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Journal of Addiction Medicine:
doi: 10.1097/ADM.0b013e318273863a
Original Research

Reward-related Brain Response and Craving Correlates of Marijuana Cue Exposure: A Preliminary Study in Treatment-seeking Marijuana-dependent Subjects

Goldman, Marina MD; Szucs-Reed, Regina P. MD, PhD; Jagannathan, Kanchana MS; Ehrman, Ronald N. PhD; Wang, Ze PhD; Li, Yin MA; Suh, Jesse J. PsyD; Kampman, Kyle MD; O'Brien, Charles P. MD, PhD; Childress, Anna Rose PhD; Franklin, Teresa R. PhD

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Author Information

From the Department of Psychiatry (MG, RPS-R, KJ, ZW, YL, JJS, KK, CPO, ARC, TRF), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Philadelphia Veterans Affairs Medical Center and VISN 4 Mental Illness Research, Education, and Clinical Center (RNE, JJS, CPO, ARC), Philadelphia; and Department of Neurology (ZW), Center for Functional Neuroimaging, University of Pennsylvania, Philadelphia.

Send correspondence and reprint requests to Marina Goldman, MD, Department of Psychiatry, University of Pennsylvania, 3900 Chestnut St, Philadelphia, PA 19104. E-mail: marinag@mail.med.upenn.edu.

A portion of the data contained in this article was presented at the 71st Annual Scientific Meeting of the College on Problems of Drug Dependence, June 20–25, 2009, Reno-Sparks, NV.

Supported by grants from the National Institute of Drug Abuse (Dr. O'Brien, principle investigator: 5-P60-DA-05186 and T32-DA-07241), the Philadelphia Veterans Affairs Medical Center and VISN 4 Mental Illness Research, Education & Clinical Center, the Pennsylvania Department of Health (Dr. Childress, principle investigator: CURE Center of Excellence: Brain Mechanisms of Relapse and Recovery), and imaging and infrastructure support for this work was kindly provided by the National Institute of Health/National Institute of NeurologicaI Disorders and Stroke (P30 NS045839). The funding agencies had no further role in the conduct of the research, preparation of the manuscript, study design, collection, analysis and interpretation of data, writing of the report, and the decision to submit the paper for publication.

The authors declare no conflict of interest.

Received February 7, 2012

Accepted September 9, 2012

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Abstract

Objective: Determining the brain substrates underlying the motivation to abuse addictive drugs is critical for understanding and treating addictive disorders. Laboratory neuroimaging studies have demonstrated differential activation of limbic and motivational circuitry (eg, amygdala, hippocampus, ventral striatum, insula, and orbitofrontal cortex) triggered by cocaine, heroin, nicotine, and alcohol cues. The literature on neural responses to marijuana cues is sparse. Thus, the goals of this study were to characterize the brain's response to marijuana cues, a major motivator underlying drug use and relapse, and determine whether these responses are linked to self-reported craving in a clinically relevant population of treatment-seeking marijuana-dependent subjects.

Methods: Marijuana craving was assessed in 12 marijuana-dependent subjects using the Marijuana Craving Questionnaire–Short Form. Subsequently, blood oxygen level dependent functional magnetic resonance imaging data were acquired during exposure to alternating 20-second blocks of marijuana-related versus matched nondrug visual cues.

Results: Brain activation during marijuana cue exposure was significantly greater in the bilateral amygdala and the hippocampus. Significant positive correlations between craving scores and brain activation were found in the ventral striatum and the medial and lateral orbitofrontal cortex (P < 0.0001).

Conclusions: This study presents direct evidence for a link between reward-relevant brain responses to marijuana cues and craving and extends the current literature on marijuana cue reactivity. Furthermore, the correlative relationship between craving and brain activity in reward-related regions was observed in a clinically relevant sample (treatment-seeking marijuana-dependent subjects). Results are consistent with prior findings in cocaine, heroin, nicotine, and alcohol cue studies, indicating that the brain substrates of cue-triggered drug motivation are shared across abused substances.

Marijuana (MJ) is the most widely used illicit drug in the United States, with 3.2 million regular users and 1.5% of the US population meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria for abuse or dependence (Compton et al., 2004; SAMHSA, 2005). Dependence is associated with negative consequences to the individual (eg, anxiety, depression, psychosis, impaired memory and learning, lung disease, suppressed immunity, and increased cancer risk) and to society (eg, driving accidents and related deaths, and health care–related and economic costs) (Tashkin et al., 1987; Bolla et al., 2002; Asbridge et al., 2005; Raphael et al., 2005). Although the literature on MJ dependence remains sparse, an MJ withdrawal syndrome has been identified, and self-reported craving for MJ has been demonstrated (Singleton et al., 2002; Budney et al., 2004; Hasin et al., 2008; Bordnick et al., 2009; Gray et al., 2011).

A variety of psychosocial and pharmacological treatments have been investigated for MJ dependence with underwhelming results (Copeland et al., 2001; Tirado et al., 2008; Haney et al., 2010; Levin et al., 2011). Trials report that fewer than 50% of MJ-dependent subjects are abstinent at 4 and 6 months after treatment (Nordstrom and Levin, 2007; Denis et al., 2008). The harmful effects of this chronic, relapsing disorder on both individuals and society underscore the importance of identifying the neurophysiological vulnerabilities that could improve treatment response.

In addiction, drug reminders or cues such as people, places, things, and internal states previously associated with drug reward can trigger craving. Drug craving is tightly coupled with drug use (Preston et al., 2009) and can be sufficiently compelling to precipitate relapse despite the presence of significant negative consequences and effort on the patient's part to maintain abstinence (O'Brien, 1978; Oslin et al., 2009).

Neuroimaging has been used to study brain changes in response to drug cues, leading to a greater understanding of the mechanisms of relapse. In line with an extensive preclinical literature, such studies have observed activation of reward-related brain circuitry during exposure to cocaine (Childress et al., 1993; Grant et al., 1996; Childress et al., 1999; Bonson et al., 2002), nicotine (Franklin et al., 2007; Janes et al., 2010), and heroin cues (Langleben et al., 2008). In addition, Janes et al. demonstrated heightened brain responses in reward-related circuitry during cigarette-smoking cue exposure in smokers who lapsed, and reduced functional connectivity between top-down cognitive control regions and emotive brain circuits that predicted time to lapse in treatment-seeking smokers (Janes et al., 2010).

There are at least 2 groups investigating brain responses to MJ cues (Filbey et al., 2009; Cousijn et al., 2012). Both studies focused on non–treatment-seeking MJ smokers. In the first study, using tactile cues, Filbey et al. observed activation in the ventral tegmental area, the thalamus, the anterior cingulate cortex (ACC), the insula, and the amygdala. They further showed that activity in the reward-related orbitofrontal cortex (OFC) and the ventral striatum correlated with problems associated with MJ use (Filbey et al., 2009). This work is consistent with the existing literature of other drugs of abuse. In the second study, Cousijn et al. observed activation (OFC, ACC, and ventral and dorsal striatum) in response to visual cues in frequent users who were separated into high and low problem severity subgroups in line with Filbey et al. They also showed that the ventral tegmental area activation during MJ cue exposure was specific to frequent cannabis users versus sporadic users and nonusers. Although the authors tested whether craving was associated with brain responses in the frequent users group, the findings were in opposition to their hypotheses and were difficult to interpret, and they concluded that further research is necessary (Cousijn et al., 2012).

The aim of this study was to expand the sparse literature by studying MJ cue reactivity in a clinically relevant treatment-seeking group of MJ-dependent subjects and to establish a link between reward-relevant brain responses to MJ cues and self-report of drug craving, a major relapse predictor. Using a blood oxygen level dependent (BOLD) block design, we examined the brain responses to MJ cues and the association between baseline craving and brain responses to cues. On the basis of the existing literature and observations in our laboratory studies of cocaine and nicotine cue reactivity (Grant et al., 1996; Childress et al., 1999; Franklin et al., 2007; Filbey et al., 2009), we hypothesized that MJ cues would activate reward-relevant regions (eg, amygdala, ventral striatum, OFC, insula, and hippocampus) and responses would be positively correlated with baseline subjective MJ craving.

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METHODS

Subjects

Treatment-seeking individuals were recruited through newspaper advertisements to the Center for the Studies of Addiction, a Perelman School of Medicine, University of Pennsylvania–affiliated treatment center. The subjects who participated in this study are a subset of those recruited to participate in a study examining the effectiveness of dronabinol and BRENDA for the treatment of MJ withdrawal. The subjects met the DSM-IV criteria for MJ dependence, had a positive urine drug screen for MJ, and had a history of 10 or more years of MJ use with an average frequency of 2 or more joints per day on 5 or more days per week.

The subjects were screened and tested on study knowledge, and their consent was obtained before psychological and physical evaluations. The Mini-International Neuropsychiatric Interview (Sheehan et al., 1998) was used to determine current DSM-IV diagnosis of psychoactive-substance dependence and to diagnose current severe psychiatric symptoms. The Wechsler Abbreviated Scale of Intelligence was used to assess intelligence quotient (Wechsler, 1999).

Exclusion criteria included a history of head injury with loss of consciousness for more than 3 minutes, current significant medical or neurological illness, current psychiatric symptoms meeting criteria for a DSM-IV axis I disorder, use of medications or illicit substances with psychoactive properties (other than MJ) within 4 weeks of starting the study, an intelligence quotient of less than 80, and psychoactive-substance dependence (other than MJ and nicotine) within 6 months from starting the study (monitored by urine drug screens). The subjects were compensated $50.

All the participants provided informed consent, and all the procedures were approved and monitored by the University of Pennsylvania institutional review board (in accordance with the Common Rule) and adhered to the Declaration of Helsinki.

Three subjects were excluded from the study—1 because of motion artifact, 1 because of structural artifact, and 1 because of technical loss of data. Of the 12 remaining subjects, 10 were men, 10 were African American, and 9 were current cigarette smokers. The subjects were 37.6 ± 10.7 years old, had 13.0 ± 2.0 years of education, and had an average intelligence quotient of 99.8 ± 14.4. The subjects used alcohol 4.1 ± 3.8 days of the last 30 days, with 2.1 ± 1.8 drinks per occasion. A 24-hour time line follow-back questionnaire was used to assess the frequency and amount of MJ use at the first screening visit and 2 subsequent visits before the scanning session (see the “Results” section).

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Study Design

The subjects were not instructed to alter their usual MJ smoking pattern, as this study was designed to investigate the naturalistic, baseline craving state in the absence of withdrawal. The subjects were scanned before randomization in a subsequent clinical trial, “Effectiveness Study of Dronabinol and BRENDA for the Treatment of Cannabis Withdrawal.” A quit date was set during the course of this subsequent clinical trial. Data from the trial are not reported here.

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Behavioral Measures

The Marijuana Craving Questionnaire-Short Form (MCQ-SF), a validated, multidimensional assessment of self-reported MJ craving, was given immediately before the imaging session. The MCQ-SF is a 4-factor structured scale covering a broad range of distinct behavioral experiences associated with the urge to use MJ (Heishman et al., 2009). It includes both appetitive and aversive aspects of drug motivation (ie, compulsivity, purposefulness, expectancy, and emotionality). The scores on each factor range from 3 to 21 (minimal to maximal intensity). Immediately before and after the imaging session, the subjects were also asked to verbally rate their craving on a scale from 1 to 9. Clinical counseling was offered to subjects to aid them in coping with any residual craving induced by the cues.

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Stimuli

Matching of visual cues with the individual's conditioning history is a critical factor in creating a cue paradigm. Marijuana smokers recruited through our center typically smoke blunts (a cigar that is emptied of its contents and filled with MJ), although other modes of administration are also used (eg, smoking joints, pipes, and/or bongs). Thus, stimuli consisted of pictures of MJ, MJ-related paraphernalia, and individuals engaged in MJ smoking through various modes of administration. Both MJ and non-MJ cues were comparable in level of complexity, type of activity, size, brightness, and luminance (Fig. 1). Stimuli were presented using E-prime software (Psychology Software Tools Inc.) onto a rear projection screen positioned behind the magnetic resonance imaging scanner.

Figure 1
Figure 1
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Imaging Session

A BOLD block design was used, consisting of six 20-second MJ cue blocks and 6 non-MJ blocks. Each block consisted of 10 pictures. The pictures were randomly selected from among 20 for each category. The blocks were presented in a rapidly alternating (2 cue blocks every minute), semirandom order using the Gellermann series (Gellermann, 1933). Each picture was presented for 1½ seconds followed by a ½-second fixation point. A 20-second distractor task was presented after each cue block. The task consisted of a fixation point presented every 2 seconds on the right or left side of the screen, after which subjects were asked to press a button to indicate on which side the fixation point was presented (Fig. 1). The entire cue session lasted 8 minutes.

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Behavioral Data Analysis

The 4 MCQ-SF factor scores for compulsivity, emotionality, expectancy, and purposefulness were highly intercorrelated (r values ranged from 0.74 to 0.95, P < 0.006). Thus, scores for each factor were combined into a single craving score, which was computed by adding the individual factor scores and then dividing by 4 to obtain a mean.

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Scanning Procedures and Parameters

Whole-brain magnetic resonance images were acquired using a Siemens 3T Trio MR scanner (Siemens AG, Erlangen, Germany). A 5-minute T1-weighted high-resolution scan was acquired for normalization and anatomical coregistration of the images. Acquisition parameters for the 3-dimensional high-resolution magnetization-prepared rapid acquisition with gradient echo (MPRAGE) structural scan in the axial plane were field of view (FOV) = 250 mm, repetition time (TR)/echo time (TE) = 1620/3 ms, 192×256 matrix, and slice thickness = 1 mm. A T2*-weighted gradient echo-planar imaging sequence was used to acquire functional images with field of view = 192 mm, 64 × 64 matrix, TR = 2 seconds, TE = 30 milliseconds, flip angle = 90°, and 33 interleaved slices with thickness of 3 mm (no gap).

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Data Processing

Statistical parametric mapping–based batch scripts were used for data analyses within SPM2 software (Wellcome Department of Cognitive Neurology, London, UK) run in MATLAB R2009b. The participants' functional images were realigned, coregistered to the anatomical T1 image, normalized to the Montreal Neurological Institute standard space, and smoothed with a Gaussian kernel of full width at half maximum 9 mm3. For each subject, experimental conditions were modeled using a general linear model with a canonical hemodynamic response function as the basis function. Contrasts between MJ and non-MJ cues were defined in the general linear model to assess the voxel-by-voxel difference. The contrast maps were entered into a random effects analysis to test for a significant main effect of condition. Simple regression analyses were conducted to test for brain-behavioral correlations with the composite craving score from the MCQ-SF as a covariate of interest. A mask was generated from our a priori regions (bilateral amygdala, ventral striatum, OFC, ventral insula, and hippocampus), defined anatomically by the Harvard-Oxford Cortical-Sub Cortical Atlas with a probability threshold set at 25. To control for type I error, Monte Carlo simulation was performed using 3dClustSim (a function from AFNI Software, afni.nimh.nih.gov/pub/dist/doc/program_help/3dClustSim.html). Parameters used with the region-of-interest mask described earlier were an individual voxel P value at P = 0.005 with 10,000 iterations, 2-sided, and full width at half maximum (estimated from statistical parametric mapping). The simulations demonstrate that a cluster extent cutoff of at least 10 contiguous voxels, exceeding a height threshold of P < 0.005, corresponds to a cluster-corrected threshold of P < 0.01. To provide hypothesis-generating information to the field, an interactive visual display of unmasked brain data in all 3 planes at P = 0.01 can be found at http://franklinbrainimaging.com.

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RESULTS

Behavioral Results

At the screening visit, the subjects used MJ an average of 28.3 ± 4.2 days of the last 30 days, using 12.0 ± 9.5 joints per day, for an average of 18.7 ± 8.2 continuous years. Marijuana use averaged 11.3 ± 2 joints per day in the week before the scan and 10.7 ± 2 joints per day 24 hours before scanning, which did not differ from use in the week before the scan (P = 0.47).

Mean MCQ-SF factor scores were the following: compulsivity, 9.0 ± 4.9; emotionality, 10.75 ± 5.9; expectancy, 11.5 ± 6.0; and purposefulness, 12.2 ± 6.9. The mean composite MCQ-SF craving score was 10.9 ± 5.5.

Change in craving scores was generated from responses to the single-item craving question acquired before and after MJ cue exposure. The scores ranged from 0 to 4 (mean = 1.2 ± 1.4) and were not significantly different from prescanning to postscanning session (P = 0.26).

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Imaging Results

Two analyses were conducted (12 blocks and 6 blocks) a priori on the basis of previous work in our laboratory, suggesting that “carryover” from repeated presentation of MJ cues would reduce contrast (see the Discussion, Methodological Considerations section).

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Drug Minus Nondrug Comparison

Compared with non-MJ cues, presentation of the MJ cues elicited significantly greater BOLD activation in a priori regions. Twelve-block analysis: Increased brain activation was observed in the left amygdala (T = 4.70, at −24, 0, −18). Six-block analysis: More robust effects were observed than were observed in the 12-block analysis, including bilateral activation of the amygdala and hippocampus (T values range from 4.43 to 8.65; see Table 1 and Fig. 2). There were no areas wherein activation was decreased.

Figure 2
Figure 2
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Table 1
Table 1
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Correlation With Baseline Craving Using the 6-block Analysis

Baseline MJ craving scores that were measured an hour before the imaging session positively correlated with brain activation to MJ cues (6-block analysis) in a large cluster containing the left ventral striatum (r = 0.87 at −3, 12, −3), the medial OFC (r = 0.89 at −3, 21, −6), and the left lateral OFC (r = 0.93 at −24, 21, −15) (Table 2 and Fig. 3). Inverse correlations with MCQ-SF scores were not observed. Given that there was no significant difference in the change score derived from the single-item craving score acquired during the functional magnetic resonance imaging cue session, we were unable to assess its association with brain responses.

Figure 3
Figure 3
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Table 2
Table 2
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DISCUSSION

Here we demonstrate, in treatment-seeking MJ-dependent subjects, that visual MJ cues elicit greater brain activation than non-MJ cues in the amygdala and the hippocampus. Furthermore, we report strong correlations between baseline craving and cue-elicited responses in reward-relevant brain regions, including the ventral striatum and both medial and lateral OFC. Results are consistent with more than 25 years of animal research examining the brain substrates of drug motivation (Cardinal et al., 2002) and are in close alignment with brain responses observed during exposure to cocaine, heroin, and nicotine cues in human neuroimaging studies (Grant et al., 1996; Childress et al., 1999; Franklin et al., 2007; Langleben et al., 2008).

To our knowledge, only 2 other neuroimaging groups have studied MJ cue reactivity. Both groups focused on non–treatment-seeking MJ users, demonstrating increased brain activation to MJ tactile cues in the ventral tegmental area, the thalamus, the ACC, the insula, and the amygdala (Filbey et al., 2009) and to visual cues in the OFC, the ACC, and the ventral and dorsal striatum (Cousijn et al., 2012). Filbey et al. also reported an association between the subjects' number of MJ problems and brain responses to tactile MJ cues in the OFC and the ventral striatum, and Cousijn et al. reported that the activation to cues in a subgroup of frequent MJ users with high problem-severity scores was different from brain responses in frequent MJ users with low problem-severity scores, sporadic users, and nonusers. Furthermore, Cousijn et al. observed an inverse correlation between self-reported craving and putamen activity. However, these findings were in opposition to their hypotheses, and they concluded that further research is necessary. They also observed a negative relationship between craving and activity in the dorsolateral prefrontal cortex, a cognitive control region involved in decision making; however, an explanation was not provided as to why this region would be considered as a neural correlate of craving (Cousijn et al., 2012). Our study augments the sparse literature by (1) linking a validated measure of MJ craving to enhanced activation in reward-relevant regions known to be involved in goal-directed drug-seeking behavior and (2) importantly, conducting the study in a clinically relevant MJ-dependent sample.

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A Priori Brain Regions

Our a priori hypotheses are based on an extensive preclinical literature demonstrating that a network of brain regions with strong reciprocal connections is involved in drug-seeking and drug-taking behavior. These include the lateral and medial aspects of the OFC, the amygdala, the hippocampus, the insula, and the ventral striatum.

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Brain Response During MJ Cue Exposure

We observed robust bilateral activation in the amygdala during MJ cue exposure. The amygdala exerts strong control over emotional and motivational behavior including craving and is involved in stimulus-reinforcement association learning (Di Chiara et al., 1999). We suggest that its activation here may reflect the motivational salience of the MJ stimuli. Bilateral activation of the hippocampus was also observed during MJ cue exposure. The hippocampus is important for memory consolidation. Its activation has been observed in other drug cue studies and may reflect memory of prior drug use (Franklin et al., 2007; Heinz et al., 2009). Given that the insula has been implicated in studies of drug craving (Franklin et al., 2007; Naqvi and Bechara, 2010), it was included in our a priori regions of interest. However, we did not observe either insula activation to MJ cues or correlations with insula and craving in this study. This could be related to a number of factors including sex, degree of satiation, or genetic variance in our sample (Tang et al., 2012). For example, in other work in our laboratory, we found and confirmed that a polymorphism in the SLC6A3 dopamine transporter gene modulated cigarette-smoking cue neuroactivity and that the involvement of the insula was strongly affected by whether smokers carried 1 or 2 copies of the 10-variable number tandem repeat allele (Franklin et al., 2009; Franklin et al., 2011). In future studies, a larger sample size will allow us to examine the effects of genetic variability on brain responses.

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Correlations With Baseline Craving

Baseline craving was positively correlated with activation in the OFC (both the medial and lateral regions). Functions of the OFC include storing the reward value of sensory stimuli and guiding actions on the basis of reward values; although the medial OFC is implicated in reward processing (monitoring and “holding in mind” of reward values), activation of the lateral OFC has been noted in response to aversive stimuli and during suppression of a previously rewarding response (Elliott et al., 2000; Small et al., 2001). Given the opposing functions of the medial and lateral OFC, it is intriguing that in our treatment-seeking sample, self-report of MJ craving was positively correlated with brain responses to MJ cues in both the medial and lateral OFC. Activation of the lateral OFC may reflect attempts to overcome (inhibit) craving or the ambivalence that the subjects feel about their MJ use. Although the MCQ-SF measures both the appetitive and aversive aspects of drug motivation, the aversive aspects reflect a person's wish to continue using MJ to relieve aversive feelings and symptoms (identified by factor 2, emotionality, and factor 3, expectancy). The MCQ-SF does not capture whether a person perceives MJ as aversive. As such, the MCQ-SF could not serve as a behavioral anchor to differentiate the lateral and medial OFC activation. Future studies that include tasks of craving modulation wherein subjects are instructed to attempt to either actively increase or inhibit their craving could directly test this hypothesis.

We report here that self-reported MJ craving was correlated with increased ventral striatal activity. Given that craving precipitates relapse and the ventral striatum is the final common pathway of conditioned drug responses, we demonstrate the clinically relevant link between subjective reports of drug craving and the brain substrate central for drug-seeking behavior.

The neurocorrelates of craving differ from those reported by Cousijn et al. (2012); however, numerous differences between Cousijn et al. and this study exist. For example, in the study of Cousijn et al., the subjects used MJ for approximately 3 years and smoked approximately 4 g per week, whereas our population used MJ for approximately 19 years and smoked more than 20 g per week. Our observation of ventral striatal and orbitofrontal neurocorrelates of craving suggest that the association between craving and reward-relevant brain activity may be contingent upon studying heavily dependent treatment-seeking MJ users. Another difference in study design that may also contribute to the differing results was that subjects in the Cousijn et al. study were abstinent from MJ use for 24 hours versus MJ use “as usual” in our study. Therefore, it is conceivable that abstinence creates a ceiling effect such that the arousal in reward-relevant regions was at its maximum in the Cousjin et al. study before cue exposure eliminating variability in brain responses and thus obviating the ability to acquire associations between ventral striatal activity and subjective reports of craving. Other differences that may contribute to the opposing findings include the imaging paradigm (event related vs block functional magnetic resonance imaging) and/or the time point at which the craving data were acquired (postscan vs prescan).

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Methodological Considerations

Rapidly alternating stimuli are susceptible to “carry-over” effects, which occur when nondrug cues begin to take on the affective valence associated with drug cues (Waters et al., 2005; Wilson et al., 2007; Sharma and Money, 2010). We anticipated that these “carry-over” effects would reduce our ability to detect contrast over time; however; the intersection between the number of blocks necessary to acquire a brain MJ cue response and the point at which carry-over effects would emerge was uncertain. Thus, as in previous work in our laboratory (Childress et al., 2008), we compared the results from the first half of the task (6 blocks) with those acquired over the full task (12 blocks). This examination allowed us to empirically determine that the first half of the task was less impacted by “carry-over” effects.

There were no significant differences between precue and postcue exposure in craving as assessed with the single-item craving question. The presence of a brain response in the absence of a within-session behavioral correlate is not unusual in BOLD paradigms. This is due to the inherent caveat of BOLD paradigms in which MJ and non-MJ cues are shown repeatedly in an interleaved manner such that both the brain and the behavioral responses are incited (MJ cues) and diminished (non-MJ cues). We believe that the use of a multidimensional, validated assessment of MJ craving (MCQ-SF), administered immediately before the imaging session, provided an anchored and broader measure of craving (Heishman et al., 2009).

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Significance of the Results

It is generally accepted in the addiction field that 2 overarching motivators to relapse are drug cue- and withdrawal-induced craving (Childress et al., 1993; Payne et al., 2006). In addition, a host of other factors may contribute to relapse vulnerability, including stress, menstrual cycle phase, sex, and negative affect (Cooney et al., 1997; Perkins et al., 2001; Sinha and Li, 2007; Dagher et al., 2009; Franklin and Allen, 2009). The advent of neuroimaging has led to an improved understanding of the impact of cues on relapse. At least 2 human neuroimaging studies have demonstrated that drug-related cues elicit dopamine release in the striatum (Volkow et al., 2006; Boileau et al., 2007). Furthermore, Janes et al. (2010) reported that enhanced reward-related brain responses to smoking cues and reduced functional connectivity between top-down cognitive control regions and emotive and motivational circuits predicted time to lapse in treatment-seeking smokers (Janes et al., 2010). These studies and the present study suggest that conjoining neuroimaging with clinical outcome measures will provide a unique opportunity to explore and evaluate the impact of drug cue vulnerabilities and other relapse predictors on treatment outcome.

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Strengths and Limitations

A particular strength of this study is that subjects are both MJ-dependent and treatment-seeking. Therefore, the brain responses reported here may reflect real-world treatment targets for MJ dependence. Another strength is the first demonstration of a direct link between reward-related brain responses to MJ cues and the subjective report of craving.

This study was limited in that a laboratory assay of last use of MJ was not acquired. Unfortunately, there are no reliable laboratory measurements to assess MJ use in long-term daily MJ smokers. This is because tetrahydrocannabinol, the psychoactive constituent in MJ, and its metabolites, are detectable for up to 28 days in heavy MJ users, precluding accurate determination of last use (Lowe et al., 2009). Nevertheless, subjects were not instructed to alter their MJ smoking and smoked approximately 11 joints within 24 hours of scanning, suggesting that withdrawal effects did not interfere with results.

Another limitation is that sample size is small, included only a small percentage of females, and racial diversity was low, with most subjects identifying themselves as African American. Further study in a larger sample with greater diversity would provide validation of the findings and ensure the best generalizability.

Another confound arises in that 75% of the MJ-dependent subjects also smoked cigarettes. Given that some MJ cues could be mistaken for cigarette cues, the inclusion of cigarette smokers precludes definitively dissociating nicotine- versus MJ-cue induced brain responses. However, we believe that the robust correlation between a measure specific to MJ craving (MCQ-SF) and a priori reward circuitry demonstrates specificity. These limitations should be addressed in future work by including an MJ-dependent group who do not smoke cigarettes.

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CONCLUSIONS

The present MJ-cue functional magnetic resonance imaging study showing increased brain responses in the limbic amygdala and hippocampus, and ventral striatal and orbitofrontal craving neuro-correlates adds to a growing body of literature showing similar reward-related responses to cues for a variety of drug classes, providing additional evidence that drugs of abuse activate a final common pathway. Importantly, we observed that baseline self-report of craving for MJ correlated with cue-induced brain responses in regions demonstrated in both animal and human studies to underlie both reward processing and suppression of response to reward. A better understanding of the neural mechanisms involved in drug motivation and relapse can guide the development of specific brain-targeted treatments, can help predict the response to these much-needed agents, and can provide an opportunity to tailor interventions to the needs of individual patients.

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ACKNOWLEDGMENTS

The authors thank Dr Anita Hole, Dr Carlos F. Tirado, Will Jens, Jonathan G. Hakun, Robert Fabianski, and the Center for Functional Neuroimaging at the University of Pennsylvania for their contribution to the study and preparation of the manuscript.

Clinical Trial Registration: Effectiveness Study of Dronabinol and BRENDA for the Treatment of Cannabis Withdrawal; NCT00480441; http://clinicaltrials.gov/ct2/show/NCT00480441.

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addiction; brain reward circuitry; cannabis; craving; marijuana cues; neuroimaging

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