Craving is one of the primary behavioral components of drug addiction, and cue-elicited craving is an especially powerful form of this construct. While cue-elicited craving and its underlying neurobiological mechanisms have been extensively studied with respect to alcohol and other drugs of abuse, the same cannot be said for marijuana. Cue-elicited craving for other drugs of abuse is associated with increased activity in a number of brain areas, particularly the reward pathway. This study used functional magnetic resonance imaging (fMRI) to examine cue-elicited craving for marijuana. Thirty-eight regular marijuana users abstained from use for 72 h and were presented with tactile marijuana-related and neutral cues while undergoing a fMRI scan. Several structures in the reward pathway, including the ventral tegmental area, thalamus, anterior cingulate, insula, and amygdala, demonstrated greater blood oxygen level dependent (BOLD) activation in response to the marijuana cue as compared with the neutral cue. These regions underlie motivated behavior and the attribution of incentive salience. Activation of the orbitofrontal cortex and nucleus accumbens was also positively correlated with problems related to marijuana use, such that greater BOLD activation was associated with greater number of items on a marijuana problem scale. Thus, cue-elicited craving for marijuana activates the reward neurocircuitry associated with the neuropathology of addiction, and the magnitude of activation of these structures is associated with severity of cannabis-related problems. These findings may inform the development of treatment strategies for cannabis dependence.cannabis ͉ cue ͉ fMRI ͉ reward

Because previous work has highlighted the significance of the cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes with respect to cannabis dependence (CD), the present study sought to characterize the neural mechanisms that underlie these genetic effects. To this end, we collected DNA samples and fMRI data using a cue-elicited craving paradigm in 37 3-day-abstinent regular marijuana users. The participants were grouped according to their genotype on two single nucleotide polymorphisms (SNPs) previously associated with CD phenotypes: rs2023239 in CNR1 and rs324420 in FAAH. Between-group comparisons showed that carriers of the CNR1 rs2023239 G allele had significantly greater activity in reward-related areas of the brain, such as the orbitofrontal cortex (OFC), inferior frontal gyrus (IFG), and anterior cingulate gyrus (ACG), during exposure to marijuana cues, as compared to those with the A/A genotype for this SNP. The FAAH group contrasts showed that FAAH rs324420 C homozygotes also had greater activation in widespread areas within the reward circuit, specifically in the OFC, ACG, and nucleus accumbens (NAc), as compared to the FAAH A-allele carriers. Moreover, there was a positive correlation between neural response in OFC and NAc and the total number of risk alleles (cluster-corrected p<.05). These findings are in accord with previously reported associations between CNR1 and FAAH and CD intermediate phenotypes, and suggest that the underlying mechanism of these genetic effects may be enhanced neural response in reward areas of the brain in carriers of the CNR1 G allele and FAAH C/C genotype in response to marijuana cues.

IMPORTANCE Co-occurrence of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) is common and associated with psychiatric and functional problems. Understanding whether exposure therapy is tolerable and efficacious for treating PTSD and AUD is critical to ensure that best practice treatments are available. OBJECTIVE To compare the efficacy of integrated (ie, targeting both PTSD and alcohol use) prolonged exposure (I-PE) therapy with present-centered integrated coping skills (I-CS) therapy, a more commonly available treatment, in reducing PTSD symptoms and alcohol use. DESIGN, SETTING, AND PARTICIPANTS This prospective randomized clinical trial with masked assessments considered 186 veterans seeking Veterans Affairs mental health services. A total of 119 veterans with PTSD and AUD were randomized. Data were collected from February 1, 2013, to May 31, 2017, before treatment, after treatment, and at 3-and 6-month follow-ups. Intention-to-treat analyses were performed. INTERVENTIONS Veterans underwent I-PE (Concurrent Treatment of PTSD and Substance Use Disorder Using Prolonged Exposure) or I-CS (Seeking Safety) therapy. MAIN OUTCOMES AND MEASURES A priori planned outcomes were PTSD symptoms (Clinician Administered PTSD Scale for DSM-5) and percentage of heavy drinking days (Timeline Follow-Back) before treatment, after treatment, and at 3-and 6-month follow-ups. RESULTS A total of 119 veterans (mean [SD] age, 41.6 [12.6] years; 107 [89.9%] male) were randomized. Linear mixture models found that PTSD symptoms decreased in both conditions, with a significantly greater decrease for I-PE treatment compared with I-CS treatment (treatment × time interaction, −2.83; F 3,233.1 = 4.92; Cohen d = 0.41; P = .002). The percentage of heavy drinking days improved in both conditions but was not statistically different between I-PE and I-CS treatment (treatment × time interaction, 1.8%; F 3,209.9 = 0.18; Cohen d = 0.04; P = .91). CONCLUSIONS AND RELEVANCE The I-PE arm had a greater reduction in PTSD symptoms than the I-CS arm and comparable drinking decreases. The study provides evidence that exposure therapy is more efficacious in treating PTSD than a more commonly available integrated treatment without exposure for comorbid PTSD and AUD.

Guilt related to combat trauma is highly prevalent among veterans returning from Iraq and Afghanistan. Trauma-related guilt has been associated with increased risk for posttraumatic psychopathology and poorer response to treatment. Trauma Informed Guilt Reduction (TrIGR) therapy is a 4-module cognitive-behavioral psychotherapy designed to reduce guilt related to combat trauma. The goals of this study were to describe the key elements of TrIGR and report results of a pilot study with 10 recently deployed combat veterans. Ten combat veterans referred from a VA Posttraumatic Stress Disorder (PTSD) or mental health clinic completed TrIGR over 4 to 7 sessions. Nine veterans completed the posttreatment assessment. This initial pilot suggests that TrIGR may help to reduce trauma-related guilt severity and associated distress. Changes in trauma-related guilt were highly correlated with reductions in PTSD and depression symptoms over the course of treatment, suggesting a possible mechanistic link with severity of posttraumatic psychopathology. TrIGR warrants further evaluation as an intervention for reducing guilt related to traumatic experiences in combat.