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Lorcaserin is a 3-benzazepine that binds 5-HT 2C serotonin receptors in the hypothalamus, where it mediates lack of hunger and/or satiety, and in the ventral tegmental area, the site of origin of the mesolimbic and mesocortical dopaminergic projections, which mediate pleasure and reward. The drug has been first developed for the treatment of obesity, where it has shown efficacy, and subsequently trialed to counter substance use (mostly cocaine, cannabis, opioids, and nicotine) and craving, but showed inconsistent effects. Since 2020, the US Food and Drug Administration obtained that the drug was voluntarily withdrawn from the US market on the grounds that its long-term use was found to be associated with a greater incidence of some types of cancer. Provided it can show to be free from cancerogenic effects, ongoing research suggests that lorcaserin may have therapeutic potential for a variety of disorders and conditions beyond obesity. Since 5-HT 2C receptors are involved in many diversified physiological functions (mood, feeding, reproductive behavior, neuronal processes related to impulsiveness, and modulating reward-related mechanisms) this drug has the potential to treat different central nervous system conditions, such as depression and schizophrenia., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Ryan T Hurt,1–4 Manpreet S Mundi,3 Jon O Ebbert5 1Division of General Internal Medicine, Mayo Clinic, Rochester, MN, USA; 2Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA; 3Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA; 4Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, KY, USA; 5Division of Primary Care Internal Medicine, Mayo Clinic, Rochester, MN, USA Abstract: Obesity is a global epidemic that is a leading cause of preventable death. In addition to lifestyle modification, there are numerous obesity treatments for clinicians to consider, including medications. Lorcaserin immediate release/extended release (IR/XR) is a US Food and Drug Administration approved medication for overweight and obese patients to be used with lifestyle modifications. Lorcaserin is thought to reduce weight by targeting the serotonin (5HT2c) system to induce satiety. Lorcaserin IR has been shown to be effective in reducing weight in overweight (body mass index [BMI] > 27 kg/m2) and obese (BMI > 30 kg/m2) participants in three large Phase III trials. In addition, lorcaserin has been shown to reduce post-cessation weight gain and improved smoking cessation in a randomized placebo-controlled trial. A recent meta-analysis suggested in overweight diabetic patients lorcaserin may be added to first-line oral hypoglycemic medications to enhance reduction in glycated hemoglobin. Lorcaserin is generally well tolerated with the most common side effect being headache, which is typically self-limiting. Lorcaserin XR (once daily) was recently approved and has been shown to be bioequivalent to lorcaserin IR (twice daily) in a pivotal study. Lorcaserin XRs, main advantage over the IR formulation is the once daily dosing regimen, which likely would lead to improved adherence and thus improved clinical effectiveness. The present review will evaluate the lorcaserin clinical studies (obesity, diabetes, and addiction), XR bioequivalence studies, pharmacogenomics of the serotonin (5HT2c) system, and adherence data in once daily versus twice daily medications. Keywords: lorcaserin, Belviq©, obese, pharmacotherapy

Background: Trying to find a drug with more clinical efficacy in treating obesity is one of the priorities. The aim of this study was to evaluate the efficacy of orlistat, sibutramine, lorcaserin and metformin on weight loss in obese people. Methods: The databases of PubMed, Scopus, Google Scholar and Cochran Library were searched up to November 2016. In present study search strategy was performed by using selected keywords. Two independent investigators scanned and extracted the relevant data. The pairwise method was used to compare the difference between the mean difference weight loss for orlistat, sibutramine, lorcaserin and metformin in two direct methods (comparison of orlistat, sibutramine, lorcaserin and metformin with the control group) and non-direct (Compare orlistat, sibutramine, lorcaserin and metformin together). We assessed the quality of included trials using the quantitative 5-point Jadad scale. The heterogeneity across studies was assessed by using Cochrane’s Q and I2 tests. Publication bias was reported by means of funnel plots and Egger’s tests. Results: The present study performed on 36 clinical studies with a population of 3672. Our study results did show that sibutramine (mean difference -4.97 kg, 95% confidence interval -6.70 to -3.23), metformin (mean difference -4.45 kg, 95% confidence interval -9.27 to 0.38), orlistat (mean difference -2.37 kg, 95% confidence interval -3.45 to -1.30), lorcaserin (mean difference -2.36 kg, 95% confidence interval -4.58 to -0.15), respectively, had the most effect on weight loss compared with the placebo group. In addition, orlistat compared to lorcaserin (mean difference -0.01 kg, 95% confidence interval -2.47 to 2.45) resulted in more weight loss, but compared to metformin (mean difference 2.07 kg, 95% confidence interval -2.78 to 7.02) and sibutramine (mean difference 0.52 kg, 95% confidence interval -4.46 to 5.50) lead to less weight loss. Conclusion: The present study indicated that orlistat had a greater effect on weight loss compared with lorcaserin, and had lower effect on weight loss compared with sibutramine and metformin in apparently healthy obese individuals.

What is known and objective: Lorcaserin is a selective serotonin 2c receptor agonist approved as an anti‐obesity agent. The additional cardiometabolic benefits associated with lorcaserin have not been conclusively established. The aim of the systematic review and meta‐analysis is to examine the effects of lorcaserin on blood pressure, heart rate and other metabolic parameters in overweight and obese patients from randomized controlled clinical trials (RCTs). Methods: A literature search was conducted on PubMed, EMBASE and Cochrane Central using the search terms 'lorcaserin' and 'randomized controlled trials' without language restrictions. RCTs with a follow‐up period of at least 24 weeks were included in the meta‐analysis. Results and discussion: Six studies with 9452 patients in the lorcaserin group and 9392 patients in the placebo group were included. Compared with placebo, lorcaserin not only reduced weight, BMI and waist circumference but also improved SBP, DBP, heart rate, LDL, triglycerides, fasting plasma glucose and HbA1c. Our findings suggest that lorcaserin has trivial though consistent and favourable effects on blood pressure, heart rate and metabolic syndrome. What is new and conclusion: Lorcaserin improved all cardiometabolic parameters modestly in addition to its weight loss effect in overweight and obese patients. More research is needed to determine its long‐term cardiovascular benefits. [ABSTRACT FROM AUTHOR]

Background: Lorcaserin is a novel, selective 5-hydroxytryptamine 2C serotonin receptor agonist, approved for the treatment of obesity. Several phase 3 randomized controlled trials (RCTs) trials have shown a significant reduction in body weight with lorcaserin. Research design and methods: We systematically searched the database of PubMed, Embase, The Cochrane Library and ClinicalTrials.gov up to 31 July 2019 and retrieved all the studies conducted with lorcaserin for ≥1 year that have explicitly reported the efficacy and safety outcomes versus placebo. Subsequently, we studied the effect of lorcaserin on weight reduction, FDA-defined valvulopathy, depression and suicidal risks in RCTs. Results: The meta-analysis of four RCTs (N = 16,856) demonstrated a significant decrease in body weight (mean ∆ −3.076 Kg; 95% CI, −3.49 to −2.66; P < 0.00001), compared to placebo. No significant difference in FDA-defined valvulopathy (RR 1.20; 95% CI, 0.89 to 1.63; P = 0.24), depression (RR 1.07; 95% CI, 0.80 to 1.43; P = 0.67) or suicidal risk (RR 1.43; 95% CI, 0.96 to 2.15; P = 0.08) has been observed with lorcaserin compared to placebo. Conclusions: Lorcaserin reduces body weight modestly, with no obvious serious adverse side effects. The common adverse events noted with lorcaserin include nausea, dizziness, and transient headache. [ABSTRACT FROM AUTHOR]

Introduction: Obesity poses a significant increase in morbidity and mortality and thus five anti-obesity drugs have been approved currently by US FDA. Several phase 3 trials have shown a significant improvement in cardio-metabolic profile including significant weight reduction with these agents compared to placebo. Areas covered: We systematically searched the database of PubMed, Embase, The Cochrane Library and The ClinicalTrials.gov up to 30 September 2019 and retrieved all the randomized controlled trials (RCTs) that were conducted with these five drugs for ≥1 year and explicitly reported their efficacy versus placebo. Subsequently, we have conducted the meta-analysis to primarily study the effect of these anti-obesity drugs on weight reduction. We additionally reviewed the effect of these drugs on other cardio-metabolic parameters including key adverse events. Expert opinion: This meta-analysis finds a significant reduction in body weight with orlistat (N = 10,435; ∆ −3.07 Kg, 95% CI, −3.76 to −2.37), phentermine plus topiramate (N = 2985; ∆ −9.77 Kg; 95% CI, −11.73 to −7.81), lorcaserin (N = 16,856; ∆ −3.08 Kg; 95% CI, –3.49 to –2.66), naltrexone plus bupropion (N = 3239; ∆ −4.39 Kg; 95% CI, −5.05 to −3.72) and liraglutide (N = 4978; ∆ −5.25 Kg; 95% CI, −6.17 to −4.32), compared to placebo (all p < 0.00001). [ABSTRACT FROM AUTHOR]

Objective: The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT2CR) agonist, improves glycemic control in association with weight loss in obese patients with T2D. Here we evaluate whether lorcaserin has an effect on glycemia without body weight loss and how this effect is achieved. Methods: Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control. Results: Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4RChAT) to exert its effects on glucose homeostasis. In contrast, MC4RChAT signaling did not impact lorcaserin's effects on feeding, indicating a divergence in the neurocircuitry underpinning lorcaserin's therapeutic glycemic and anorectic effects. Hyperinsulinemic-euglycemic clamp studies reveal that lorcaserin reduces hepatic glucose production, increases glucose disposal and improves insulin sensitivity. Conclusions: These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.

The molecular mechanisms underlying acute leptin and serotonin 2C receptor-induced hypophagia remain unclear. Here, we show that neuronal and pro-opiomelanocortin (Pomc)-specific loss of transient receptor potential cation 5 (TrpC5) subunits is sufficient to decrease energy expenditure and increase food intake resulting in elevated body weight. Deficiency of Trpc5 subunits in Pomc neurons is also sufficient to block the anorexigenic effects of leptin and serotonin 2C receptor (Ht2Cr) agonists. The loss of acute anorexigenic effects of these receptors is concomitant with a blunted electrophysiological response to both leptin and Ht2Cr agonists in arcuate Pomc neurons. We also demonstrate that the Ht2Cr agonist lorcaserin-induced improvements in glucose and insulin tolerance are blocked by TrpC5 deficiency in Pomc neurons. Together, our results link TrpC5 subunits in the brain with leptin- and serotonin 2C receptor-dependent changes in neuronal activity, as well as energy balance, feeding behavior, and glucose metabolism.

Binge eating disorder (BED) is characterized by dysregulated feeding and reward-related processes, and treatment is often challenged by limited therapeutic options. The serotonin (5-HT) 5-HT2A receptor (5-HT2AR) and 5-HT2CR are implicated in both feeding-related and reward-related behaviors and are thus poised to regulate BED-related behaviors. The purpose of this study was to assess the efficacy of the FDA-approved medications pimavanserin, a 5-HT2AR antagonist/inverse agonist, and lorcaserin, a 5-HT2CR agonist, in a rodent model of binge eating. The effects of pimavanserin (0.3–3.0 mg/kg), lorcaserin (0.25–1.0 mg/kg), and the lowest effective dose of pimavanserin (0.3 mg/kg) plus lorcaserin (1.0 mg/kg) were tested in a high-fat food (HFF) intermittent access binge eating model in adult male Sprague-Dawley rats (n = 64). We assessed three measures related to binge eating – binge episode occurrence, binge intake, and weight gain associated with HFF access. Pimavanserin decreased binge intake and weight gain associated with HFF access, but did not prevent binge episode occurrence. Lorcaserin decreased binge intake, but did not prevent binge episode occurrence or weight gain associated with HFF access. Combined pimavanserin plus lorcaserin prevented binge episode occurrence in addition to decreasing binge intake and weight gain associated with HFF access. These preclinical findings in male rats suggest that pimavanserin and lorcaserin may be effective in treating patients with BED. Our studies further indicate that administration of one or both drugs may be more effective in certain sub-populations of patients with BED because of the unique profile each treatment elicits. These data support future assessment in clinical populations with BED.

Summary: Study objectives: To evaluate weight loss with lorcaserin in persons with obstructive sleep apnea (OSA). Methods: This retrospective analysis evaluated weight loss of lorcaserin (10 mg twice daily) versus placebo in persons with obesity or overweight persons with OSA from a pooled database of three randomized, controlled trials. Primary end points were reductions in the baseline body weight of ≥5% and ≥10% at year 1 and overall weight change at year 1. Changes in heart rate and blood pressure were also evaluated. Results: A total of 336 persons with OSA were identified in the overall pooled population (N = 6,636). At year 1, more patients receiving lorcaserin lost ≥5% (47.2% lorcaserin vs. 25.6% placebo; p < 0.0001) and 10% (22.2% lorcaserin vs. 13.1% placebo; p < 0.0354) of their baseline body weight. Weight loss at year 1 was 6.4 kg versus 3.5 kg in the lorcaserin and placebo groups, respectively (p < 0.0001). Similar results were observed for change in blood pressure and heart rate, with responders having larger benefits. Weight loss was similar between persons with and without OSA. Conclusions: In this retrospective analysis, persons with OSA showed significant and meaningful weight loss, blood pressure and heart rate reductions in patients treated with lorcaserin versus placebo. Persons with OSA lost just as much weight as those without OSA. Health care providers can expect persons with OSA to lose weight by diet, exercise and the weight loss medication lorcaserin comparable with persons without OSA. Further prospective research is warranted to evaluate impact of weight loss on OSA and overall outcomes for patients. [ABSTRACT FROM AUTHOR]

Varenicline, a nicotinic acetylcholine receptor partial agonist, is used to treat nicotine dependence. Lorcaserin, a 5-HT2C receptor agonist has been approved in some countries to treat obesity. Based on preclinical and preliminary clinical evidence, lorcaserin may have potential to treat nicotine dependence. These experiments examined in rats the effects of combining varenicline (0.5 or 1 mg/kg) and lorcaserin (0.3, 0.6 and 1 mg/kg) on nicotine self-administration, reinstatement of nicotine seeking, responding for food and impulsive action. Both drugs alone reduced nicotine self-administration. Combining varenicline and 0.6 mg/kg lorcaserin reduced responding to a greater extent than either drug alone. In a relapse model, extinguished nicotine seeking was reinstated by a priming injection of nicotine and nicotine-associated cues. Reinstatement was reduced by varenicline (1 mg/kg) and by lorcaserin (0.3 mg/kg). Combining lorcaserin (0.3 mg/kg) with varenicline (0.5 or 1 mg/kg) reduced reinstatement to a greater degree than either drug alone. Both drugs had minimal effects on responding for food, alone or in combination. In the five-choice serial reaction time test, varenicline (0.5 or 1 mg/kg) increased impulsivity, measured as increased premature responding. This effect was reduced by lorcaserin (0.3 mg/kg). Plasma levels of varenicline or lorcaserin were not altered by co-administration of the other drug. Varenicline and lorcaserin have additive effects on nicotine self-administration, and on nicotine seeking. Lorcaserin prevents impulsivity induced by varenicline. This pattern of effects suggests that co-administration of varenicline and lorcaserin has potential as a treatment for nicotine dependence that may exceed the value of either drug alone. [ABSTRACT FROM AUTHOR]

Summary: Four new medicines—liraglutide, lorcaserin, bupropion/naltrexone, and phentermine/topiramate—have been recently added to the pharmacological arsenal for obesity treatment and could represent important tools to manage this epidemic disease. To achieve satisfactory anti‐obesity goals, the use of these new medicines should be optimized and tailored to specific patient subpopulations also by applying dose adjustments if needed. In the present review, we posit that gender could be among the factors influencing the activity of the new obesity drugs both because of pharmacokinetic and pharmacodynamic factors. Although evidence from premarketing clinical studies suggested that no dose adjustment by gender is necessary for any of these new medicines, these studies were not specifically designed to identify gender‐related differences. This observation, together with the strong theoretical background supporting the hypothesis of a gender‐dimorphic response, strongly call upon an urgent need of new real‐life data on gender‐related difference in the pharmacology of these new obesity drugs. [ABSTRACT FROM AUTHOR]

Abstract Obesity is a chronic disease with a continuously rising prevalence that currently affects more than half a billion people worldwide. Energy balance and appetite are highly regulated via central and peripheral mechanisms, and weight loss triggers a homeostatic response leading to weight regain. Lifestyle and behavioral modifications are the cornerstones of obesity management; however, they often fail to achieve or sustain long-term weight loss. Pharmacotherapy added onto lifestyle modifications results in an additional, albeit limited, weight reduction. Regardless, this weight reduction of 5–10% conveys multiple cardiovascular and metabolic benefits. In this review, evidence on the food and drug administration (FDA)-approved medications, i.e., orlistat, lorcaserin, phentermine/topiramate, liraglutide and naltrexone/bupropion, is summarized. Furthermore, anti-obesity agents in the pipeline for potential future therapeutic use are presented. Highlights • Obesity is a chronic, multifactorial disease, initially managed with lifestyle modifications • Upon failure an FDA approved medication can be started based on patient comorbidities • Many novel anti-obesity agents are currently in clinical trials • Bariatric surgery studies highlight the role of gut-derived hormones in weight loss • Agents referring to gastrointestinal hormones will more likely reach the market [ABSTRACT FROM AUTHOR]

Abstract Tobacco addiction each year causes millions of deaths worldwide. Brain nicotinic acetylcholine receptors have been shown to be central to tobacco addiction. Nicotine replacement therapy aids tobacco cessation, but the success rate is still far too low. This may in part be due to the fact that neurons with nicotinic receptors are not the only neural systems involved in tobacco addiction. Interacting neural systems also play important roles in tobacco addiction. Nicotine increases the release of a variety of neurotransmitters, including dopamine and serotonin. Dopamine, in particular dopamine D 1 receptors, has been shown to be involved in the reinforcing action of nicotine. Serotonin through its actions on 5-HT 2C receptors has been shown to play a key role in modulating the reinforcement of addictive drugs, including nicotine and alcohol. Combination of treatments could provide greater treatment efficacy. These studies were conducted to evaluate combination therapies utilizing nicotine replacement therapy in conjunction with either a dopamine D 1 receptor antagonist SCH-23390 or a serotonin 5-HT 2C receptor agonist, lorcaserin. Female Sprague-Dawley rats were given access to self-administer nicotine via IV infusions. Osmotic pumps were implanted to reproduce the kinetic of chronic nicotine patch therapy. SCH-23390 (0.02 mg/kg) or lorcaserin (0.6 mg/kg) were administered prior to nicotine self-administration sessions. Reproducing earlier findings SCH-23390, lorcaserin and nicotine replacement therapy were effective at reducing IV nicotine self-administration. 5HT 2C agonist treatment had additive effects with chronic nicotine infusion for significantly lowering nicotine self-administration. This study demonstrates the feasibility of combination of chronic nicotine with therapies targeting non-nicotinic receptors as treatment options for tobacco addiction. Highlights • Reproducing earlier findings SCH-23390, lorcaserin and nicotine reduced nicotine self-administration. • The 5HT2C agonist treatment had additive effects with chronic nicotine infusion. • This demonstrates the feasibility of combination of chronic nicotine with therapies targeting non-nicotinic receptors. [ABSTRACT FROM AUTHOR]

Abstract Preclinical studies indicate that lorcaserin (Belviq®), an FDA-approved serotonin 2 C receptor agonist, may be a promising medication for the treatment of stimulant addiction. However, few studies have investigated its effects on self-administration of drugs of abuse from other pharmacological classes, including opioids. Here, adult male rhesus macaques (N = 3) responded under a fixed ratio 30 schedule of food (1-g banana-flavored pellets) and IV heroin delivery. Following stable self-administration of a range of heroin doses (0.32–32 μg/kg/inj, IV), the effects of acute pretreatment with lorcaserin (0.32–1.0 mg/kg, IM) on heroin- and food-maintained responding was determined. The ability of repeated treatment with lorcaserin (1.0 mg/kg) to produce sustained decreases in heroin and/or food intake and reinforcing strength were then analyzed using behavioral economic demand procedures. Results show that self-administration of intravenous heroin was dose-dependent, with peak responding maintained, on average, by the unit dose of 3.2 μg/kg/inj. Lorcaserin pretreatment produced a dose-dependent flattening of the dose-response function for heroin self-administration in each subject. On the other hand, lorcaserin did not decrease food-maintained responding. Repeated lorcaserin treatment reduced heroin intake by selectively decreasing its reinforcing strength, as evidenced by a leftward shift in the demand curves for heroin and the absence of comparable changes in the reinforcing strength of food. These results indicate that serotonin 2 C receptor agonists, such as lorcaserin, have behaviorally selective effects on IV self-administration behavior, and deserve further consideration as candidates for the management of opioid use disorder. [ABSTRACT FROM AUTHOR]

Summary: Anti‐obesity medication may help people maintain diet‐induced reductions in appetite. The present exploratory analysis assessed the effects of lorcaserin on changes at 24 weeks post‐randomization in emotion‐ and stress‐related eating, food cravings and other measures of appetite (i.e. binge eating, cognitive restraint, disinhibition, hunger, preoccupation with eating and fullness). The parent study investigated the efficacy of combined lorcaserin and behavioural treatment in facilitating weight loss maintenance (WLM) in 137 adults (mean age = 46.1 years, 86.1% female, 68.6% black) who had lost ≥5% of initial weight during a 14‐week, low‐calorie diet (LCD) run‐in. Participants were randomly assigned to lorcaserin or placebo and were provided with group WLM counselling sessions. Emotion‐ and stress‐related eating, food cravings and appetite were measured at the start of the LCD (week −14), randomization (0) and week 24. From randomization, lorcaserin‐treated participants had significantly greater improvements in emotion‐ and stress‐related eating compared to placebo‐treated participants (P = 0.04). However, groups did not differ significantly after randomization in changes in the frequency of food cravings, binge eating or other measures of appetite (Ps > 0.05). Compared to placebo, lorcaserin may improve emotion‐ and stress‐related eating. [ABSTRACT FROM AUTHOR]

Highlights • We examined if 5-HT-based anorectic treatment reversed NAcc-driven feeding in the rat. • NAcc μ-opioid receptor stimulation followed systemic d -fenfluramine or lorcaserin. • Systemic d -fenfluramine or lorcaserin treatment reduced vegetable shortening intake. • d -fenfluramine or lorcaserin blocked NAcc μ-opioid enhancement of fat intake. • Systemic serotonin-based anorectics inhibit feeding promoted by brain reward circuits. Abstract Multiple laboratories have shown that the stimulation of μ-opioid receptors in the nucleus accumbens (NAcc) powerfully increases intake of palatable and high-fat diets. Separate studies have demonstrated that serotonin agonists advance satiety processes, and several serotonin-targeting agents have been prescribed to promote weight loss. However, it is unknown if serotonin signaling can modulate the increased feeding elicited by activation of NAcc μ-opioid receptors. These experiments assessed the effects of systemic treatments with the serotonin agonists d -fenfluramine and lorcaserin on the binge-like feeding induced by μ-opioid receptor stimulation of the NAcc in Sprague-Dawley rats. Consistent with previous reports, stimulation of NAcc μ-opioid receptors (with 0.025 μg/0.5 μl/side DAMGO) significantly increased consumption of high-fat vegetable shortening, and systemic treatment with d -fenfluramine and lorcaserin dose-dependently decreased intake. Interestingly, d -fenfluramine and lorcaserin reversed the binge-like feeding observed following stimulation of NAcc μ-opioid receptors. Both serotonergic drugs also attenuated the increases of ambulation observed following administration of DAMGO in the NAcc. These data demonstrate that serotonergic anorectics, in addition to their known role in advancing satiety processes during normal feeding, can also inhibit the binge-like feeding that is elicited by activation of μ-opioid receptors within the ventral striatum. [ABSTRACT FROM AUTHOR]

Aims: The serotonin (5‐HT2c) receptor is known to be involved in the mechanism of urethral closure in a model of stress incontinence. Lorcaserin (Belviq®) has received Food and Drug Administration approval for the treatment of obesity. However, it is unclear whether this selective 5‐HT2c receptor agonist enhances urethral closure in stress urinary incontinence (SUI) models. Therefore, we investigated whether lorcaserin could enhance urethral closure in female rats with vaginal distention (VD). Methods: Normal female rats and rats with stress incontinence induced by VD were tested. We evaluated the effect of a single dose of lorcaserin (0.03, 0.3, or 0.9 mg/kg with cumulative administration) on the urethral pressure amplitude during electrical stimulation (A‐URE) and on the urethral baseline pressure (UBP). The manual compression‐induced leak point pressure (LPP) was also measured. Results: In VD rats, a single intravenous injection of lorcaserin (0.3 and 0.9 mg/kg) significantly increased both A‐URE and LPP compared to saline (P < 0.05). In normal rats, intravenous lorcaserin (0.3 and 0.9 mg/kg) also significantly increased A‐URE and LPP compared to saline (P < 0.05). The changes of A‐URE and LPP, which are parameters of active urethral closure, were significantly larger in normal rats than in VD rats. Conclusions: We showed that lorcaserin can activate the external urethral sphincter and pelvic floor muscles, suggesting an influence on active closure mechanisms. 5‐HT2c receptors agonists may have dual effects in patients with SUI, not only by reducing obesity but also by enhancing active urethral closure. [ABSTRACT FROM AUTHOR]

Objective: Comparison of the efficacy and tolerability of five newer anti-obesity medications to guide clinical decision making, examining bupropion–naltrexone combination, liraglutide, lorcaserin, orlistat, and phentermine–topiramate combination. Methods: A brief literature review and internet search for high-powered, randomized and placebo-controlled drug trials was conducted. Drug trial information was established for five currently approved anti-obesity medications. Secondarily, a statistical comparison of medications through Number Needed to Treat (NNT) and Number Needed to Harm (NNH) analyses were attempted as a way to provide a clinical analysis across these varied medications. Finally, a commentary about clinical application is issued for each agent accounting for typical side-effects, serious side-effects, mechanism of action and ease of use. Results: All five agents are currently approved oral medications to lower weight. The NNT range was 3–12, and NNH range was 4–17. The agent with the best NNT is phentermine–topiramate combination (NNT=3) and the agent with the best NNH is bupropion–naltrexone combination (NNH=17). Conclusion: When considering each patient’s clinical presentation, knowledge of each drug’s mechanism of action, side-effect profile, efficacy, and NNT and NNH values can help in selecting an anti-obesity medication to augment his or her weight loss efforts.

Context: Individual responses to weight loss (WL) medications vary widely and prediction of response remains elusive., Objective: We investigated biomarkers associated with use of lorcaserin (LOR), a 5HT2cR agonist that targets proopiomelanocortin (POMC) neurons that regulate energy and glucose homeostasis, to identify predictors of clinical efficacy., Methods: Thirty individuals with obesity were treated with 7 days of placebo and LOR in a randomized crossover study. Nineteen participants continued on LOR for 6 months. Cerebrospinal fluid (CSF) POMC peptide measurements were used to identify potential biomarkers that predict WL. Insulin, leptin, and food intake during a meal were also studied., Results: LOR induced a significant decrease in CSF levels of the POMC prohormone and an increase in its processed peptide β-endorphin after 7 days; β-endorphin/POMC increased by 30% (P < .001). This was accompanied by a substantial decrease in insulin, glucose, and homeostasis model assessment of insulin resistance before WL. Changes in CSF POMC peptides persisted after WL (6.9%) at 6 months that were distinct from prior reports after diet alone. Changes in POMC, food intake, or other hormones did not predict WL. However, baseline CSF POMC correlated negatively with WL (P = .07) and a cutoff level of CSF POMC was identified that predicted more than 10% WL., Conclusion: Our results provide evidence that LOR affects the brain melanocortin system in humans and that effectiveness is increased in individuals with lower melanocortin activity. Furthermore, early changes in CSF POMC parallel WL-independent improvements in glycemic indexes. Thus, assessment of melanocortin activity could provide a way to personalize pharmacotherapy of obesity with 5HT2cR agonists., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Trying to find a drug with more clinical efficacy in treating obesity is one of the priorities. The aim of this study was to evaluate the efficacy of orlistat, sibutramine, lorcaserin and metformin on weight loss in obese people. Methods: The databases of PubMed, Scopus, Google Scholar and Cochran Library were searched up to November 2016. In present study search strategy was performed by using selected keywords. Two independent investigators scanned and extracted the relevant data. The pairwise method was used to compare the difference between the mean difference weight loss for orlistat, sibutramine, lorcaserin and metformin in two direct methods (comparison of orlistat, sibutramine, lorcaserin and metformin with the control group) and non-direct (Compare orlistat, sibutramine, lorcaserin and metformin together). We assessed the quality of included trials using the quantitative 5-point Jadad scale. The heterogeneity across studies was assessed by using Cochrane’s Q and I2 tests. Publication bias was reported by means of funnel plots and Egger’s tests. Results: The present study performed on 36 clinical studies with a population of 3672. Our study results did show that sibutramine (mean difference -4.97 kg, 95% confidence interval -6.70 to -3.23), metformin (mean difference -4.45 kg, 95% confidence interval -9.27 to 0.38), orlistat (mean difference -2.37 kg, 95% confidence interval -3.45 to - 1.30), lorcaserin (mean difference -2.36 kg, 95% confidence interval -4.58 to -0.15), respectively, had the most effect on weight loss compared with the placebo group. In addition, orlistat compared to lorcaserin (mean difference -0.01 kg, 95% confidence interval -2.47 to 2.45) resulted in more weight loss, but compared to metformin (mean difference 2.07 kg, 95% confidence interval -2.78 to 7.02) and sibutramine (mean difference 0.52 kg, 95% confidence interval -4.46 to 5.50) lead to less weight loss. Conclusion: The present study indicated that orlistat had a greater effect on weight loss compared with lorcaserin, and had lower effect on weight loss compared with sibutramine and metformin in apparently healthy obese individuals. [ABSTRACT FROM AUTHOR]

Abstract Objective This study aimed to evaluate the effects of lorcaserin on body weight, cardiovascular risk factors, and safety in obese patients in Taiwan. Methods In this double-blind, randomised controlled trial, 171 obese adults were assigned to receive lorcaserin at a dose of 10 mg, or placebo, twice a day for 24 weeks. Diet and exercise counselling were given to all patients through the treatment period. Primary outcomes were proportion of patients achieving at least 5% and 10% reduction in body weight and mean change in body weight. Safety and tolerability endpoints such as Beck Depression Inventory-II, blood biochemistry, vital signs, and electrocardiogram were monitored. Results More patients receiving lorcaserin lost at least 5% body weight than receiving placebo (52.4% and 28.1%, P = 0.001) with an average weight reduction of 5.8 kg (95% CI: −6.91, −4.70) in lorcaserin group and those of 3.6 kg (95% CI: −4.95, −2.33) in placebo group (P < 0.05). The most common adverse effect with greater incidence in the lorcaserin group was self-limited dizziness. Serious adverse effect were rare and was reported by slightly more patients taking placebo than lorcaserin. Conclusions In this multicentre, double-blinded placebo-controlled trial, lorcaserin was effective and well-tolerable in Asia group. [ABSTRACT FROM AUTHOR]

Asymmetric syntheses of N -protected ( R )-4-halo-6,6a,7,8,9,10-hexahydro-5 H -pyrazino[1,2- a ][1, n ]naphthyridines, advanced intermediates for the synthesis of highly potent and selective 5-HT 2C agonists, are described. The key transformation involves ring opening of N -protected bicyclic sulfamidate ( R )-hexahydro-3 H -pyrazino[1,2- c ][1,2,3]oxathiazine 1,1-dioxide with (4-halo-2-fluoropyridin-3-yl)lithiums or (3-bromo-5-fluoropyridin-4-yl)lithium. In situ hydrolyses of the resultant sulfamic acids and subsequent intramolecular nucleophilic aromatic substitutions (S N Ar) produce the enantiopure tricycles. The two step procedure represents new methodology for the stereoselective syntheses of tetrahydronaphthyridines. [ABSTRACT FROM AUTHOR]

Acylation of enantiomerically pure ( R )-2-(3-chlorophenyl)propan-1-amine using chloroacetyl chloride, followed by borane reduction and aluminum chloride catalyzed cyclization yielded enantiopure lorcaserin. [ABSTRACT FROM AUTHOR]

The prevalence of obesity and associated comorbidities is rising. Despite their weight-loss efficacy, new generation anti-obesity medications are only prescribed to a minority of adults with obesity, possibly, which in part may be due to safety concerns. This review presents detailed safety profiles for orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion and liraglutide 3.0 mg, and discusses the associated risk-benefit profiles. Two anti-obesity medications presented safety issues that warranted further discussion; phentermine/topiramate (fetal toxicity) and liraglutide 3.0 mg (risk of gallstone disease and mild, acute pancreatitis), whereas the adverse events associated with orlistat, lorcaserin, and naltrexone/bupropion were mostly transient tolerability issues. The difficulties surrounding the objective determination of risk-benefit for anti-obesity medications is discussed. The need for more long-term data, thorough patient assessment, individualization of pharmacological interventions and adherence to stopping rules to maximize risk-benefit are highlighted. Overall, the majority of new generation anti-obesity medications present encouraging tolerability profiles; however, in some cases a lack of long-term clinical trials confounds the accurate determination of risk-benefit. [ABSTRACT FROM AUTHOR]

Obesity is a major cause of type 2 diabetes and may complicate type 1 diabetes. Weight loss for obese individuals with diabetes has many health benefits, often leads to improvement in glucose control and sometimes, in type 2 diabetes, near normalisation of abnormal glucose metabolism. Weight loss is difficult to maintain and attempts to lose weight may be undermined by some diabetes treatments such as sulfonylureas, thiazolidinediones and insulin. Whilst lifestyle support should be the primary approach to aid individuals who wish to lose weight, pharmacological approaches can also be considered. These include choosing glucose-lowering drugs or drug combinations that are weight neutral or result in weight loss or prescribing drugs that are specifically approved as anti-obesity medication. Given that some of the newer glucose-lowering medications that cause weight loss, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), are also being used or considered for use as anti-obesity drugs, it seems that the distinction between glucose-lowering medication and weight loss medication is becoming blurred. This review discusses the main pharmacological approaches that can be used to support weight loss in individuals with diabetes. [ABSTRACT FROM AUTHOR]

Lorcaserin, plus diet and exercise, has demonstrated significant weight loss and improved cardiometabolic parameters vs. placebo in patients with overweight/obesity in three randomized, placebo-controlled trials. We examined whether lorcaserin is also associated with greater improvements in health-related quality of life ( HRQOL) and whether these improvements are wholly attributable to weight loss. Pooled data from Behavioral Modification and Lorcaserin for Overweight and Obesity Management ( BLOOM), Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM) and BLOOM-Diabetes Mellitus (BLOOM-DM) trials were analysed ( n = 5624). HRQOL was assessed at baseline and 52 weeks using the Impact of Weight on Quality of Life-Lite ( IWQOL-Lite) questionnaire. Multiple mediation analyses were conducted to evaluate the mechanisms underlying improved HRQOL. Greater HRQOL improvements were observed at 52 weeks in lorcaserin vs. placebo ( P < 0.0001). A greater percentage of lorcaserin patients (54.1%) experienced meaningful improvements in IWQOL-Lite total score than placebo patients (48.2%) ( P < 0.001). Body mass index ( BMI) reduction was the primary driver of improved HRQOL ( P < 0.0001), with depressive symptoms and total cholesterol also playing a role ( P < 0.05). Improved HRQOL varied by gender, age, race and presence of diabetes and other comorbidities. Lorcaserin treatment significantly improves HRQOL compared with placebo. Although BMI reduction accounts for the majority of these improvements, improvement in depressive symptoms and total cholesterol are contributing factors. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence suggests that the FDA-approved serotonin 5-HT2C receptor agonist, lorcaserin (Belviq®), may be a promising candidate for the management of substance use disorders, including nicotine addiction. The present study was conducted to determine the efficacy and selectivity of acute or continuous lorcaserin treatment for decreasing the reinforcing effects of nicotine in a primate species.Methods: Adult rhesus monkeys (n=4) with a history of nicotine self-administration (>2years) responded for injections of nicotine (0.32-100μg/kg IV) or food pellets under a fixed-ratio schedule of reinforcement during daily 100-min sessions. When responding was stable, lorcaserin was administered either as an acute pretreatment (0.1-1.0mg/kg, IM) or by continuous infusion (0.1mg/kg/hr, SC for 3-5days). Daily activity patterns were also monitored immediately following experimental sessions.Results: Results indicate that acute lorcaserin pretreatment produced significant and dose-dependent decreases in nicotine-maintained responding across a >100-fold range of self-administered nicotine doses. Continuous lorcaserin treatment decreased intake of 10μg/kg/inj nicotine to about 50% of baseline values. Food-maintained responding was only moderately decreased in 3 of 4 subjects after acute administration and unaffected in all subjects during continuous treatment. Daily activity also was significantly decreased-to ≤50% of control values-following experimental sessions in which acute lorcaserin was administered.Conclusions: These data indicate that lorcaserin reduces IV self-administration of nicotine at a dose that decreases motoric activity but less consistently disrupts food-maintained responding. Further research into lorcaserin's potential utility for the management of nicotine dependence is warranted. [ABSTRACT FROM AUTHOR]

Rationale: Addiction involves maladaptive choice behavior in which immediate drug effects are valued more than delayed nondrug rewards. Objectives and methods: To model this behavior and extend our earlier work with the prescription opioid oxycodone, we allowed rats to choose between immediate intravenous delivery of the short-acting opioid remifentanil and delayed delivery of highly palatable food pellets. Treatment drugs were tested on a baseline where remifentanil was preferred over food. Results: Treatment with a high dose of the opioid antagonist naltrexone decreased but did not reverse the preference for remifentanil. Treatment with the serotonin 5-HT agonist lorcaserin decreased remifentanil and food self-administration nonselectively. Across conditions in which the alternative to delayed food was either a moderate dose of oxycodone, a moderate or high dose of remifentanil, a smaller more immediate delivery of food, or timeout with no primary reinforcement, choice was determined by both the length of the delay and the nature of the alternative option. Delayed food was discounted most steeply when the alternative was a high dose of remifentanil, which was preferred over food when food was delayed by 30 s or more. Within-subject comparisons showed no evidence for trait-like impulsivity or sensitivity to delay across these conditions. Conclusions: Choice was determined more by the current contingencies of reinforcement than by innate individual differences. This finding suggests that people might develop steep delay-discounting functions because of the contingencies in their environment, and it supports the use of contingency management to enhance the relative value of delayed nondrug reinforcers. [ABSTRACT FROM AUTHOR]

The selective 5-HT2C receptor agonist lorcaserin entered clinical obesity trials with the prevalent view that satiety was a primary mechanism of action. Subsequent Phase II and III trials demonstrated efficacy in terms of weight loss, although the overall effect size (~3% placebo-corrected change) is considered modest. Lorcaserin has been approved by the FDA for the treatment of obesity with lifestyle modification, but since its introduction in 2013 its sales are in decline, probably due to its overall modest effect. However, in some individuals, lorcaserin has a much more clinically significant effect (i.e. >10% placebo-corrected change), although what common features, if any, define these high responders is presently unknown. In the present article we highlight the evidence that alternative mechanisms to satiety may contribute to the anti-obesity effect of lorcaserin, namely effects on constructs of primary and conditioned reward and impulsivity. This may better inform the clinical evaluation of lorcaserin (and any future 5-HT2C receptor agonists) to subgroups of obese subjects characterized by overeating due to maladaptive impulsivity and reward mechanisms. One such population might be individuals diagnosed with binge eating disorder. [ABSTRACT FROM AUTHOR]

Objective The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT 2C R) agonist, improves glycemic control in association with weight loss in obese patients with T2D. Here we evaluate whether lorcaserin has an effect on glycemia without body weight loss and how this effect is achieved. Methods Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control. Results Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4R ChAT ) to exert its effects on glucose homeostasis. In contrast, MC4R ChAT signaling did not impact lorcaserin's effects on feeding, indicating a divergence in the neurocircuitry underpinning lorcaserin's therapeutic glycemic and anorectic effects. Hyperinsulinemic-euglycemic clamp studies reveal that lorcaserin reduces hepatic glucose production, increases glucose disposal and improves insulin sensitivity. Conclusions These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease. [ABSTRACT FROM AUTHOR]

Serotonin modulates many motivated behaviours via multiple receptor subtypes. Agonists at 5-HT 2 C receptors have potential for treating behavioural problems associated with obesity and drug use. In this work we examined the impact of the 5-HT 2C receptor agonist lorcaserin on several motivated behaviours related to feeding, reward and waiting impulsivity, and on neuronal activation in key brain areas mediating those behaviours. In male C57BL/6J mice effects of lorcaserin (0.2, 1 and 5 mg/kg) were examined on feeding, and on operant responding for a palatable reward. Feeding was reduced only at 5 mg/kg, whereas operant responding was reduced at 1 mg/kg. At a much lower dose range lorcaserin 0.05–0.2 mg/kg also reduced impulsive behaviour measured as premature responding in the 5-choice serial reaction time (5-CSRT) test, without affecting attention or ability to perform the task. Lorcaserin induced Fos expression in brain regions related to feeding (paraventricular nucleus and arcuate nucleus), reward (ventral tegmental area), and impulsivity (medial prefrontal cortex, VTA) although these effects did not show the same differential sensitivity to lorcaserin as the behavioural measures. These results indicate a broad profile of action of 5-HT 2C receptor stimulation on brain circuitry and on motivated behaviours, but with clear evidence of differential sensitivity across behavioural domains. This is exemplified by the fact that impulsive behaviour was reduced at a much lower dose range than was feeding behaviour. Along with previous work, and some clinical observations, this work supports the idea that 5-HT 2C agonists may be useful for behavioural problems associated with impulsivity. • The 5-HT 2C agonist lorcaserin reduced feeding, operant responding, and impulsivity. • Lorcaserin activated brain regions mediating all three behavioural domains. • Impulsive behaviour was much more sensitive to effects of lorcaserin than was feeding. • 5-HT 2C agonists may be useful for behavioural problems associated with impulsivity. [ABSTRACT FROM AUTHOR]