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.

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.

Efficacy of Integrating the Management of Pain and Addiction via Collaborative Treatment (IMPACT) in Individuals With Chronic Pain and Opioid Use Disorder: Protocol for a Randomized Clinical Trial of a Digital Cognitive Behavioral Treatment.

BACKGROUND: Chronic pain is common among individuals with opioid use disorder (OUD) who are maintained on medications for OUD (MOUD; eg, buprenorphine or methadone). Chronic pain is associated with worse retention and higher levels of substance use. Treatment of individuals with chronic pain receiving MOUD can be challenging due to their increased clinical complexity. Given the acute and growing nature of the opioid crisis, MOUD is increasingly offered in a wide range of settings, where high-quality, clinician-delivered, empirically validated behavioral treatment for chronic pain may not be available. Therefore, digital treatments that support patient self-management of chronic pain and OUD have the potential for wider implementation to fill this gap. OBJECTIVE: This study aims to evaluate the efficacy of Integrating the Management of Pain and Addiction via Collaborative Treatment (IMPACT), an interactive digital treatment program with asynchronous coach feedback, compared to treatment as usual (TAU) in individuals with chronic pain and OUD receiving MOUD. METHODS: Adult participants (n=160) receiving MOUD and reporting bothersome or high-impact chronic pain will be recruited from outpatient opioid treatment programs in Connecticut (United States) and randomized 1:1 to either IMPACT+TAU or TAU only. Participants randomized to IMPACT+TAU will complete an interactive digital treatment that includes 9 modules promoting training in pain and addiction coping skills and a progressive walking program. The program is augmented with a weekly personalized voice message from a trained coach based on daily participant-reported pain intensity and interference, craving to use opioids, sleep quality, daily steps, pain self-efficacy, MOUD adherence, and engagement with IMPACT collected through digital surveys. Outcomes will be assessed at 3, 6, and 9 months post randomization. The primary outcome is MOUD retention at 3 months post randomization (ie, post treatment). Secondary outcomes include pain interference, physical functioning, MOUD adherence, substance use, craving, pain intensity, sleep disturbance, pain catastrophizing, and pain self-efficacy. Semistructured qualitative interviews with study participants (n=34) randomized to IMPACT (completers and noncompleters) will be conducted to evaluate the usability and quality of the program and its outcomes. RESULTS: The study has received institutional review board approval and began recruitment at 1 site in July 2022. Recruitment at a second site started in January 2023, with a third and final site anticipated to begin recruitment in January 2024. Data collection is expected to continue through June 2025. CONCLUSIONS: Establishing efficacy for a digital treatment for addiction and chronic pain that can be integrated into MOUD clinics will provide options for individuals with OUD, which reduce barriers to behavioral treatment. Participant feedback on the intervention will inform updates or modifications to improve engagement and efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT05204576; https://clinicaltrials.gov/ct2/show/NCT05204576. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54342.

The relationship of pain intensity and opioid craving with delayed methadone dose: A preliminary study of individuals with opioid use disorder.

AIMS: Despite a strong theoretical link between opioid craving and pain, little is known about the temporal relationship between pain and craving and the acute experience of pain in the context of methadone treatment. Using a cross-over design, the current study evaluated the time course of pain and craving and objective experience of pain as a function of the last methadone dose. METHODS: Participants (n = 20) presented for the study in the morning and either received methadone dose as scheduled or delayed dose until the afternoon. During the 4-h study visit, participants completed a series of tasks, including repeated assessment of pain and craving at 0, +40, +70, +130, +160 and +240 min and a cold pressor test (CPT) at +15 and +220 min. RESULTS: Separate mixed model results demonstrated no effect of dosing condition on craving; however, there was a significant dosing condition by time interaction (F(5,209) = 3.38, P = .006) such that pain increased over time in the delayed methadone condition but decreased in time in the scheduled methadone condition. A mixed model predicting self-reported pain revealed a three-way interaction between dosing condition, craving and time (F(5,197) = 2.39, P = .039) explained by a positive association between craving and pain at each time point (except 240 min) in delayed condition (P-range = .004-.0001). A separate mixed model on CPT data indicated a significant condition by time interaction such that pain threshold decreased in the delayed, but not scheduled, condition (F(1,57) = 4.01, P = .050). CONCLUSIONS: These preliminary findings highlight the potential for increased risks after even a short delay in receiving a methadone dose.

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.

Associations Between Childhood Trauma and Tobacco Use Outcomes in Adults after Overnight Abstinence.

INTRODUCTION: Childhood trauma is known to be associated with nicotine dependence, yet limited smoking outcomes have been examined and few studies have assessed associations between specific trauma subscales and smoking. Additionally, sex differences in trauma-smoking relations are understudied. This study examined associations between childhood trauma and several smoking-related outcomes in adults who smoke after overnight abstinence. AIMS AND METHODS: People who smoke (N = 205) completed self-report and biochemical assessments evaluating childhood trauma, affect, nicotine dependence, smoking urges, withdrawal, and plasma cortisol and cotinine levels. Smoking outcomes were compared between those with and without a history of moderate to severe childhood trauma among the total sample and by sex. RESULTS: Relative to those with no to minimal abuse, those with moderate to severe abuse had higher negative affect, withdrawal severity, and plasma cotinine levels. Exploratory analyses revealed that women were more likely than men to have urges to smoke for negative reinforcement and have higher withdrawal severity, but no interactions between abuse group and sex were observed. Examining specific trauma subscales, the moderate to severe emotional abuse group had more severe nicotine dependence, negative affect, and withdrawal compared to the no to minimal group. The moderate to severe sexual abuse group had more severe nicotine dependence and withdrawal compared to the no to minimal group. CONCLUSIONS: Exposure to childhood trauma is associated with more severe nicotine dependence, negative affect, withdrawal, and higher plasma cotinine levels. Findings also indicate that different types of trauma may differentially affect smoking behaviors. IMPLICATIONS: This study of adults who smoke finds that childhood trauma history may be a marker for smoking susceptibility and suggests that individuals with experiences of emotional and sexual abuse may require targeted forms of smoking cessation interventions. Moreover, findings suggest that smoking risks may differ for men and women. Findings inform public health interventions intended to reduce cigarette use in individuals with exposure to childhood trauma.

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.

Integrating cognitive bias modification for pain and opioid cues into medication for opioid use disorder clinical care: Feasibility, acceptability, and preliminary results.

BACKGROUND: Despite high co-occurrence, chronic pain is often unaddressed in treatment for opioid use disorder (OUD) and little is known about mechanisms that may underlie associations between pain and opioid use. Using an attentional bias (AB) task with both pain and opioid cues, we evaluated a cognitive bias modification (CBM) task administered during regularly scheduled medications for OUD (mOUD) dosing visits. The current study evaluated the feasibility, acceptability, and preliminary efficacy of the CBM task. Outcomes for AB tasks used traditional mean-based score and trial-level bias scores (TLBS). METHODS: In a double-blind, randomized controlled trial, 28 individuals with OUD and chronic pain engaged in mOUD were randomized to either CBM or an AB control condition and completed up to three tasks per week for four weeks. Standard AB task was completed at baseline and post-treatment. Participants completed feasibility and acceptability measures, and preliminary efficacy (i.e., change in AB) was assessed using ANOVA models. RESULTS: Participants attended 83.3% of scheduled sessions and generally reported the task was enjoyable, credible, and easy to complete. Preliminary results demonstrated a condition by time interaction highlighting a reduction in AB in the CBM group but not the control group in opioid TLBS variability (F[1,26]=5.01, p = .034) and pain TLBS towards (F[1,26]=6.42, p = .018) and pain TLBS variability (F[1,26]=5.24, p = .03). CONCLUSIONS: The current study supports integrating brief, computer-based tasks designed to reduce AB into mOUD clinical care. The preliminary results suggest that TLBS outcomes may be more sensitive to capture changes in AB; however, larger studies are required.

Examining racial differences in smoking outcomes among smokers enrolled in an intravenous nicotine infusion study.

INTRODUCTION: Large racial disparities exist in the prevention and treatment of smoking-related diseases, and minoritized populations carry a heavier burden of smoking-related morbidity and mortality. To date, most studies investigating smoking-related illnesses have been conducted in samples in which the majority, or totality, self-identified as White or Caucasian. While Black individuals who smoke tend to have a lower rate of nicotine clearance, in part due to the use of mentholated cigarettes, less is known about how slower clearance affects their acute subjective and physiologic responses in response to either overnight abstinence or subsequent nicotine administration. This study aimed to investigate differences between the experiences of Black and White individuals who smoke across these outcomes after a period of short-term abstinence and after IV nicotine infusion. METHODS: The study included 206 smokers (N = 103 Black, N = 103 White, by self-report). The study investigated self-report, physiological, and biochemical smoking-related outcomes following confirmed overnight abstinence followed by IV nicotine infusion. The outcome measures were separately analyzed with repeated-measures mixed-models. RESULTS: Black individuals had lower rates of nicotine clearance and were more likely to smoke mentholated cigarettes than White individuals. Despite these differences, no differences in withdrawal, cravings, or physiological outcomes were observed between the two groups. There were some trends toward differences in subjective experiences, in that an interaction with trend level significance between race and dose was observed for negative subjective drug effects, with White smokers trending towards endorsing higher levels of negative affect after abstinence and nicotine infusion. We also observed that Black individuals trended towards experiencing more negative drug effects in response to initial nicotine delivery than to saline, whereas White individuals had no differences in negative drug effects across saline or nicotine doses. CONCLUSIONS: Despite slower nicotine clearance, Black participants exhibited withdrawal and urges to smoke as severe as White participants, and did not have blunted physiological responses to overnight abstinence or administration of nicotine, which were contrary to our hypotheses. Our findings suggest minimal differences across races in the acute pharmacologic effects of nicotine. We observed trend-level differences in subjective and affective responses to nicotine. Greater insight into these differences may lead to improved prevention and treatment strategies for smoking-related illnesses for Black individuals who smoke.

A systematic review evaluating PTSD treatment effects on intermediate phenotypes of PTSD.

OBJECTIVE: Although the efficacy of evidence-based treatments for posttraumatic stress disorder (PTSD) has been well established, high rates of treatment dropout and/or nonresponse or under-response to treatment suggest a need to explore novel treatment approaches. Most current research has focused on DSM-based categorical outcomes as primary indicators of treatment response, which may obscure the phenotypic heterogeneity of PTSD and limit the ability to map symptoms to underlying neurobiology. This systematic review aimed to identify intermediate phenotypes (IPs) of PTSD and evaluate IP sensitivity to PTSD treatments. METHOD: Five databases were searched for empirical studies published in English between January 1, 2010 and August 1, 2022 examining behavioral and pharmacological PTSD treatment effects on biobehavioral PTSD outcomes. RESULTS: Twenty-two studies met the inclusion criteria. Most studies evaluated behavioral treatment outcomes (n = 20), while only two studies evaluated pharmacological interventions. Five PTSD IPs were identified, including "impairments in working memory," "alterations in cognitive control," "unstable threat processing," "heightened fear or startle response," and "disturbances in sleep and wakefulness." This review offers preliminary support to suggest the utility of IP measures in assessing treatment efficacy; however, risk of bias and methodological limitations constrain the validity and generalizability of the results. CONCLUSIONS: The paucity of research combined with the heterogeneity of study methodologies and significant study limitations makes it difficult to draw strong conclusions regarding IP sensitivity to treatment. However, the existing body of research incorporating this framework shows potential for the IP approach to improve the translation of treatment efficacy from clinical trials to clinical settings. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Threshold for the pleasurable effects of nicotine are lower than its reinforcing effects during self-administration.

A recent study demonstrated that during a single sampling period, 0.1 mg of intravenous (IV) nicotine (vs. placebo) was found to be the threshold for subjective and physiological drug effects. The present study is a secondary analysis evaluating whether the threshold for subjective and physiological effects is similar when the subject has repeated opportunities to choose blinded doses of nicotine versus placebo. We also examined whether cigarette craving, withdrawal, and rate of nicotine metabolism affected nicotine reinforcement, defined by a greater number of nicotine choices than placebo. Young adult (n = 34; 68% male), daily smokers had five laboratory sessions after overnight abstinence. After sampling an IV dose of nicotine (0.0125, 0.025, 0.05, 0.1, or 0.2 mg/70 kg) versus saline (placebo), participants completed a nicotine self-administration (NSA) procedure that included 10 opportunities to self-administer IV dose of nicotine or placebo. The threshold for subjective positive effects of nicotine during the NSA was equal to or lower than the sampling period, 0.05-0.1 mg versus 0.1 mg. The threshold for nicotine-induced heart rate increase was higher during the NSA than during the sampling period (0.2 mg vs. 0.1 mg). Higher baseline craving and nicotine metabolite ratio (NMR) were associated with nicotine reinforcement at 0.2 mg and 0.1 mg doses, respectively (p < .05). The results suggest that subjective effects during NSA are reported at doses lower than the sampling period. Taken together, tobacco products thought to be subthreshold for reinforcement should be carefully evaluated for their subjective effects, including their discriminative stimulus effects. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Opioid use disorder with chronic pain increases disease burden and service use.

To address the ongoing opioid epidemic, there has been an increased focus on the treatment and evaluation of opioid use disorder (OUD). OUD and chronic pain (CP) frequently co-occur; however, little is known about the additional comorbidities that present when they occur together as compared to when either condition presents alone. Using data from Fiscal Year 2012 Veteran's Health Administration, all veterans diagnosed with both OUD + CP were compared to those diagnosed with OUD or CP alone on socioenvironmental characteristics, medical and mental health diagnoses, and Veterans Affairs (VA) clinical service use. Veterans with OUD + CP (n = 33,166), compared to those with OUD only (n = 12,517), had higher numbers of medical conditions. Compared to those with CP only (n = 2,015,368), veterans with OUD + CP had higher rates of homelessness and substance use diagnoses. Most mental health diagnoses, numbers of psychotropic medication fills, opioid prescriptions, and use of all other services were higher in the OUD + CP group than in either single disorder group. Multinomial regression analysis revealed stronger effects for medical disorders and medical-surgical outpatient service use in the comparison of OUD + CP with OUD only and stronger effects for substance use and mental health disorders and use of prescription opiates in the comparison with CP only. These findings suggest that concurrent OUD + CP imposes exceptional disease and clinical service burdens that likely require the development of simultaneous, integrated approaches to treatment. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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.

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.

Modafinil Does Not Reduce Cocaine Use in Methadone-Maintained Individuals.

Introduction: There are no approved medications for the treatment of cocaine use disorder (CUD). Modafinil, a cognitive-enhancer with weak stimulant-like effects, has shown promise in initial studies as a treatment for CUD. Its potential efficacy has not been examined in individuals dually dependent on cocaine and opioids. Methods: This study examined the efficacy of modafinil, in combination with contingency management (CM), for reducing cocaine and opioid use and improving cognitive function in methadone-stabilized individuals with opioid and cocaine dependence. We conducted a 17-week, double-blind, randomized controlled trial in which participants were randomized to one of four conditions: 1) modafinil + CM; 2) modafinil + yoked-control (YC); 3) placebo +CM; or 4) placebo + YC. Additionally, all subjects received platform treatments of cognitive behavioral therapy (CBT) and methadone. While the original planned sample size was N=160, a total of 91 participants were randomized. The two primary cocaine use outcomes were percentage of urine specimens positive for cocaine and percent of days of self-reported abstinence from cocaine during treatment. Cognitive function, opioid use, and secondary cocaine use outcomes were also considered. Results: Modafinil was well-tolerated with minimal reports of adverse effects. Modafinil was no more effective than placebo in reducing cocaine or opioid use or improving cognitive performance. Conclusions: In the context of a trial with robust control conditions and platform treatments, findings did not provide support for the efficacy of modafinil treatment for the treatment of CUD in methadone-stabilized individuals with dual opioid and cocaine dependence.

Effect of progesterone administration in male and female smokers on nicotine withdrawal and neural response to smoking cues: role of progesterone conversion to allopregnanolone.

BACKGROUND: Progesterone administration has therapeutic effects in tobacco use disorder (TUD), with females benefiting more than males. Conversion of progesterone to the neurosteroid allopregnanolone is hypothesized to partly underlie the therapeutic effects of progesterone; however, this has not been investigated clinically. METHODS: Smokers (n = 18 males, n = 21 females) participated in a randomized, double-blind, placebo-controlled crossover study of 200 mg progesterone daily across 4 days of abstinence. The ratio of allopregnanolone:progesterone was analyzed in relationship to nicotine withdrawal, smoking urges, mood states, subjective nicotine effects, and neural response to smoking cues. RESULTS: Allopregnanolone:progesterone ratio interacted with sex to predict withdrawal symptoms (p = 0.047), such that females with higher allopregnanolone:progesterone ratios reported lower withdrawal severity (b = - 0.98 [- 1.95, - 0.01]; p = 0.048). In addition, allopregnanolone:progesterone ratio interacted with sex to predict confusion (p = 0.014) and fatigue (p = 0.034), such that females with higher allopregnanolone:progesterone ratios reported less confusion (b = - 0.45 [- 0.78, - 0.12]; p = 0.008) and marginally lower fatigue (b = - 0.50 [- 1.03, 0.02]; p = 0.062. Irrespective of sex, higher ratios of allopregnanolone:progesterone were associated with stronger "good effects" of nicotine (b = 8.39 [2.58, 14.20]); p = 0.005) and weaker "bad effects" of nicotine (b = - 7.13 [- 13.53, - 0.73]; p = 0.029). CONCLUSIONS: Conversion of progesterone to allopregnanolone correlated with smoking-related outcomes in both sex-dependent and sex-independent ways. Sex-dependent effects suggest that conversion of progesterone to allopregnanolone may contribute to greater therapeutic benefits in females but not males with TUD. Trial registration Clinicaltrials.gov registration, retrospectively registered: NCT01954966; https://clinicaltrials.gov/ct2/show/NCT01954966 \.

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.

Pilot examination of stress, heart rate variability, and alcohol craving and use among female veterans.

Rates of alcohol use disorder (AUD) are increasing among civilian and veteran populations of women in the United States, and stress pathophysiology (i.e., abnormal acute and long-term change in physiological responses to stress) is central to the maintenance of alcohol misuse within this population. Heart rate variability (HRV) is one measure of stress regulation that may help to explain the association of stress with alcohol misuse among women. In the current analysis of pilot data, 20 women veterans attended an in-person laboratory session and completed 35 daily assessments of their alcohol use and craving. During the lab session, the effects of a stress induction procedure on self-reported alcohol craving and HRV were assessed. HRV was continuously measured and indexed in the time domain, using the root mean square of successive differences between normal heartbeats (RMSSD). Alcohol craving and use during the longitudinal 35-day study period were measured via self-report questionnaires sent to participants' phones. Results indicated that resting HRV in the lab was positively associated with odds of daily craving. Moreover, HRV during the stressor, as measured in lab, was positively associated with (1) overall alcohol craving in the lab (i.e., with resting and post-stress craving), and (2) number of daily drinks during the 35-day study period. This pilot study suggests the potential role of HRV in response to stressors in predicting alcohol craving and use among female veterans. It provides pilot data for research on stress-reactive HRV as a biomarker for alcohol misuse among women, and discusses directions for future research.

Progesterone Increases Nicotine Withdrawal and Anxiety in Male but Not Female Smokers During Brief Abstinence.

INTRODUCTION: Although exogenous progesterone may hold promise as a treatment for nicotine use disorders, it is unclear whether it is similarly effective in males and females. This study examined the effects of progesterone on nicotine use disorder comprehensively using behavioral, psychological, and neural measures in male and female smokers exposed to brief abstinence. AIMS AND METHODS: Thirty-three male and 33 female non-treatment-seeking smokers participated in a double-blind, randomized, placebo-controlled crossover study of 200 mg of progesterone or placebo daily over a four-day abstinence period. Smoking behavior and subjective effects of nicotine were assessed at baseline and after final drug administration. Nicotine withdrawal, smoking urges, mood states, and neural response to smoking cues were measured at baseline, after the first drug administration, and after the final drug administration. RESULTS: No main effect of drug (progesterone vs. placebo) emerged for any outcome. Significant sex by drug interactions emerged for nicotine withdrawal (p = .020), perceived strength of nicotine (p = .040), and perceived bad effects of nicotine (p = .029). Males receiving progesterone reported worse nicotine withdrawal (p = .046) and a trend towards decreased bad effects of nicotine (p = .070). Males on progesterone also reported greater tension and anxiety relative to placebo (p = .021). Females on progesterone perceived nicotine's effects as being stronger relative to placebo (p = .046). CONCLUSIONS: Progesterone causes sex-dependent effects on smoking-related outcomes during brief abstinence. Specifically, progesterone in males may increase rather than decrease nicotine withdrawal and negative affect during abstinence, potentially hindering efforts to quit smoking. IMPLICATIONS: In male and female smokers undergoing a brief period of abstinence, we examined the effects of progesterone on smoking outcomes. While progesterone had limited effects in female smokers, in males, it worsened nicotine withdrawal and negative affect. Our findings emphasize the importance of analyzing sex differences in future studies examining progesterone as a potential treatment and suggest that progesterone in males could potentially exacerbate aspects of nicotine dependence. CLINICALTRIALS.GOV REGISTRATION: NCT01954966. https://clinicaltrials.gov/ct2/show/NCT01954966.

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.