CANNABIS TREATMENT OUTCOME AND FMRI
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SUPPLEMENTARY MATERIALS
fMRI Data Acquisition and Preprocessing
Data Acquisition: Data were acquired with a Siemens Tim-Trio 3T scanner
(Siemens AG, Erlangen, Germany). Functional images were collected using a gradient
echo, echoplanar sequence (TR/TE = 1500/27ms; flip angle = 60°; field of view [FOV]
220mm X 220mm; 25 x 4 mm slices; 1mm skip). High-resolution 3D Magnetization
Prepared Rapid Gradient Echo (MPRAGE) structural images were also collected for
multi-subject registration (TR/TE = 2530/3.34ms; flip angle = 7°; FOV = 256mm x
256mm; 176 x 1mm slices).
Preprocessing: Six initial volumes from each run were removed prior to
preprocessing. Functional images were preprocessed using SPM5 (Wellcome Functional
Imaging Laboratory, London, UK), following our prior published methods (Kober et al,
2010). This included slice-time correction to the first slice of each volume; SPM’s twopass realign-to-mean strategy; coregistration of the anatomical image and the average of
the realigned functional images; coregistration of all functional images using the
parameters obtained from coregistration of the mean image; application of the SPM
Unified Segmentation process to the anatomical scan, using prior information from the
International Consortium for Brain Mapping (ICBM) Tissue Probabilistic Atlas and
estimation of non-linear warping parameters (Ashburner and Friston, 2005); warping the
functional images to the Montreal Neurological Institute (MNI) template space; reslicing
into isometric 3x3x3 mm³ voxels; smoothing of functional images using a 6mm isometric
Gaussian kernel. All images were inspected for signal-to-noise ratio and motion in excess
of one voxel; no participants were excluded from analyses for poor quality or excessive
motion.
Result Labeling: Anatomical labels of all results were confirmed visually and
using human brain atlases (Duvernoy, 1999) and the Talairach Daemon toolbox
(Lancaster et al, 2000).
Randomized Clinical Trial Treatment Conditions (Carroll et al, 2012)
CANNABIS TREATMENT OUTCOME AND FMRI
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Overview: For the 12-week clinical trial, participants were randomly assigned to
one of four treatment conditions: cognitive-behavioral therapy (CBT; N=7), contingency
management to promote abstinence (CMabstinence; N=3); CBT in addition to CMabstinence
(N=6) and finally, CBT in addition to CM to promote treatment adherence (CMadherence;
N=4).
Cognitive Behavioral Therapy (CBT): Individuals assigned to CBT were offered
weekly 50-minute individual sessions of clinician-delivered CBT. All clinicians met prespecified criteria for CBT-competence and administered the treatment in accordance with
the manual guidelines (Carroll, 1998).
Contingency Management (CM): Individuals assigned to a CM condition earned
the opportunity to draw for possible prizes of various sizes following successful
demonstration of abstinence (cocaine-negative urine submitted) in the CMabstinence
condition, or demonstration of CBT treatment adherence (e.g., complete CBT homework
assignments) in the CMadherence condition. Prize draws were administered on an escalating
schedule (e.g., increasing draws for consecutive days abstinence; (Petry, 2000; Petry et
al, 2005).
Treatment Admission Prompted by the Legal System
Nearly all cannabis-dependent participants in this study had their admission to
treatment initially prompted by the legal system. However, participants were not
mandated to participate in the study. They were referred to treatment by their probation
officers, but were made aware that their decision to participate or not in the clinical trial
or fMRI was voluntary, and would have no consequences regarding their legal status.
All were aware they could drop out of the trial or the fMRI component at any time.
Furthermore, all were made aware that none of the clinical data collected for this study
could be shared with the clinic or with the legal system.
Correlations with post-treatment abstinence
Two participants did not provide any follow-up data and were excluded from this
analysis. One year follow-up data were available for 18 subjects in the fMRI sample and
percent self-reported abstinence during follow-up was calculated for all N=18 subjects
CANNABIS TREATMENT OUTCOME AND FMRI
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with any follow-up data. However, 5 participants had not completed follow-up reporting
for the entire 364 days period, and data were missing for the end of the follow-up period
as these subjects did not attend their final sessions, while the remaining subjects all had
364 days of follow-up data. Several steps were taken to ensure that results were not
driven by the subjects with missing data. In order to check whether the subjects with
missing follow-up sessions or data may have been driving or otherwise biasing our
results, we carried out several post-hoc analyses. Subjects with missing follow-up
sessions or missing follow-up data did not differ substantially in terms of demographics,
baseline severity or within-treatment clinical outcomes from those with complete data. To
ensure that the fMRI results were not biased by these subjects, we re-ran the fMRI
correlation analyses including only the 13 participants who had completed follow-ups for
the entire 364 day period. The results of these confirmatory analyses were consistent with
the original findings for the sample of participants with any follow-up data (N=18).
In addition, given the infrequent collection of urine toxicology during follow-up
(3-month intervals) and the complications of urine toxicology in assessing abstinence
from cannabis (e.g., long half-life), and the data supporting the validity of the Timeline
Followback and for consistency with our previous published work, self-report data were
used to calculate abstinence during follow-up. This is a common approach for assessing
clinical outcomes over follow-up periods (e.g., Babor et al, 2000; Donovan et al, 2012).
Speed/Accuracy Trade-Off
To investigate whether the behavioral Stroop data demonstrated the expected
speed-accuracy trade-off, we performed correlations between number of errors and (1)
RT during incongruent trials, (2) RT during congruent trials and (3) Stroop effect
magnitude (mean RT for incongruent vs. congruent trials). As shown in Table S3 and
Figures S10-11, we found the expected speed/accuracy trade-off. Specifically, we found
negative correlations between errors and all measures of RT, such that longer RTs on
both congruent and incongruent trials and a smaller Stroop effect were associated with
fewer errors. These correlations were statistically significant for both the Stroop effect
and Incongruent trial RT across the entire sample (N=26 participants with data; r(25)=.49, p=.01; r(25)=-51, p<.01) and for the Cannabis-Dependent group (r(11)=-.72, p<.01;
CANNABIS TREATMENT OUTCOME AND FMRI
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r(11)=.70, p=.01). Interestingly, the correlations within the Healthy Control group did not
reach statistical significance (p>.1; Table S2; Figures S10).
The speed-accuracy trade-off should be more pronounced when subjects are
speeding towards their limits on any task. So, the stronger association between RT and
errors in the Cannabis-Dependent group could be consistent with them finding the task
more difficult. However, we performed a Fisher r-to-z transformation to assess the
significance of the difference between the two correlation coefficients. We found that the
differences in strength of the correlations between the Cannabis and Healthy groups was
not significant for the Stroop effect/error correlation (z=1.21, p>.1) and incongruent
RT/errors correlation (z=1.17, p>.1).
Role of Cigarette Smoking
Cigarette smoking is becoming a greater point of consideration in cannabis
smoking and relapse (e.g., Haney et al, 2013). Given this important consideration and in
order to assess the role of cigarette smoking in our treatment outcomes and neuroimaging
findings, we took several steps:
First, we assessed whether pre-treatment days of cigarette smoking was associated
with our clinical abstinence outcomes (within treatment or during follow-up). In order to
do this we ran 4 separate partial correlations between pre-treatment days of cigarette
smoking and the 4 clinical outcome variables, each one controlling for pre-treatment days
of cannabis use. One of four correlations was significant at p=.022. However, because we
ran four correlations, we do not believe this indicates a strong relationship between pretreatment cigarette smoking and cannabis outcomes in this sample (since .022 in one of
four correlations would not survive correction for multiple comparisons).
Second, within the cannabis-dependent group only, we ran a correlation between
the fMRI Stroop Incongruent>Congruent contrast and past-month days of cigarette use.
We found no statistically significant clusters in a whole-brain analysis. Even when we
adjusted the threshold to be more lenient (e.g., p=0.01, k=50) and did not use standard
approaches to correct for multiple comparison (e.g., FWE), there were still no clusters
that exhibited a relationship between smoking and Stroop-related neural activity. As
such, pre-treatment fMRI Stroop effect does not seem to correlate with pre-treatment
CANNABIS TREATMENT OUTCOME AND FMRI
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days smoking in this patient group (i.e., those who do not smoke cigarettes do not show
the ‘best’ Stroop-related activity).
Third, to further assess the relationship between cigarette smoking and fMRI
Stroop effect in this sample, we re-ran the main Stroop contrast (Incongruent>Congruent)
controlling for pre-treatment cigarette smoking. Including this covariate in analysis did
not significantly alter the results.
Taken together, these additional analyses strongly suggest that cigarette smoking
status does not confound or alter the reported results in the present manuscript.
CANNABIS TREATMENT OUTCOME AND FMRI
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References
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Petry NM (2000). A comprehensive guide to the application of contingency management
procedures in clinical settings. Drug and alcohol dependence 58(1-2): 9-25.
Petry NM, Alessi SM, Marx J, Austin M, Tardif M (2005). Vouchers versus prizes:
Contingency management treatment of substance abusers in community settings. Journal
of Consulting and Clinical Psychology; Journal of Consulting and Clinical Psychology
73(6): 1005-1014.
CANNABIS TREATMENT OUTCOME AND FMRI
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Supplementary Figures:
Figure S1. Stroop-Related Neural Activity Within and Between Groups
Stroop-related neural activity was computed as incongruent>congruent. For within-group
contrasts, warm colors represent relatively greater activity during incongruent trials than
during congruent trials, and cool colors represent relatively greater activity during
congruent trials than incongruent trials. For the between-group contrast, warm colors
represent relatively greater Stroop-effect activity in healthy-comparison than in cannabisdependent individuals. All results are family-wise-error corrected (FWE) at p<0.05. Left
side of the brain is displayed on the left. A) Stroop-related neural activity in healthycomparison individuals, N=20. B) Stroop-related neural activity in cannabis-dependent
individuals, N=20. C) Between group comparison of Stroop-related neural activity:
Healthy-comparison (incongruent>congruent) > cannabis-dependent
(incongruent>congruent), N=40.
CANNABIS TREATMENT OUTCOME AND FMRI
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Figure S2. Stroop-Related Neural Activity in Healthy-Comparison Individuals.
Whole-brain axial slices showing full results. Stroop-related neural activity was
computed as incongruent>congruent. Warm colors represent relatively greater activity
during incongruent trials than during congruent trials, and cool colors represent relatively
greater activity during congruent trials than incongruent trials. Results are family-wiseerror corrected (FWE) at p<0.05. Left side of the brain is displayed on the left. N=20.
CANNABIS TREATMENT OUTCOME AND FMRI
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Figure S3. Stroop-Related Neural Activity in Cannabis-Dependent Individuals.
Whole-brain axial slices showing full results. Stroop-related neural activity was
computed as incongruent>congruent. Warm colors represent relatively greater activity
during incongruent trials than during congruent trials, and cool colors represent relatively
greater activity during congruent trials than incongruent trials. Results are family-wiseerror (FWE) corrected at p<0.05. Left side of the brain is displayed on the left. N=20.
CANNABIS TREATMENT OUTCOME AND FMRI 10
Figure S4. Between-Group Differences in Stroop-Related Neural Activity.
Whole-brain axial slices showing full results. Between-group differences in Stroop-Effect
were computed as: Healthy-comparison (incongruent>congruent) > cannabis-dependent
(incongruent>congruent). Warm colors represent relatively greater activity in healthycomparison individuals than cannabis-dependent individuals. Results are family-wiseerror (FWE) corrected at p<0.05. Left side of the brain is displayed on the left. N=40.
CANNABIS TREATMENT OUTCOME AND FMRI 11
Figure S5. Conjunction of Three Correlations Between Pre-Treatment Stroop-Related
Neural Activity and Within-Treatment Cannabis Abstinence.
Whole-brain axial slices showing full results. Robust correlations were computed
between Stroop-related neural activity (incongruent > congruent) and three different
measures of within-treatment abstinence in cannabis-dependent individuals: (1)
maximum consecutive days of self-reported cannabis abstinence, (2) percent of days of
self-reported cannabis abstinence, and (3) percent cannabis-negative urines. Conjunction
was computed as: map1*map2*map3. Regions of overlap are shown at a conjunction
threshold of p<0.000125, with a cluster threshold of 20 3x3x3mm voxels. Left side of the
brain is displayed on the left. N=20.
CANNABIS TREATMENT OUTCOME AND FMRI 12
Figure S6. Correlation Between Pre-Treatment Stroop-Related Neural Activity and
Maximum Consecutive Days of Self-Reported Abstinence During Treatment.
This correlation was one of the three entered into the conjunction analysis (Figure S5).
Whole-brain axial slices showing full results are below. Stroop-related neural activity
was computed as incongruent > congruent, and the correlation was computed robustly.
Warm colors represent positive correlations between neural activity and duration of
abstinence, and cool colors represent negative correlations between neural activity and
duration of abstinence. Results shown at p<.05 with a cluster threshold of 20 3x3x3mm
voxels (for visualization). Left side of the brain is displayed on the left. N=20.
CANNABIS TREATMENT OUTCOME AND FMRI 13
Figure S7. Correlation Between Pre-Treatment Stroop-Related Neural Activity and
Percent Days of Self-Reported Abstinence During Treatment.
This correlation was one of the three entered into the conjunction analysis (Figure S5).
Whole-brain axial slices showing full results are below. Stroop-related neural activity
was computed as incongruent > congruent, and the correlation was computed robustly.
Warm colors represent positive correlations between neural activity and percent days of
abstinence, and cool colors represent negative correlations between neural activity and
percent days of abstinence. Results shown at p<.05 with a cluster threshold of 20
3x3x3mm voxels (for visualization). Left side of the brain is displayed on the left. N=20.
CANNABIS TREATMENT OUTCOME AND FMRI 14
Figure S8. Correlation Between Pre-Treatment Stroop-Related Neural Activity and
Percent of Cannabis-Negative Urines During Treatment.
This correlation was one of the three entered into the conjunction analysis (Figure S5).
Whole-brain axial slices showing full results are below. Stroop-related neural activity
was computed as incongruent > congruent, and the correlation was computed robustly.
Warm colors represent positive correlations between neural activity and percent
cannabis-negative urines, and cool colors represent negative correlations between neural
activity and percent cannabis-negative urines. Results shown at p<.05 with a cluster
threshold of 20 3x3x3mm voxels (for visualization). Left side of the brain is displayed on
the left. N=20.
CANNABIS TREATMENT OUTCOME AND FMRI 15
Figure S9. Correlation Between Pre-Treatment Stroop-Related Neural Activity and
Percent Days of Abstinence During One-Year Follow-Up.
Whole-brain axial slices showing full results. Stroop-related neural activity was
computed as incongruent > congruent, and the correlation was computed robustly. Warm
colors represent positive correlations between neural activity and percent days abstinence
during 1-year follow-up, and cool colors represent negative correlations between neural
activity and percent days abstinence. Results are family-wise-error (FWE) corrected to
p<0.05. Left side of the brain is displayed on the left. N=18 (cannabis-dependent
individuals with follow-up data).
CANNABIS TREATMENT OUTCOME AND FMRI 16
Figure S10. Speed-Accuracy Trade-Off for Stroop Performance.
RT=reaction time (milliseconds); Mean Stroop Effect RT= Mean (Incongruent trial RT –
Congruent trial RT); Solid gray line represents best fit regression line for those
individuals for whom response time data were available (cannabis-dependent N=12;
healthy-comparison N=14).
CANNABIS TREATMENT OUTCOME AND FMRI 17
Supplementary Table Legends
Table S1. Side-by-side comparison of fMRI subsample to parent randomized controlled
trial sample
1
CBT=Cognitive Behavioral Therapy; CM=Contingency Management, see (Carroll et
al, 2012) for details.
2
CM Adherence = participants were rewarded for session attendance and homework
CANNABIS TREATMENT OUTCOME AND FMRI 18
completion, see (Carroll et al, 2012) for details.
3
CM Abstinence = participants were rewarded for clean urines, see (Carroll et al, 2012)
for details.
4
One year follow up data were only available for 18 subjects in the fMRI sample and %
self-reported abstinence during follow-up was calculated for all N=18 subjects with any
follow-up data. In the RCT sample (as reported in Carroll et al, 2012), N=105 had days
of follow-up information and % abstinence was calculated from individuals with full
follow-up data only.
Table S2. Correlations between incongruent error rates and reaction time measures
Data represent Pearson correlation coefficients and p-values [r (p)]. Significant results are
in bold, trends are underlined. RT= response times; Inc=incongruent trials;
Con=Congruent trials.
Table S3. Cannabis abstinence at treatment onset, completion and follow-up
1
Percent days self-reported abstinence during a) 28 days prior to treatment; b) entire 84day treatment window; c) days of self-report data collected during follow-up (out of
possible 364 total days)
2
N (%) of subjects who self-reported ≥7 consecutive days of abstinence leading up to a)
pre-treatment baseline; b) end of the 84-day treatment window; c) final follow-up
assessment. Missing N's represent subjects who did not provide self-report data during
the allotted timeframe.
3
N(%) of subjects who submitted at least one cannabis-positive urine within the following
time windows: a) 28 days prior to treatment; b) final 7 days of the 84-day treatment
window; c) final 7 days prior to the final follow-up assessment. Missing N's represent
subjects who did not provide urine toxicology data during the allotted timeframe.
CANNABIS TREATMENT OUTCOME AND FMRI 19
Table S4. Demographics, Treatment Engagement, and Clinical Outcomes within
subsample with Stroop behavioral data
Table S4. Demographics, Treatment Engagement, and Clinical Outcomes within subsample with Stroop behavioral data
Participant Groups
Group Statistics
Healthy Comparison
Cannabis-dependent
Characteristic
(N=14)1
(N=12)1
N
%
N
%
X2
df
p-value
Demographics
Gender (N Male)
12
100
14
100
0.00
1
1.00
Race
4.22
3
0.24
Caucasian
3
25
8
57
African American
7
58
6
43
Hispanic or Biracial
2
16
0
0
Highest Education Level
12.43
5
0.03
Graduate School Completed
0
0
1
7
College Graduate
1
8
6
43
Partial College
1
8
4
29
High School Graduate (or GED)
4
33
3
21
Did not complete high school
6
50
0
0
Baseline Clinical and Substance Use Measures
Psychiatric Diagnosis
Lifetime Major Depression
1
8
0
0
1.13
1
0.29
Current Major Depression
0
0
0
0
0.00
1
1.00
Lifetime Anxiety Disorder
1
8
0
0
1.21
1
0.27
Antisocial Personality Disorder
3
25
0
0
3.96
1
0.05
Lifetime Alcohol Use Disorder
4
33
0
0
5.16
1
0.02
Current Alcohol Abuse
0
0
0
0
0.00
1
1.00
Daily Cigarette Smoker
6
50
2
14
3.87
1
0.05
Treatment Admission Prompted by Legal System
Treatment Groups3
CBT
CBT + CM Adherence
CM Abstinence
CBT + CM Abstinence
Demographics
Age (Years)
Estimated IQ (Shipley Institute of Living Scale)
Baseline Clinical and Substance Use Measures2
Days Use in 28 Days Prior to Treatment
Cannabis
Cigarette
Alcohol
Lifetime Years of Substance Use
Cannabis
Alcohol
Lifetime Number of Arrests
Treatment Engagement and Outcome
Days in Treatment
Cannabis Use Within-Treatment
Percent Negative Urines
Maximum Self-Reported Consecutive Days
Abstinence
Percent Days Self-Reported Abstinence
Cannabis Use During Follow-Up
# Follow-up Sessions Attended
Days of Follow-Up Information Collected
% Days Self-Reported Abstinence During Follow-Up
1
11
92
5
3
1
3
Mean
19
12
4
12
SD
Mean
SD
T
df
p-value
27.75
95.5
12.23
12.76
30.21
107.57
11.11
10.91
0.54
2.60
24
24
0.6
0.02
15
17.67
5.08
9.71
11.91
5.47
13.08
10.58
5.5
13.13
11.37
3.87
57
25.26
32.2
33.92
40.25
71.33
30.33
38.41
2.33
295.27
65.91
1.67
111.55
31.64
Stroop behavioral data were only available for 12 cannabis-dependent and 14 healthy
comparison participants. The remaining behavioral (response time) data were not
available due to technical failures during data collection. This table represents the
subsample of individuals for whom Stroop behavioral data were available.
CANNABIS TREATMENT OUTCOME AND FMRI 20
2
Some clinical data, including past month days of cigarette and alcohol use measures
were not available for the healthy control group.
3
CBT=Cognitive Behavioral Therapy; CM=Contingency Management; CM Adherence =
participants were rewarded for session attendance and homework completion; CM
Abstinence = participants were rewarded for clean urines; see Carroll et al., 2012 for
details.