Mindfulness and clinical correlates in methamphetamine use disorder.

BACKGROUND: Mindfulness-based interventions are increasingly used for the treatment of substance use disorders, including methamphetamine use disorder (MUD). Literature indicates that trait mindfulness may play a key role in the effectiveness of these treatments on therapeutic outcome, yet no prior studies have tested for differences in trait mindfulness between individuals with MUD and healthy control participants. Such differences are important for treatment implementation. OBJECTIVES: The goals of this study were to evaluate trait mindfulness and to determine its clinical correlates in individuals with MUD. METHODS: A group of participants with MUD at varying lengths of abstinence from methamphetamine (< 1h to 90 days; mean 5.4 ± 12.5 days; N=95, 53 female, 42 male) and a healthy control group (N=65, 30 female, 35 male) completed the Mindfulness Attention Awareness Scale (MAAS). Group differences and relationships between trait mindfulness and several measures of drug use and psychiatric symptoms were evaluated. RESULTS: In participants with MUD, trait mindfulness was 10% lower than in healthy controls (p < 0.001), but it was not significantly correlated with measures of drug use or craving. Across both groups, trait mindfulness was negatively correlated with state anxiety, depression, emotional dysregulation, impulsivity, and a history of childhood trauma, while it was positively correlated with self-compassion (ps < 0.001). CONCLUSION: The deficit in trait mindfulness in MUD presents a capacity that can be targeted for improved treatment outcome with mindfulness-based therapies. Trait mindfulness is inversely related to mood dysregulation.

Decomposing risky decision-making in methamphetamine use disorder: Behavioral updating and D2 dopamine receptors.

BACKGROUND: Escalating misuse of amphetamine-type stimulants, mainly methamphetamine, has led to a staggering rise in associated overdose deaths and a pressing need to understand the basis of methamphetamine use disorder (MUD). MUD is characterized by disadvantageous decision-making, and people with MUD perform below controls on the Balloon Analogue Risk Task (BART), a laboratory test of decision-making under uncertainty. The BART presents a series of choices with progressively higher stakes-greater risk of loss and greater potential monetary reward. This research aimed to clarify whether impaired behavioral updating contributes to maladaptive performance on the BART. METHODS: Two groups (28 drug-abstinent participants with MUD and 16 healthy control participants) were compared on BART performance. Using a computational model, we deconstructed behavior into risk-taking and behavioral updating. A subset of participants (22 MUD, 15 healthy control) underwent [18F]fallypride positron emission tomography scans to measure dopamine D2-type receptor availability (BPND) in the striatum (caudate and accumbens nuclei and putamen) and the globus pallidus. RESULTS: Participants with MUD exhibited slower behavioral updating than the healthy controls (p = 0.0004, d=1.77). BPND in all four bilateral volumes of interest were higher in the healthy control group (ps < 0.005, ds < 2.16), and updating rate correlated positively with BPND in the caudate nucleus (p = 0.002), putamen (p = 0.002), and globus pallidus (p = 0.03). CONCLUSIONS: The findings indicate that behavioral updating contributes to maladaptive decision-making in MUD and suggest that dysregulation of D2-type receptor signaling in the striatum and globus pallidus contributes to this behavioral deficit.

Nicotine dependence and insula subregions: functional connectivity and cue-induced activation.

Nicotine dependence is a major predictor of relapse in people with Tobacco Use Disorder (TUD). Accordingly, therapies that reduce nicotine dependence may promote sustained abstinence from smoking. The insular cortex has been identified as a promising target in brain-based therapies for TUD, and has three major sub-regions (ventral anterior, dorsal anterior, and posterior) that serve distinct functional networks. How these subregions and associated networks contribute to nicotine dependence is not well understood, and therefore was the focus of this study. Sixty individuals (28 women; 18-45 years old), who smoked cigarettes daily, rated their level of nicotine dependence (on the Fagerström Test for Nicotine Dependence) and, after abstaining from smoking overnight (~12 h), underwent functional magnetic resonance imaging (fMRI) in a resting state. A subset of these participants (N = 48) also completing a cue-induced craving task during fMRI. Correlations between nicotine dependence and resting-state functional connectivity (RSFC) and cue-induced activation of the major insular sub-regions were evaluated. Nicotine dependence was negatively correlated with connectivity of the left and right dorsal, and left ventral anterior insula with regions within the superior parietal lobule (SPL), including the left precuneus. No relationship between posterior insula connectivity and nicotine dependence was found. Cue-induced activation in the left dorsal anterior insula was positively associated with nicotine dependence and negatively associated with RSFC of the same region with SPL, suggesting that craving-related responsivity in this subregion was greater among participants who were more dependent. These results may inform therapeutic approaches, such as brain stimulation, which may elicit differential clinical outcomes (e.g., dependence, craving) depending on the insular subnetwork that is targeted.

Denial and Diagnosis of Methamphetamine Dependence Severity.

Introduction: Denial, or lack of awareness of problems related to substance misuse, is a common feature of drug use disorders and can affect engagement in treatment and recovery. This study tested for association of denial with severity of symptoms used in the diagnosis of Methamphetamine Dependence. Methods: This secondary analysis used data from 69 participants (52.2% male) who met criteria for the diagnosis of Methamphetamine Dependence on the Structured Clinical Interview for DSM-IV (SCID). The association between diagnostic severity, determined from a SCID summary score (8 items), and denial, measured by the University of Rhode Island Change Assessment Scale (URICA) Precontemplation score, was tested by Pearson correlation. In post hoc t-tests, participants who differed on individual SCID items were compared on the Precontemplation score. The additional URICA subscales (Contemplation, Maintenance, Action) were also tested on a secondary basis. Results: SCID summary scores were negatively correlated with URICA Precontemplation scores (P = .003). Post-hoc tests revealed that participants who denied continued methamphetamine use despite persistent or recurrent problems (SCID item 6) had significantly higher Precontemplation scores than those who endorsed these problems (t = 3.066, P = .003). In contrast, positive correlations were observed between diagnostic severity and greater openness/willingness to change on the URICA (eg, Maintenance, r = .26; P = .01). Conclusions: The findings highlight the importance of a patient's insight regarding their addiction in clinical diagnosis. Because minimizing the impact of methamphetamine use may preclude or delay treatment, it is advised that self-report be supplemented to improve accuracy of diagnosis.

Cortical thickness and related depressive symptoms in early abstinence from chronic methamphetamine use.

Methamphetamine use is surging globally as a cause of morbidity and mortality. Treatment is typically sought in early abstinence, when craving and depressive symptoms are intense, contributing to relapse and poor outcomes. To advance an understanding of this problem and identify therapeutic targets, we conducted a retrospective analysis of brain structure in 89 adults with Methamphetamine Use Disorder who were in early abstinence and 89 healthy controls. Unlike most prior research, the participants did not significantly differ in age, sex and recent use of alcohol and tobacco (p-values ≥ 0.400). We analysed thickness across the entire cerebral cortex by fitting a general linear model to identify differences between groups. Follow-up regressions were performed to determine whether cortical thickness in regions showing group differences was related to craving, measured on a visual analogue scale, or to the Beck Depression Inventory score. Participants in early methamphetamine abstinence (M ± SD = 22.1 ± 25.6 days) exhibited thinner cortex in clusters within bilateral frontal, parietal, temporal, insular, and right cingulate cortices relative to controls (p-values < 0.001, corrected for multiple comparisons). Unlike craving (ß = 0.007, p = 0.947), depressive symptoms were positively correlated with cortical thickness across clusters (ß = 0.239, p = 0.030) and with thickness in the anterior cingulate cluster (ß = 0.246, p = 0.027) in the methamphetamine-dependent group. Inasmuch as anterior cingulate pathology predicts response to antidepressants for Major Depressive Disorder, cingulate structure may also identify patients with Methamphetamine Use Disorder who can benefit from antidepressant medication.

Age Influences Loss Aversion Through Effects on Posterior Cingulate Cortical Thickness.

Decision-making strategies shift during normal aging and can profoundly affect wellbeing. Although overweighing losses compared to gains, termed "loss aversion," plays an important role in choice selection, the age trajectory of this effect and how it may be influenced by associated changes in brain structure remain unclear. We therefore investigated the relationship between age and loss aversion, and tested for its mediation by cortical thinning in brain regions that are susceptible to age-related declines and are implicated in loss aversion - the insular, orbitofrontal, and anterior and posterior cingulate cortices. Healthy participants (n = 106, 17-54 years) performed the Loss Aversion Task. A subgroup (n = 78) provided structural magnetic resonance imaging scans. Loss aversion followed a curvilinear trajectory, declining in young adulthood and increasing in middle-age, and thinning of the posterior cingulate cortex mediated this trajectory. The findings suggest that beyond a threshold in middle adulthood, atrophy of the posterior cingulate cortex influences loss aversion.

Functional connectivity of the anterior insula during withdrawal from cigarette smoking.

Currently available therapies for smoking cessation have limited efficacy, and potential treatments that target specific brain regions are under evaluation, with a focus on the insula. The ventral and dorsal anterior subregions of the insula serve distinct functional networks, yet our understanding of how these subregions contribute to smoking behavior is unclear. Resting-state functional connectivity (RSFC) provides a window into network-level function associated with smoking-related internal states. The goal of this study was to determine potentially distinct relationships of ventral and dorsal anterior insula RSFC with cigarette withdrawal after brief abstinence from smoking. Forty-seven participants (24 women; 18-45 years old), who smoked cigarettes daily and were abstinent from smoking overnight (~12 h), provided self-reports of withdrawal and underwent resting-state fMRI before and after smoking the first cigarette of the day. Correlations between withdrawal and RSFC were computed separately for ventral and dorsal anterior insula seed regions in whole-brain voxel-wise analyses. Withdrawal was positively correlated with RSFC of the right ventral anterior insula and dorsal anterior cingulate cortex (dACC) before but not after smoking. The correlation was mainly due to a composite effect of craving and physical symptoms of withdrawal. These results suggest a role of right ventral anterior insula-dACC connectivity in the internal states that maintain smoking behavior (e.g., withdrawal) and present a specific neural target for brain-based therapies seeking to attenuate withdrawal symptoms in the critical early stages of smoking cessation.

Sex Differences in the Association of Cigarette Craving With Insula Structure.

BACKGROUND: Cigarette craving, which can negatively impact smoking cessation, is reportedly stronger in women than in men when they initiate abstinence from smoking. Identifying approaches to counteract craving in people of different sexes may facilitate the development of personalized treatments for Tobacco Use Disorder, which disproportionately affects women. Because cigarette craving is associated with nicotine dependence and structure of the insula, this study addressed whether a person's sex influences these associations. METHODS: The research participants (n = 99, 48 women) reported daily cigarette smoking and provided self-reports of nicotine dependence. After overnight abstinence from smoking, they underwent structural magnetic resonance imaging scanning to determine cortical thickness of the left and right anterior circular insular sulcus, and self-rated their cigarette craving before and after their first cigarette of the day. RESULTS: Women reported stronger craving than men irrespective of smoking condition (i.e., pre- and post-smoking) (P = .048), and smoking reduced craving irrespective of sex (P < .001). A 3-way interaction of sex, smoking condition, and right anterior circular insular sulcus thickness on craving (P = .033) reflected a negative association of cortical thickness with pre-smoking craving in women only (P = .012). No effects of cortical thickness in the left anterior circular insular sulcus were detected. Nicotine dependence was positively associated with craving (P < .001) across groups and sessions, with no sex differences in this association. CONCLUSIONS: A negative association of right anterior insula thickness with craving in women only suggests that this region may be a relevant therapeutic target for brain-based smoking cessation interventions in women.

The relationship between duration of abstinence and gray-matter brain structure in chronic methamphetamine users.

Background: Brain structural findings in chronic methamphetamine users have been inconsistent. Identifying contributing influences (e.g., sex, abstinence duration) can help clarify the clinical course of recovery.Objectives: We studied the effects of long-term methamphetamine abstinence on gray-matter volume. Our hypothesis was that smaller volume early in abstinence would precede long-term recovery.Methods: Individuals who used methamphetamine (≥100 g lifetime use, mandated to residential treatment for methamphetamine-positive urine; 40 men, 21 women), undergoing supervised abstinence (men: 12-400 days; women: 130-594 days), were compared to healthy controls (49 men, 36 women) using T1-weighted MRI. Volumes of orbitofrontal, anterior cingulate and parietal cortex, hippocampus, and striatum were measured using Freesurfer software. Associations of volumes with abstinence duration were tested in males and females separately because their abstinence times differed (121.5 ± 124.5 vs. 348.0 ± 128.6 days, p < 0.001); only males were studied in early abstinence. The General Linear Model was used to test effects of abstinence duration and group (methamphetamine users vs. controls).Results: In males, duration of abstinence was multivariate significant for gray-matter volumes (p = 0.017). Abstinence duration was associated with increases in volumes of the orbitofrontal and parietal cortices (ps = 0.031, 0.016) and hippocampi (ps = 0.044). Irrespective of abstinence, male methamphetamine users had smaller hippocampi than male controls (p = 0.008). Females showed no significant effects of group or abstinence.Conclusions: In males, abstinence from methamphetamine appears to result in volumetric increases in regions important for cognitive function, which may affect recovery during the course of treatment. Data from the period of early abstinence are required to evaluate volumetric changes in females.

CYP2D6 genotype may moderate measures of brain structure in methamphetamine users.

Chronic methamphetamine use is linked to abnormalities in brain structure, which may reflect neurotoxicity related to metabolism of the drug. As the cytochrome P450 2D6 (CYP2D6) enzyme is central to the metabolism of methamphetamine, genotypic variation in its activity may moderate effects of methamphetamine on brain structure and function. This study explored the relationship between CYP2D6 genotype and measures of brain structure and cognition in methamphetamine users. Based on the function of genetic variants, a CYP2D6 activity score was determined in 82 methamphetamine-dependent (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria) and 79 healthy-control participants who completed tests of cognitive function (i.e., attention, memory, and executive function); most were also evaluated with structural magnetic resonance imaging (MRI) (66 methamphetamine-dependent and 52 controls). The relationship between CYP2D6 activity score and whole brain cortical thickness differed by group (interaction p = 0.024), as increasing CYP2D6 activity was associated with thinner cortical thickness in the methamphetamine users (ß = -0.254; p = 0.035), but not in control subjects (ß = 0.095; p = 0.52). Interactions between CYP2D6 activity and group were nonsignificant for hippocampal volume (ps > 0.05), but both hippocampi showed trends similar to those observed for cortical thickness (negative relationships in methamphetamine users [ps < 0.05], and no relationships in controls [ps > 0.50]). Methamphetamine users had lower cognitive scores than control subjects (p = 0.007), but there was no interaction between CYP2D6 activity score and group on cognition (p > 0.05). Results suggest that CYP2D6 genotypes linked to higher enzymatic activity may confer risk for methamphetamine-induced deficits in brain structure. The behavioral consequences of these effects are unclear and warrant additional investigation.

Neural Basis of Smoking-Related Difficulties in Emotion Regulation.

BACKGROUND: Negative emotional states contribute to cigarette smoking, and difficulties in regulating these states can hinder smoking cessation. Understanding the neural bases of these difficulties in smokers may facilitate development of novel therapies for Tobacco Use Disorder. METHODS: Thirty-seven participants (18 smokers, 19 nonsmokers; 16-21 years old) completed the Difficulties in Emotion Regulation Scale (DERS), which is comprised of 6 subscales (lack of emotional clarity, lack of emotional awareness, limited access to emotion regulation strategies, nonacceptance of emotional responses, difficulties engaging in goal-directed behaviors, and impulse control difficulties) that combine to provide a total score. Participants also underwent functional magnetic resonance imaging to determine resting-state functional connectivity of the amygdala. Separate ANOVAs were used to determine group differences in self-reports on the DERS. Voxel-wise linear mixed models were performed to determine whether group influenced relationships between whole-brain functional connectivity of the amygdala and scores on the DERS. RESULTS: Compared with nonsmokers, smokers reported greater difficulties in emotion regulation, denoted by higher total scores on the DERS. Group differences were observed on a subscale of lack of emotional clarity, but no other subscale differences on the DERS were observed. Nonsmokers exhibited a greater negative correlation than smokers between lack of emotional clarity scores and connectivity of the amygdala with the left inferior frontal gyrus. Finally, this amygdala-to-left inferior frontal gyrus connectivity was weaker in smokers than in nonsmokers. CONCLUSIONS: These findings suggest that difficulties in emotion regulation in smokers are at least partially due to lack of emotional clarity. Given the role of the inferior frontal gyrus in understanding emotional states, strengthening connectivity between the amygdala and the inferior frontal gyrus may improve emotional clarity to help smokers regulate their negative emotions, thereby improving their ability to quit smoking.

No effect of attentional bias modification training in methamphetamine users receiving residential treatment.

RATIONALE: Attentional bias toward drug-related stimuli is a feature of drug addiction that is linked to craving and drug-seeking behavior. OBJECTIVES/METHOD: An attentional bias modification (ABM) program was tested in 42 methamphetamine-dependent clients (DSM-IV criteria) receiving residential treatment for their drug use. Participants were randomly assigned to one of two groups (N = 21 each), receiving 12 sessions of either computerized ABM training (designed to train attention away from methamphetamine stimuli 100% of the time) or an attentional control condition (designed to train attention away from methamphetamine stimuli 50% of the time). Outcome measures included attentional bias to methamphetamine-related stimuli on a probe detection task, self-reported craving, and preferences to view methamphetamine-related images on a Simulated Drug Choice Task. A subset of participants (N = 17) also underwent fMRI in a cue-induced craving paradigm. RESULTS: Poor split-half reliability was observed for the probe detection task. Using this task, attentional bias toward methamphetamine-related stimuli was greater after training than at baseline, irrespective of group (p = 0.037). Spontaneous and cue-induced methamphetamine craving diminished with time (ps < 0.01), but ABM training did not influence these effects (group by time interactions, ps > 0.05). ABM training did not influence selection of methamphetamine-related pictures in the Simulated Drug Choice task (p > 0.05). In the fMRI assessment, cue-induced activation in the ventromedial prefrontal cortex was reduced over time, without an effect of ABM training. CONCLUSIONS: ABM training did not improve several clinically relevant variables in treatment-seeking methamphetamine users. Additional research is needed to improve the measurement of attentional bias.

Cognitive deficit in methamphetamine users relative to childhood academic performance: link to cortical thickness.

Individuals with cognitive problems may be predisposed to develop substance use disorders; therefore, differences in cognitive function between methamphetamine users and control participants may be attributable to premorbid factors rather than methamphetamine use. The goal of this study was to clarify the extent to which this is the case. Childhood academic transcripts were obtained for 37 methamphetamine-dependent adults and 41 control participants of similar educational level and premorbid IQ. Each participant completed a comprehensive cognitive battery and received a structural magnetic resonance imaging scan. Data from control participants and linear regression were used to develop a normative model to describe the relationship between childhood academic performance and scores on the cognitive battery. Using this model, cognitive performance of methamphetamine users was predicted from their premorbid academic scores. Results indicated that methamphetamine users' childhood grade point average was significantly lower than that of the control group (p < 0.05). Further, methamphetamine users' overall cognitive performance was lower than was predicted from their grade point average prior to methamphetamine use (p = 0.001), with specific deficits in attention/concentration and memory (ps < 0.01). Memory deficits were associated with lower whole-brain cortical thickness (p < 0.05). Thus, in addition to having an apparent premorbid weakness in cognition, methamphetamine users exhibit subsequent cognitive function that is significantly lower than premorbid estimates would predict. The results support the view that chronic methamphetamine use causes a decline in cognition and/or a failure to develop normative cognitive abilities, although aside from methamphetamine use per se, other drug use and unidentified factors likely contribute to the observed effects.

Mixture models of delay discounting and smoking behavior.

BACKGROUND: Smokers exhibit an unusually high willingness to forgo a delayed reward of greater magnitude to receive a smaller, more immediate reward. The functional form of such "delay discounting" behavior is central to the discounting-based operationalization of impulsivity, and has implications for theories regarding the basis of steep discounting among smokers and treatment approaches to addiction. OBJECTIVES: We examined the discounting behavior of current smokers, ex-smokers, and never-smokers to determine whether the functional form of discounting differs between these groups. METHODS: Participants completed a 27-item delay discounting questionnaire (25). We used finite mixture modeling in analyzing data as the product of two simultaneous data-generating processes (DGPs), a hyperbolic function and an exponential function, and compared results to a quasi-hyperbolic (QH) approximation, in a relatively large sample (n = 1205). RESULTS: Consistent with prior reports, current smokers exhibited steeper discounting relative to never-smokers across exponential, hyperbolic, and QH models. A mixture model provided significant support for exponential and hyperbolic discounting in the data, and both accounted for roughly 50% of the participants' choices. This mixture model showed a statistically significantly better fit to the data than the exponential, hyperbolic, or QH functions alone. Contrary to the prevailing view, current smokers were not more likely to discount hyperbolically than nonsmokers, and, thus, were not more prone to time-inconsistent discounting. CONCLUSIONS: The results inform the interpretation of steep discounting among smokers and suggest that treatment approaches could be tailored to the type of discounting behavior that smokers exhibit.

Increased self-reported impulsivity in methamphetamine users maintaining drug abstinence.

BACKGROUND: Impulsivity has been proposed as an important factor in the initiation and maintenance of addiction. Indirect evidence suggests that some methamphetamine users report less impulsivity when they are using methamphetamine compared to when abstaining from drug use, but this hypothesis has not been directly tested. OBJECTIVES/METHODS: In this study, self-reports of impulsivity were obtained from 32 methamphetamine-dependent (DSM-IV) research participants and 41 healthy control subjects, using the Barratt Impulsiveness Scale-11. The methamphetamine users were assessed during an active period of methamphetamine use, as determined through urinalysis, and again after approximately 1 week of confirmed abstinence. Control subjects likewise completed two assessments. A subset of participants also completed serial assessments of the Beck Depression Inventory (Methamphetamine Group, N = 17, Control Group, N = 38) and the Methamphetamine Withdrawal Questionnaire (Methamphetamine Group, N = 12). RESULTS: There was a significant interaction of group with time on impulsivity (p = 0.044), reflecting a significant increase from the first to the second assessment in the methamphetamine users (p = 0.013), but no change among healthy control subjects. In contrast, depressive and withdrawal symptoms significantly decreased between the first and second assessments in the methamphetamine users (ps ≤0.01). Change in impulsivity in methamphetamine users was not significantly correlated with change in withdrawal or depression (ps >0.05). CONCLUSIONS: These findings suggest that methamphetamine users report more impulsivity when abstaining from drug use, an effect that is not significantly related to methamphetamine withdrawal. Attenuation of impulsivity may reinforce continued methamphetamine use in these individuals.

Sex Differences in Midbrain Dopamine D2-Type Receptor Availability and Association with Nicotine Dependence.

Women differ from men in smoking-related behaviors, among them a greater difficulty in quitting smoking. Unlike female smokers, male smokers have lower striatal dopamine D2-type receptor availability (binding potential, BPND) than nonsmokers and exhibit greater smoking-induced striatal dopamine release. Because dopamine D2-type autoreceptors in the midbrain influence striatal dopamine release, a function that has been linked to addiction, we tested for sex differences in midbrain dopamine D2-type receptor BPND and in relationships between midbrain BPND, nicotine dependence and striatal dopamine D2-type receptor BPND. Positron emission tomography was used with [18F]fallypride to measure BPND in a midbrain region, encompassing the substantia nigra and ventral tegmental area, in 18 daily smokers (7 women, 11 men) and 19 nonsmokers (10 women, 9 men). A significant sex-by-group interaction reflected greater midbrain BPND in female but not male smokers than in corresponding nonsmokers (F1, 32=5.089, p=0.03). Midbrain BPND was positively correlated with BPND in the caudate nucleus and putamen in nonsmokers and female smokers but not in male smokers and with nicotine dependence in female but not in male smokers. Striatal BPND was correlated negatively with nicotine dependence and smoking exposure. These findings extend observations on dopamine D2-type receptors in smokers and suggest a sex difference in how midbrain dopamine D2-type autoreceptors influence nicotine dependence.

Emotion dysregulation and amygdala dopamine D2-type receptor availability in methamphetamine users.

BACKGROUND: Individuals who use methamphetamine chronically exhibit emotional and dopaminergic neurochemical deficits. Although the amygdala has an important role in emotion processing and receives dopaminergic innervation, little is known about how dopamine transmission in this region contributes to emotion regulation. This investigation aimed to evaluate emotion regulation in subjects who met DSM-IV criteria for methamphetamine dependence, and to test for a relationship between self-reports of difficulty in emotion regulation and D2-type dopamine receptor availability in the amygdala. METHOD: Ninety-four methamphetamine-using and 102 healthy-control subjects completed the Difficulties in Emotion Regulation Scale (DERS); 33 of those who used methamphetamine completed the Addiction Severity Index (ASI). A subset of 27 methamphetamine-group and 20 control-group subjects completed positron emission tomography with [(18)F]fallypride to assay amygdala D2-type dopamine receptor availability, measured as binding potential (BPND). RESULTS: The methamphetamine group scored higher than the control group on the DERS total score (p<0.001), with DERS total score positively correlated with the Drug Composite Score on the ASI (p=0.02) in the methamphetamine group. The DERS total score was positively correlated with amygdala BPND in both groups and the combined group of participants (combined: r=0.331, p=0.02), and the groups did not differ in this relationship. CONCLUSION: These findings highlight problems with emotion regulation linked to methamphetamine use, possibly contributing to personal and interpersonal behavioral problems. They also suggest that D2-type dopamine receptors in the amygdala contribute to emotion regulation in both healthy and methamphetamine-using subjects.

Striatal Dopamine D2/D3 Receptor Availability Is Associated with Executive Function in Healthy Controls but Not Methamphetamine Users.

BACKGROUND: Dopamine D2/D3 receptor availability in the striatum has been linked with executive function in healthy individuals, and is below control levels among drug addicts, possibly contributing to diminished executive function in the latter group. This study tested for an association of striatal D2/D3 receptor availability with a measure of executive function among research participants who met DSM-IV criteria for methamphetamine dependence. METHODS: Methamphetamine users and non-user controls (n = 18 per group) completed the Wisconsin Card Sorting Test and positron emission tomography with [18F]fallypride. RESULTS: The methamphetamine users displayed significantly lower striatal D2/D3 receptor availability on average than controls after controlling for age and education (p = 0.008), but they did not register greater proportions of either perseverative or non-perseverative errors when controlling for education (both ps ≥ 0.622). The proportion of non-perseverative, but not perseverative, errors was negatively correlated with striatal D2/D3 receptor availability among controls (r = -0.588, p = 0.010), but not methamphetamine users (r = 0.281, p = 0.258), and the group-wise interaction was significant (p = 0.030). CONCLUSIONS: These results suggest that cognitive flexibility, as measured by perseverative errors on the Wisconsin Card Sorting Test, is not determined by signaling through striatal D2/D3 receptors in healthy controls, and that in stimulant abusers, who have lower D2/D3 receptor availability, compensation can effectively maintain other executive functions, which are associated with D2/D3 receptor signaling in controls.

Denial in methamphetamine users: Associations with cognition and functional connectivity in brain.

BACKGROUND: Despite harmful consequences of drug addiction, it is common for individuals with substance use disorders to deny having problems with drugs. Emerging evidence suggests that some drug users lack insight into their behavior due to neurocognitive dysfunction, but little research has examined potential neurocognitive contributions to denial. METHODS: This study explored the relationship between denial, cognitive performance and functional connectivity in brain. The participants were 58 non-treatment-seeking, methamphetamine-dependent participants who completed the URICA precontemplation scale, a self-report measure of denial of drug problems warranting change, as well as a cognitive test battery. A subset of participants (N = 21) had functional MRI scans assessing resting-state functional connectivity. Given literature indicating roles of the rostral anterior cingulate (rACC), anterior insula and precuneus in self-awareness, relationships between denial and resting-state connectivity were tested using seeds placed in these regions. RESULTS: The results revealed a negative relationship between denial and an overall cognitive battery score (p = 0.001), the effect being driven particularly by performance on tests of memory and executive function. Denial was negatively associated with strength of connectivity between the rACC and regions of the frontal lobe (precentral gyri, left ventromedial prefrontal cortex, left orbitofrontal cortex), limbic system (left amygdala, left hippocampus and left parahippocampal gyrus), occipital lobes and cerebellum; and between the precuneus and the midbrain and cerebellum. Anterior insula connectivity was unrelated to denial. CONCLUSIONS: These findings suggest that denial by methamphetamine users is linked with a cognitive and neural phenotype that may impede the development of insight into their behavior.

Low Dopamine D2/D3 Receptor Availability is Associated with Steep Discounting of Delayed Rewards in Methamphetamine Dependence.

BACKGROUND: Individuals with substance use disorders typically exhibit a predilection toward instant gratification with apparent disregard for the future consequences of their actions. Indirect evidence suggests that low dopamine D2-type receptor availability in the striatum contributes to the propensity of these individuals to sacrifice long-term goals for short-term gain; however, this possibility has not been tested directly. We investigated whether striatal D2/D3 receptor availability is negatively correlated with the preference for smaller, more immediate rewards over larger, delayed alternatives among research participants who met DSM-IV criteria for methamphetamine (MA) dependence. METHODS: Fifty-four adults (n = 27 each: MA-dependent, non-user controls) completed the Kirby Monetary Choice Questionnaire, and underwent positron emission tomography scanning with [(18)F]fallypride. RESULTS: MA users displayed steeper temporal discounting (p = 0.030) and lower striatal D2/D3 receptor availability (p < 0.0005) than controls. Discount rate was negatively correlated with striatal D2/D3 receptor availability, with the relationship reaching statistical significance in the combined sample (r = -0.291, p = 0.016) and among MA users alone (r = -0.342, p = 0.041), but not among controls alone (r = -0.179, p = 0.185); the slopes did not differ significantly between MA users and controls (p = 0.5). CONCLUSIONS: These results provide the first direct evidence of a link between deficient D2/D3 receptor availability and steep temporal discounting. This finding fits with reports that low striatal D2/D3 receptor availability is associated with a higher risk of relapse among stimulant users, and may help to explain why some individuals choose to continue using drugs despite knowledge of their eventual negative consequences. Future research directions and therapeutic implications are discussed.