Transcript PowerPoint Presentation - University of Kentucky

Marijuana Self-Administration Under a Modified Progressive-Ratio Procedure in Humans:
Effects of Marijuana Use History
Lee, D.C., Lile, J. A. Robbins, G., Martin, C.A., and Kelly, T.H.
University of Kentucky
Results
Background
Marijuana is the most widely used illicit drug in the United States (SAMHSA, 2008). Recent
research has suggested that marijuana use history alters the effects of an acute dose of THC
on subjective and performance measures, with heavy users showing less sensitivity to
subjective and performance-related effects of THC at large doses (Kirk and deWit, 1999;
Ramaekers et al., 2009). However, it is unclear if marijuana use history also predicts drugtaking behavior. This study examined marijuana self-administration using a modified
progressive-ratio procedure as a function of marijuana use history. It was hypothesized that
the reinforcing effects of marijuana would be greater in heavy users.
Supported by DA-05312 and RR-15592.
Method
Subjects: Sixteen healthy adults, ages 18 to 29, completed medical screening and gave
written consent to participate.
Marijuana Use History: Marijuana use history groups were divided based upon a median
split with 8 light users < 8 uses per month (0.33 - 8.00) and 8 heavy users > 10 uses per
month (10 - 25)
Procedure: Each participant completed an eight-session study consisting of four twosession testing occasions. On the first ‘sample’ session of each two-day testing occasion,
subjects received 8 puffs from cigarettes containing a test concentration of THC. On the
second ‘self-administration’ session, subjects earned up to 8 of the puffs administered on
the previous day by completing a progressive-ratio task.
Daily Schedule: After successfully completing intake evaluations, including urine
pregnancy and drug-use testing, subjects completed assessments before (I.e., baseline)
and at hourly intervals for three hours after consuming puffs administered (sample
sessions) or earned (self-administration sessions).
Drug Testing: Across the four two-session testing occasions, the effects of marijuana
containing 0, 1.7 and 3.5% THC were examined under randomized, double-blind
conditions. Each concentration was tested once after the first 2-session practice testing
occasion.
Data Analysis: On sample sessions mixed-model ANOVA’s were conducted with between(marijuana use history) and within-group (THC concentration, time) factors to examine the
effects of THC on assessment task performance and marijuana self-administration.
Group Demographics
Light
4.7 (3.0)
Heavy
16.8 (5.8)*
Gender (Female/Male)
Age
Education
(3/5)
23.4 (4.1)
14.7 (1.9)
(3/5)
22.8 (3.2)
14.3 (2.1)
Caffeine (mg/day)
Tobacco (cigs/day)
Alcohol (drinks/week)
123.9 (155.5)
0.1 (0.2)
4.7 (5.4)
95.0 (93.7)
2.2 (3.1)
6.9 (5.1)
Marijuana use
(occasions/month)
Light
Users
Heavy
Users
* Significant difference from Light group, p<0.001
Table 1 Summarizes demographic and drug-use variables among light and heavy marijuana
users. Significant group differences were observed on marijuana use history. Groups did not
differ on other demographic or alcohol/tobacco use variables.
Assessment Tasks
Figure 3: THC concentration and time effects on verbal report measures associated with the negative drug effects (panels A-F) among light (top row) and heavy (bottom row)
marijuana users. Significant marijuana use history by THC concentration interactions were observed on VAS Light-Headed (Panels A and B) and Forgetful (Panels C and D)
and ARCI LSD (Panels E and F) ratings. Simple effects tests indicated that light users reported greater increases in light-headed and forgetful ratings than heavy users
following 1.75 and 3.5% THC, only. Light users also reported greater ARCI LSD ratings than heavy users at the 1.75% THC condition, only. Error bars represent + 1 SEM.
Light
Users
Progressive-Ratio Task: Participants could earn up to eight puffs on a marijuana
cigarette by completing progressively increasing ratio button click requirements on a
computer mouse. The first puff could be earned by completing 50 responses, and the
response requirement for each subsequent puff was systematically doubled, such that
12,750 responses were required to earn all 8 puffs.
Addiction Research Center Inventory (ARCI): The 49-item short form of the true-false
ARCI provided reports of drug effects on five scales: Lysergic acid diethylamide (LSD),
Amphetamine (A), Benzedrine Group (BG), Morphine-Benzedrine Group (MBG) and
Pentobarbital, Chlorpromazine, Alcohol Group (PCAG).
Visual-Analog Rating Scales (VAS): Ratings of ‘Any Effect,’ ‘Bad Effect,’ ‘Good Effect,’
‘High,’ ‘Stoned,’ ‘Like Drug,’ ‘Take Again,’ ‘Pay for Drug,’ ‘Sedated,’ ‘Anxious,’
‘Nauseated,’ ‘Jittery,’ ‘Discomfort,’ ‘Light-headed,’ ‘See/Hear Unusual,’ ‘Hungry,’ ‘Thirsty,’
‘Forgetful,’ ‘Confused,’ and Suspicious’ were obtained by placing marks on a 100-unit
line anchored with "Not at all" on the left and "Extremely" on the right.
Digit-Symbol Substitution Task (DSST - 2 minutes): Nine random 3-row by 3-column
arrays of open and filled boxes (one filled box per row), labeled 1-9 from left to right,
were displayed at the top of the computer monitor. A randomly generated number,
between 1 and 9, was displayed in the center of the monitor, indicating which of the nine
arrays should be reproduced on a given trial. Subjects reproduced an array by pressing
the buttons on a 3-row by 3-column keypad that corresponded to the positions of the
filled boxes in the screen array.
Figure 1: Panel A presents the effects of THC concentration on PR breakpoint among light and heavy users.
There was a significant effect of THC concentration on PR breakpoint with the 3.5 % THC breakpoint significantly
greater than 0% THC. Breakpoints were unrelated to marijuana use history. Error bars represent + 1 SEM. Panel
B presents a scatter plot of the relationship between marijuana use history and the change in breakpoint between
the 3.5 % THC concentration and placebo. There was no significant correlation between marijuana uses per
month and progressive-ratio change scores.
Figure 4: THC concentration and time effects on heart rate (panels A, B) and Repeated Acquisition Task (panels C, D) and DSST (Panels E, F) performance among light (top
row) and heavy (bottom row) marijuana users. THC concentration by time interactions on heart rate were observed, with significant increases occurring immediately after
smoking 1.75 and 3.5% THC (e.g. 5 minutes post-smoke). A main effect of time was observed on Repeated Acquisition Task accuracy, with proportion correct decreasing
immediately following marijuana smoking, independent of THC concentration. Main effects of both THC concentration and time were observed on DSST performance, with
accuracy decreased by 3.5% THC. Accuracy impairment was greatest 60 and 120 minutes post smoking. There were no effects of marijuana use history on cardiovascular or
task performance measures. Error bars represent + 1 SEM.
Repeated Acquisition Task (3 minutes): Subjects were required to learn a new randomly
determined ten-response sequence of responding on four buttons. Correct responses in
the sequence increased a position counter, while incorrect responses engendered a 1second time out (blank screen). The tenth correct response in the sequence increased a
point counter and reset the position counter.
Conclusions
Rapid Information Processing Task (5 minutes): Single digits were presented in the
center of the monitor, and subjects were instructed to press a key whenever three
consecutive even or odd digits were presented. Following correct responses, the speed
of digit presentation was increased, and following incorrect responses or missed
signals, the speed of digit presentation was decreased.
Balloon Analog Risk Task (BART): Simulated balloons were inflated on a computer by
clicking a mouse button. A successful inflation resulted in an addition of money to a
temporary bank and increased the probability of the balloon popping on the next
inflation. If a subject chose to stop inflating a balloon and move to another balloon, the
amount of money accrued in the temporary bank was placed in a permanent bank; if a
subject chose to inflate the balloon and it popped, money in the temporary bank was
lost.
Cardiovascular Measures: Heart rate and blood pressure were recorded immediately
after completing computer tasks.
Heavy
Users
1) THC functioned as a reinforcer, as evidenced by increases in breakpoints on a progressive-ratio task and reports of
drug liking as a function of THC concentration in smoked marijuana.
2) Marijuana use history did not account for differences in the self-administration of smoked marijuana, cardiovascular
function, or task performance in this study.
3) However, light users reported greater negative effects following administration of smoked marijuana, suggesting that:
Figure 2: Panels A and B present VAS Pay for Drug, with a significant interaction between marijuana use history
and THC concentration. Simple effects indicated that heavy user Pay for Drug ratings were greater than light
users at 1.7 and 3.5% THC concentrations. Error bars represent + 1 SEM.
a. heavy users may be more tolerant to the negative effects of smoked marijuana, and/or
b. increased negative effects associated with smoking marijuana may be contributing to the decreased frequency of
reported marijuana use among light users in this study.