Addictive drugs impact corticostriatal glutamate signaling and have immunomodulatory effects which may underlie drug-associated behaviors during different phases of the addiction cycle. Here we hypothesize that glutamate dyshomeostasis induced by addictive drug use and withdrawal is heavily orchestrated by the neuroimmune system. We systematically define how drug-induced pathologies within the nucleus accumbens (NA) glutamate tripartite synapse are tightly regulated by neuroimmune signaling. Targets within the neuroimmune system represent a novel approach that can be leveraged for clinical studies with immunomodulatory therapeutics to reverse neurobiological changes induced by addictive drugs, and thus meaningfully reduce negative clinical outcomes relevant to substance use disorders (SUDs). We outline a novel hypothesis that control of a newly defined neuroimmune-glutamate circuit and inflammasome is heavily dependent upon the type of addictive drug as well as on phase of the addiction cycle. We further provide translational evidence underscoring the tenet that neuroimmunomodulation by addictive drugs functions according to an opponent process, and we outline predictions of our opponent process hypothesis when applied to relevant polysubstance use patterns in people who use drugs. This framework could be strategically leveraged in the experimental design of clinical studies of novel SUD therapeutics.

The prevalence of methamphetamine use disorder (MUD) remains discouragingly high. Relatively few clinical trials have focused on identifying new pharmacotherapies for MUD, and no medications have received US Food and Drug Administration approval. The lack of available pharmacotherapies may be due to failure to follow a rational, translational medications development pipeline progressing from preclinical work to the human laboratory to clinical trials. Our review thus has 2 primary goals: to (1) assess the scope of the literature evaluating candidate medications for MUD and (2) identify drugs screened to treat MUD across research domains, analyzing concordance across contexts. We identified 36 randomized, double-blind, placebo-controlled clinical trials that evaluated 25 candidate medications for MUD. Only 5 of these putative treatments (aripiprazole, bupropion, d-amphetamine, modafinil, and naltrexone) had also been evaluated in human laboratory and preclinical laboratory contexts. Overall, most studies showed no change in methamphetamine use (ie, no effects of treatment) across contexts. Although literature from these contexts imply a high degree of negative predictive validity, we encountered limitations at each level of analysis that prevented us from fully confirming concordance (eg, lack of positive predictive validity). These trends and limitations highlight the extent to which methamphetamine treatments are under-researched relative to other substance use disorders, such as cocaine use disorder. To address this gap in the literature, we advocate for future work that identifies therapeutic targets and, by consequence, classes of medications (repurposed or novel) to treat MUD. We conclude this review with additional comments about future research directions and treatment considerations. SIGNIFICANCE STATEMENT: Investment in methamphetamine use disorder (MUD) medications development remains poor. To date, no pharmacotherapies have received US Food and Drug Administration (FDA) approval to treat MUD, and few candidate medications have been systematically evaluated using a translational medications development pipeline (eg, beginning with preclinical research and progressing to human laboratory research and clinical trials). Adhering to the translational pipeline while incorporating new FDA guidance, such as evaluating nonabstinence outcomes, may be useful in facilitating MUD medications development.

Polysubstance use, particularly opioid-stimulant co-use, is a public health concern associated with higher overdose risk and poor treatment outcomes. Preclinical evidence suggests that oxycodone withdrawal increases cocaine consumption and disrupts nucleus accumbens glutamate homeostasis. N-acetylcysteine (NAC), a cysteine prodrug that restores glutamate homeostasis, has shown preclinical promise in reducing drug seeking in single substance seeking models. However, no studies have evaluated the efficacy of NAC in reducing behavioral outcomes, including self-administration, following opioid-stimulant polysubstance use. Here, we evaluated NAC as a pharmacotherapeutic for oxycodone-cocaine sequential use using our previously established rat intravenous self-administration model, which utilized an A-B-A-B design. We previously found that rats increase cocaine consumption during oxycodone withdrawal. Thus, here, we tested if NAC could reduce this effect and reduce oxycodone self-administration. Male and female rats first underwent oxycodone or food self-administration acquisition, followed by cocaine self-administration in Phase 2. Rats were subsequently treated with NAC (100 mg/kg) or vehicle during Phase 3, where the reinforcer switched back to the one presented in Phase 1. In Phase 4, we assessed cocaine self-administration and somatic signs during an oxycodone-free period. NAC treatment did not alter oxycodone or cocaine consumption, response discrimination, or somatic signs during drug onboard and drug-free periods. Cocaine consumption was inversely associated with somatic signs at early but not more protracted timepoints independent of NAC treatment. While NAC did not attenuate cocaine or oxycodone intake-related behaviors in our sequential use model, these results underscore the need for expanded polysubstance use pharmacotherapeutic and model development. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Decision making occurs in dynamic contexts in which the individual and reward attributes change, requiring that predicted reward values of options be updated continually and applied to future choices to maximize reward. Value processing relies on corticostriatal dopamine, which is dysregulated in people with cocaine use disorder (pwCocUD), but whether these individuals differ in value-based decision making has only recently been considered. A probabilistic concurrent monetary choice task with reversals, reinforcement learning modeling, and functional magnetic resonance imaging were used to assess value-based decision making in nontreatment-seeking pwCocUD and matched controls (n = 17 [8F and 9M] per group; n = 34 total). Both groups were sensitive to reinforcement probabilities, but pwCocUD made significantly fewer choices for the high probability reward option. Reinforcement learning modeling revealed that pwCocUD had lower β parameter estimates, indicating reduced consistency in using relative option values to make choices. Significant correlations between the application of value (i.e., β parameter) and value-modulated activity during choice deliberation were identified in brain regions previously linked to reinforcement learning and exploiting versus exploring choice options in both groups. A significant group difference in the strength of this relationship was found in medial frontal control regions, including the dorsal anterior cingulate cortex, which has been associated with the explore-exploit trade-off, suggesting that the differential engagement of these areas contributed to group differences in choice behavior. This research contributes to our understanding of suboptimal decisions made by pwCocUD in uncertain, low-reward contexts and support targeting networks involved in value-based decision making for neuromodulation intervention development. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

PURPOSE OF REVIEW:Preclinical (nonhuman) research on neurobehavioral underpinnings of addiction often focuses on one addictive drug studied in isolation, however, this does not reflect real-world substance use patterns of polysubstance use (PSU). Here we make a case against purity, incorporating patterns of clinically relevant PSU into preclinical models. We argue that the meaningful inclusion of people with living experience as integral collaborators in translational addiction models is critical to advance the identification of novel efficacious therapeutics to reduce the harms associated with PSU. RECENT FINDINGS:Substance use disorders are complex as clinically defined and diagnosed. Further, PSU is highly prevalent and individuals may use multiple substances within the illicit drug supply which continually evolves and is tracked via surveillance efforts (e.g., the National Drug Early Warning System). Preclinical models often model monosubstance use patterns which do not reflect real world drug use and omits expertise from people who use drugs in driving preclinical addiction science. SUMMARY:Here, we argue a case against purity in the development, design, and implementation of preclinical translational studies of addictive drugs, a need for inclusion of individuals with living experience, and highlight the need for additional research on PSU across the translational spectrum.

As interest in the potential therapeutic benefits of cannabis-derived products grows, accurate predictors of abuse potential will be vital for informing regulatory decisions. Currently, the Food and Drug Administration recommends using subjective effect ratings of Drug Liking as the primary measure in human abuse potential studies. However, dissociations between subjective ratings and drug-taking behavior have been previously reported. This retrospective analysis determined if any subjective effects questionnaire items uniquely predicted cannabis self-administration in people who use cannabis daily (N = 89; 71 male and 18 female). Data from 4 previous studies across 2 research sites that included cannabis self-administration and subjective effects assessments were combined. Concentrations of Δ9-tetrahyrdocannabinol (THC) were similar across studies (5.5%, 5.6%, or 5.9%), although milligram THC dose varied based on administration procedures. Ratings of Good Effect, High, Sedated/Tired, Drug Liking, Stimulated, and Willingness to Take Again were used as predictors. In each study, a money option ($0.50 or $1.00) was scheduled as an alternative to cannabis puffs in self-administration procedures. Proportion of choices for cannabis puffs over total choice trials (3 or 8 trials) was used as the primary outcome. Generalized linear models revealed that higher ratings of Willingness to Take Again (OR = 1.04) were associated with increased odds of self-administering active THC cannabis, while higher ratings of Stimulated were associated with decreased odds of self-administering placebo cannabis (OR = 0.94). These results suggest that subjective ratings of Willingness to Take Again should be considered as a primary outcome when assessing abuse potential for novel cannabinoid products. Significance Statement This retrospective analysis found that subjective ratings of Willingness to Take Again was a more predictive measure of cannabis self-administration than Drug Liking in people who use cannabis daily. Refining human abuse potential assessments to prioritize measures that better align with drug-taking behavior could improve regulatory evaluations of novel cannabinoid products.

Both laboratory model and real-world study data suggest that cocaine use is associated with impulsivity and risk-taking. Further, many people who use cocaine report polysubstance use; however, there is a lack of research investigating associations between and among impulsivity, risk-taking, and polysubstance use. Polysubstance use involving cannabis is especially relevant given its use by over half of Americans who use cocaine. No work to date has examined the potential relations between concurrent use of cannabis and cocaine and outcomes of impulsivity and risk-taking. The present study compared participants whose urine was positive for cocaine, positive for cocaine and cannabis, and negative for cocaine and cannabis during an initial pretreatment baseline visit for 122 participants prior to enrollment in a randomized clinical trial for cocaine use disorder. Data suggest participants who co-used cocaine and cannabis were likely to use more cocaine and other substances (e.g., alcohol, other drugs) and self-report risky sexual behavior. Participants who abstained from cocaine and cannabis prior to the baseline appointment gambled at greater rates in a gambling task. Groups did not differ with respect to self-reported impulsivity. Co-use of cocaine and cannabis among those with cocaine use disorder is associated with increased drug use but may have limited association with self-reported impulsivity. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

In the United States, complete abstinence persists as the standard for demonstrating recovery success from substance use disorders (SUDs), apart from alcohol use disorder (AUD). Although the FDA has recently indicated openness for non-abstinence outcomes as treatment targets, the traditional benchmark of complete abstinence for new medications to treat SUDs remains a hurdle and overshadows other non-abstinent outcomes desired by people with SUDs (e.g., improved sleep, employment, family reunification). This study sought to expand the definition of recovery to include non-abstinent pathways by exploring non-abstinence-based outcomes desired by people who use methamphetamine (PWUM). Participants (n = 100) were recruited from existing National Institute on Drug Abuse (NIDA) projects including a treatment-seeking sample of people recently released from prison (all of whom endorsed recent methamphetamine use) and a sample of people using syringe service programs. In a convergent survey design, participants responded to closed-ended questions regarding recovery outcomes, followed by open-ended items to gain a better understanding of PWUM and their conception of recovery. The importance of non-abstinent outcomes was measured in five categories (substance use, physical health, cognitive functioning, mental health, and financial/social/relationships). Participants were primarily White (88

Serotonin 1b (5-HT 1b ) receptors play an important role in preclinical cocaine effects. Zolmitriptan, a commercially available 5-HT 1b/1d agonist migraine medication, selectively attenuates the reinforcing and other abuse-related effects of cocaine. This project sought to advance these promising preclinical findings into humans, thereby demonstrating that the 5-HT 1b/1d system plays a key role in the abuse-related effects of cocaine in people with cocaine use disorder (CUD). Twelve nontreatment-seeking individuals (four female human subjects) with CUD participated in this within-subject human laboratory study. Participants were maintained on 0, 2.5, 5, and 10 mg oral zolmitriptan/day in random order. After at least 3 days of maintenance on each target dose, participants completed experimental sessions in which the reinforcing, subjective, physiological, and cognitive-behavioral effects of 0, 10, and 30 mg/70 kg of intravenous cocaine were determined. Cocaine functioned as a reinforcer and produced prototypic dose-related subjective and physiological effects (e.g. increased ratings of ‘stimulated’ and heart rate). Zolmitriptan produced limited changes in oral temperature after 10 mg/70 kg cocaine. Cocaine administration improved working memory impairments observed under the 5 mg zolmitriptan condition. Zolmitriptan did not alter any other effects of cocaine. Data indicate that activating the 5-HT 1b/1d systems through zolmitriptan maintenance produces limited changes in the pharmacodynamic effects of cocaine in humans, contrasting preclinical findings, suggesting this may not be a promising pharmacotherapeutic strategy for CUD. Failing to translate from preclinical to clinical models could be because of methodological or species differences, suggesting the field needs to better address this translational gap.

OBJECTIVE:Objectively verified reductions in cocaine use may be a more viable treatment target compared to complete abstinence. However, few studies have examined the associated health benefits of this change. This study assessed how quality-of-life outcomes (psychological functioning, social functioning, sleep) change with reductions in cocaine-positive urine drug screens. METHOD:Participants (n = 107) with cocaine use disorder enrolled in a 12-week contingency management trial and were randomly assigned to high-value, low-value, or noncontingent control groups. Quality of life was measured at predetermined intervals over the course of the trial. Linear mixed models disaggregated the proportion of cocaine-negative urine screens into between-subject (i.e., a participant's average use across the trial) and within-subject (i.e., a participant's deviation from their average) components to separately estimate their associations with quality-of-life outcomes. RESULTS:Overall, higher proportions of cocaine-negative urine test results were associated with statistically significant, although modest, between- and within-subject changes in several quality-of-life measures, including psychosocial functioning, mental health, and sleep. Participants who reached at least 75% cocaine-negative urine test results during treatment demonstrated improvements in all Short Inventory of Problems-Cocaine outcomes, excluding Total Score. CONCLUSIONS:These findings indicate that reducing cocaine use improves quality-of-life outcomes in people with cocaine use disorder. These results also extend prior research on more robust health improvements that emerge when participants attain 75% negative urine test results over a trial. Future research should explore the extent to which these beneficial outcomes apply to other cocaine use disorder samples, including those with more severe comorbid psychosocial challenges at baseline. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Introduction Limited prospective research has evaluated the health benefits associated with changing levels of drug use, aside from complete abstinence. This study determined whether lower levels of cocaine use impacted physiological indices (e.g., mean arterial pressure) and biomarkers (e.g., stromal cell derived factor-1a [SDF-1a], soluble intercellular adhesion molecule-1 [ICAM-1], neutrophil activating peptide-2 [CXCL7]) of cardiovascular health. Methods Treatment seeking participants enrolled in a 12-week single-blind, randomized, controlled cocaine contingency management trial. Participants were randomly assigned to High Value Reinforcers for cocaine abstinence (n = 41), Low Value Reinforcers for cocaine abstinence (n = 33) or a non-contingent Control group (n = 33). Physiological indices were collected at each clinic visit and averaged over each week of treatment. Biomarkers were assayed at 6-week intervals. Percent benzoylecgonine negative urines matching measurement timeframes were used to predict changes in outcomes using generalized linear models. Results Reductions in mean arterial pressure were observed in the High Value group, particularly during follow-up (χ(1,107)2= 6.6, p < .05). Regardless of group, less cocaine use was associated with decreased SDF-1a and increased ICAM-1 and CXCL7 levels (all χ(1,107)2> 4.7; p values < 0.05). Conclusions Improved blood pressure was observed in the High Value treatment group, who provided the greatest percent of cocaine negative urine samples but did not achieve total abstinence. Less cocaine use was also associated with changes in cardiac biomarkers that may indicate tissue repair. These results indicate that less cocaine use, even without complete abstinence, can improve blood pressure, and potentially heal cardiovascular insult, in individuals with Cocaine Use Disorder.

Individuals with opioid use disorder (OUD) frequently use other substances, including cocaine. Opioid withdrawal is associated with increased likelihood of cocaine use, which may represent an attempt to ameliorate opioid withdrawal effects. Clinically, 30% of co-using individuals take opioids and cocaine exclusively in a sequential manner. Preclinical studies evaluating mechanisms of drug use typically study drugs in isolation. However, polysubstance use is a highly prevalent clinical issue and thus, we established a novel preclinical model of sequential oxycodone and cocaine self-administration (SA) whereby rats acquired oxycodone and cocaine SA in an A-B-A-B design. Somatic signs of withdrawal were evaluated at 0, 22, and 24h following oxycodone SA, with the 24h timepoint representing somatic signs immediately following cocaine SA. Preclinically, aberrant glutamate signaling within the nucleus accumbens core (NAcore) occurs following use of cocaine or opioids, whereby medium spiny neurons (MSNs) rest in a potentiated or depotentiated state, respectively. Further, NAcore glial glutamate transport via GLT-1 is downregulated following SA of either drug alone. However, it is not clear if cocaine can exacerbate opioid-induced changes in glutamate signaling. In this study, NAcore GLT-1 protein and glutamate plasticity were measured (via AMPA/NMDA ratio) following SA. Rats acquired SA of both oxycodone and cocaine regardless of sex, and the acute oxycodone-induced increase in somatic signs at 22h was positively correlated with cocaine consumption during the cocaine testing phase. Cocaine use following oxycodone SA downregulated GLT-1 and reduced AMPA/NMDA ratios compared to cocaine use following food SA. Further, oxycodone SA alone was associated with reduced AMPA/NMDA ratio. Together, behavioral signs of oxycodone withdrawal may drive cocaine use and further dysregulate NAcore glutamate signaling.