Alcohol Use Disorder and Chronic Pain: An Overlooked Epidemic.

Alcohol use disorder (AUD) and chronic pain disorders are pervasive, multifaceted medical conditions that often co-occur. However, their comorbidity is often overlooked, despite its prevalence and clinical relevance. Individuals with AUD are more likely to experience chronic pain than the general population. Conversely, individuals with chronic pain commonly alleviate their pain with alcohol, which may escalate into AUD. This narrative review discusses the intricate relationship between AUD and chronic pain. Based on the literature available, the authors present a theoretical model explaining the reciprocal relationship between AUD and chronic pain across alcohol intoxication and withdrawal. They propose that the use of alcohol for analgesia rapidly gives way to acute tolerance, triggering the need for higher levels of alcohol consumption. Attempts at abstinence lead to alcohol withdrawal syndrome and hyperalgesia, increasing the risk of relapse. Chronic neurobiological changes lead to preoccupation with pain and cravings for alcohol, further entrenching both conditions. To stimulate research in this area, the authors review methodologies to improve the assessment of pain in AUD studies, including self-report and psychophysical methods. Further, they discuss pharmacotherapies and psychotherapies that may target both conditions, potentially improving both AUD and chronic pain outcomes simultaneously. Finally, the authors emphasize the need to manage both conditions concurrently, and encourage both the scientific community and clinicians to ensure that these intertwined conditions are not overlooked given their clinical significance.

Glial modulators as novel therapeutics for comorbid pain and opioid use disorder.

Chronic pain and opioid use disorder (OUD) are major public health problems, with rising opioid-related overdose deaths linked to increased opioid prescriptions for pain management. Novel treatment approaches for these commonly comorbid disorders are needed. Growing evidence supports a role for glial activation for both chronic pain and substance use disorders, including OUD. This review provides an overview of glial modulators as a novel treatment approach for comorbid pain and OUD. We aim to synthesize clinical studies investigating the efficacy of glial modulators in treating these comorbid disorders. We conducted a literature search of PubMed and Google Scholar databases in October 2023 to identify relevant clinical trials. The included studies varied in terms of patient population, study methodology and outcomes assessed, and were often limited by small sample sizes and other methodological issues. Additionally, several glial modulators have yet to be studied for chronic pain and OUD. Despite these limitations, these studies yielded positive signals that merit further investigation. Both chronic pain and OUD remain significant public health problems, with many treatment challenges. Glial modulators continue to hold promise as novel therapeutics for comorbid pain and OUD, given positive indications that they can improve pain measures, and reduce addiction-related outcomes. As our understanding of the mechanisms underlying the contributions of glial modulators to pain and addiction behaviours deepens, we will be better equipped to identify more specific therapeutic targets for chronic pain and OUD.

Assessing pain in persons with opioid use disorder: Approaches, techniques and special considerations.

Pain and opioid use disorder (OUD) are inextricably linked, as the former can be a risk factor for the development of the latter, and over a third of persons with OUD suffer concomitant chronic pain. Assessing pain among people with OUD is challenging, because ongoing opioid use brings changes in pain responses and most pain assessment tools have not been validated for this population. In this narrative review, we discuss the fundamentals of pain assessment for populations with OUD. First, we describe the biological, psychological and social aspects of the pain experience among people with OUD, as well as how opioid-related phenomena may contribute to the pain experience in this population. We then review methods to assess pain, including (1) traditional self-reported methods, such visual analogue scales and structured questionnaires; (2) behavioural observations and physiological indicators; (3) and laboratory-based approaches, such as quantitative sensory testing. These methods are considered from a perspective that encompasses both pain and OUD. Finally, we discuss strategies for improving pain assessment in persons with OUD and implications for future research, including educational strategies for multidisciplinary teams. We highlight the substantial gaps that persist in this literature, particularly regarding the applicability of current pain assessment methods to persons with OUD, as well as the generalizability of the existing results from adjacent populations on chronic opioid therapy but without OUD. As research linking pain and OUD evolves, considering the needs of diverse populations with complex psychosocial backgrounds, clinicians will be better equipped to reduce these gaps.

From taboo to treatment: The emergence of psychedelics in the management of pain and opioid use disorder.

The rise of psychedelics in contemporary medicine has sparked interest in their potential therapeutic applications. While traditionally associated with countercultural movements and recreational use, recent research has shed light on the potential benefits of psychedelics in various mental health conditions. In this review, we explore the possible role of psychedelics in the management of chronic pain and opioid use disorder (OUD), 2 critical areas in need of innovative treatment options. Pain control remains a significant clinical challenge, particularly for individuals with OUD and those who receive long-term opioid therapy who develop marked tolerance to opioid-induced analgesia. Despite the magnitude of this problem, there is a scarcity of controlled studies investigating pain management alternatives for these populations. Drawing from preclinical and human evidence, we highlight the potential of psychedelics to act on shared neurobiological substrates of chronic pain and OUD, potentially reversing pain- and opioid-induced neuroadaptations, such as central sensitization. We elaborate on the multifaceted dimensions of the pain experience (sensory, affective and cognitive) and their intersections that overlap with opioid-related phenomena (opioid craving and withdrawal), hypothesizing how these processes can be modulated by psychedelics. After summarizing the available clinical research, we propose mechanistic insights and methodological considerations for the design of future translational studies and clinical trials, building on a shared clinical and neurobiological understanding of chronic pain and OUD. Our intention is to provide timely perspectives that accelerate the development and exploration of novel therapeutics for chronic pain and OUD amidst the escalating opioid crisis.

The impact of cannabis on non-medical opioid use among individuals receiving pharmacotherapies for opioid use disorder: a systematic review and meta-analysis of longitudinal studies.

Background: The relationship between cannabis use and the risk of returning to using opioids non-medically during treatment for opioid use disorder (OUD) remains unclear.Objective: We sought to quantify the impact of cannabis use on the risk of non-medical opioid use among people receiving pharmacotherapies for OUD.Methods: A comprehensive search was performed using multiple databases from March 1 to April 5 of 2023. Eligible studies longitudinally assessed the association between cannabis use and non-medical opioid use among people with OUD receiving treatment with buprenorphine, methadone, or naltrexone. We utilized a random-effects model employing the restricted maximum likelihood method. A sensitivity analysis was conducted to understand potential differences between each OUD treatment modality.Results: A total of 10 studies were included in the final meta-analysis. There were 8,367 participants (38% female). The average follow-up time across these studies was 9.7 months (SD = 3.77), ranging from 4 to 15 months. The pharmacotherapies involved were methadone (76.3%) buprenorphine (21.3%), and naltrexone (2.4%). The pooled odds ratio did not indicate that cannabis use significantly influenced non-medical opioid use (OR: 1.00, 95% CI: 0.97-1.04, p = .98). There is evidence of moderate heterogeneity and publication bias.Conclusion: There was no significant association between cannabis use and non-medical opioid use among patients receiving pharmacotherapies for OUD. These findings neither confirm concerns about cannabis increasing non-medical opioid use during MOUD, nor do they endorse its efficacy in decreasing non-medical opioid use with MOUD. This indicates a need for individualized approaches for cannabis use and challenges the requirement of cannabis abstinence to maintain OUD pharmacotherapies.

Sex Differences in the Acute Effects of Oral THC: A Randomized, Placebo-Controlled, Crossover Human Laboratory Study.

Rationale: Recent reports have shown increased cannabis use among women, leading to growing concerns about cannabis use disorder (CUD). Some evidence suggests a faster progression to addiction in women, known as the "telescoping effect." While there is preclinical evidence suggesting biological sex influences cannabinoid effects, human research remains scant. We investigated sex differences in the response to oral tetrahydrocannabinol (THC) in humans. Methods: 56 healthy men and women with prior exposure to cannabis but no history of CUD participated in a randomized, placebo-controlled, human laboratory study where they received a single 10 mg dose of oral THC (dronabinol). Subjective psychoactive effects were assessed by the visual analog scale of "high", psychotomimetic effects by the Clinician-Administered Dissociative Symptoms Scale and Psychotomimetic States Inventory, verbal learning and memory by Rey Auditory Verbal Learning Test (RAVLT), and physiological effects by heart rate. Outcomes were regularly measured on the test day, except for the RAVLT, which was assessed once. Peak differences from baseline were analyzed using a nonparametric method for repeated measures. Results: Oral THC demonstrated significant dose-related effects in psychotomimetic and physiological domains, but not in RAVLT outcomes. A notable interaction between THC dose and sex emerged concerning the subjective "high" scores, with women reporting heightened sensations (p=0.05). No other significant effects of sex and THC dose interaction were observed. Conclusion: Oral THC yields similar psychotomimetic and physiological effects across sexes, but women may experience a pronounced subjective psychoactive effect. Further research is needed to identify individual vulnerabilities and facilitate tailored interventions addressing CUD.

Brief report: The influence of childhood trauma on the effects of delta-9-tetrahydrocannabinol in persons with opioid use disorder.

BACKGROUND AND OBJECTIVES: Childhood trauma (CT) increases addiction vulnerability. We examined CT's impact on delta-9-tetrahydrocannabinol (THC) effects. METHODS: This is a post-hoc analysis of a randomized, placebo-controlled, crossover trial investigating the effects of oral THC (10, 20 mg) among 25 persons receiving methadone for opioid use disorder (OUD). RESULTS: Greater CT was associated with lower aversive effects from higher THC doses (20 mg) (p = .006). DISCUSSION AND CONCLUSIONS: CT may reduce the subjective aversive effects of THC, potentially leading to greater cannabis use in individuals with OUD. SCIENTIFIC SIGNIFICANCE: These findings offer insights into THC's risks versus benefits in OUD subgroups and emphasize assessing CT in OUD treatment and research.

Delta-9-tetrahydrocannabinol modulates pain sensitivity among persons receiving opioid agonist therapy for opioid use disorder: A within-subject, randomized, placebo-controlled laboratory study.

The opioid and cannabinoid receptor systems are inextricably linked-overlapping at the anatomical, functional and behavioural levels. Preclinical studies have reported that cannabinoid and opioid agonists produce synergistic antinociceptive effects. Still, there are no experimental data on the effects of cannabinoid agonists among humans who receive opioid agonist therapies for opioid use disorder (OUD). We conducted an experimental study to investigate the acute effects of the delta-9-tetrahydrocannabinol (THC) among persons receiving methadone therapy for OUD. Using a within-subject, crossover, human laboratory design, 25 persons on methadone therapy for OUD (24% women) were randomly assigned to receive single oral doses of THC (10 or 20 mg, administered as dronabinol) or placebo, during three separate 5-h test sessions. Measures of experimental and self-reported pain sensitivity, abuse potential, cognitive performance and physiological effects were collected. Mixed-effects models examined the main effects of THC dose and interactions between THC (10 and 20 mg) and methadone doses (low-dose methadone defined as <90 mg/day; high dose defined as >90 mg/day). Results demonstrated that, for self-reported rather than experimental pain sensitivity measures, 10 mg THC provided greater relief than 20 mg THC, with no substantial evidence of abuse potential, and inconsistent dose-dependent cognitive adverse effects. There was no indication of any interaction between THC and methadone doses. Collectively, these results provide valuable insights for future studies aiming to evaluate the risk-benefit profile of cannabinoids to relieve pain among individuals receiving opioid agonist therapy for OUD, a timely endeavour amidst the opioid crisis.

Developing non-opioid therapeutics to alleviate pain among persons with opioid use disorder: a review of the human evidence.

The opioid crisis remains a major public health concern, causing significant morbidity and mortality worldwide. Pain is frequently observed among individuals with opioid use disorder (OUD), and the current opioid agonist therapies (OAT) have limited efficacy in addressing the pain needs of this population. We reviewed the most promising non-opioid analgesic therapies for opioid-dependent individuals synthesising data from randomised controlled trials in the Medline database from December 2022 to March 2023. Ketamine, gabapentin, serotoninergic antidepressants, and GABAergic drugs were found to be the most extensively studied non-opioid analgesics with positive results. Additionally, we explored the potential of cannabinoids, glial activation inhibitors, psychedelics, cholecystokinin antagonists, alpha-2 adrenergic agonists, and cholinergic drugs. Methodological improvements are required to advance the development of novel analgesic strategies and establish their safety profile for opioid-dependent populations. We highlight the need for greater integration of experimental pain methods and abuse liability assessments, more granular assessments of prior opioid exposure, greater uniformity of pain types within study samples, and a particular focus on individuals with OUD receiving OAT. Finally, future research should investigate pharmacokinetic interactions between OAT and various non-opioid analgesics and perform reverse translation basic experiments, particularly with methadone and buprenorphine, which remain the standard OUD treatment.

Pharmacological Treatments for Cocaine Craving: What Is the Way Forward? A Systematic Review.

BACKGROUND: cocaine craving is a core feature of cocaine use disorder and remains a critical challenge for abstinence and relapse prevention. This review summarizes the anti-craving efficacy of pharmacotherapies tested for cocaine use disorder, in the context of randomized-controlled clinical trials. OBJECTIVES: we assessed the databases of the U.S. National Library of Medicine, Google Scholar, and PsycINFO, without date restrictions up to August 2022, to identify relevant studies. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: we included double-blinded randomized-controlled trials investigating pharmacotherapies for cocaine craving and/or cocaine use disorder whose outcomes included cocaine craving. STUDY APPRAISAL AND SYNTHESIS METHODS: Two authors screened studies' titles and abstracts for inclusion, and both read all the included studies. We systematically gathered information on the following aspects of each study: title; author(s); year of publication; sample size; mean age; sample characteristics; study set-ting; whether participants were treatment-seeking; study design; craving measures; study interventions; drop-out rates; and other relevant outcomes. RESULTS: Overall, we appraised 130 clinical trials, including 8137 participants. We further considered the drugs from the studies that scored equal to or greater than six points in the quality assessment. There was a correlation between craving and cocaine use outcomes (self-reports, timeline follow-back or urinary benzoylecgonine) in the vast majority of studies. In the short-term treatment, acute phenylalanine-tyrosine depletion, clonidine, fenfluramine, meta-chlorophenylpiperazine (m-CPP) and mecamylamine presented promising effects. In the long term, amphetamine, biperiden, carbamazepine, lisdexamfetamine, lorcaserin, methamphetamine, mirtazapine, pioglitazone, progesterone, guanfacine, levodopa, nefazodone presented promising anti-craving effects. Unfortunately, the highly tested medications were not successful in most of the trials, as follows: propranolol in the short term; amantadine, aripiprazole, bromocriptine, citicoline, ketamine, modafinil, olanzapine, topiramate in the long term. The remaining 52 medications had no positive anti-craving outcomes. LIMITATIONS: Our review was limited by high heterogeneity of craving assessments across the studies and by a great range of pharmacotherapies. Further, the majority of the studies considered abstinence and retention in treatment as the main outcomes, whereas craving was a secondary outcome and some of the studies evaluated patients with cocaine use disorder with comorbidities such as opioid or alcohol use disorder, schizophrenia, bipolar disorder or attention deficit hyperactivity. Lastly, most of the studies also included non-pharmacological treatments, such as counseling or psychotherapy. CONCLUSIONS: There is a direct association between craving and cocaine use, underscoring craving as an important treatment target for promoting abstinence among persons with cocaine use disorder. Clonidine, fenfluramine and m-CPP showed to be promising medications for cocaine craving in the short-term treatment, and amphetamine, biperiden, carbamazepine, lisdexamfetamine, lorcaserin, methamphetamine, mirtazapine, pioglitazone, progesterone, guanfacine, levodopa, nefazodone in the long-term treatment.

Alleviation of opioid withdrawal by cannabis and delta-9-tetrahydrocannabinol: A systematic review of observational and experimental human studies.

BACKGROUND: While six U.S. states have already officially authorized cannabinoids to substitute opioids and treat opioid use disorder, the therapeutic benefits of cannabinoids remain unclear, especially when weighted against their adverse effects. METHODS: We conducted a systematic review of studies examining the association between opioid withdrawal and cannabis use or delta-9-tetrahydrocannabinol (THC) administration. We searched multiple databases from inception to July 30, 2022, and assessed study quality. RESULTS: Eleven studies were identified, with a total of 5330 participants, of whom 64 % were male. Nine observational studies examined the association between cannabis use and opioid withdrawal. Two randomized, placebo-controlled clinical trials (RCTs) investigated the withdrawal-alleviating effects of dronabinol, a synthetic form of THC. Four observational studies found an association between cannabis use and the alleviation of opioid withdrawal; one reported exacerbation of opioid withdrawal symptoms; and four reported no association. RCTs reported that THC alleviated opioid withdrawal, albeit with dose-dependent increases in measures of abuse liability, dysphoria, and tachycardia. There was high heterogeneity in measurements of opioid withdrawal and the type and dose of opioid at baseline. CONCLUSIONS: Although there is preliminary evidence that cannabis and its main psychoactive constituent, THC, may alleviate opioid withdrawal, these effects are likely to have a narrow therapeutic window. Further, the potential of cannabinoids to alleviate opioid withdrawal is determined by complex interactions between patient characteristics and pharmacological factors. Collectively, these findings have clinical, methodological, and mechanistic implications for treating opioid withdrawal during cannabinoid use, and for efforts to alleviate opioid withdrawal using non-opioid therapeutics.

Cocaine Use Disorder (CUD): Current Clinical Perspectives.

Cocaine use disorder (CUD) is a devastating disorder, impacting both individuals and society. Individuals with CUD face many barriers in accessing treatment for CUD, and most individuals with CUD never receive treatment. In this review, we provide an overview of CUD, including risk factors for CUD, common co-occurring disorders, acute and chronic effects of cocaine use, and currently available pharmacological and behavioral treatments. There are no FDA-approved pharmacological treatments for CUD. Future studies with larger sample sizes and testing treatment combinations are warranted. However, individuals with CUD and co-occurring disorders (eg, a mood or anxiety disorder) may benefit from medication treatments. There are behavioral interventions that have demonstrated efficacy in treating CUD - contingency management (CM) and cognitive-behavioral therapy for substance use disorders (CBT-SUD) in particular - however many barriers remain in delivering these treatments to patients. Following the discussion of current treatments, we highlight some promising emerging treatments, as well as offer a framework that can be used in building a treatment plan for individuals with CUD.

Helpful or Harmful? The Therapeutic Potential of Medications with Varying Degrees of Abuse Liability in the Treatment of Substance Use Disorders.

Purpose of Review: This review summarizes recent clinical trial research on pharmacological treatments for substance use disorders, with a specific focus on agents with potential abuse liability. Recent Findings: Pharmacological treatments for substance use disorders may include gabapentinoids, baclofen, modafinil, ketamine, cannabinoids, gamma-hydroxybutyrate, and psychedelics. Gabapentinoids may decrease negative subjective effects of withdrawal in alcohol and cannabis use disorders. Cannabinoids similarly appear to decrease use and withdrawal symptoms in cannabis use disorder, while research shows stimulant medications may reduce cravings and increase abstinence in cocaine use disorder. Ketamine and psychedelics may help treat multiple substance use disorders. Ketamine may reduce withdrawal symptoms, promote abstinence, and diminish cravings in alcohol and cocaine use disorders and psychedelics may promote remission, decrease use, and reduce cravings in alcohol and opioid use disorders. Summary: Regardless of current regulatory approval statuses and potentials for abuse, multiple agents should not be dismissed prematurely as possible treatments for substance use disorders. However, further clinical research is needed before effective implementation can begin in practice. Supplementary Information: The online version contains supplementary material available at 10.1007/s40429-022-00432-9.

Development of pulsed intravenous nicotine infusions as a model for inhaled nicotine in humans.

RATIONALE: Although nicotine from cigarettes is delivered in puff-sized amounts, most preclinical and human intravenous (IV) nicotine studies have used bolus or continuous infusions. OBJECTIVES: To determine the feasibility of a pulsed-nicotine infusion model in smokers. METHODS: Following overnight abstinence, 12 adult smokers underwent 5 laboratory sessions. Using a crossover design, in each session, participants were assigned to 1 of 5 conditions: (1) high/fast: 1.0 mg nicotine delivered over 5 pulsed-infusions, then 15 saline infusions; (2) high/slow: 1.0 mg nicotine delivered over 20 pulsed-infusions; (3) low/fast: 0.2 mg nicotine delivered over 5 pulsed-infusions, then 15 saline infusions; (4) low/slow: 0.2 mg nicotine delivered over 20 pulsed-infusions; and (5) placebo: Saline delivered over 20 pulsed-infusions. Subjective drug effects, urges to smoke, nicotine withdrawal, and cognitive performance were measured in each session. RESULTS: Both the high/fast and high/slow conditions were associated with greater "head rush" and "high" (p < 0.05). The high/fast condition also provided greater suppression of urges to smoke and nicotine withdrawal (p < 0.05), indexed by the Questionnaire of Urges to Smoke-Brief, and the Minnesota Nicotine Withdrawal Scale, respectively. The high/fast and high/slow conditions produced greater increases in heart rate (p < 0.01) than saline. Finally, there were no main effects of dosing conditions on cognitive performance, indexed by the continuous performance test. CONCLUSIONS: These findings demonstrate the feasibility of pulsed-nicotine infusions to model nicotine delivery by smoking. This model could inform future studies testing novel smoking cessation therapies and tobacco regulatory studies testing the impact of nicotine reduction approaches.

Multimodal Correlates of Cannabis Use among U.S. Veterans with Bipolar Disorder: An Integrated Study of Clinical, Cognitive, and Functional Outcomes.

Objective: Cannabis use (CU) is common among persons with bipolar disorder (BD). Evidence suggests that CU is associated with poorer outcomes among persons with BD; however, these findings remain inconsistent. The present exploratory study aims to examine clinical, functional, and cognitive correlates of CU among persons with BD. Methods: U.S. veterans with BD type I who participated in a large-scale, nationwide study were categorized into four groups: current CU, past CU, past other drug use, and no drug use. Bivariate analyses, univariate analyses of covariance, and Levene's Test for Equality of Variance were used to compare groups on clinical, cognitive, and functional measures. Results: Of 254 (84.6% male) veterans with BD type I included in the analyses, 13 (5.1%) had current CU, 37 (14.5%) past CU, 77 (30.3%) past other drug use, and 127 (50%) reported no drug use. BD with CU was associated with post-traumatic stress disorder (PTSD) and experiencing lifetime suicidal ideation. Notably, current CU was associated with higher working memory performance, compared to both past CU and no drug use. Likewise, current CU was associated with higher functional capacity, compared to past CU as well as no drug use. Conclusions: These findings contribute to the growing literature on the complex effects of cannabis on BD. As the commercialization and legalization of cannabis increases, further research in this area is warranted to quantify posed risks to this population, and thereby guide clinical decision-making.

Brain Correlates of the Alcohol Use Disorder Pharmacotherapy Response: A Systematic Review of Neuroimaging Studies.

BACKGROUND: Although Alcohol Use Disorder (AUD) is highly prevalent worldwide, treating this condition remains challenging. Further, potential treatments for AUD do not fully address alcohol-induced neuroadaptive changes. Understanding the effects of pharmacotherapies for AUD on the human brain may lead to tailored, more effective treatments, and improved individual clinical outcomes. OBJECTIVES: We systematically reviewed the literature for studies investigating pharmacotherapies for AUD that included neuroimaging-based treatment outcomes. We searched the PubMed, Scielo, and PsycINFO databases up to January 2021. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: Eligible studies included those investigating pharmacotherapies for AUD and employing functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and/or proton magnetic resonance spectroscopy (H-MRS). STUDY APPRAISAL AND SYNTHESIS METHODS: Two independent reviewers screened studies' titles and abstracts for inclusion. Data extraction forms were shared among all the authors to standardize data collection. We gathered information on the following variables: sample size; mean age; sociodemographic and clinical characteristics; alcohol use status; study design and methodology; main neuroimaging findings and brain-regions of interest (i.e., brain areas activated by alcohol use and possible pharmacological interactions); and limitations of each study. RESULTS: Out of 177 studies selected, 20 studies provided relevant data for the research topic. Findings indicate that: (1) Acamprosate and gabapentin may selectively modulate limbic regions and the anterior cingulate cortex; (2) Naltrexone and disulfiram effects may involve prefrontal, premotor, and cerebellar regions; (3) Pharmacotherapies acting on glutamate and GABA neurotransmission involve primarily areas underpinning reward and negative affective states, and; (4) Pharmacotherapies acting on opioid and dopamine systems may affect areas responsible for the cognitive and motor factors of AUD. LIMITATIONS: Most of the studies were focused on naltrexone. A small number of studies investigated the action of disulfiram and gabapentin, and no neuroimaging studies investigated topiramate. In addition, the time between medication and neuroimaging scans varied widely across studies. CONCLUSIONS: We identified key-brain regions modulated by treatments available for AUD. Some of the regions modulated by naltrexone are not specific to the brain reward system, such as the parahippocampal gyrus (temporal lobe), parietal and occipital lobes. Other treatments also modulate not specific regions of the reward system, but play a role in the addictive behaviors, including the insula and dorsolateral prefrontal cortex. The role of these brain regions in mediating the AUD pharmacotherapy response warrants investigation in future research studies.

Impact of delivery rate on the acute response to intravenous nicotine: A human laboratory study with implications for regulatory science.

Faster delivery rate enhances the abuse potential of drugs of abuse, yet systematic studies on the impact of delivery rate on the acute effects of nicotine in humans are lacking. Using an intravenous (IV) nicotine infusion procedure that allows precise control of rate of delivery, we examined the impact of nicotine delivery rate on the positive subjective drug effects, smoking urges, withdrawal, heart rate, blood pressure and attention function in smokers. Twenty-four male and female (ages 21-35) dependent smokers attended five experimental sessions, following overnight abstinence from smoking. Using a crossover design, participants attended five sessions, where they were assigned to a random sequence of saline infusion or 1 mg nicotine delivered over 1, 2.5, 5 or 10 min at rates of 1, 0.4, 0.2 or 0.1 mg/min, respectively. The positive subjective effects of nicotine were most robust under the two faster delivery rate conditions, 1- and 0.4-mg nicotine/min. In contrast, all nicotine delivery rates were equally more effective than saline in alleviating urges to smoke. Likewise, nicotine-induced heart rate increases did not vary with the rate of nicotine delivery. Lastly, the cognitive enhancing effects of nicotine were observed only under the two slowest delivery rate conditions-0.1- and 0.2-mg nicotine/min. Collectively, these findings support the critical role of delivery rate in optimizing nicotine's abuse potential versus potential therapeutic effects and have timely implications for developing novel therapeutics for nicotine dependence, as well as for tobacco regulatory science.