Given the prevalence of substance use disorder (SUD), elevated overdose death rates, and limited approved pharmacotherapies for SUD, new treatment approaches are necessary. Neuromodulation is a potential adjunctive treatment for SUD to reduce substance use and risk factors associated with drug use recurrence, such as craving. One form of neuromodulation, focused ultrasound (FUS), has significant potential given that it is non-invasive and capable of targeting subcortical structures implicated in the brain’s reward circuity with great precision.
Targeting Mu opioid receptor neurons of the habenula to limit naloxone aversion
Opioid use disorder is a chronic, relapsing condition that continues to rise worldwide. Naloxone (Narcan®), an opioid antagonist, reverses overdose but triggers strong negative affect. The neuronal circuits underlying these aversive effects remain unclear. We previously identified mu opioid receptor–expressing habenular neurons (Hb-MOR) as key encoders of negative emotional states and hypothesized that they also mediate naloxone aversion.
Potential Cocaine Addiction Targets Identified Through Genetic Mapping in Rats
Scientists at the University of California San Diego have reported the results of a genome-wide association study in rats that identified key biological drivers of cocaine addiction. Using a genetically diverse group of nearly 900 rats to map genetic markers associated with compulsive drug use, the researchers uncovered a potential new therapeutic target that resides in the liver rather than in the brain.
Current research in this field often focuses on the brain, but the UC San Diego team’s findings suggest that how the body metabolizes cocaine may be just as critical in determining whether somebody develops an addiction.
“Finding a liver-based enzyme that shapes cocaine-taking behavior was a real ‘aha’ moment for us,” said Olivier George, PhD, a professor of psychiatry at UC San Diego School of Medicine. The George lab led the addiction behavioral studies that provided the foundation for the research. “It reminds us that addiction isn’t only in the brain. It’s a complex puzzle involving how the entire body processes the drug.”
George is co-corresponding author of the team’s published paper in Nature Communications, titled “Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats.”
Cocaine use disorder (CUD) has a strong genetic component, the authors noted. “Twin studies estimate the heritability of cocaine dependence to be as high as 70%, a finding supported by recent comprehensive reviews,” they wrote. GWAS have also uncovered a significant heritable component, the team continued, with single nucleotide polymorphism (SN)-based heritability estimated at 27-30%. However, scientists have struggled to pinpoint the specific genes that make certain individuals more vulnerable to addiction.
“The paucity of significant and replicated associations for CUD limits our understanding of this disorder, hampering our ability to identify novel pharmacological targets,” the investigators added. Co-corresponding author Abraham A. Palmer, PhD, professor of psychiatry at UC San Diego School of Medicine, who led the project’s intensive genetic modeling and analysis, further commented, “Identifying those genes in an important goal, because drugs could then be developed to target those genes, shifting genetically susceptible people to become more like genetically resistant people.”
To investigate further, the team carried out a GWAS in nearly 900 outbred Heterogeneous Stock (HS) rats—a model system capable of mimicking the vast genetic diversity found in human populations. By using HS rats the team was able to capture the critical differences between individuals who are genetically susceptible to addiction and those who are naturally more resistant. “Prior work has established the phenotypic diversity of HS rats across a broad range of addiction-relevant behaviors, including cocaine self-administration,” the researchers commented.
“The extended access model allowed us to characterize escalating intake, increased motivation to take the drug, and compulsive-like behavior despite negative consequences.” In addition to the GWAS results the researchers carried out a range of secondary analysis strategies to uncover what they describe as novel genetic drivers of cocaine self-administration behaviors.
Analyzing millions of genetic markers in each animal, the team discovered six major genetic regions linked to addiction-like behaviors, such as the escalation of drug intake and the time elapsed between doses. The researchers identified in the rats a specific group of carboxylesterase genes that are orthologous to the human CES1 gene, which are responsible for creating the enzyme that metabolizes cocaine. The study found that variations in these genes are closely linked to how frequently and compulsively rats self-administered the drug.
The findings also replicated a known genetic link found in humans (Trak2), providing a vital translational bridge between animal research and human medicine. This replication strengthens the argument that the biological pathways identified in the lab could eventually lead to real-world therapies. “Genes associated with CUD in humans remain limited, however our GWAS identified one gene (Trak2) that has also been identified by human GWAS of CUD, and the novel identification of Ces1 offers a fresh avenue for future studies,” they stated.
The collective findings suggest that by targeting the enzymes that metabolize cocaine with medicines, scientists might be able to alter how the drug affects the body, potentially reducing its addictive impact. In their paper they concluded “Our results replicate previous loci associated with CUD in humans and provide several novel biological insights including the potential of pharmacological strategies targeting carboxylesterases.”
Palmer said, “This work showcases the power of long-term, team-science collaboration that pairs experts in rodent behavior with quantitative geneticists. A decade of coordinated effort across multiple cohorts and federal partners made possible a discovery that no single lab could achieve alone.”
First author Montana Kay Lara, PhD, a postdoctoral researcher at UC San Diego School of Medicine, who helped bridge the gap between the study’s behavioral and genetic components, said, “Seeing the Ces1 signal validate a hypothesis that has been circulating for decades is incredibly exciting. It gives us a concrete target to test whether changing how cocaine is metabolized can blunt the drive toward compulsive use.”
The research team is now moving into the next phase of the project, which involves investigating exactly how these genetic mutations change function of the enzyme. They also hope to use the study’s extensive Preclinical Addiction Biobanks—collections of blood, urine, brain and other tissue samples—to identify biological markers that could one day help predict an individual’s risk of developing a substance use disorder.
The researchers hope that by leveraging this resource, they and other scientists working in this space will be able to translate genetic discoveries into diagnostic tools and new treatments that can help stabilize individuals struggling with addiction.
The post Potential Cocaine Addiction Targets Identified Through Genetic Mapping in Rats appeared first on GEN – Genetic Engineering and Biotechnology News.
Tracking the longitudinal course of physiologic and mental health functioning among individuals in substance use disorder treatment
IntroductionMental health monitoring is crucial to long-term recovery in substance use disorder (SUD) treatment; however, little is known about how changes in physiological indicators align with changes in self-reported mental health over time.MethodsWe examined longitudinal associations of resting heart rate (RHR) and heart rate variability (HRV) collected via a WHOOP® photoplethysmography device with self-reported stress, anxiety, and depressive symptoms among individuals in SUD treatment. Participants (N = 59) continuously wore the device and completed at least two mental health and stress assessments during the first month of residential treatment. ResultsLinear regression results indicated favorable changes in mental health and/or physiologic metrics, with notable heterogeneity in concurrent subject-level trends. Among participants with decreased RHR (better physiological functioning), 39% (N=23) also endorsed decreased stress, 42% (N=25) decreased anxiety, and 39% (N=23) improved depressive symptoms. Of those with increased HRV (greater stress adaptability), 39% (N=23) endorsed decreased stress, 39% (N=23) improved anxiety, and 41% (N=24) reduced depressive symptoms.DiscussionConcurrent changes in physiologic and mental health metrics during the first month of treatment varied across participants. These findings highlight the importance of integrating subjective mental health measures with physiological indicators to capture clinically relevant change during early SUD treatment.
Association between plasma proBDNF levels and cognitive impairment in patients with alcohol dependence: a case–control and longitudinal study
BackgroundAlcohol dependence is frequently accompanied by cognitive impairment. Brain-derived neurotrophic factor (BDNF) signaling plays a critical role in synaptic plasticity, while the precursor form, proBDNF, has been increasingly implicated in neurodegenerative and psychiatric disorders. However, the association between plasma proBDNF levels and cognitive impairment in alcohol dependence remains unclear.MethodsEighty male patients with alcohol dependence and forty-two matched healthy controls were enrolled. Plasma proBDNF levels were measured via enzyme-linked immunosorbent assay (ELISA). Cognitive function was assessed using the Mini-Mental State Examination (MMSE), the Modified Wisconsin Card Sorting Test (M-WCST), and the Verbal Fluency Test (VFT). Forty-one patients were reassessed after four weeks of abstinence. Group comparisons and correlation analyses were performed.ResultsPatients with alcohol dependence exhibited significantly elevated plasma proBDNF levels and impaired cognitive performance compared with controls. Plasma proBDNF levels were positively correlated with alcohol consumption severity, and linked to global cognitive deficits alongside nuanced executive performance variations. After four weeks of abstinence, plasma proBDNF levels decreased and cognitive performance improved; however, changes in proBDNF were weakly associated with cognitive recovery.ConclusionsElevated plasma proBDNF levels are associated with alcohol dependence severity and cognitive impairment, suggesting that proBDNF may serve as a peripheral biomarker reflecting the dynamic neurocognitive status in alcohol dependence.
Are Republicans turning against medications for treating opioid addiction?
When Robert F. Kennedy Jr. took office in February 2025, he broke new ground as the first health secretary openly in recovery from addiction to drugs and alcohol.
At a public appearance soon after, he delivered precisely the message that many substance use experts had hoped to hear: that evidence-based medications for treating opioid addiction, in particular, would remain essential components of the country’s response to its drug overdose crisis.
Gaming-based program for internet gaming disorder: feasibility and preliminary outcomes of a structured camp program
BackgroundAlthough controlled trials support several psychosocial interventions for adolescent internet gaming disorder (IGD), short, highly structured residential camp formats remain underreported, particularly regarding feasibility, safety, and process data from routine service settings.ObjectiveTo evaluate the feasibility, safety, and short-term entry-to-exit signals of a structured gaming-based camp program using retrospective, de-identified routinely collected service data, with a focus on implementation evidence for a brief, highly structured residential format.MethodsWe conducted a single-group entry-to-exit evaluation of a 7-day structured camp in 12 adolescents aged 11–16 years clinically diagnosed with IGD by psychiatrists using DSM-5 criteria. Entry and exit assessments were organized hierarchically, with the Gaming Disorder Screening Scale (GDSS), the Game Addiction Scale–7 (GAS-7), and the Visual Analog Scale (VAS) craving score as primary outcomes; the Barratt Impulsiveness Scale–11 (BIS-11), Zung Self-Rating Depression Scale (SDS), Zung Self-Rating Anxiety Scale (SAS), Social Avoidance and Distress Scale (SADS), and Chinese version of the Interpersonal Reactivity Index (IRI-C) as supportive secondary outcomes; and camp residential counselor–rated Conners scores and the Stroop task as exploratory external-rating and objective complementary indicators, respectively. Wilcoxon signed-rank tests reported effect size r and Hodges–Lehmann (HL) median difference with 95% CI. Exploratory Spearman correlations examined baseline characteristics and change.ResultsCompletion was 100% (12/12) and attendance 98.6% (142/144), with no serious adverse events; two participants had a brief single-session interruption (coded as non-attendance for that session-person) but completed subsequent sessions and exit assessment. Primary outcomes decreased at exit: GDSS 50.00 (SD 8.32) to 28.67 (SD 8.98), p<0.001, r=0.88, HL −20.5 (95% CI −27.0 to −16.5); GAS-7 21.50 (SD 6.57) to 13.33 (SD 4.44), p=0.003, r=0.89, HL −8.5 (95% CI −12.5 to −6.0); VAS 4.25 (SD 2.63) to 2.75 (SD 2.05), p=0.012, r=0.85, HL −2.0 (95% CI −3.0 to −1.0). High-risk GDSS decreased from 66.7% to 0%, GAS-7 positivity from 58.3% to 8.3%, and moderate-to-severe craving from 58.3% to 25.0%. BIS-11, SDS, and IRI-C showed supportive short-term changes, and counselor-rated Conners scores showed exploratory external-rating changes, whereas SAS and SADS did not. Stroop reaction time decreased and accuracy increased in both conditions, while interference effects did not change significantly. Baseline PSQI correlated with change in VAS craving (ρ=0.767, p=0.004).ConclusionsThis pilot program evaluation suggests that a short, highly structured gaming-based residential camp can be delivered feasibly and safely and may be associated with short-term reductions in IGD symptom severity and craving. Its main value is to provide early implementation and short-term signal data for a service-based camp format that should be tested in subsequent controlled studies with follow-up.
Intellectual-cultural orientation of family environment and adolescent depressive symptoms: the mediating role of game addiction
IntroductionExisting data indicate that an increasing number of adolescents are becoming addicted to online games, while the prevalence of depressive symptoms within this demographic is also on the rise. Depression is a primary comorbidity associated with game addiction, but the influencing factors and mechanisms remain unclear. This study aims to explore the mediating role of game addiction in the relationship between the intellectual-cultural orientation of family environment and adolescent depressive symptoms.MethodsA cross-sectional study was conducted on 1,105 pairs of mothers and adolescents in a high school in Henan Province, China, through online investigation from November 17, 2021 to December 11, 2021. The intellectual-cultural orientation, game addiction and adolescent depressive symptoms were measured by the subscale of Intellectual-cultural orientation in Family Environment Scale, Game Addiction Scale for Adolescents and Children’s Depression Inventory respectively. The SPSS PROCESS macro 3.3 software was used to analyze the mediating effect.ResultsThe findings revealed that Intellectual-cultural orientation was negatively correlated with both adolescent game addiction and depressive symptoms. Game addiction served as a significant mediator between Intellectual-cultural orientation and depressive symptoms in adolescents. Furthermore, gender and annual household income significantly associated with the strength of the mediating effect of game addiction on the relationship between Intellectual-cultural orientation and adolescent depressive symptoms. Specifically, boys and adolescents from low-incomefamilies were more likely to suffer from game addiction.DiscussionThese findings suggest that future family based interventions aimed at preventing adolescent depression should specifically target the reduction of game time, particularly among boys and adolescents from low-income families.
GLP-1 Drugs Linked to Lower Rates of Substance Use Disorders
A study led by researchers at the University of Texas at El Paso (UTEP) has found that people with type 2 diabetes or obesity who were prescribed GLP-1 receptor agonists (GLP-1 RAs) had substantially lower odds of developing alcohol, opioid, nicotine, and cocaine use disorders compared with similar individuals who were not taking the medications. The research, published in the journal Frontiers in Psychiatry, used health data from more than 142,000 patients from the All of Us Research Program and adds to a growing body of evidence indicating that GLP-1 medications may have an influence on dopamine signaling and other neural pathways that drive cravings not just for food but other substances.
“Our findings add to growing evidence that GLP-1 medications may influence more than appetite and blood sugar regulation,” said lead author Tadesse Abegaz, PhD, an assistant professor in the School of Pharmacy, University of Texas at El Paso. “These medications appear to affect brain pathways involved in reward and craving, which could help explain the lower rates of substance use disorders observed in our study.”
Substance use disorders are a significant public health challenge contributing to illness, premature death, and higher healthcare costs. While current treatment methods that combine medications and behavioral therapy can be effective, relapse rates remain high, often exceeding 50% within the first year after treatment, suggesting a need for additional ways to treat this disease.
An emerging candidate for this are GLP-1 receptor agonists such as semaglutide and liraglutide. Developed to treat type 2 diabetes and obesity, these drugs have drawn attention because GLP-1 receptors are found not only in areas involved in metabolic regulation but also in brain regions associated with reward and reinforcement.
“Animal studies have demonstrated that GLP-1 RAs reduce the self-administration of alcohol, opioid, nicotine, and cocaine effects [that] are believed to be mediated through interactions with the mesolimbic dopamine system,” the researchers wrote. Small human studies and observational analyses have also suggested reductions in substance cravings, relapse rates, and alcohol-related hospitalizations among some patients receiving GLP-1 therapies.
The El Paso investigators said they initiated their research to move beyond smaller studies because “the real-world impact of GLP-1 RA on multiple co-occurrence of SUD (substance use disorder) has not been systematically investigated.”
To address this gap, the team conducted a retrospective nested case-control study using data from the NIH’s All of Us Research Program. The study examined individuals with type 2 diabetes or obesity and identified cases involving new diagnoses of alcohol use disorder, opioid use disorder, nicotine use disorder, or cocaine use disorder. These individuals were compared with matched control participants who had diabetes or obesity but no documented history of substance use disorders.
Analyses of these data showed consistent associations across all categories studied. GLP-1 receptor agonist use was associated with a 74% reduction in the odds of alcohol use disorder, a 69% reduction in the odds of opioid use disorder, a 68% reduction in the odds of nicotine use disorder, and a 75% reduction in the odds of cocaine use disorder. The researchers also reported 75% lower odds of any substance use disorder among GLP-1 users compared with non-users.
“Exposure to GLP-1 RAs was consistently associated with significantly reduced odds of SUD cases,” the researchers wrote. “These findings suggest that GLP-1 RAs may exert behavioral-modifying effects that extend beyond glycemic control and weight loss.”
The researchers noted that their research was observational and does not establish cause and effect. “We do not support prescribing these medications for addiction treatment at this time,” said senior author Gabriel Frietze, PhD, an assistant professor of pharmaceutical sciences at UTEP. “Because this was an observational study in a specific clinical population, randomized clinical trials are needed before GLP-1 medications can be recommended for treating addiction.”
The team believes the findings could help guide future approaches to addressing substance use-related health issues by identifying biological pathways that may be targeted therapeutically. The authors noted that mechanisms potentially involved include modulation of dopamine release, suppression of neuroinflammation, and attenuation of stress-related neural circuits.
“Our next goal is to conduct prospective research that follows individuals initiating GLP-1 therapy over time,” Abegaz said. “We aim to evaluate whether changes in the substance use behaviors occur after treatment begins and whether these changes related to improvements in mental health and quality of life. Ultimately, this work will help inform whether GLP-1 medications could become part of future treatment strategies for substance use disorders.”
The post GLP-1 Drugs Linked to Lower Rates of Substance Use Disorders appeared first on Inside Precision Medicine.
<![CDATA[Lawsuits, research, and clinicians clash over youth screen addiction—learn more about how problematic social platform use evades diagnosis and how we can curb harm.]]>