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ObjectiveTo provide an up-to-date evidence summary about the comparative benefits and harms of drugs for adults with overweight or obesity to inform decision making for policymakers, payers, clinicians, and patients.DesignSystematic review and network meta-analysis of 24 outcomes using frequentist random effects models and bayesian dose-response models, the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach, and the Cochrane Risk of Bias 2 tool.Data sourcesMedline, Embase, and Cochrane Library, searched up to 12 November 2025.Study selectionRandomised controlled trials of 12 weeks' duration or longer comparing one or more drugs with lifestyle modification, placebo, or another drug.ResultsThis network meta-analysis comprised 262 trials (99 791 participants) evaluating 19 drugs with follow-up from 12 to 172 weeks. Compared with lifestyle modification alone, at one year, moderate to high certainty evidence shows substantial weight loss with tirzepatide (mean difference -14.9%, 95% confidence interval -16.0% to -13.9%), cagrilintide-semaglutide (CagriSema, -14.8%, -16.9% to -12.7%), oral semaglutide (-10.9%, -12.7% to -9.1%), orforglipron (-9.9%, -12.4% to -7.5%), subcutaneous semaglutide (-9.8%, -10.6% to -9.1%), and phentermine-topiramate (-8.1%, -9.7% to -6.5%). Emerging agents (ecnoglutide, mazdutide, retatrutide) may produce similar or greater reductions (13.1-14.6%; very low to low certainty). Moderate to high certainty evidence supports discontinuation because of adverse events to be highest with orforglipron, naltrexone-bupropion, liraglutide, phentermine-topiramate, CagriSema, and oral semaglutide (risk ratios from 1.9 to 4.2); gastrointestinal events were most increased with naltrexone-bupropion, oral semaglutide, orforglipron, and tirzepatide (risk ratios from 3.1 to 4.2). Fatigue risk increased, particularly with naltrexone-bupropion (risk ratio 8.9; absolute increase 331 per 1000 people over one year), orforglipron (3.4; 100 more per 1000), and CagriSema (3.2; 92 more per 1000). Tirzepatide reduced fat mass the most (by 25.7%) but also lean mass the most (by 8.3%). Subcutaneous semaglutide was the only drug associated with reduced all cause mortality (risk ratio 0.81, 95% confidence interval 0.72 to 0.93) and myocardial infarction (0.72, 0.61 to 0.85), with these estimates largely informed by cardiovascular outcome trials in high risk populations. Subcutaneous semaglutide (0.43, 0.21 to 0.84) and tirzepatide (0.49, 0.27 to 0.88) reduced heart failure risk. No drugs convincingly reduced kidney failure or improved quality of life (43 trials with 45 663 participants) beyond established minimally important differences (all mean differences ConclusionsObesity drugs produce variable weight loss at one year, with larger benefits generally accompanied by greater harms and discontinuation. Most agents do not improve quality of life meaningfully and few show cardiovascular benefits. Decisions in clinical practice should consider trade-offs between benefits and harms within the context of shared decision making.Systematic review registrationPROSPERO CRD42024507993.

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BackgroundPharmacotherapy offers a potential solution for individuals with overweight and obesity to decrease their body weight. However, there is limited knowledge of the effects of antiobesity agents on the distribution of body fat.MethodsThe PubMed, Embase, and Cochrane Library databases were reviewed for randomized controlled trials (RCTs) of weight-lowering drugs between inception and May 23, 2023. The main results were visceral and subcutaneous adipose tissue (VAT and SAT). Secondary outcomes were altered body weights and waist circumferences. For the statistical analysis, STATA 14.0 was utilized, and the frequentist method was used for random-effect network meta-analyses.ResultsA total of 39 articles including 41 RCTs with 2741 patients were included. GLP-1 receptor agonists and SGLT-2 inhibitors were observed to lower VAT (-0.90 [-1.32 to -0.47] and -0.66 [-1.22 to -0.10]) after a mean of 29.4 weeks, whereas only GLP-1 receptor agonists reduced SAT (-1.01 [-1.58 to -0.43]). Naltrexone-bupropion, GLP-1 receptor agonists, SGLT-2 inhibitors, and metformin were found to reduce body weight (-5.60 [-8.64 to -2.56] kg, -4.73 [-5.58 to -3.88] kg, -3.20 [-4.69 to -1.72] kg, and -1.93 [-3.01 to -0.85] kg). Lastly, waist circumference was decreased by GLP-1 receptor agonists, metformin, SGLT-2 inhibitors, and naltrexone-bupropion.ConclusionThis analysis demonstrated that GLP-1 receptor agonists may have advantages over other antiobesity agents in reducing VAT and SAT. SGLT-2 inhibitors were more helpful to reduce VAT. The clinical significance relates to physicians being able to choose appropriate weight-loss agents in accordance with a patient's fat distribution.

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IntroductionIn response to the increasing prevalence of online behavioral addictions, researchers have investigated various treatment approaches, including pharmacotherapies. This systematic review aimed to summarize pharmacotherapeutic studies of online behavioral addictions.MethodsPubMed, MEDLINE, and Embase were searched to identify randomized controlled trials or quasi-experimental studies of pharmacotherapy for online behavioral addictions. Studies were excluded if they only targeted offline behavioral addictions. Study findings were summarized, and the Effective Public Health Practice Project Quality Assessment Tool was used for quality assessment.ResultsThis systematic review included 20 studies (1016 participants). Bupropion, selective serotonin reuptake inhibitors (SSRIs), and opioid receptor antagonists were most frequently studied and showed preliminary promise in reducing symptom severity. Many pharmacotherapeutic studies addressed co-occurring concerns, such as depression.ConclusionsPharmacotherapies for online behavioral addictions appear promising, but the evidence base was limited by small samples, few randomized controlled trials, and short follow-up periods. Given preliminary support for psychotherapy + pharmacotherapy for problematic gaming, future research may evaluate the efficacy of combined treatment for a broader range of online behavioral addictions. Future research should also investigate pharmacotherapies for emerging problematic online behaviors, such as AI-based sexual engagement and problematic cryptocurrency trading.

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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.

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