of consciousness greater than
three min;

7. History of psychosis or any current DSM-IV axis I disorder (other than caffeine or
nicotine dependence, or simple phobia);

8. Family history of psychosis (except that related to acute drug intoxication) in a
first-degree relative;

9. Donation of more than 500 mL of blood within 30 days of study drug administration;

10. Regular use of alcohol (greater than or equal to five standard drinks per day) four
or more times per week in the month prior to study entry;

11. If female, pregnant or nursing;

12. ADHD Screening Rating Scale score greater than or equal to 24 on either the A or B
subscale;

13. Allergy to sesame seed oil (ingredient in dronabinol capsules), propylene glycol,
ethanol, or peppermint oil (ingredients in Sativex(Registered Trademark));

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

15. Claustrophobia that precludes being able to tolerate an fMRI session.

16. Magnetizable metal on or within the body that cannot be removed.

Eligibility Criteria for Controls

The goal of the eligibility criteria for control subjects is to obtain a group
approximately comparable to the cannabis users in terms of age, sex, ethnicity, tobacco
use, and intelligence.

INCLUSION CRITERIA:

1. 18 to 45 years of age;

2. BP and HR at or below the following values while sitting after five min rest: SBP 140
mm Hg, DBP 90 mm Hg, HR 100 bpm;

3. Ability to communicate well with the investigator and to comply with study
requirements;

4. If female with reproductive potential, must be using a reliable method of birth
control or abstaining from vaginal sexual intercourse;

5. Estimated IQ greater than or equal to 85 determined by the Wechsler Abbreviated Scale
of Intelligence;

6. Right-handed.

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. Clinically significant is defined as being likely to affect
the safety of the subject during his/her participation in this trial, or preclude
achievement of the protocol objectives.

2. A positive urine test for any illicit drug at any time during screening or study
participation;

3. Current physical dependence on any substance other than nicotine or caffeine;
Self-reported lifetime use of any illicit drug other than cannabis; Self-reported
lifetime use of cannabis greater than ten times, or use within the last year;

4. Positive serological tests for syphilis or HIV infection;

5. History of epileptic seizures or head trauma with loss of consciousness greater than
three min;

6. History of psychosis or any current DSM-IV axis I disorder (other than caffeine or
nicotine dependence, or simple phobia);

7. Regular use of alcohol (greater than or equal to five standard drinks per day) four
or more times per week in the month prior to study entry;

8. If female, pregnant or nursing;

9. ADHD Screening Rating Scale score greater than or equal to 24 on either the A or B
subscale;

10. Claustrophobia that precludes being able to tolerate an fMRI session;

11. Magnetizable metal on or within the body that cannot be removed.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Double-Blind

Outcome Measure:

Pharmacokinetics/Pharmacodynamics

Authority:

United States: Federal Government

Study ID:

999907423

NCT ID:

NCT01037608

Start Date:

May 2007

Completion Date:

December 2011

Related Keywords:

  • Cannabis
  • Dependence
  • Cannabis Abuse
  • Pharmacokinetics
  • fMRI
  • Sativex
  • fMRI
  • Alternative Matrices
  • Brain Imaging
  • THC
  • Marijuana Abuse

Name

Location

National Institute on Drug Abuse, Biomedical Research Center (BRC)Baltimore, Maryland  21224