Optimally combining transcranial magnetic stimulation with antidepressants in major depressive disorder: A systematic review and Meta-analysis.

There is a critical knowledge gap in optimally combining transcranial magnetic stimulation (TMS) and antidepressants to treat patients with major depressive disorder (MDD). TMS is effective in treating MDD in patients who have failed at least one antidepressant trial, with accelerated protocols showing faster remission in treatment-resistant depression (TRD). Although clinicians routinely augment antidepressants with TMS, there is a knowledge gap in stopping versus continuing antidepressants or the dosing strategies when starting or tapering TMS. These considerations are important when considering maintenance TMS (delivered alone or in combination with suitable antidepressants) to maintain remission in MDD after the index course of TMS. As the first step towards filling this knowledge gap, we reviewed randomized controlled trials (RCTs) and open-label trials from 2 databases (PubMed/Medline and EMBASE) that compared active TMS combined with a pre-specified antidepressant dosed in the same manner for adults with MDD versus sham TMS combined with the same antidepressant as in the active arm. All studies were published between January 1, 2000, and December 31, 2023. We excluded case reports, case series, and clinical studies that augmented TMS with antidepressants and vice versa. We found 10 RCTs (n = 654 participants) and performed a meta-analysis. This showed active TMS combined with pre-specified antidepressants had greater efficacy for MDD treatment than sham TMS combined with the same antidepressants as in the active arm (Hedge's g = 1; 95 % CI [0.27, 1.73]). The review and meta-analysis indicate greater short-term efficacy in combining antidepressants with TMS from the get-go in MDD. Given the increasing role of accelerated TMS protocols in expediting remission in MDD and the results of our meta-analysis, we advocate for RCTs examining the short-term and long-term effects of various antidepressant classes on these TMS protocols in MDD. This can also optimize and individualize maintenance TMS protocols to prevent relapse in MDD.

Intermittent theta burst stimulation and functional connectivity in people living with HIV/AIDS who smoke tobacco cigarettes: a preliminary pilot study.

Background: People living with HIV (PLWHA) smoke at three times the rate of the general population and respond poorly to cessation strategies. Previous studies examined repetitive transcranial magnetic stimulation (rTMS) over left dorsolateral prefrontal cortex (L. dlPFC) to reduce craving, but no studies have explored rTMS among PLWHA who smoke. The current pilot study compared the effects of active and sham intermittent theta-burst stimulation (iTBS) on resting state functional connectivity (rsFC), cigarette cue attentional bias, and cigarette craving in PLWHA who smoke. Methods: Eight PLWHA were recruited (single-blind, within-subject design) to receive one session of iTBS (n=8) over the L. dlPFC using neuronavigation and, four weeks later, sham iTBS (n=5). Cigarette craving and attentional bias assessments were completed before and after both iTBS and sham iTBS. rsFC was assessed before iTBS (baseline) and after iTBS and sham iTBS. Results: Compared to sham iTBS, iTBS enhanced rsFC between the L. dlPFC and bilateral medial prefrontal cortex and pons. iTBS also enhanced rsFC between the right insula and right occipital cortex compared to sham iTBS. iTBS also decreased cigarette craving and cigarette cue attentional bias. Conclusion: iTBS could potentially offer a therapeutic option for smoking cessation in PLWHA.

Adverse childhood experiences and early initiation of substance use: A survival analysis.

OBJECTIVE: Early adversity, such as adverse childhood experiences (ACEs), is a risk factor for the development of substance use disorder (SUD). ACEs are associated with earlier initiation of substance use. This study examined the relationship between ACEs and age of initiation of substance use using survival analysis. It is hypothesized that individuals with higher ACEs will have an earlier age of initiation. METHOD: Participants were recruited from the University of Kentucky's Laboratory for Human Behavioral Pharmacology. Participants were 18 years or older, English speaking, and actively engaged in substance use. Participants were not in substance abuse treatment nor were they seeking treatment. ACE scores were calculated, and age of substance use initiation was recorded. A Cox proportional hazard model was used to examine the effect of ACE score on age of substance use initiation. RESULTS: A total of 107 participants completed the study. An average number of 2.3 ACEs (SD = 2.2) were endorsed with 24% of participants reporting 4 or more ACEs. Higher ACE scores were associated with cigarette smoking and non-medical prescription opioid use onset ( hazard ratio (HR) = 1.14, 95% CI=1.02-1.28, p = 0.02, and HR=1.19, 95% CI = 1.04-1.37, p = 0.01, respectively. CONCLUSIONS: A significant association was found between higher ACE scores and earlier initiation of cigarette and non-medical prescription opioid use, consistent with prior research. Primary prevention of ACEs, screening for ACEs during childhood, and interventions for ACEs if detected, may help to reduce the risk of substance use/SUD in adulthood.

Cocaine abstinence during the "critical period" of a contingency management trial predicts future abstinence in people with cocaine use disorder.

BACKGROUND: Contingency Management (CM) is being piloted as a treatment for stimulant use disorder in several US states, highlighting the need for treatment optimization. One important goal of optimization is decreasing drug use during the early stages of treatment, which has predicted success in other interventions. However, this "critical period" has not been reported in CM trials. The purpose of this analysis was to determine if, after accounting for baseline abstinence and incentive condition, abstinence in a CM trial for people with Cocaine Use Disorder (CUD) could be predicted by cocaine use during a first-week critical period. METHODS: Eighty-seven participants with CUD were randomized to receive contingent high or low value incentives for cocaine abstinence or were in a non-contingent control group. Generalized estimating equations (GEE) were used to analyze urine test results over 36 timepoints during the 12-week intervention. To assess for a critical period, the first three visits were included in the GEE as a covariate for remaining urine test results. RESULTS: Participants who provided more negative samples during the critical period were significantly more likely to produce a negative urine sample during the remainder of the trial, though some effects of group remained after controlling for the critical period. CONCLUSIONS: These results indicate that a critical period exists for CM trials, and it can explain a substantial amount of future performance. Early contact with an abstinence-contingent high magnitude alternative reinforcer may explain additional performance beyond the critical period, further justifying the use of high magnitude alternative reinforcers.

Comparing cigarette-cue attentional bias between people with HIV/AIDS and people with opioid use disorder who smoke.

Background: Special populations like people living with HIV/AIDS (PLWHA) and people with opioid use disorder (OUD) smoke tobacco cigarettes at rates three to four times greater than the general population. Patients with tobacco use disorder exhibit attentional bias (AB) for cigarette cues. Eye tracking can quantify this bias by measuring fixation time (FT) on cigarette and matched neutral cues, to calculate an AB score. Although previous studies have measured this bias in people who smoke without any other comorbid conditions, no study, to our knowledge, has measured or compared this bias in special populations. Methods: We performed exploratory analyses on eye tracking data collected in two separate randomized clinical trials (RCTs) (NCT05049460, NCT05295953). We compared FT and cigarette-cue AB score (measured by subtracting FT on neutral cues from FT on cigarette cues) between PLWHA and people with OUD who smoke, using a visual probe task and Tobii Pro Fusion eye tracker. We used two cigarette cue types, one encompassing people smoking cigarettes and the other consisting of cigarette paraphernalia. We used two cue presentation times, 1000 and 2000 milliseconds (ms). Results: Cues of people smoking cigarettes elicited greater AB than cues of cigarette paraphernalia across both subject groups when cues were presented for 2000 ms, but not 1000 ms. PLWHA who smoke exhibited greater AB for cues of people smoking cigarettes than cigarette paraphernalia when presented for 2000 ms compared to people with OUD who smoke. Conclusion: We use cigarette-cue AB to quantify craving and cigarette consumption in two populations smoking at elevated rates. The addition of social cues potentiates cigarette cue AB, based on cue type and stimulus presentation time. Understanding the neurobiology of this relationship can help design novel smoking cessation treatments that target AB and prevent relapse in these populations with suboptimal response to smoking cessation treatments. Trial registration: Clinical trials that provided the data for post hoc analyses are NCT05049460 and NCT05295953.

Use of drug purchase tasks in medications development research: orexin system regulation of cocaine and drug demand.

Commodity purchase tasks provide a useful method for evaluating behavioral economic demand in the human laboratory. Recent research has shown how responding to purchase tasks for blinded drug administration can be used to study abuse liability. This analysis uses data from a human laboratory study to highlight how similar procedures may be particularly useful for understanding momentary changes in drug valuation when screening novel interventions. Eight nontreatment-seeking participants with cocaine use disorder (one with partial data) were enrolled in a cross-over, double-blind, randomized inpatient study. Participants were maintained on the Food and Drug Administration-approved insomnia medication suvorexant (oral; 0, 5, 10, 20 mg/day) in randomized order with experimental sessions completed after at least 3 days of maintenance on each suvorexant dose. Experimental sessions included administration of a sample dose of 0, 10 and 30 mg/70 kg intravenous cocaine. Analyses focused on purchase tasks for the blinded sample dose as well as alcohol, cigarettes and chocolate completed 15 min after the sample dose. As expected based on abuse liability, near zero demand was observed for placebo with dose-related increases in cocaine demand. Suvorexant maintenance increased cocaine demand in a dose-related manner with the greatest increase observed for the 10 mg/kg cocaine dose. Increased demand under suvorexant maintenance was also observed for alcohol. No effect of cocaine administration was observed for alcohol, cigarette, or chocolate demand. These data support the validity of demand procedures for measuring blinded drug demand. Findings also parallel self-administration data from this study by showing increases in cocaine use motivation under suvorexant maintenance.

Naltrexone-bupropion combinations do not affect cocaine self-administration in humans.

The FDA has not yet approved a pharmacotherapy for cocaine use disorder despite nearly four decades of research. This study determined the initial efficacy, safety, and tolerability of naltrexone-bupropion combinations as a putative pharmacotherapy for cocaine use disorder. Thirty-one (31) non-treatment seeking participants with cocaine use disorder completed a mixed-design human laboratory study. Participants were randomly assigned to the naltrexone conditions (i.e., 0, 50 mg/day; between-subject factor) and maintained on escalating doses of bupropion (i.e., 0, 100, 200, 400 mg/day; within-subject factor) for at least four days prior to the conduct of experimental sessions. Cocaine self-administration (IN, 0, 40, 80 mg) was then determined using a modified progressive ratio and relapse procedure. Subjective and cardiovascular effects were also measured. Cocaine produced prototypical dose-related increases in self-administration, subjective outcomes (e.g., "Like Drug"), and cardiovascular indices (e.g., heart rate, blood pressure) during placebo maintenance. Naltrexone and bupropion alone, or in combination, did not significantly decrease self-administration on either procedure. Low doses of bupropion (i.e., 100 mg) blunted the effects of the cocaine on subjective measures of "Like Drug" and "Stimulated". No unexpected adverse effects were observed with naltrexone and bupropion, alone and combined, in conjunction with cocaine. Together, these results do not support the use of these bupropion-naltrexone combinations for the treatment of cocaine use disorder. Future research should determine if novel drug combinations may decrease cocaine self-administration.

Intranasal Use of Prescription Stimulants Among Adults Aged 18 to 30: Results From A Crowdsourcing Platform.

OBJECTIVE: Few studies of prescription stimulant non-oral, non-medical use (NMU) (defined by use not as prescribed) have been conducted in adults beyond the college population. The purpose of this study was to characterize prescription stimulant non-oral use, specifically intranasal (IN) use (snorting) in young adults. METHOD: Amazon's MTurk platform was used to recruit participants for an online survey. Data were collected from March to April 2020. RESULTS: Thirty-two percent (n = 157) of survey respondents (N = 975), aged 18 to 30, reported IN prescription stimulant use (average of 32.1 episodes of lifetime IN use). Adderall was the most-reported prescription stimulant used intranasally (89.2%). Most IN users (82%; n = 68) reported spending no more than 5 minutes tampering with prescription stimulants. Intranasal users said they would take the medication orally if unable to tamper or manipulate medication for IN use. CONCLUSION: These data help quantify a complex public health issue of ongoing IN use of prescription stimulants and suggest a potential role for manipulation-deterrent medications.

Suvorexant maintenance enhances the reinforcing but not subjective and physiological effects of intravenous cocaine in humans.

Preclinical research has sought to understand the role of the orexin system in cocaine addiction given the connection between orexin producing cells in the lateral hypothalamus and brain limbic areas. Exogenous administration of orexin peptides increased cocaine self-administration whereas selective orexin-1 receptor antagonists reduced cocaine self-administration in non-human animals. The first clinically available orexin antagonist, suvorexant (a dual orexin-1 and orexin-2 receptor antagonist), attenuated motivation for cocaine and cocaine conditioned place preference, as well as cocaine-associated impulsive responding, in rodents. This study aimed to translate those preclinical findings and determine whether suvorexant maintenance altered the pharmacodynamic effects of cocaine in humans. Seven non-treatment seeking subjects with cocaine use disorder completed this within-subject human laboratory study, and a partial data set was obtained from one additional subject. Subjects were maintained for at least three days on 0, 5, 10 and 20 mg oral suvorexant administered at 2230 h daily in random order. Subjects completed experimental sessions in which cocaine self-administration of 0, 10 and 30 mg/70 kg of intravenous cocaine was evaluated on a concurrent progressive ratio drug versus money choice task. Subjective and physiological effects of cocaine were also determined. Cocaine functioned as a reinforcer and produced prototypic dose-related subjective and physiological effects (e.g., increased ratings of "Stimulated" and heart rate). Suvorexant (10, 20 mg) increased self-administration of 10 mg/70 kg cocaine and decreased oral temperature but did not significantly alter any other effects of cocaine. Future research may seek to evaluate the effects of orexin-1 selective antagonists in combination with cocaine.

Clinical neuropharmacology of cocaine reinforcement: A narrative review of human laboratory self-administration studies.

Cocaine use is an unrelenting public health concern. To inform intervention and prevention efforts, it is crucial to develop an understanding of the clinical neuropharmacology of the reinforcing effects of cocaine. The purpose of this review is to evaluate and synthesize human laboratory studies that assess pharmacological manipulations of cocaine self-administration. Forty-one peer-reviewed, human cocaine self-administration studies in which participants received a pretreatment drug were assessed. The pharmacological action and treatment regimen for all drugs reviewed were considered. Drugs that increase extracellular dopamine tend to have the most consistent effects on cocaine self-administration. The ability of nondopaminergic drugs to impact cocaine reinforcement might be related to their downstream effects on dopamine, though it is difficult to draw conclusions because pharmacologically selective compounds are not widely available for human testing. The ability of acute versus chronic drug treatment to differentially affect human cocaine self-administration was not determined because buprenorphine was the only pretreatment drug that was assessed under both acute and chronic dosing regimens. Future research directly comparing acute and chronic drug treatment and/or comparing drugs with different mechanisms of action, is needed to make more conclusive determinations about the clinical neuropharmacology of cocaine reinforcement.

Differential impacts of economic and demographic variables on substance use patterns during the COVID-19 pandemic.

Background: The COVID-19 pandemic and subsequent economic crisis has provided a unique opportunity to investigate the effects of economic shifts on substance use. Existing literature on this relationship is limited and conflicting, warranting further exploration.Objective: This study aimed to identify relationships between socioeconomic status (SES), demographic variables, and substance use patterns before and after government-mandated business closures due to COVID-19.Methods: Participants were recruited based on self-reported substance use through Amazon's Mechanical Turk (MTurk). Qualifying participants (N = 315, 43% female, mean age = 35.35) reported their substance use and SES for two-week periods before and after pandemic-related business closures. Regression models analyzed relationships between substance use and study variables.Results: Regression models found that, during COVID-19 closures, greater financial strain predicted decreased benzodiazepine (ß = -1.12) and tobacco (ß = 1.59) use. Additionally, certain predictor variables (e.g., participants' age [ß = 1.22], race [ß = -4.43], psychiatric disorders including ADHD [ß = -2.73] and anxiety [ß = 1.53], and concomitant substance use [ß = 3.38]) predicted changes in substance use patterns; however, the directionality of these associations varied across substances.Conclusion: Specific substance use patterns were significantly and differentially impacted by economic strain, psychiatric diagnoses, and concomitant substance use. These results can help direct harm reduction efforts toward populations at greatest risk of harmful substance use following the pandemic.

Exercise increases attentional bias towards food cues in individuals classified as overweight to obese.

BACKGROUND: The obesity epidemic continues to be a major public health concern. Although exercise is the most common weight loss recommendation, weight loss outcomes from an exercise program are often suboptimal. The human body compensates for a large percentage of the energy expended through exercise to maintain energy homeostasis and body weight. Increases in energy intake appear to be the most impactful compensatory behavior. Research on the mechanisms driving this behavior has not been fully elucidated. PURPOSE: To determine if exercise influences the attentional processing towards food cues (attentional bias) and inhibitory control for food cues among individuals classified as overweight to obese who do not exercise. METHODS: Thirty adults classified as overweight to obese participated in a counterbalanced, crossover trial featuring two assessment visits on separate days separated by at least one week. Attentional bias and inhibitory control towards food cues was assessed prior to and after a bout of exercise where participants expended 500 kcal (one assessment visit) and before and after a 60 min bout of watching television (second assessment visit). Attentional bias was conceptualized as the percentage of time fixated on food cues when both food and neutral (non-food) cues were presented during a food-specific dot-probe task. Inhibitory control, specifically motor impulsivity, was assessed as percentage of inhibitory failures during a food-specific Go/NoGo task. RESULTS: A significant condition by time effect was observed for attentional bias towards food cues, independent of hunger, whereas attentional bias towards food cues was increased pre-post exercise but not after watching TV. Inhibitory control was not affected by exercise or related to attentional bias for food cues. CONCLUSIONS: An acute bout of exercise increased attentional bias for food cues, pointing to a mechanism that may contribute to the weight loss resistance observed with exercise. Future trials are needed to evaluate attentional bias towards food cues over a longitudinal exercise intervention.

Topiramate-phentermine combinations reduce cocaine self-administration in humans.

RATIONALE: Cocaine use disorder is an unrelenting public health concern. Despite nearly four decades of research, an FDA approved medication is not yet available. OBJECTIVES: The objective of this human laboratory study was to demonstrate the initial efficacy, safety and tolerability of topiramate-phentermine combinations for cocaine use disorder. METHODS: Thirty-one (31) participants with cocaine use disorder completed this mixed-model inpatient laboratory study. Participants were maintained on topiramate (0 [N = 11], 50 [N = 9] or 100 [N = 11] mg/day). Each topiramate group was concurrently maintained on phentermine (0, 15, 30 mg). Drug self-administration, subjective responses and cardiovascular effects following acute doses of intranasal cocaine (0, 40, 80 mg) were determined during separate experimental sessions after at least seven (7) days of maintenance on each condition. RESULTS: The three groups of participants were well matched demographically and generally did not differ significantly in their responses to a range of doses of intranasal cocaine (0, 10, 20, 40, 80 mg) during a medical safety session. Maintenance on topiramate and phentermine alone significantly decreased cocaine self-administration although these effects were modest in magnitude. Combining topiramate and phentermine robustly decreased cocaine self-administration. Topiramate and phentermine were well tolerated alone and combined, as well as in conjunction with cocaine. CONCLUSIONS: The results of the present study support advancing topiramate-phentermine combinations as a putative pharmacotherapeutic for cocaine use disorder.

Influence of n-acetylcysteine maintenance on the pharmacodynamic effects of oral ethanol.

RATIONALE: Glutamate systems play an important role in the abuse related effects of alcohol. n-Acetylcysteine, a drug that promotes glutamate homeostasis, attenuates a range of alcohol effects in preclinical models. OBJECTIVES: This human laboratory study determined the influence of n-acetylcysteine maintenance on alcohol self-administration using a model predictive of treatment effectiveness, along with the subjective, performance and physiological effects of alcohol. We hypothesized that n-acetylcysteine would attenuate alcohol self-administration, as well as positive subjective effects of alcohol. METHODS: Nine subjects with alcohol use disorder completed this within-subjects study. Subjects were maintained on placebo, 1.2 and 2.4 g n-acetylcysteine in random order on an outpatient basis. After five days of maintenance on the target dose, subjects completed overnight inpatient experimental sessions in which the pharmacodynamic effects of alcohol were determined. RESULTS: Alcohol produced prototypic effects (e.g., increased breath alcohol concentration, increased ratings of Feel Drink). n-Acetylcysteine did not alter the effects of alcohol. CONCLUSIONS: These results indicate that although n-acetylcysteine can safely be combined with alcohol, it does not attenuate the abuse related effects of alcohol and is unlikely to be an effective standalone alcohol use disorder treatment. However, considering study limitations, future work is needed to further understand whether and how n-acetylcysteine might be used as a treatment for alcohol use disorder (e.g., in combination with a behavioral treatment or another pharmacological agent).

An update on the clinical pharmacology of methylphenidate: therapeutic efficacy, abuse potential and future considerations.

INTRODUCTION: Methylphenidate remains a first-line medication for treating ADHD in children and adults. However, its behavioral pharmacological similarities to methamphetamine and cocaine have historically created concern for its potential as a drug of abuse. In September 2019, the FDA published a docket requesting comments for the development of abuse deterrent formulations for CNS stimulants, emphasizing the abuse of methylphenidate as a public health concern. AREAS COVERED: We conducted a narrative review of research on the clinical pharmacology, therapeutic efficacy, and abuse potential of methylphenidate. EXPERT OPINION: Several studies indicate that methylphenidate has at least some abuse potential. Methylphenidate, amphetamine, methamphetamine, and cocaine overlap in their subjective, reinforcing, and discriminative stimulus effects. Regardless, methylphenidate remains an efficacious treatment for ADHD in children and adults when properly adhered to, especially when paired with non-pharmacological treatments. The development of abuse deterrent formulations of methylphenidate is warranted.

Acute methylphenidate administration reduces cocaine-cue attentional bias.

Mechanistic research on behavioral processes underlying substance use disorder might help identify novel targets for interventions development. Drug-related attentional bias and response inhibition deficits have received a great deal of consideration in substance use research, broadly, and cocaine use research, specifically. Studies investigating pharmacological mechanisms that may ameliorate, or further impair, these behaviors relevant to cocaine use are relatively lacking. This study evaluated the impact of acute administration of methylphenidate, a dopamine-favoring reuptake inhibitor, on both gaze-related cocaine-cue-attentional bias and cocaine-cue related disruptions in response inhibition among individuals with cocaine use disorder. Participants (N = 12; 33% female) completed a within-subject, outpatient, acute dosing study. Two sessions were completed in which methylphenidate (60 mg) or placebo were administered followed by completion of an attentional bias task using eye-tracking technology and neutral-cue and cocaine-cue response inhibition tasks. Subjective and physiological effects were also recorded. Significant cocaine cue attentional bias and response inhibition failures were observed during placebo administration. Acute methylphenidate administration reduced cocaine-cue attentional bias as measured by cocaine-cue gaze fixations (dz = 1.04; Bayes Factor = 12.37). No statistically significant effects of methylphenidate were observed on response inhibition (Bayes Factors = 0.17-1.04). Methylphenidate produced prototypical subjective and physiological effects. Although the small sample should be considered, these findings indicate acute manipulation of dopaminergic activity reduced cue-related attentional allocation related to cocaine use disorder. Future research evaluating alternative dopaminergic agents and applications within a clinical setting are needed to determine the clinical significance of targeting this neurobehavioral mechanism.

Comparing Changes in Controlled Substance Prescribing Trends by Provider Type.

BACKGROUND AND OBJECTIVES: Forty-nine out of 50 states have implemented Prescription Drug Monitoring Programs (PDMPs) to monitor controlled substance (CS) prescribing. PDMPs change health care provider behavior, but few studies have examined changes in CS prescription by health care provider type. METHODS: Aggregated yearly data, including number of CS prescriptions, doses, and doses per prescription by health care provider type (physician, advanced practice registered nurse [APRN], and dentist) for each year from 2011 to 2017 was provided by the state PDMP, Kentucky All Schedule Prescription Electronic Reporting System (KASPER). In aggregate, this data set included 64,578,307 total prescriptions and 3,982,130,994 total doses of Schedule II-V medications. RESULTS: Physicians and dentists showed a trend of decreasing prescriptions and doses for Schedule II opioids from 2012 to 2017 (27-32% reduction in 2017 compared to 2011). APRNs showed a substantive increase in the number of doses and prescriptions (121-204% increase in 2017 compared to 2011), with increases remaining when controlling for number of providers. Physicians increased doses and prescriptions of Schedule II stimulants (37% increase for both doses and prescriptions), but by a smaller magnitude than APRN increases in stimulants (334-360% increase). Dentists showed decreases in Schedule II stimulants prescribed (69-80% reduction). Similar trends, but more modest in magnitude, were observed for Schedule III-IV. DISCUSSION AND CONCLUSIONS: Although monitoring and continuing education requirements are similar across all providers in Kentucky, differences in prescription trends for Schedule II opioids and stimulants were noted for physicians, APRNs, and dentists. SCIENTIFIC SIGNIFICANCE: Changes in prescribing following introduction of mandatory use of KASPER markedly differed based on provider type, with increases observed for APRNs compared with physicians and dentists. These findings advance prior research by providing a detailed examination of prescribing trends by provider type subsequent to a PDMPs mandatory use law. (Am J Addict 2019;00:00-00).

Inhibitory-control training for cocaine use disorder and contingency management for clinic attendance: A randomized pilot study of feasibility, acceptability and initial efficacy.

BACKGROUND: Cocaine abusers have impaired inhibitory Cocaine use is associated with impaired inhibitory control. This study determined the feasibility, acceptability, and initial efficacy of inhibitory-control training to cocaine or neutral images in cocaine use disorder patients. METHODS: Participants were randomly assigned to inhibitory-control training to cocaine (N = 20) or neutral (N = 20) images. Feasibility was assessed by percent of patients eligible for participation after a behavioral qualification session, time-to-target enrollment, percent of clinic visits attended, percent of participants who completed 80 % or more training sessions, and percent of follow-up visits attended. Acceptability was determined using a Treatment Acceptability Questionnaire. Initial efficacy was determined during training and a follow-up phase with urine samples tested qualitatively and quantitatively for cocaine. Participants in both conditions received monetary incentives delivered on an escalating schedule for clinic attendance. RESULTS: The groups were well matched and no differences on demographic or substance use variables were observed. Attendance was stable during the treatment period with high overall attendance in both groups (average sessions attended: cocaine image group = 97 %; neutral image group = 90 %). No group differences were observed in the percentage of follow-up sessions attended (95 % for the cocaine-image group; 88 % of neutral-image group). Ratings on the Treatment Acceptability Questionnaire were high (i.e., mean scores ≥ 80 for all items rated on 101-unit visual analog scales). Participants in the cocaine- and neutral-image conditions did not differ significantly in terms of cocaine use during the training nor follow-up phase. Inhibitory-control training improved stop signal performance but not delay discounting. CONCLUSION: The procedures were feasible and acceptable. Inhibitory-control training to cocaine images did not reduce cocaine use relative to the neutral image training condition. The inability to detect significant differences in cocaine use across the groups is not surprising given the small sample size. More research is needed to determine the utility of inhibitory-control training for cocaine use disorder. Future trials should determine whether inhibitory-control training to cocaine images augments the efficacy of other behavioral interventions.

Pharmacological validation of a translational model of cocaine use disorder: Effects of d-amphetamine maintenance on choice between intravenous cocaine and a nondrug alternative in humans and rhesus monkeys.

Drug self-administration procedures are the gold standard for laboratory research to study mechanisms of drug use disorders and evaluate candidate medications. However, preclinical-to-clinical translation has been hampered by a lack of coordination. To address this limitation, we previously developed homologous intravenous (IV) cocaine choice self-administration procedures in rhesus monkeys and humans, and then demonstrated their functional equivalence. The present studies sought to determine the sensitivity of these procedures to d-amphetamine maintenance. Three (N = 3) rhesus monkeys with histories of cocaine self-administration and 16 (N = 16) humans with cocaine use disorder completed the studies. Monkeys were maintained on IV d-amphetamine (0, 0.019, 0.037 and 0.074 mg/kg/h), and then completed 7 sessions during each condition in which they completed 9 choice trials to receive 0.14 mg/kg/injection IV cocaine (corresponding to 10 mg/70 kg in humans) or 10 food pellets under independent, concurrent progressive-ratio schedules. Humans were maintained on oral extended release d-amphetamine (0, 30 and 60 mg/day, corresponding to the lowest 3 doses in monkeys) and participated in 12 sessions in which they chose money ($6.00) or IV cocaine (0, 3, 10 and 30 mg/70 kg). Blood samples were taken to compare d-amphetamine plasma levels across species. In monkeys and humans, d-amphetamine reduced the number of cocaine choices and produced comparable blood levels at equivalent daily doses. d-Amphetamine had similar efficacy, though lower potency, at reducing choice for an equivalent cocaine dose in monkeys relative to humans. These coordinated studies support the utility of these procedures as a translational model for cocaine use disorder. (PsycInfo Database Record (c) 2020 APA, all rights reserved).