Development and Feasibility Study of an Addiction-Focused Phenotyping Assessment Battery.

BACKGROUND AND OBJECTIVES: Current methods of classifying individuals with substance use disorder (SUD) result in vast heterogeneity among persons within a given diagnosis. These approaches, while clinically allowing for distinctions between patient groups, are less than ideal when attempting to recruit a neurobehaviorally defined subset of subjects into clinical trials. To address this gap, alternative strategies have been proposed, including behavioral phenotyping. The NIDA Phenotyping Assessment Battery (PhAB) is a modular package of assessments and neurocognitive tasks that was developed for use in clinical trials. The goal of the present study is to assess the feasibility of the NIDA PhAB with regard to ease of administration and time burden. METHODS: Healthy controls, persons with cocaine use disorder (CocUD), opioid use disorder (OUD), cannabis use disorder (CanUD), and combined opioid and cocaine use disorder (OCUD) were recruited from various sources (N = 595). Participants completed screening and one to three assessment visits. Time to complete the measures was recorded and a satisfaction interview was administered. RESULTS: Of the participants enrolled, 381 were deemed eligible. The majority of eligible participants (83%) completed all assessments. The average completion time was 3 hours. High participant satisfaction ratings were noted, with over 90% of participants endorsing a willingness to participate in a similar study and recommend the study to others. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: These findings corroborate the ease with which the PhAB may be easily incorporated into a study assessment visit without undue participant burden. The PhAB is an efficient method for behavioral phenotyping in addiction clinical trials. (Am J Addict 2021;00:00-00).

Cognitive impairment in substance use disorders.

Cognitive impairments in substance use disorders have been extensively researched, especially since the advent of cognitive and computational neuroscience and neuroimaging methods in the last 20 years. Conceptually, altered cognitive function can be viewed as a hallmark feature of substance use disorders, with documented alterations in the well-known "executive" domains of attention, inhibition/regulation, working memory, and decision-making. Poor cognitive (sometimes referred to as "top-down") regulation of downstream motivational processes-whether appetitive (reward, incentive salience) or aversive (stress, negative affect)-is recognized as a fundamental impairment in addiction and a potentially important target for intervention. As addressed in this special issue, cognitive impairment is a transdiagnostic domain; thus, advances in the characterization and treatment of cognitive dysfunction in substance use disorders could have benefit across multiple psychiatric disorders. Toward this general goal, we summarize current findings in the abovementioned cognitive domains of substance use disorders, while suggesting a potentially useful expansion to include processes that both precede (precognition) and supersede (social cognition) what is usually thought of as strictly cognition. These additional two areas have received relatively less attention but phenomenologically and otherwise are important features of substance use disorders. The review concludes with suggestions for research and potential therapeutic targeting of both the familiar and this more comprehensive version of cognitive domains related to substance use disorders.

Results of a randomized, double-blind, placebo-controlled trial of lorcaserin in cocaine use disorder.

BACKGROUND: Cocaine use disorder (CUD) is a major public health problem for which there is no approved pharmacotherapy. The primary purpose of this study was to evaluate the ability of lorcaserin, a 5-hydroxytryptamine2 C (5-HT2 C) receptor agonist, to facilitate abstinence in individuals seeking treatment for CUD. METHODS: This was a 12-site, randomized, parallel arm study with a 13-week Treatment Phase that included a 1-week, single-blind run-in period when all participants received twice daily 15mg acetazolamide capsules (a medication adherence marker), followed by randomization to either twice daily 10mg lorcaserin or placebo capsules for the remaining 12 weeks. Pre-randomization data were utilized in an enrichment strategy aimed at achieving high levels of medication adherence and low placebo response rates in a subgroup of participants that qualified for the "efficacy population." For lorcaserin vs. placebo, the primary efficacy endpoint was the proportion of participants in the efficacy population achieving abstinence during the last three weeks of treatment, as evidenced by self-report of no cocaine use, confirmed by urine testing. RESULTS: Within the efficacy population, 1.1% of 91 participants receiving lorcaserin and 4.3% of 92 receiving placebo achieved abstinence during the last 3 weeks of treatment. Among all randomized participants, 2.5% of 118 receiving lorcaserin and 5.6% of 124 receiving placebo achieved similar abstinence. Study participants receiving lorcaserin exhibited significantly greater reductions in body weight and BMI, indicating that medication adherence was sufficient to produce a pharmacological effect. CONCLUSIONS: Twice daily 10mg lorcaserin failed to demonstrate efficacy in the treatment of CUD.

Neuroimaging Biomarkers in Addiction.

As a neurobiological process, addiction involves pathological patterns of engagement with substances and a range of behaviors with a chronic and relapsing course. Neuroimaging technologies assess brain activity, structure, physiology, and metabolism at scales ranging from neurotransmitter receptors to large-scale brain networks, providing unique windows into the core neural processes implicated in substance use disorders. Identified aberrations in the neural substrates of reward and salience processing, response inhibition, interoception, and executive functions with neuroimaging can inform the development of pharmacological, neuromodulatory, and psychotherapeutic interventions to modulate the disordered neurobiology. Based on our systematic search, 409 protocols registered on ClinicalTrials.gov include the use of one or more neuroimaging paradigms as an outcome measure in addiction, with the majority (N=268) employing functional magnetic resonance imaging (fMRI), followed by positron emission tomography (PET) (N=71), electroencephalography (EEG) (N=50), structural magnetic resonance imaging (MRI) (N=35) and magnetic resonance spectroscopy (MRS) (N=35). Furthermore, in a PubMed systematic review, we identified 61 meta-analyses including 30 fMRI, 22 structural MRI, 8 EEG, 7 PET, and 3 MRS meta-analyses suggesting potential biomarkers in addictions. These studies can facilitate the development of a range of biomarkers that may prove useful in the arsenal of addiction treatments in the coming years. There is evidence that these markers of large-scale brain structure and activity may indicate vulnerability or separate disease subtypes, predict response to treatment, or provide objective measures of treatment response or recovery. Neuroimaging biomarkers can also suggest novel targets for interventions. Closed or open loop interventions can integrate these biomarkers with neuromodulation in real-time or offline to personalize stimulation parameters and deliver the precise intervention. This review provides an overview of neuroimaging modalities in addiction, potential neuroimaging biomarkers, and their physiologic and clinical relevance. Future directions and challenges in bringing these putative biomarkers from the bench to the bedside are also discussed.

Initial Validation of a Behavioral Phenotyping Model for Substance Use Disorder.

Standard nosological systems, such as DSM-5 or ICD-10, are relied upon as the diagnostic basis when developing treatments for individuals with substance use disorder (SUD). Unfortunately, the vast heterogeneity of individuals within a given SUD diagnosis results in a variable treatment response and/or difficulties ascertaining the efficacy signal in clinical trials of drug development. Emerging precision medicine methods focusing on targeted treatments based on phenotypic subtypes rather than diagnosis are being explored as alternatives. The goal of the present study was to provide initial validation of emergent subtypes identified by an addiction-focused phenotyping battery. Secondary data collected as part of a feasibility study of the NIDA phenotyping battery were utilized. Participants completed self-report measures and behavioral tasks across six neurofunctional domains. Exploratory and confirmatory factor analysis (EFA/CFA) were conducted. A three-factor model consisting of negative emotionality, attention/concentration, and interoception and mindfulness, as well as a four-factor model adding a second negative emotion domain, emerged from the EFA as candidate models. The CFA of these models did not result in a good fit, possibly resulting from small sample sizes that hindered statistical power.

Behavioral and neurocognitive factors distinguishing post-traumatic stress comorbidity in substance use disorders.

Significant trauma histories and post-traumatic stress disorder (PTSD) are common in persons with substance use disorders (SUD) and often associate with increased SUD severity and poorer response to SUD treatment. As such, this sub-population has been associated with unique risk factors and treatment needs. Understanding the distinct etiological profile of persons with co-occurring SUD and PTSD is therefore crucial for advancing our knowledge of underlying mechanisms and the development of precision treatments. To this end, we employed supervised machine learning algorithms to interrogate the responses of 160 participants with SUD on the multidimensional NIDA Phenotyping Assessment Battery. Significant PTSD symptomatology was correctly predicted in 75% of participants (sensitivity: 80%; specificity: 72.22%) using a classification-based model based on anxiety and depressive symptoms, perseverative thinking styles, and interoceptive awareness. A regression-based machine learning model also utilized similar predictors, but failed to accurately predict severity of PTSD symptoms. These data indicate that even in a population already characterized by elevated negative affect (individuals with SUD), especially severe negative affect was predictive of PTSD symptomatology. In a follow-up analysis of a subset of 102 participants who also completed neurocognitive tasks, comorbidity status was correctly predicted in 86.67% of participants (sensitivity: 91.67%; specificity: 66.67%) based on depressive symptoms and fear-related attentional bias. However, a regression-based analysis did not identify fear-related attentional bias as a splitting factor, but instead split and categorized the sample based on indices of aggression, metacognition, distress tolerance, and interoceptive awareness. These data indicate that within a population of individuals with SUD, aberrations in tolerating and regulating aversive internal experiences may also characterize those with significant trauma histories, akin to findings in persons with anxiety without SUD. The results also highlight the need for further research on PTSD-SUD comorbidity that includes additional comparison groups (i.e., persons with only PTSD), captures additional comorbid diagnoses that may influence the PTSD-SUD relationship, examines additional types of SUDs (e.g., alcohol use disorder), and differentiates between subtypes of PTSD.

New approaches to deep phenotyping in addictions.

OBJECTIVE: The causes of substance use disorders (SUDs) are largely unknown and the effectiveness of their treatments is limited. One crucial impediment to research and treatment progress surrounds how SUDs are classified and diagnosed. Given the substantial heterogeneity among individuals diagnosed with a given SUD (e.g., alcohol use disorder [AUD]), identifying novel research and treatment targets and developing new study designs is daunting. METHOD: In this article, we review and integrate two recently developed frameworks, the National Institute on Drug Abuse's Phenotyping Assessment Battery (NIDA PhAB) and the Hierarchical Taxonomy of Psychopathology (HiTOP), that hope to accelerate progress in understanding the causes and consequences of psychopathology by means of deep phenotyping, or finer-grained analysis of phenotypes. RESULTS AND CONCLUSIONS: NIDA PhAB focuses on addiction-related processes across multiple units of analysis, whereas HiTOP focuses on clinical phenotypes and covers a broader range of psychopathology. We highlight that NIDA PhAB and HiTOP together provide deep and broad characterizations of people diagnosed with SUDs and complement each other in their efforts to address widely known limitations of traditional classification systems and their diagnostic categories. Next, we show how NIDA PhAB and HiTOP can be integrated to facilitate optimal rich phenotyping of addiction-related phenomena. Finally, we argue that such deep phenotyping promises to advance our understanding of the neurobiology of SUD and addiction, which will guide the development of personalized medicine and interventions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Attentional function and inhibitory control in different substance use disorders.

Attentional function in substance use disorder (SUD) is not well understood. To probe attentional function in SUD as a function of primary substance of abuse, we administered the attentional network task (ANT) to 44 individuals with Cocaine Use Disorder (CoUD), 49 individuals with Cannabis Use Disorder (CaUD), 86 individuals with Opioid Use Disorder (OUD), and 107 controls with no SUD, along with the stop-signal task (SST). The ANT quantifies the effects of (temporal) alerting cues and (spatial) orienting cues to reduce reaction time (RT) to targets, as well as probing how conflicting (target-incongruent) stimuli slow RT. The SST quantifies individuals' ability to inhibit already-initiated motor responses. After controlling for sex representation and age, OUD and CaUD participants showed blunted alerting effects compared to controls, whereas CaUD and CoUD participants showed greater stimulus conflict (flanker) effects. Finally, CoUD participants showed a trend toward increased orienting ability. In SST performance, no SUD group showed a prolonged stop-signal reaction compared to controls. However, the OUD group (and CoUD group at trend level) showed prolonged "go" RT to targets and reduced hit rates. These data indicate differences in attentional function in persons with SUD as a function of the primary substance use.

Sex Specific Sleep Parameters Among People With Substance Use Disorder.

Introduction: Sleep can have substantial impacts in substance use disorder (SUD) pathogenesis, treatment, and recovery. Sex differences exist in both sleep and SUD, but how sleep is uniquely associated with SUD by sex is not known. The study objective was to compare, within sex, sleep parameters between individuals with SUD and non-substance misusing controls. Methods: Secondary analyses of a parent cross-sectional study examining the feasibility and acceptability of a novel neurocognitive phenotyping assessment battery were completed. SUD and control subjects were recruited through local advertising and an established research registry. Subjects with SUD were also recruited through a university-based outpatient SUD treatment clinic. Self-reported sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Sex-stratified t-tests compared sleep between SUD and control subjects while Crosstab analyses explored group differences in the proportion of individuals reporting poor sleep (defined as PSQI ≥ 5). Results: Data from 162 males (44 controls, 118 SUD) and 146 females (64 controls, 82 SUD) were included in the present study. For females only, a significantly lower proportion of controls reported PSQI-defined poor sleep than individuals with any SUD or specifically with opioid use disorder. Male, but not female, controls reported shorter sleep latency, longer sleep duration, and less sleep disturbance than males with each SUD type. Discussion/Implications: Sleep holds promise as an avenue to address SUD within a biopsychosocial model. Future work at the intersection of SUD and sleep should prioritize investigations of their interplay with sex to identify targets for tailored SUD interventions.

Preliminary Findings of Weaker Executive Control Network Resting State fMRI Functional Connectivity in Opioid Use Disorder compared to Healthy Controls.

Objective: Resting state functional magnetic resonance imaging (fMRI) functional connectivity has been used as a tool to study brain mechanisms associated with addictions. Recent research in substance use disorders has focused on three brain networks termed the default mode network (DMN), salience network (SN), and executive control network (ECN). The purpose of this study was to examine the functional connectivity of those three networks in opioid use disorder (OUD) subjects compared to healthy control subjects (HC). Methods: The present study investigated functional connectivity differences between OUD subjects compared to HC using independent component analysis. This study also examined the relationship between functional connectivity and negative urgency scores, as well as compared the functional connectivity of severe OUD to mild or moderate OUD. Results: In OUD subjects (n=25) compared to HC (n=25), a cluster in the left dorsolateral prefrontal cortex within the left ECN had significantly weaker functional connectivity. No significant differences were found between groups for the functional connectivity of the DMN, SN, or right ECN. No significant associations were found between functional connectivity and negative urgency, and no differences were found between severe OUD and mild or moderate OUD. Conclusion: These novel preliminary results suggest that ECN functional connectivity may differ between OUD and HC. This finding is consistent with previous research showing altered executive function in OUD and supports further examination of ECN functional connectivity in association with treatment response in OUD. Given our relatively small sample size (50 subjects total; 25 subjects per group), our results should be treated as preliminary for hypothesis generation, and replication will be needed in future studies.

Social Information Processing in Substance Use Disorders: Insights From an Emotional Go-Nogo Task.

Positive social connections are crucial for recovery from Substance Use Disorder (SUD). Of interest is understanding potential social information processing (SIP) mediators of this effect. To explore whether persons with different SUD show idiosyncratic biases toward social signals, we administered an emotional go-nogo task (EGNG) to 31 individuals with Cocaine Use Disorder (CoUD), 31 with Cannabis Use Disorder (CaUD), 79 with Opioid Use Disorder (OUD), and 58 controls. Participants were instructed to respond to emotional faces (Fear/Happy) but withhold responses to expressionless faces in two task blocks, with the reverse instruction in the other two blocks. Emotional faces as non-targets elicited more "false alarm" (FA) commission errors as a main effect. Groups did not differ in overall rates of hits (correct responses to target faces), but participants with CaUD and CoUD showed reduced rates of hits (relative to controls) when expressionless faces were targets. OUD participants had worse hit rates [and slower reaction times (RT)] when fearful faces (but not happy faces) were targets. CaUD participants were most affected by instruction effects (respond/"go" vs withhold response/"no-go" to emotional face) on discriminability statistic A. Participants were faster to respond to happy face targets than to expressionless faces. However, this pattern was reversed in fearful face blocks in OUD and CoUD participants. This experiment replicated previous findings of the greater salience of expressive face images, and extends this finding to SUD, where persons with CaUD may show even greater bias toward emotional faces. Conversely, OUD participants showed idiosyncratic behavior in response to fearful faces suggestive of increased attentional disruption by fear. These data suggest a mechanism by which positive social signals may contribute to recovery.

Safety and Preliminary Efficacy of Lorcaserin for Cocaine Use Disorder: A Phase I Randomized Clinical Trial.

Background and Objectives: Preclinical studies show serotonin (5-HT) 5-HT2C receptor (5-HT2CR) agonists reduce cocaine-seeking and cocaine intake. This study examined safety of the 5-HT2CR agonist lorcaserin administered with cocaine in participants with cocaine use disorder (CocUD). Secondarily, subjective response to cocaine and choice of cocaine vs. money were examined. Methods: A double-blind, randomized, placebo-controlled trial of 25 inpatient non-treatment seeking participants with CocUD. Participants were randomized to either lorcaserin (n = 17) or placebo (n = 8). Primary outcome measures included cardiovascular measures and plasma cocaine levels. Secondary measures of subjective response to cocaine were assessed using a visual analog scale (VAS) and cocaine vs. money progressive ratio choice sessions. Results: Thirteen randomized participants were included in the final analysis. No serious or unexpected adverse events were related to lorcaserin. There were no significant interactions between cocaine and lorcaserin on cardiovascular measures, plasma cocaine, or subjective ratings. After multiple comparisons correction, cocaine significantly increased blood pressure, heart rate, and QTc. Lorcaserin significantly decreased VAS ratings of "feel irritable," "feel hungry," and "I am craving." For the cocaine vs. money choice procedure, there was a significant interaction between choice (cocaine vs. money) and lorcaserin. Participants treated with lorcaserin were more likely to choose cocaine. Discussion and Conclusions: This study showed safety of lorcaserin administered with cocaine but lack of efficacy to reduce the reinforcing effects of cocaine. Scientific Significance: This study is the first to show a disconnect between effects of 5-HT2CR agonists on craving and cocaine choice in human cocaine users.

Effects of lorcaserin on oxycodone self-administration and subjective responses in participants with opioid use disorder.

BACKGROUND: Lorcaserin, a high-affinity 5-HT2C receptor agonist approved for treating obesity, decreased self-administration of oxycodone and cue-induced reinstatement of drug-seeking behavior in preclinical studies. The current investigation is the first clinical trial to evaluate the ability of lorcaserin to alter the reinforcing and subjective effects of oxycodone. METHODS: In this 7-week inpatient trial, 12 non-treatment-seeking volunteers (11 males) with moderate-to-severe opioid use disorder were detoxified from opioids. In a randomized cross-over fashion, participants were first stabilized on lorcaserin (10 mg BID) or placebo (0 mg BID). Participants underwent a two-week testing period during which the reinforcing and subjective effects of intranasal oxycodone were examined in verbal choice, cue-exposure, and progressive-ratio choice sessions. The two testing weeks were identical with the exception that during the first week, active oxycodone (10 mg) was available during verbal choice (self-administration) sessions, and during the second week placebo oxycodone was available. Subsequently, participants were stabilized on the other medication condition (placebo or lorcaserin) and underwent the same testing procedures again. RESULTS: Lorcaserin did not alter oxycodone self-administration. However, lorcaserin had a trend to increase "wanting heroin" when oxycodone was available, and to accentuate oxycodone-induced miosis. CONCLUSION: Under the current experimental conditions, lorcaserin at a dose of 10 mg BID did not reliably decrease the abuse liability of oxycodone, even though the study was sufficiently powered (≥80 %) to detect clinically meaningful differences in the main outcome variables between the placebo and active lorcaserin condition. Future research could explore a wider dose range of lorcaserin and oxycodone.

The state of clinical outcome assessments for cannabis use disorder clinical trials: A review and research agenda.

There is considerable variability in the use of outcome measures in clinical trials for cannabis use disorder (CUD), and a lack of consensus regarding optimal outcomes may have hindered development and approval of new pharmacotherapies. The goal of this paper is to summarize an evaluation of assessment measures and clinical endpoints for CUD clinical trials, and propose a research agenda and priorities to improve CUD clinical outcome assessments. The primary recommendation is that sustained abstinence from cannabis should not be considered the primary outcome for all CUD clinical trials as it has multiple limitations. However, there are multiple challenges to the development of a reliable and valid indicator of cannabis reduction, including the lack of a standard unit of measure for the various forms of cannabis and products and the limitations of currently available biological and self-report assessments. Development of a core toolkit of assessments is needed to both allow flexibility for study design, while facilitating interpretation of outcomes across trials. Four primary agenda items for future research are identified to expedite development of improved clinical outcome assessments for this toolkit: (1) determine whether minimally invasive biologic assays could identify an acute level of cannabis use associated with psychomotor impairment or other cannabis-related harms; (2) create an indicator of quantity of cannabis use that is consistent across product types; (3) examine the presence of cannabis-specific functional outcomes; and (4) identify an optimal duration to assess changes in CUD diagnostic criteria.

Measures of outcome for stimulant trials: ACTTION recommendations and research agenda.

BACKGROUND: The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence. METHODS: In March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations. The goal was to establish a research agenda for the development of a meaningful outcome measure that may be used as an endpoint in clinical trials for stimulant use disorders. RESULTS AND CONCLUSIONS: Based on guidelines for the selection of clinical trial endpoints, the lessons learned from prior addiction clinical trials, and the process that led to identification of a meaningful indicator of treatment success for alcohol use disorders, several recommendations for future research were generated. These include a focus on the validation of patient reported outcome measures of functioning, the exploration of patterns of stimulant abstinence that may be associated with physical and/or psychosocial benefits, the role of urine testing for validating self-reported measures of stimulant abstinence, and the operational definitions for reduction-based measures in terms of frequency rather than quantity of stimulant use. These recommendations may be useful for secondary analyses of clinical trial data, and in the design of future clinical trials that may help establish a meaningful indicator of treatment success.