A dose-ranging study of the physiological and self-reported effects of repeated, rapid infusion of remifentanil in people with opioid use disorder and physical dependence on fentanyl.

RATIONALE: Understanding mechanisms of drug use decisions will inform the development of treatments for opioid use disorder (OUD). Decision-making experiments using neurobehavioral approaches require many trials or events of interest for statistical analysis, but the pharmacokinetics of most opioids limit dosing in humans. OBJECTIVES: This experiment characterized the effects of repeated infusions of the ultra-short acting opioid remifentanil in people with OUD and physical opioid dependence. METHODS: An inpatient study using a within-subjects, single-blind, escalating, within-session, pre-post design was conducted. Seven (3 female) subjects were maintained on oral oxycodone (40-60 mg, 4x/day = 160-240 total mg/day) for seven days prior to the dose-ranging session. Subjects received infusions of three ascending remifentanil doses (0.03, 0.1, 0.3 mcg/kg/infusion in 2 subjects; 0.1, 0.3, 1.0 mcg/kg/infusion in 5 subjects) every minute for 40 min per dose, with infusions administered over 5 s to model naturalistic delivery rates. End tidal carbon dioxide, respiration rate, oxygen saturation (SpO2) and heart rate were measured continuously. Blood pressure (BP), pupil diameter and self-reported drug effects were measured every 5 min. RESULTS: Pupil diameter, SpO2 and systolic BP decreased, and ratings on prototypic subjective effects questionnaire items increased, as a function of remifentanil dose. The number of infusions held because of sedation or physiological parameters exceeding predetermined cutoffs also increased with dose. CONCLUSIONS: This experiment established doses and procedures for the safe delivery of rapid, repeated remifentanil infusions to individuals with OUD and physical fentanyl dependence, which can be applied to the mechanistic study of opioid use decisions.

Confronting Colonialism in Canadian Dietetics Curricula.

Many Canadian universities have committed to becoming more accountable to Indigenous Peoples by confronting the systemic, historical, and ongoing colonialism and anti-Indigenous racism that shape their campuses. In this Perspective in Practice piece, we invite the field of dietetics to consider how colonialism has shaped dietetics research, teaching, and practice. We also consider how we might transform the field of dietetics in ways that accept settler responsibility for interrupting racism and colonial harm; support the resurgence of Indigenous food and health practices; and recognise the connections between struggles to ensure that Indigenous Peoples can access culturally appropriate food and health care, and struggles for Indigenous sovereignty and self-determination. We do this by reviewing the history of the dietetics field, examining critical responses to existing Indigenisation and decolonisation efforts, and reflecting on recent changes to required dietetics competencies. We argue that curricula in dietetics programmes must teach the history of the colonial food system and equip students to identify and interrupt the individual and institutional colonial dynamics that contribute to the ongoing dispossession of Indigenous Peoples' lands and food sources and negatively impact Indigenous patients.

Combining noninvasive brain stimulation with behavioral pharmacology methods to study mechanisms of substance use disorder.

Psychotropic drugs and transcranial magnetic stimulation (TMS) are effective for treating certain psychiatric conditions. Drugs and TMS have also been used as tools to explore the relationship between brain function and behavior in humans. Combining centrally acting drugs and TMS has proven useful for characterizing the neural basis of movement. This combined intervention approach also holds promise for improving our understanding of the mechanisms underlying disordered behavior associated with psychiatric conditions, including addiction, though challenges exist. For example, altered neocortical function has been implicated in substance use disorder, but the relationship between acute neuromodulation of neocortex with TMS and direct effects on addiction-related behaviors is not well established. We propose that the combination of human behavioral pharmacology methods with TMS can be leveraged to help establish these links. This perspective article describes an ongoing study that combines the administration of delta-9-tetrahydrocannabinol (THC), the main psychoactive compound in cannabis, with neuroimaging-guided TMS in individuals with problematic cannabis use. The study examines the impact of the left dorsolateral prefrontal cortex (DLPFC) stimulation on cognitive outcomes impacted by THC intoxication, including the subjective response to THC and the impairing effects of THC on behavioral performance. A framework for integrating TMS with human behavioral pharmacology methods, along with key details of the study design, are presented. We also discuss challenges, alternatives, and future directions.

Exponentiated model of drug demand is preferred over exponential models in people with daily/near daily cannabis use.

Cannabis use is a growing health concern emphasizing the need to better understand the complexities of drug choice in people with daily/near daily cannabis use. Hypothetical purchasing tasks provide a means to collect data on drug consumption behavior without requiring drug administration and have been used to isolate behavioral economic factors of choice, including facets of drug demand in substance using populations. Various models are used for analyzing hypothetical purchasing task data, but challenges exist in modeling data sets with consumption values of zero. Additionally, a single model or approach may not be best for all commodities and drug classes. This study compared two common demand models (exponential vs. exponentiated) applied to identical hypothetical purchasing task data from 21 (n = 21) individuals with daily/near daily cannabis use. The exponential model was fit using three common levels of replacement values for zero consumption (.1, .01, .001) and compared to the exponentiated model without replacement values. We found that the exponentiated model produced significantly better model fits for individual data, compared to all exponential models. Additionally, significant differences for model derived values of demand elasticity and intensity were found between the exponentiated model and different levels of the exponential model. We conclude that the exponentiated model is preferred over the exponential model for performing demand analysis on hypothetical purchasing task data from individuals with daily/near daily cannabis use. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Heightened motor impairment as a protective factor against heavy drinking in individuals with high alcohol-induced disinhibition.

BACKGROUND: Behavioral disinhibition and motor impairment are both acutely elevated following alcohol consumption, and individual differences in sensitivity to alcohol-induced increases in these effects are associated with drinking habits. Specifically, high alcohol-induced disinhibition and low motor impairment have been identified as separate markers for alcohol-related problems. This study tested the degree to which alcohol-induced disinhibition and motor impairment jointly predict heavy drinking. We hypothesized that heavier drinkers would exhibit a combination of high sensitivity to alcohol-induced disinhibition and low sensitivity to its motor impairing effect. METHODS: Data from three studies were aggregated to comprise a sample of 96 young adults. Participants' motor coordination (grooved pegboard) and behavioral disinhibition (cued go/no-go) were assessed following consumption of 0.65 g/kg alcohol and a placebo during separate sessions. RESULTS: As BAC was ascending, alcohol increased motor impairment and disinhibition compared to placebo. Combined effects at this time of alcohol on motor impairment and disinhibition predicted typical drinking habits. Specifically, a combination of high sensitivity to alcohol's disinhibiting effect and low sensitivity to its motor impairing effect was associated with heavy drinking. As BAC was descending, only reduced sensitivity to motor impairment remained as a predictor of heavy drinking. CONCLUSIONS: The findings suggest that although motor impairment following alcohol consumption is associated with certain negative outcomes (e.g., increased risk for physical injury and motor vehicle accidents), such heightened motor impairment from alcohol may actually serve as a protective factor against the excessive drinking that can accompany the disinhibiting effect of alcohol.

"Sensitivity to the disinhibiting effect of alcohol: The role of trait impulsivity and sex differences": Clarification.

Reports a clarification to "Sensitivity to the disinhibiting effect of alcohol: The role of trait impulsivity and sex differences" by Holley C. Allen, Michael J. Wesley, Jessica Weafer and Mark T. Fillmore (Psychology of Addictive Behaviors, Advanced Online Publication, May 05, 2022, np). In the original article, simultaneous linear regression analyses examined the role of sex and trait impulsivity differences in participants' unintoxicated level of behavioral impulsivity and sensitivity to alcohol-induced increases in disinhibition. High levels of trait impulsivity were associated with higher unintoxicated disinhibition; however, no sex difference in this relationship was obtained. Similarly, high attention impulsivity was associated with elevated unintoxicated disinhibition, but no sex difference in this relationship was obtained. It is likely that the inclusion of participants with ADHD in the original analyses disproportionately accounted for the sex differences initially obtained. This reanalysis suggests that behavioral disinhibition serves as a broad indicator of trait impulsivity in both men and women. (The following abstract of the original article appeared in record 2022-58551-001). OBJECTIVE: Higher trait impulsivity is associated with more impulsive responding on certain behavioral measures of disinhibition. Additionally, behavioral disinhibition is acutely elevated following alcohol consumption. The present study examined the possibility that trait impulsivity may predict individual differences in sensitivity to the disinhibiting effect of alcohol. Specifically, the present study tested the hypothesis that those with elevated trait impulsivity also experience heightened sensitivity to the disinhibiting effect of alcohol, which might further compound their tendency toward impulsive action. METHOD: To test this hypothesis, data from six studies were aggregated to comprise a sample of 190 young adults. Participants completed the Barratt Impulsiveness Scale-11 (BIS-11), and behavioral disinhibition was assessed using a cued go/no-go task following consumption of 0.65 g/kg alcohol and a placebo. RESULTS: Alcohol increased disinhibition overall, but higher impulsivity did not predict increased sensitivity to alcohol-induced disinhibition. In men, higher levels of trait impulsivity predicted heightened disinhibition in the unintoxicated state following placebo, but this relationship was not present in women. CONCLUSIONS: These findings suggest significant sex differences in the relationship between trait impulsivity and disinhibition. This sex difference may explain inconsistent research findings in studies assessing links between trait and behavioral measures of impulsivity. The data also point to trait impulsivity and sensitivity to alcohol-induced disinhibition as independent constructs. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Sensitivity to the disinhibiting effect of alcohol: The role of trait impulsivity and sex differences.

[Clarification Notice: A clarification for this article was reported online in Psychology of Addictive Behaviors on Aug 18 2022 (see record 2022-92429-001). In the original article, simultaneous linear regression analyses examined the role of sex and trait impulsivity differences in participants' unintoxicated level of behavioral impulsivity and sensitivity to alcohol-induced increases in disinhibition. High levels of trait impulsivity were associated with higher unintoxicated disinhibition; however, no sex difference in this relationship was obtained. Similarly, high attention impulsivity was associated with elevated unintoxicated disinhibition, but no sex difference in this relationship was obtained. It is likely that the inclusion of participants with ADHD in the original analyses disproportionately accounted for the sex differences initially obtained. This reanalysis suggests that behavioral disinhibition serves as a broad indicator of trait impulsivity in both men and women.] Objective: Higher trait impulsivity is associated with more impulsive responding on certain behavioral measures of disinhibition. Additionally, behavioral disinhibition is acutely elevated following alcohol consumption. The present study examined the possibility that trait impulsivity may predict individual differences in sensitivity to the disinhibiting effect of alcohol. Specifically, the present study tested the hypothesis that those with elevated trait impulsivity also experience heightened sensitivity to the disinhibiting effect of alcohol, which might further compound their tendency toward impulsive action. METHOD: To test this hypothesis, data from six studies were aggregated to comprise a sample of 190 young adults. Participants completed the Barratt Impulsiveness Scale-11 (BIS-11), and behavioral disinhibition was assessed using a cued go/no-go task following consumption of 0.65 g/kg alcohol and a placebo. RESULTS: Alcohol increased disinhibition overall, but higher impulsivity did not predict increased sensitivity to alcohol-induced disinhibition. In men, higher levels of trait impulsivity predicted heightened disinhibition in the unintoxicated state following placebo, but this relationship was not present in women. CONCLUSIONS: These findings suggest significant sex differences in the relationship between trait impulsivity and disinhibition. This sex difference may explain inconsistent research findings in studies assessing links between trait and behavioral measures of impulsivity. The data also point to trait impulsivity and sensitivity to alcohol-induced disinhibition as independent constructs. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Influence of pregabalin maintenance on cannabis effects and related behaviors in daily cannabis users.

No medications are approved for cannabis use disorder (CUD), though a small clinical trial demonstrated that the voltage-dependent calcium channel (VDCC) ligand gabapentin reduced cannabis use in treatment seekers. VDCCs are modulated by cannabinoid (CB) ligands, and there are shared effects between CB agonists and VDCC ligands. This overlapping neuropharmacology and the initial clinical results supported the evaluation of pregabalin, a "next-generation" VDCC ligand, as a CUD medication. Two separate placebo-controlled, double-blind, counterbalanced, within-subjects human laboratory studies tested placebo and 300 (N = 2 females, 11 males; Experiment [EXP] 1) or 450 (N = 3 females, 11 males; EXP 2) mg/day pregabalin in cannabis users who were not seeking treatment or trying to reduce/quit their cannabis use. The protocol consisted of two outpatient maintenance phases (11 days in EXP 1 and 15 days in EXP 2) that concluded with four experimental sessions within each phase. During experimental sessions, maintenance continued, and participants completed two 2-day blocks of sampling and self-administration sessions to determine the reinforcing effects of smoked cannabis (0% and 5.9% delta9-tetrahydrocannabinol [THC]), as well as subjective, attentional bias, performance, and physiological responses. In addition, naturalistic cannabis use, side effects, sleep quality, craving, and other self-reported substance use were measured during pregabalin maintenance. Cannabis was self-administered and produced prototypical effects, but pregabalin generally did not impact the effects of cannabis or alter naturalistic use. These human laboratory results in cannabis users not trying to reduce/quit their use do not support the efficacy of pregabalin as a stand-alone pharmacotherapy for CUD. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Exploratory examination of the effects of d-amphetamine on active-state functional connectivity: Influence of impulsivity and sensation-seeking status.

Recent advances in diagnostic research identified that individuals with higher impulsivity and sensation-seeking scores tend to report more positive subjective responses to stimulant drugs such as amphetamine. The current exploratory study hypothesized that differences in underlying mesocorticolimbic circuitry may mediate the relationship between personality and responses to stimulants due to its previously established implication in reward processes as well as the overlap between its dopaminergic projections and the pharmacodynamics of many stimulants. Forty participants (20 female) were recruited with relatively high- and low-impulsivity and sensation-seeking scores as defined by the Zuckerman-Kuhlman Personality Questionnaire (Form IIIR; Zuckerman, Kuhlman, Joireman, Teta, & Kraft, 1993) for a double-blind, placebo-controlled, intranasal amphetamine administration study conducted within an MRI scanner. Active state seed-to-voxel connectivity analyses assessed the effects of amphetamine, personality, subjective responses to amphetamine, and their interactions with mesocorticolimbic seeds on data collected during monetary incentive delay and go/no-go task performance. Results indicated that amphetamine administration largely disrupted brain activity as evidenced by connectivity values shifting toward no correlation among brain stem, striatal, and frontal cortex regions. Additionally, associations of impulsivity and connectivity between ventral tegmental and medial orbitofrontal as well as lateral orbitofrontal and putamen regions were inverted from negative to positive during the placebo and amphetamine conditions, respectively. Personality was unrelated to subjective responses to amphetamine. Results are interpreted as providing evidence of underlying differences in mesocorticolimbic circuitry being a potential target for requisite diagnostic and treatment strategies implicated with stimulant use disorders, but further research is needed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Predicting their past: Machine language learning can discriminate the brains of chimpanzees with different early-life social rearing experiences.

Early life experiences, including separation from caregivers, can result in substantial, persistent effects on neural, behavioral, and physiological systems as is evidenced in a long-standing literature and consistent findings across species, populations, and experimental models. In humans and other animals, differential rearing conditions can affect brain structure and function. We tested for whole brain patterns of morphological difference between 108 chimpanzees reared typically with their mothers (MR; N = 54) and those reared decades ago in a nursery with peers, human caregivers, and environmental enrichment (NR; N = 54). We applied support vector machine (SVM) learning to archival MRI images of chimpanzee brains to test whether we could, with any degree of significant probability, retrospectively classify subjects as MR and NR based on variation in gray matter within the entire brain. We could accurately discriminate MR and NR chimpanzee brains with nearly 70% accuracy. The combined brain regions discriminating the two rearing groups were widespread throughout the cortex. We believe this is the first report using machine language learning as an analytic method for discriminating nonhuman primate brains based on early rearing experiences. In this sense, the approach and findings are novel, and we hope they stimulate application of the technique to studies on neural outcomes associated with early experiences. The findings underscore the potential for infant separation from caregivers to leave a long-term mark on the developing brain.

Acute rewarding and disinhibiting effects of alcohol as indicators of drinking habits.

RATIONALE: Laboratory studies have reliably shown that heightened sensitivity to the rewarding effects of alcohol is associated with heavier drinking patterns. More recently, there has been research to suggest that heightened sensitivity to the disinhibiting effects of alcohol might also contribute to drinking habits. Most research on the acute effects of alcohol has focused on drinking magnitudes averaged across participants with little attention paid to how individual differences influence alcohol abuse potential. In large part, this is due to limited sample sizes in previous laboratory studies. OBJECTIVES: This study overcomes previous limitations by testing the degree to which individual differences in acute sensitivity and tolerance to the rewarding and disinhibiting effects of alcohol relate to drinking behavior in a large sample size. METHODS: Data from six laboratory studies were aggregated to comprise a sample of 181 adults. Participants' level of "liking" (the effects of alcohol) and disinhibition were assessed following 0.65 g/kg alcohol once during the ascending limb of the blood alcohol concentration (BAC) curve and again at the same BAC during the descending limb of the curve. The measures were also assessed following placebo. RESULTS: Alcohol increased ratings of liking and behavioral disinhibition. Heavier drinking was associated with heightened sensitivity to liking on the ascending limb. Additionally, those who showed reduced acute tolerance to both disinhibition and liking were also heavier drinkers. CONCLUSIONS: These data suggest that individual variability in liking the effects of alcohol and persistent disinhibition are key indicators of drinking habits.

Effects of multisensory stop signals on alcohol-induced disinhibition in adults with ADHD.

Multisensory environments facilitate behavioral functioning in humans. The redundant signal effect (RSE) refers to the observation that individuals respond more quickly to stimuli when information is presented as multisensory, redundant stimuli (e.g., aurally and visually) rather than as a single stimulus presented to either modality alone. RSE appears to be because of specialized multisensory neurons in the superior colliculus and association cortex that allow intersensory coactivation between the visual and auditory channels. Our studies show that the disinhibiting effects of alcohol are attenuated when stop signals are multisensory (e.g., Visual + Auditory stop signals) versus unisensory (Roberts, Monem, & Fillmore, 2016). The present study expanded on this research to test the degree to which multisensory stop signals could also attenuate the disinhibiting effects of alcohol in those with attention-deficit hyperactivity disorder (ADHD), a clinical population characterized by poor impulse control. The study compared young adults with ADHD (n = 22) with healthy controls (n = 22) and examined the acute impairing effect of alcohol on response inhibition to stop signals that were presented as a unisensory (visual) stimulus or a multisensory (Visual + Auditory) stimulus. For controls, results showed alcohol impaired response inhibition to unisensory stop signals but not to multisensory stop signals. Response inhibition of those with ADHD was impaired by alcohol regardless of whether stop signals were unisensory or multisensory. The failure of multisensory stimuli to attenuate alcohol impairment in those with ADHD highlights a specific vulnerability that could account for heightened sensitivity to the disruptive effects of alcohol. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Influence of tiagabine maintenance on cannabis effects and related behaviors in daily cannabis users.

No medications are approved for cannabis use disorder (CUD). Gamma-aminobutyric acid (GABA) reuptake is modulated by cannabinoid (CB) receptor agonists, and there are shared effects between CB agonists and the GABA reuptake inhibitor tiagabine. This overlapping neuropharmacology suggested that tiagabine might be useful for CUD. The study determined the ability of tiagabine maintenance to reduce cannabis self-administration using a placebo-controlled, double-blind, counterbalanced, within-subjects design. Nontreatment-seeking daily cannabis users (N = 12; 3 female, 9 male) completed two 12-day outpatient maintenance phases (0 or 12 mg of tiagabine/day). Each phase consisted of a safety session, 7 maintenance days, and 4 experimental sessions. During experimental sessions, maintenance continued and participants completed two 2-day blocks of sampling and self-administration sessions to determine the reinforcing effects of smoked cannabis (0% and 5.9% Δ9-tetrahydrocannabinol). Naturalistic cannabis use, the subjective, performance and physiological response to cannabis, as well as side effects, sleep quality, craving, other self-reported substance use, and observer ratings were also measured. Cannabis functioned as a reinforcer and produced prototypical effects (e.g., increased heart rate and ratings of "high"), but tiagabine generally did not impact the effects of cannabis, or alter naturalistic use. Furthermore, tiagabine produced small, but significant, increases on 2 subscales of a Marijuana Craving Questionnaire, and reductions in both the amount of time slept in the past 24 hr and ratings of positive mood upon awakening. These human laboratory results from a sample of nontreatment-seeking cannabis users do not support the potential efficacy of 12 mg of tiagabine as a stand-alone pharmacotherapy for CUD. (PsycINFO Database Record

Neurophysiological capacity in a working memory task differentiates dependent from nondependent heavy drinkers and controls.

BACKGROUND: Determining the neurobehavioral profiles that differentiate heavy drinkers who are and are not alcohol dependent will inform treatment efforts. Working memory is linked to substance use disorders and can serve as a representation of the demand placed on the neurophysiology associated with cognitive control. METHODS: Behavior and brain activity (via fMRI) were recorded during an N-Back working memory task in controls (CTRL), nondependent heavy drinkers (A-ND) and dependent heavy drinkers (A-D). Typical and novel step-wise analyses examined profiles of working memory load and increasing task demand, respectively. RESULTS: Performance was significantly decreased in A-D during high working memory load (2-Back), compared to CTRL and A-ND. Analysis of brain activity during high load (0-Back vs. 2- Back) showed greater responses in the dorsal lateral and medial prefrontal cortices of A-D than CTRL, suggesting increased but failed compensation. The step-wise analysis revealed that the transition to Low Demand (0-Back to 1-Back) was associated with robust increases and decreases in cognitive control and default-mode brain regions, respectively, in A-D and A-ND but not CTRL. The transition to High Demand (1-Back to 2-Back) resulted in additional engagement of these networks in A-ND and CTRL, but not A-D. CONCLUSION: Heavy drinkers engaged working memory neural networks at lower demand than controls. As demand increased, nondependent heavy drinkers maintained control performance but relied on additional neurophysiological resources, and dependent heavy drinkers did not display further resource engagement and had poorer performance. These results support targeting these brain areas for treatment interventions.

Predicting the knowledge-recklessness distinction in the human brain.

Criminal convictions require proof that a prohibited act was performed in a statutorily specified mental state. Different legal consequences, including greater punishments, are mandated for those who act in a state of knowledge, compared with a state of recklessness. Existing research, however, suggests people have trouble classifying defendants as knowing, rather than reckless, even when instructed on the relevant legal criteria. We used a machine-learning technique on brain imaging data to predict, with high accuracy, which mental state our participants were in. This predictive ability depended on both the magnitude of the risks and the amount of information about those risks possessed by the participants. Our results provide neural evidence of a detectable difference in the mental state of knowledge in contrast to recklessness and suggest, as a proof of principle, the possibility of inferring from brain data in which legally relevant category a person belongs. Some potential legal implications of this result are discussed.

Cocaine-dependent adults and recreational cocaine users are more likely than controls to choose immediate unsafe sex over delayed safer sex.

Cocaine users have a higher incidence of risky sexual behavior and HIV infection than nonusers. Our aim was to measure whether safer sex discount rates-a measure of the likelihood of having immediate unprotected sex versus waiting to have safer sex-differed between controls and cocaine users of varying severity. Of the 162 individuals included in the primary data analyses, 69 met the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) criteria for cocaine dependence, 29 were recreational cocaine users who did not meet the dependence criteria, and 64 were controls. Participants completed the Sexual Discounting Task, which measures a person's likelihood of using a condom when one is immediately available and how that likelihood decreases as a function of delay to condom availability with regard to 4 images chosen by the participants of hypothetical sexual partners differing in perceived desirability and likelihood of having a sexually transmitted infection. When a condom was immediately available, the stated likelihood of condom use sometimes differed between cocaine users and controls, which depended on the image condition. Even after controlling for rates of condom use when one is immediately available, the cocaine-dependent and recreational users groups were more sensitive to delay to condom availability than controls. Safer sex discount rates were also related to intelligence scores. The Sexual Discounting Task identifies delay as a key variable that impacts the likelihood of using a condom among these groups and suggests that HIV prevention efforts may be differentially effective based on an individual's safer sex discount rate. (PsycINFO Database Record

Separate and combined effects of gabapentin and [INCREMENT]9-tetrahydrocannabinol in humans discriminating [INCREMENT]9-tetrahydrocannabinol.

The aim of the present study was to examine a potential mechanism of action of gabapentin to manage cannabis-use disorders by determining the interoceptive effects of gabapentin in cannabis users discriminating [INCREMENT]-tetrahydrocannabinol ([INCREMENT]-THC) using a pharmacologically selective drug-discrimination procedure. Eight cannabis users learned to discriminate 30 mg oral [INCREMENT]-THC from placebo and then received gabapentin (600 and 1200 mg), [INCREMENT]-THC (5, 15, and 30 mg), and placebo alone and in combination. Self-report, task performance, and physiological measures were also collected. [INCREMENT]-THC served as a discriminative stimulus, produced positive subjective effects, elevated heart rate, and impaired psychomotor performance. Both doses of gabapentin substituted for the [INCREMENT]-THC discriminative stimulus and engendered subjective and performance-impairing effects that overlapped with those of [INCREMENT]-THC when administered alone. When administered concurrently, gabapentin shifted the discriminative-stimulus effects of [INCREMENT]-THC leftward/upward, and combinations of [INCREMENT]-THC and gabapentin generally produced larger effects on cannabinoid-sensitive outcomes relative to [INCREMENT]-THC alone. These results suggest that one mechanism by which gabapentin might facilitate cannabis abstinence is by producing effects that overlap with those of cannabinoids.

Abnormal medial prefrontal cortex activity in heavy cannabis users during conscious emotional evaluation.

RATIONALE: Long-term heavy cannabis users (cannabis users) who are not acutely intoxicated have diminished subconscious neural responsiveness to affective stimuli. OBJECTIVE: This study sought to determine if abnormal processing extends to the conscious evaluation of emotional stimuli. METHODS: Functional magnetic resonance imaging (fMRI) was used to examine brain activity as cannabis users (N = 16) and non-cannabis-using controls (N = 17) evaluated and categorized standardized International Affective Picture System (IAPS) stimuli. Individual judgments were used to isolate activity during the evaluation of emotional (i.e., emotional evaluation) or neutral (i.e., neutral evaluation) stimuli. Within- and between-group analyses were performed. RESULTS: Both groups judged the same stimuli as emotional and had activations in visual, midbrain, and middle cingulate cortices during emotional evaluation, relative to neutral. Within-group analyses also revealed amygdalar and inferior frontal gyrus activations in controls, but not cannabis users, and medial prefrontal cortex (mPFC) deactivations in cannabis users, but not controls, during emotional evaluation, relative to neutral. Between-group comparisons found that mPFC activity during positive and negative evaluation was significantly hypoactive in cannabis users, relative to controls. CONCLUSIONS: Abnormal neural processing of affective content extends to the level of consciousness in cannabis users. The hypoactive mPFC responses observed resembles the attenuated mPFC responses found during increased non-affective cognitive load in prior research. These findings suggest that abnormal mPFC singling in cannabis users during emotional evaluation might be associated with increased non-affective cognitive load.

Choosing Money over Drugs: The Neural Underpinnings of Difficult Choice in Chronic Cocaine Users.

Addiction is considered a disorder that drives individuals to choose drugs at the expense of healthier alternatives. However, chronic cocaine users (CCUs) who meet addiction criteria retain the ability to choose money in the presence of the opportunity to choose cocaine. The neural mechanisms that differentiate CCUs from non-cocaine using controls (Controls) while executing these preferred choices remain unknown. Thus, therapeutic strategies aimed at shifting preferences towards healthier alternatives remain somewhat uninformed. This study used BOLD neuroimaging to examine brain activity as fifty CCUs and Controls performed single- and cross-commodity intertemporal choice tasks for money and/or cocaine. Behavioral analyses revealed preferences for each commodity type. Imaging analyses revealed the brain activity that differentiated CCUs from Controls while choosing money over cocaine. We observed that CCUs devalued future commodities more than Controls. Choices for money as opposed to cocaine correlated with greater activity in dorsal striatum of CCUs, compared to Controls. In addition, choices for future money as opposed to immediate cocaine engaged the left dorsolateral prefrontal cortex (DLPFC) of CCUs more than Controls. These data suggest that the ability of CCUs to execute choices away from cocaine relies on activity in the dorsal striatum and left DLPFC.

Age-related differences in advantageous decision making are associated with distinct differences in functional community structure.

Human decision making is dependent on not only the function of several brain regions but also their synergistic interaction. The specific function of brain areas within the ventromedial prefrontal cortex has long been studied in an effort to understand choice evaluation and decision making. These data specifically focus on whole-brain functional interconnectivity using the principles of network science. The Iowa Gambling Task (IGT) was the first neuropsychological task used to model real-life decisions in a way that factors reward, punishment, and uncertainty. Clinically, it has been used to detect decision-making impairments characteristic of patients with prefrontal cortex lesions. Here, we used performance on repeated blocks of the IGT as a behavioral measure of advantageous and disadvantageous decision making in young and mature adults. Both adult groups performed poorly by predominately making disadvantageous selections in the beginning stages of the task. In later phases of the task, young adults shifted to more advantageous selections and outperformed mature adults. Modularity analysis revealed stark underlying differences in visual, sensorimotor and medial prefrontal cortex community structure. In addition, changes in orbitofrontal cortex connectivity predicted behavioral deficits in IGT performance. Contrasts were driven by a difference in age but may also prove relevant to neuropsychiatric disorders associated with poor decision making, including the vulnerability to alcohol and/or drug addiction.