EFFFECTS OF CHRONIC MARIJUANA USE AND

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EFFFECTS OF CHRONIC MARIJUANA USE AND THC ON
BRAIN FUNCTION IN HUMANS AN FMRI STUDY
Alan S. Bloom, Ph.D. Medical College of Wisconsin
APA 2004
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• PROBLEM
• The frequent use of marijuana by young people in
  our society continues to be a problem. It is the
  illicit drug that is most commonly used by youths
  today.
• Anatomically, the distribution of CB1 cannabinoid
  receptors in the animal and human brain is well
  described. High densities of receptors are
  located in hippocampus, cerebellum, cortex,
  substantia nigra, globus pallidus and other
  striatal regions. Receptor density is low in
  hypothalamus and lower brainstem.
• In general, the distribution of receptors in
  the brain is reasonable, if we take into account
  the known pharmacological actions of marijuana.
  They are found in areas associated with memory,
  coordination, attention and endocrine regulation.
• The goal of this research is to elucidate sites
  of action of ?9-tetrahydrocannabinol (THC), the
  major psychoactive constituent of marijuana, in
  the human brain and to determine those sites that
  are related to the drugs psychoactive properties
  and cognitive effects.

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MARIJUANA (THC) EFFECTS

• Euphoria
• Memory Impairment
• Perceptual-Motor alterations
• Cardiovascular
• Pulmonary
• Reproductive
• Psychopathological Effects

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CB1 Receptor Distribution and Functional Areas

• High density in brain areas concerned with
  memory, cognition, motor coordination and reward

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CANNABIS AND HUMAN BRAIN IMAGING

• Volkow et al. (1996)- PET - iv THC -brain glucose
  metabolism in chronic marijuana users. Prior to
  drug administration, chronic users showed lower
  relative cerebellar metabolism than normal
  control subjects. THC iv (2 mg) increased
  relative cerebellar metabolism in both chronic
  users and controls, but only chronic users showed
  increases in orbitofrontal cortex, prefrontal
  cortex and basal ganglia.
• Mathew - effects of THC on CBF - 15O-PET - THC (3
  to 5 mg iv, over 20 min) increased CBF in the
  frontal regions bilaterally, insula and cingulate
  gyrus and subcortical regions -somewhat greater
  effects in the right hemisphere. The increase in
  blood flow correlated with the subjective sense
  of intoxication.
• ? OLeary (2000, 2002, 2003) examined the effects
  of smoked marijuana on task activation measured
  using 15O-PET. They reported that smoked
  marijuana produced no change in whole brain blood
  flow. However, significantly altered activation
  by a dichotic listening task in multiple brain
  regions was observed after smoking marijuana. In
  general, this occurred in the absence of
  significant decreases in task performance.
  Overall, they reported increased rCBF in
  anterior brain paralimbic regions and cerebellum
  that may be related to marijuana effects on mood
  and reduced rCBF in auditory and visual sensory
  regions and other regions that may be involved in
  attention. They proposed that decreases in these
  regions may be involved in the perceptual and
  cognitive effects of marijuana.

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AIMS

• To quantify ?9-THC action using BOLD imaging to
  determine its pharmacodynamic properties within
  the human brain and to relate them in time and
  intensity to observed physiological and
  behavioral actions of intravenous ?9-THC.
• To determine the ability of ?9-THC and frequent
  marijuana use to alter functional brain activity
  using perceptual-motor and cognitive tasks that
  activate specific brain regions containing
  cannabinoid receptors as experimental probes.

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METHODS SUBJECTS Right-handed subjects, ages
19 to 45 years, were recruited using newspaper,
radio and television advertisements and gave
informed consent to this IRB-approved study prior
to participation. Handedness was assessed using
the Edinburgh Inventory (Oldfield, 1971).
THC-using subjects were experienced heavy
marijuana users with at least one year of current
use (average use 15 times/month). They were
all generally healthy based upon history and
physical examination and were not currently
symptomatic of any major psychiatric disorder nor
currently using any abuse substance other than
cigarettes, alcohol or marijuana. Subjects in
the control group were not current or recent
marijuana users and met all other inclusion
criteria. Subjects presented to the General
Clinical Research Center at the Medical College
of Wisconsin, received a physical examination, a
urine screen for drugs of abuse (Triage) and
blood tests for pregnancy, HIV, hepatitis, liver
function and CBC. All subjects that met the
inclusion criteria agreed to receive up to 3
doses (O.5, 1.0 3.0 mg.) of THC or ethanol
vehicle as described by Volkow (1996) while
undergoing functional MR imaging. Each injection
was given on a separate day.
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Behavioral Ratings

• Administered doses are rated behaviorally
  effective by experienced marijuana users similar
  to those used in a social setting and produce a
  dose-related increase in HR.
• Data obtained during scanning should reflect
  changes similar to those experienced socially.

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Pharmacokinetic Principles

• There are time-related changes in drug
  concentration within the circulation and body
  compartments. They are measurable, predictable
  and well known for most drugs.
• Plasma pharmacokinetics consist of a distribution
  phase (absorption) and an elimination phase
  (redistribution/metabolism) that follows first
  order kinetics and can be modeled as the
  difference of 2 exponentials, one rate constant
  for the absorption phase and another for the
  elimination phase.

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INJECTION
40 MIN
INJECTION
Non-linear curve fitting model used to determine
drug effects and representative voxel time
courses for positive and negative change in BOLD
signal (kin - 2 to 10 min kout - 30 to 120 min)
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Effects of THC on Brain Activity
0.5 and 1.0 mg. THC 3.0 mg THC Negative changes
in AUC Positive changes in AUC Superior temporal
gyrus right anterior cingulate middle frontal
and precentral gyrus superior middle and
inferior anterior cingulate frontal
gyrus insula bilateral posterior
cingulate Cerebellum caudate N.
Accumbens Positive changes in AUC middle frontal
gyrus Negative changes in AUC posterior
cingulate superior temporal cortex globus
pallidus insula left caudate
cerebellum N. Accumbens
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3 MG. THC
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NUCLEUS ACCUMBENS

• The reinforcing (rewarding) properties of THC are
  controversial.
• Although it is readily self-administered by
  humans, this is not always the case in other
  species including primates and rodents.
• A body of work by Gardner has demonstrated clear
  reinforcing properties of THC in an appropriate
  rat strain.
• We focused down on THCs effects in the n.
  accumbens due to this regions association with
  the reinforcing properties of abuse substances.

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0.5 mg
1.0 mg
EFFECTS OF THC ON ACTIVITY WITHIN N.
ACCUMBENS Subjects were injected with 0.5, 1, or
3 mg of THC. Colorized areas represent those
voxels in which mean percent area under the curve
was greater than the null hypothesis at plevel.
3.0 mg
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Effects of THC on activation in the n. accumbens.
Activation was determined by making a combined
(OR) mask of the activations produced by all
three doses in the accumbens. That mask was then
used to to describe a functional region in which
the mean percent area under the time-effect curve
was calculated for each subject. Values shown
are the mean the SEM. P0.05 compared to
vehicle, p0.05 compared to other doses.
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Task Activation Data Analysis

• Data from each task were analyzed using a phase
  shifted input function representing the on/off
  active-rest pattern of task presentation.
• Activation intensity was calculated for each
  pixel by dividing the mean signal intensity
  during the active periods by the mean intensity
  during the "rest" periods.
• The resultant functional images were averaged
  across all subjects for each task to produce mean
  activation maps for each condition.
• Areas of significant activation were determined
  for the group on a voxel by voxel basis using a
  one sample, 3-D t-test against the null
  hypothesis of no change and a minimum cluster
  size of 300µ1.
• Comparisons between pre- and post-drug activation
  were made by determining the mean task activation
  within functional and standard brain region masks
  (AFNI).

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CONCEPT FORMATION TASK
Based on a task described by Levine (1966),
tests for concept formation and working memory by
asking the subject to make choices based on rules
of selection that they must deduce. Four
variables are used Color (RED vs. BLUE), Size
(BIG vs. SMALL), Letter (X vs. T) and Position
(LEFT vs. RIGHT). Pairs of letters with these
attributes are presented sequentially to the
subject who must choose one of the 2 options. The
subject is then given feedback by the computer
with correct or wrong appearing on the screen.
This continues for 4 presentations at which time
the subject should have all the information to
make the correct final determination of the sort
criteria. Each sequence of 4 screens can be
solved in 30 sec and is followed by a 30 sec rest
period. This rest-task cycle is repeated 7 times
in each imaging run.
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This task is modeled after a task that was
described by Cohen (1993). The 2-back VSWM task
presents fifteen outline squares, arranged in a
pseudorandom fashion on the screen. During each
30 sec task block, one of the squares turns black
sequentially every 1.5 sec in a random order. The
subject is instructed to press a button if the
same square is filled in black twice, separated
by any other one square (i.e. a two-back working
memory task). A 30 sec 'rest' period where only
a central fixation cross was presented alternates
with each 30 second active period.
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PARTICIPANT DEMOGRAPHICS
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Effects of 1 mg of ?9-THC on task performance
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CF TASK
Pre-Drug
Post-Drug
Effects of iv THC (1 mg) on activation by a
concept formation task. Colorized areas
represent those voxels in which the mean task
activation was greater than 0.5 and was
significantly different from the null hypothesis
of no activation (p0.01). Oranges represent
positive and blues negative activation.
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CONCEPT FORMATION TASK
Re-Drug Activations Post Drug Decreases or L
R post parietal cortex lack of significant
SMA activation Cingulate (BA
32) middle front gyrus/DEPFC LR premotor (BA6)
cortex post-parietal L R premotor (BA6)
cortex SMA R MFG including DLPFC (BA 46,
10) cingulate L MFG thalamus R L lateral
occipital cortex (BA 18, 19) pons R.
Thalamus cerebellum L R cerebellum including
declive, culmen and vermis New area negative
activation pons posterior cingulate Negative
activation ant. cingulate (BA 32)
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VSWM TASK
Pre-Drug
Post-Drug
Effects of iv THC (1 mg) on activation by a
visuospatial working memory task. Colorized
areas represent those voxels in which the mean
task activation was greater than 0.5 and was
significantly different from the null hypothesis
of no activation (p0.01). Oranges represent
positive and blues negative activation.
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VISUOSPATIAL WORKING MEMORY TASK
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MOTOR TASK Bilateral Finger Tapping
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• RESULTS AND CONCLUSIONS
• The 1 mg dose of THC produced a moderate
  marijuana-like high. Performance (accuracy and
  reaction time) on the CF AND VSWM task was not
  affected by this dose of THC.
• THC administration decreased brain activation
  induced by each of the tasks. The effect was
  greater on the CF task than the VSWM task. The
  effects of THC on the finger tapping task were
  time-dependent. Both motor and visual cortex
  activations were significantly decreased at 15
  minutes after drug administration. There was a
  significant return of activation at 35 minutes.
• Overall, these data suggest that THC can decrease
  brain activation induced by cognitive and simple
  motor tasks and the effect is greater on a task
  with higher cognitive demands. The decreases in
  activation were not associated with decreased
  task performance. However, it is possible that
  this could change with higher doses of THC or
  tasks of greater difficulty. Possible
  explanations for the observed decreases in task
  activation include receptor mediated drug-induced
  alterations in neurovascular coupling or drug
  related behavioral mechanisms.

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SUMMARY
We have detected THC-induced changes in both fMRI
signal (neuronal activity) and brain activation
by a cognitive task. Furthermore, the fact that
we observed both increases and decreases in fMRI
signal as a result of THC injection and
regionally specific changes in task activation
strongly suggests that they are not due to either
global vascular or peripheral cardiovascular drug
effects. Taken as a whole, these studies
demonstrate that THC produces significant
effects on regional brain activity and cognitive
task-induced activation at a dose that produces
effects that are similar to those produced by
marijuana in a social situation and that this
dose range does not produce significant global
effects on brain blood flow.
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Acknowledgements

• Research supported by
• NIDA grants DA11326 and DA09465
• GCRC grant 5M01RR00058

Robert Risinger, M.D. Jeffrey Benson, M.D. S. J.
Li, Ph.D. Kathleen LaGrave Linda Piacentine,
M.S., ACNP Raymond Hoffman, Ph.D. Elliot Stein,
Ph.D.