Food preference-based screening method for identification of effectors of substance use disorders using Caenorhabditis elegans.

Substance use disorder (SUD) affects over 48 million Americans aged 12 and over. Thus, identifying novel chemicals contributing to SUD will be critical for developing efficient prevention and mitigation strategies. Considering the complexity of the actions and effects of these substances on human behavior, a high-throughput platform using a living organism is ideal. We developed a quick and easy screening assay using Caenorhabditis elegans. C. elegans prefers high-quality food (Escherichia coli HB101) over low-quality food (Bacillus megaterium), with a food preference index of approximately 0.2, defined as the difference in the number of worms at E. coli HB101 and B. megaterium over the total worm number. The food preference index was significantly increased by loperamide, a µ-opioid receptor (MOPR) agonist, and decreased by naloxone, a MOPR antagonist. These changes depended on npr-17, a C. elegans homolog of opioid receptors. In addition, the food preference index was significantly increased by arachidonyl-2'-chloroethylamide, a cannabinoid 1 receptor (CB1R) agonist, and decreased by rimonabant, a CB1R inverse agonist. These changes depended on npr-19, a homolog of CB1R. These results suggest that the conserved opioid and endocannabinoid systems modulate the food preference behaviors of C. elegans. Finally, the humanoid C. elegans strains where npr-17 was replaced with human MOPR and where npr-19 was replaced with human CB1R phenocopied the changes in food preference by the drug treatment. Together, the current results show that this method can be used to rapidly screen the potential effectors of MOPR and CB1R to yield results highly translatable to humans.

Prescription Drug Dispensing and Patient Costs After Implementation of a No Behavioral Health Cost-Sharing Law.

Importance: On January 1, 2022, New Mexico implemented a No Behavioral Cost-Sharing (NCS) law that eliminated cost-sharing for mental health and substance use disorder (MH/SUD) treatments in plans regulated by the state, potentially reducing a barrier to treatment for MH/SUDs among the commercially insured; however, the outcomes of the law are unknown. Objective: To assess the association of implementation of the NCS with out-of-pocket spending for prescription for drugs primarily used to treat MH/SUDs and monthly volume of dispensed drugs. Design, Settings, and Participants: This retrospective cohort study used a difference-in-differences research design to examine trends in outcomes for New Mexico state employees, a population affected by the NCS, compared with federal employees in New Mexico who were unaffected by NCS. Data were collected on prescription drugs for MH/SUDs dispensed per month between January 2021 and June 2022 for New Mexico patients with a New Mexico state employee health plan and New Mexico patients with a federal employee health plan. Data analysis occurred from December 2022 to January 2024. Exposure: Enrollment in a state employee health plan or federal health plan. Main Outcomes and Measures: The primary outcomes were mean patient out-of-pocket spending per dispensed MH/SUD prescription and the monthly volume of dispensed MH/SUD prescriptions per 1000 employees. A difference-in-differences estimation approach was used. Results: The implementation of the NCS law was associated with a mean (SE) $6.37 ($0.30) reduction (corresponding to an 85.6% decrease) in mean out-of-pocket spending per dispensed MH/SUD medication (95% CI, -$7.00 to -$5.75). The association of implementation of NCS with the volume of prescriptions dispensed was not statistically significant. Conclusions and Relevance: These findings suggest that the implementation of the New Mexico NCS law was successful in lowering out-of-pocket spending on prescription medications for MH/SUDs, but that there was no association of NCS with the volume of medications dispensed in the first 6 months after implementation. A key challenge is to identify policies that protect from high out-of-pocket spending while also promoting access to needed care.

Targeting the cytoskeleton as a therapeutic approach to substance use disorders.

Substance use disorders (SUD) are chronic relapsing disorders governed by continually shifting cycles of positive drug reward experiences and drug withdrawal-induced negative experiences. A large body of research points to plasticity within systems regulating emotional, motivational, and cognitive processes as drivers of continued compulsive pursuit and consumption of substances despite negative consequences. This plasticity is observed at all levels of analysis from molecules to networks, providing multiple avenues for intervention in SUD. The cytoskeleton and its regulatory proteins within neurons and glia are fundamental to the structural and functional integrity of brain processes and are potentially the major drivers of the morphological and behavioral plasticity associated with substance use. In this review, we discuss preclinical studies that provide support for targeting the brain cytoskeleton as a therapeutic approach to SUD. We focus on the interplay between actin cytoskeleton dynamics and exposure to cocaine, methamphetamine, alcohol, opioids, and nicotine and highlight preclinical studies pointing to a wide range of potential therapeutic targets, such as nonmuscle myosin II, Rac1, cofilin, prosapip 1, and drebrin. These studies broaden our understanding of substance-induced plasticity driving behaviors associated with SUD and provide new research directions for the development of SUD therapeutics.

Substance use disorder of equimolar oxygen-nitrous oxide mixture in French sickle-cell patients: results of the PHEDRE study.

BACKGROUND: In many countries, nitrous oxide is used in a gas mixture (EMONO) for short-term analgesia. Cases of addiction, with significant misuse, have been reported in hospitalized patients. Patients suffering from sickle cell disease (SCD) could represent a high-risk population for substance use disorder (SUD) due to their significant pain crisis and repeated use of EMONO. The objective of the PHEDRE study was to assess the prevalence of SUD for EMONO in French SCD patients. RESULTS: A total of 993 patients were included. Among 339 EMONO consumers, only 38 (11%) had a SUD, with very few criteria, corresponding mainly to a mild SUD due to a use higher than expected (in quantity or duration) and relational tensions with the care teams. Almost all patients (99.7%) were looking for an analgesic effect, but 68% of patients were also looking for other effects. The independent risks factors associated with at least one SUD criterion were: the feeling of effects different from the expected therapeutic effects of EMONO, at least one hospitalization for vaso occlusive crisis in the past 12 months and the presence of a SUD for at least one other analgesic drug. CONCLUSIONS: The use of EMONO was not problematic for the majority of patients. Manifestations of SUD that led to tensions with healthcare teams should alert and lead to an evaluation, to distinguish a true addiction from a pseudoaddiction which may be linked to an insufficient analgesic treatment related to an underestimation of pain in SCD patients. TRIAL REGISTRATION: Clinical Trials, NCT02580565. Registered 16 October 2015, https://clinicaltrials.gov/.

Modafinil, an atypical CNS stimulant?

Modafinil is a central nervous system stimulant approved for the treatment of narcolepsy and sleep disorders. Due to its wide range of biochemical actions, modafinil has been explored for other potential therapeutic uses. Indeed, it has shown promise as a therapy for cognitive disfunction resulting from neurologic disorders like ADHD, and as a smart drug in non-medical settings. The mechanism(s) of actions underlying the therapeutic efficacy of this agent remains largely elusive. Modafinil is known to inhibit the dopamine transporter, thus decreasing dopamine reuptake following neuronal release, an effect shared by addictive psychostimulants. However, modafinil is unique in that only a few cases of dependence on this drug have been reported, as compared to other psychostimulants. Moreover, modafinil has been tested, with some success, as a potential therapeutic agent to combat psychostimulant and other substance use disorders. Modafinil has additional, but less understood, actions on other neurotransmitter systems (GABA, glutamate, serotonin, norepinephrine, etc.). These interactions, together with its ability to activate selected brain regions, are likely one of the keys to understand its unique pharmacology and therapeutic activity as a CNS stimulant. In this chapter, we outline the pharmacokinetics and pharmacodynamics of modafinil that suggest it has an "atypical" CNS stimulant profile. We also highlight the current approved and off label uses of modafinil, including its beneficial effects as a treatment for sleep disorders, cognitive functions, and substance use disorders.

Prescribed safer opioid supply: A scoping review of the evidence.

BACKGROUND: Safer opioid supply programs provide prescription pharmaceutical opioids, often with supportive services, to people at high risk of experiencing harms related to substance use. However, questions regarding the effectiveness and safety of this practice remain. We conducted a scoping review of literature describing client outcomes from formal opioid supply programs providing prescriptions for pharmaceutical opioids, and the perceptions of involved clients/providers. METHODS: We performed a scoping review of peer-reviewed studies and grey literature published between January 1, 2012, to September 12, 2023. We included articles reporting either safer opioid supply client outcomes or clients/providers perspectives. Extracted data included study objectives, substance use patterns, client outcomes, client/provider perspectives, and estimates of effectiveness and/or harm. RESULTS: Our search yielded 1,597 articles. Following removal of duplicates and application of exclusion criteria, 24 publications comprising 17 peer-reviewed and seven grey literature publications were included in our study. We generated eight themes summarizing topics in the available literature: opioid-related toxicities, infectious complications, other clinical outcomes, client-reported outcomes, program access barriers, diversion, program retention, and costs to the healthcare system. Specific findings included low rates of opioid toxicities, improved physical and mental health, and improved quality of life among clients. A lack of access to adequate opioid doses and the limited range of opioid options offered within safer opioid supply programs was described by clients and providers as a potential reason for diversion and a barrier to program access. CONCLUSIONS: Generally, evidence suggests that safer opioid supply programs are beneficial to clients through measurable outcomes. However, the available literature has important limitations, including limited inferences about the effectiveness, safety, and potential for diversion within safer opioid supply programs. Further research is needed to support the ongoing evaluation of safer opioid supply programs as one component of a multifactorial response to escalating rates of substance-related harms.

Associations between cannabis policies and state-level specialty cannabis use disorder treatment in the United States, 2004-2019.

BACKGROUND: Cannabis use disorder (CUD) treatment prevalence decreased in the US between 2002 and 2019, yet structural mechanisms for this decrease are poorly understood. We tested associations between cannabis laws becoming effective and self-reported CUD treatment. METHODS: Restricted-use 2004-2019 National Surveys on Drug Use and Health included people ages 12+ classified as needing CUD treatment (i.e., past-year DSM-5-proxy CUD or last/current specialty treatment for cannabis). Time-varying indicators of medical cannabis laws (MCL) with/without cannabis dispensary provisions differentiated state-years before/after laws using effective dates. Multi-level logistic regressions with random state intercepts estimated individual- and state-adjusted CUD treatment odds by MCLs and model-based changes in specialty CUD treatment state-level prevalence. Secondary analyses tested associations between CUD treatment and MCL or recreational cannabis laws (RCL). RESULTS: Using a broad treatment need sample definition in 2004-2014, specialty CUD treatment prevalence decreased by 1.35 (95 % CI = -2.51, -0.18) points after MCL without dispensaries and by 2.15 points (95 % CI = -3.29, -1.00) after MCL with dispensaries provisions became effective, compared to before MCL. Among people with CUD in 2004-2014, specialty treatment decreased only in MCL states with dispensary provisions (aPD = -0.91, 95 % CI = -1.68, -0.13). MCL were not associated with CUD treatment use in 2015-2019. RCL were associated with lower CUD treatment among people classified as needing CUD treatment, but not among people with past-year CUD. CONCLUSIONS: Policy-related reductions in specialty CUD treatment were concentrated in states with cannabis dispensary provisions in 2004-2014, but not 2015-2019, and partly driven by reductions among people without past-year CUD. Other mechanisms (e.g., CUD symptom identification, criminal-legal referrals) could contribute to decreasing treatment trends.

Feeling safer: effectiveness, feasibility, and acceptability of continuous pulse oximetry for people who smoke opioids at overdose prevention services in British Columbia, Canada.

BACKGROUND: Smoking is the most common mode of unregulated opioid consumption overall and implicated in fatal overdoses in British Columbia (BC). In part, perception of decreased risk (e.g., fewer who smoke carry naloxone kits) and limited smoking-specific harm reduction services contribute to overdose deaths. Overdose prevention services (OPS) offer supervised settings for drug use. Continuous pulse oximetry, common in acute care, allows real-time, remote oxygen monitoring. We evaluated the effectiveness of a novel continuous pulse oximetry protocol aimed at allowing physical distancing (as required by COVID-19, secluded spaces, and to avoid staff exposure to vaporized opioids), its feasibility, and acceptability at OPS for people who smoke opioids. METHODS: This was a mixed methods survey study. We developed a continuous pulse oximetry protocol in collaboration with clinical experts and people with lived/living experience of substance use. We implemented our protocol from March to August 2021 at four OPS in BC permitting smoking. We included adults (≥ 18 years) presenting to OPS to smoke opioids. Peer researchers collected demographic, health, and substance use information, and conducted structured observations. OPS clients participating in our study, OPS staff, and peer researchers completed post-monitoring surveys. We analyzed responses using a thematic inductive approach and validated themes with peer researchers. RESULTS: We included 599 smoking events. OPS clients participating in our study had a mean age of 38.5 years; 73% were male. Most (98%) reported using "down", heroin, or fentanyl; 48% concurrently used other substances (32% of whom reported stimulants); 76% reported smoking alone in the last 3 days; and 36% reported an overdose while smoking. Respondents reported that the protocol facilitated physical distancing, was easy to use, high satisfaction, improved confidence, improved sense of safety, and that they would use it again. CONCLUSIONS: Continuous pulse oximetry allowed safe physical distancing, was feasible, and acceptable in monitoring people who smoke opioids at OPS.

IUPHAR Review: New strategies for medications to treat substance use disorders.

Substance use disorders (SUDs) and drug overdose are a public health emergency and safe and effective treatments are urgently needed. Developing new medications to treat them is expensive, time-consuming, and the probability of a compound progressing to clinical trials and obtaining FDA-approval is low. The small number of FDA-approved medications for SUDs reflects the low interest of pharmaceutical companies to invest in this area due to market forces, characteristics of the population (e.g., stigma, and socio-economic and legal disadvantages), and the high bar regulatory agencies set for new medication approval. In consequence, most research on medications is funded by government agencies, such as the National Institute on Drug Abuse (NIDA). Multiple scientific opportunities are emerging that can accelerate the discovery and development of new medications for SUDs. These include fast and efficient tools to screen new molecules, discover new medication targets, use of big data to explore large clinical data sets and artificial intelligence (AI) applications to make predictions, and precision medicine tools to individualize and optimize treatments. This review provides a general description of these new research strategies for the development of medications to treat SUDs with emphasis on the gaps and scientific opportunities. It includes a brief overview of the rising public health toll of SUDs; the justification, challenges, and opportunities to develop new medications; and a discussion of medications and treatment endpoints that are being evaluated with support from NIDA.

Availability of Long-Acting Injectable Buprenorphine at Substance Use Treatment Facilities in 2021.

This study assesses the proportion of US substance use and mental health care facilities that offered any medications for opioid use disorder and, specifically, long-acting injectable buprenorphine in 2021.

Treatment of Posttraumatic Stress Disorder: A State-of-the-art Review.

This narrative state-of-the-art review paper describes the progress in the understanding and treatment of Posttraumatic Stress Disorder (PTSD). Over the last four decades, the scientific landscape has matured, with many interdisciplinary contributions to understanding its diagnosis, etiology, and epidemiology. Advances in genetics, neurobiology, stress pathophysiology, and brain imaging have made it apparent that chronic PTSD is a systemic disorder with high allostatic load. The current state of PTSD treatment includes a wide variety of pharmacological and psychotherapeutic approaches, of which many are evidence-based. However, the myriad challenges inherent in the disorder, such as individual and systemic barriers to good treatment outcome, comorbidity, emotional dysregulation, suicidality, dissociation, substance use, and trauma-related guilt and shame, often render treatment response suboptimal. These challenges are discussed as drivers for emerging novel treatment approaches, including early interventions in the Golden Hours, pharmacological and psychotherapeutic interventions, medication augmentation interventions, the use of psychedelics, as well as interventions targeting the brain and nervous system. All of this aims to improve symptom relief and clinical outcomes. Finally, a phase orientation to treatment is recognized as a tool to strategize treatment of the disorder, and position interventions in step with the progression of the pathophysiology. Revisions to guidelines and systems of care will be needed to incorporate innovative treatments as evidence emerges and they become mainstream. This generation is well-positioned to address the devastating and often chronic disabling impact of traumatic stress events through holistic, cutting-edge clinical efforts and interdisciplinary research.

Social Media as Pharmacovigilance: The Potential for Patient Reports to Inform Clinical Research on Glucagon-Like Peptide 1 (GLP-1) Receptor Agonists for Substance Use Disorders.

The surge in popularity of semaglutide (Ozempic, Wegovy, Rybelsus) and other glucagon-like-peptide 1 (GLP-1) receptor agonists has been accompanied by widespread reports of unintended reductions in alcohol use (and other addictive behaviors) during treatment. With clinical trials of GLP-1 receptor agonists for substance use only recently under way, anecdotal reports (including via social media) are now a primary reason for interest in potential effects of GLP-1 receptor agonists on alcohol use in patient populations. The nature and volume of these reports raises the prospect that social media data can potentially be leveraged to inform the study of novel addiction treatments and the prioritization of behavioral or neurobiological targets for mechanistic research. This approach, which aligns with recent efforts to apply social media data to pharmacovigilance, may be particularly relevant for drug repurposing efforts. This possibility is illustrated by a thematic analysis of anonymous online reports concerning changes in alcohol use or alcohol-related effects during treatment with GLP-1 receptor agonists. These reports not only support the rationale for clinical trials but also point to potential neurobehavioral mechanisms (e.g., satiety, craving/preoccupation, aversion, altered subjective response) that might inform hypotheses for human laboratory and neuroscience studies. Refined methods for capturing patient reports of incidental medication effects on addictive behaviors at large scale could potentially lead to novel, pharmacovigilance-based approaches to identify candidate therapies for drug repurposing efforts.

Could psychostimulant drug use among university students be related to ADHD symptoms? A preliminary study.

We aimed to explore if psychostimulant use among student could be linked to attention deficit-hyperactivity disorder (ADHD) symptoms using a self-administered questionnaire sent by email to French students in 2021. Participants were asked about their psychostimulant use and the presence of ADHD symptoms using the Wender Utah Rating Scale and the Adult Self-Report Scale. Among the 4431 respondents, the prevalence of psychostimulant use was concerning and significantly associated with ADHD symptoms. This association could be related to undiagnosed ADHD or to psychobehavioral impairments induced by psychostimulant use underlining the need of ADHD screening and targeted prevention measures.

Drug addiction and treatment: An epigenetic perspective.

Drug addiction is a complex disease affected by numerous genetic and environmental factors. Brain regions in reward pathway, neuronal adaptations, genetic and epigenetic interactions causing transcriptional enhancement or repression of multiple genes induce different addiction phenotypes for varying duration. Addictive drug use causes epigenetic alterations and similarly epigenetic changes induced by environment can promote addiction. Epigenetic mechanisms include DNA methylation and post-translational modifications like methylation, acetylation, phosphorylation, ubiquitylation, sumoylation, dopaminylation and crotonylation of histones, and ADP-ribosylation. Non-coding RNAs also induce epigenetic changes. This review discusses these above areas and stresses the need for exploring epidrugs as a treatment alternative and adjunct, considering the limited success of current addiction treatment strategies. Epigenome editing complexes have lately been effective in eukaryotic systems. Targeted DNA cleavage techniques such as CRISPR-Cas9 system, CRISPR-dCas9 complexes, transcription activator-like effector nucleases (TALENs) and zinc-finger nucleases (ZFNs) have been exploited as targeted DNA recognition or anchoring platforms, fused with epigenetic writer or eraser proteins and delivered by transfection or transduction methods. Efficacy of epidrugs is seen in various neuropsychiatric conditions and initial results in addiction treatment involving model organisms are remarkable. Epidrugs present a promising alternative treatment for addiction.

The Effect of Methylphenidate on Cognition in Patients with Comorbid Attention Deficit/Hyperactivity Disorder and Amphetamine Use Disorder: An Exploratory Single-Blinded within-Subject Study.

INTRODUCTION: Attention deficit/hyperactivity disorder (ADHD) with co-occurring substance use disorder (SUD) is associated with poor treatment outcomes. Two randomized controlled trials, utilizing robust doses of stimulants, demonstrated a significant effect on treatment outcomes in patients with ADHD/SUD. This study aimed to investigate differences in executive functioning and explore the dose-dependent effect of OROS-methylphenidate (MPH) in patients with comorbid ADHD and amphetamine use disorder (ADHD+AMPH) and patients with ADHD only. METHODS: Three groups (ADHD+AMPH, ADHD only, and healthy controls) were assessed repeatedly with a neuropsychological test battery. An exploratory within-subject single-blinded design was employed where the ADHD only group received a maximum dose of 72 mg OROS-MPH, the ADHD+AMPH group a maximum dose of 180 mg, whereas the healthy subjects did not receive any study medication. Both ADHD groups received the same dose titration up to 72 mg OROS-MPH. RESULTS: The ADHD+AMPH group demonstrated a significantly poorer motor inhibition and spatial working memory and reported more severe ADHD symptoms compared to the ADHD only group. 180 mg OROS-MPH was associated with a significant improvement in executive functioning in the dual diagnosis group. However, the exploratory study design and recruitment issues do not allow for any conclusion to be drawn regarding the effect of 180 mg OROS-MPH. CONCLUSION: Patients with ADHD+AMPH present with more severe neurocognitive deficits compared to ADHD only. The effect of 180 mg OROS-MPH on cognition in patients with ADHD+AMPH was inconclusive. Future studies should consider recruitment issues and high drop-out rates in this study population.

IUPHAR-review: The integration of classic psychedelics into current substance use disorder treatment models.

Substance use disorders (SUDs) have an enormous impact on public health. With classic psychedelic-assisted therapies showing initial promise in treating multiple SUDs, it is possible that these treatments will become legally available options for patients with SUDs in the future. This article highlights how classic psychedelic-assisted therapies might be integrated into current clinical practice. We first describe contemporary evidence-based treatments for SUDs and highlight how classic psychedelic-assisted therapies might fit within each treatment. We suggest that classic psychedelic-assisted therapies can be integrated into most mainstream evidence-based SUD treatments that are currently used in clinical settings, indicating broad compatibility of classic psychedelics with contemporary SUD treatment paradigms.

Effects of Beta Lactams on Behavioral Outcomes of Substance Use Disorders: A Meta-Analysis of Preclinical Studies.

INTRODUCTION: Preclinical studies demonstrated that beta-lactams have neuroprotective effects in conditions involving glutamate neuroexcitotoxicity, including substance use disorders (SUDs). This meta-analysis aims to analyze the existing evidences on the effects of beta-lactams as glutamate transporter 1 (GLT-1) upregulators in animal models of SUDs, identification of gaps in the literature, and setting the stage for potential translation into clinical phases. METHODS: Meta-analysis was conducted on preclinical studies retrieved systematically from MEDLINE and ScienceDirect databases. Abused substances were identified by refereeing to the National Institute on Drug Abuse (NIDA). The results were quantitatively described with a focus on the behavioral outcomes. Treatment effect sizes were described using standardized mean difference, and they were pooled using random effect model. I2-statistic was used to assess heterogeneity, and Funnel plot and Egger's test were used for assessment of publication bias. RESULTS: Literature search yielded a total of 71 studies that were eligible to be included in the analysis. Through these studies, the effects of beta-lactams were evaluated in animal models of nicotine, cannabis, amphetamines, synthetic cathinone, opioids, ethanol, and cocaine use disorders as well as steroids-related aggressive behaviors. Meta-analysis showed that treatments with beta-lactams consistently reduced the pooled undesired effects of the abused substances in several paradigms, including drug-self administration, conditioned place preference, drug seeking behaviors, hyperlocomotion, withdrawal syndromes, tolerance to analgesic effects, hyperalgesia, and hyperthermia. CONCLUSION: This meta-analysis revealed that enhancing GLT-1 expression in the brain through beta-lactams seemed to be a promising treatment approach in the context of substance use disorders, as indicated by results in animal models.