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Cannabis Use Disorder (CUD) has no FDA-approved treatment. Serotonin-2c (5HT2c) agonists have preclinical and human laboratory evidence for their potential efficacy for CUD. We assessed the tolerability and effects of lorcaserin (5HT2c agonist) on CUD. In a 10-week, open label, uncontrolled trial, the tolerability of lorcaserin was tested in outpatients with CUD. Adverse events (AE) were assessed weekly. Cannabis use was assessed twice weekly by the Timeline follow-back and quantitative urine metabolites. Seventeen participants enrolled, and 14 received medication. Participants' average age was 35 years; majority were male (N = 12). The medication was well tolerated in males. There were no serious adverse events (SAE). The most common AE's were headache/migraine (N = 4, all females), anorexia (N = 3), and irritability (N = 2). Participants decreased their frequency of cannabis use significantly (p < 0.001), adjusted for baseline use. By the end of the trial, participants decreased by 1.76 (SE = 0.47) cannabis using days/week. Average daily amount of cannabis and urine THC metabolite levels did not change significantly. Lorcaserin was well tolerated in males but not females, suggesting possible sex differences. Future trials of other 5HT2c agonists (lorcaserin was withdrawn at the request of the FDA) should consider longer dose titration phases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cannabis is the most widely used psychoactive substance after alcohol and tobacco; 4% of the global adult population (200 million people) endorses its use (Figure 1). Cannabis use disorder (CUD) [...]

The article reviews modern anti-obesity drugs to identify new trends in effective and safe risk factors reduction (diabetes, cardiovascular and musculoskeletal diseases, cancer). Some anti-obesity drugs have a high risk of adverse effects on the CNS and cardiovascular system, so they should be used for a short-term therapy only. These drugs are cannabinoid receptor antagonists (Rimonabant), neuronal NE and 5-HT reuptake inhibitors (Sibutramine), neuronal NE, 5-HT, DA reuptake inhibitor (Tesofensine), 5HT2с receptors agonist (Lorcaserin) and other drugs affecting the central and peripheral mediator systems. That is why the treatment of obesity should focus on safe drugs that affected fat absorption (Orlistat), activated energy metabolism (Adipokines), methionine aminopeptidase 2 (MetAP2) inhibitors (Beloranib) etc. The combination of anti-obesity drugs with various mechanisms of action increases the effectiveness and reduces adverse effects (Contrave®, Empatic™, Qsymia etс).

Byline: Aarthi. Balaji, Smilu. Mohanlal, Divya. Pachat, Sachin. Babu, E. Suresh Kumar, Najiya. Mamukoya, Syama. Das Introduction: The recent evolution of genomics has led to the development of targeted therapeutics, [...]

Although drugs have been reported to modulate the gut microbiota, the effects of anti-obesity drugs on the gut microbiota remain unclear. Lorcaserin (LS) and phentermine (PT) are commonly used anti-obesity drugs. However, to our best knowledge, no studies have simultaneously assessed the effects of LS and PT on obesity and gut microbiota. This study aimed to explore the relationship between the anti-obesity effects of LS and PT and re-modulation of host gut microbiota. To test hypothesis, we fed C57BL/6J mice with a high-fat diet supplemented with LS and PT via oral gavage for 8 weeks. After sacrifice, body weight, fat accumulation, and serum biomarkers were measured, and the gut microbial composition was analyzed using 16 s rRNA amplicon sequencing. LS and PT were observed to modulate the gut microbial composition and restore gut microbial dysbiosis, as indicated by an increased Firmicutes/Bacteroidetes ratio. Significantly modulated genera by LS and PT treatment were strongly correlated with obesity-related markers. Additionally, LS and PT increased the mRNA level of G protein-coupled receptor 120 (GPR120) in the colon tissue. ASV3566, which corresponds to Eubacterium coprostanoligenes, was correlated with GPR120 and obesity-related markers such as glutamic pyruvic transaminase (GPT) and serum triglyceride (TG). In conclusion, LS and PT can modulate the gut microbiota dysbiosis and the gut microbiota plays a role in mediating the anti-obesity effect of drugs. [ABSTRACT FROM AUTHOR]

Lorcaserin is a serotonin 2c receptor agonist that promotes weight loss while contributing to the prevention and improvement of type 2 diabetes and improvement of atherogenic lipid profiles, without higher rates of major cardiovascular events. The full spectrum of possible lorcaserin-induced improvements in cardiometabolic health remains to be clarified. Thus, we investigated the way in which lorcaserin treatment may alter cardiovascular disease risk, either independently or through changes in body weight. We measured, for the first time, lipid particle quantification, lipid peroxidation, appetite-regulating hormones and mRNA expression of the 5-hydroxytryptamine 2c receptor (5-HT2c receptor). A total of 48 obese participants were enrolled in this six-month, randomized (1:1), placebo-controlled, double-blinded clinical trial. Lorcaserin treatment reduced fat mass (P

Objective: Overweight and obesity are endemic in developed countries, with a substantial negative impact on human health. Medications developed to treat obesity include agonists for the G-protein coupled receptors glucagon-like peptide-1 (GLP-1R; e.g. liraglutide), serotonin 2C (5-HT2CR; e.g, lorcaserin), and melanocortin4 (MC4R) which reduce body weight primarily by suppressing food intake. However, the mechanisms underlying the therapeutic food intake suppressive effects are still being defined and were investigated here. Methods: We profiled PPG neurons in the nucleus of the solitary tract (PPGNTS) using single nucleus RNA sequencing (Nuc-Seq) and histochemistry. We next examined the requirement of PPGNTS neurons for obesity medication effects on food intake by virally ablating PPGNTS neurons. Finally, we assessed the effects on food intake of the combination of liraglutide and lorcaserin. Results: We found that 5-HT2CRs, but not GLP-1Rs or MC4Rs, were widespread in PPGNTS clusters and that lorcaserin significantly activated PPGNTS neurons. Accordingly, ablation of PPGNTS neurons prevented the reduction of food intake by lorcaserin but not MC4R agonist melanotan-II, demonstrating the functional significance of PPGNTS 5-HT2CR expression. Finally, the combination of lorcaserin with GLP-1R agonists liraglutide or exendin-4 produced greater food intake reduction as compared to either monotherapy. Conclusions: These findings identify a necessary mechanism through which obesity medication lorcaserin produces its therapeutic benefit, namely brainstem PPGNTS neurons. Moreover, these data reveal a strategy to augment the therapeutic profile of the current frontline treatment for obesity, GLP-1R agonists, via coadministration with 5-HT2CR agonists.

Nonalcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease and affects a considerable proportion of the general population worldwide. Obesity is a major risk factor for development and progression of NAFLD and weight loss is an effective intervention for the management of NAFLD. However, few patients achieve substantial and sustained weight loss with lifestyle measures. Therefore, antiobesity agents are frequently considered in patients with NAFLD but there are limited data on their safety and efficacy. In the present review, we discuss the role of antiobesity agents in the management of NAFLD. All approved antiobesity agents appear to reduce transaminase levels and to improve steatosis in patients with NAFLD. However, their effects on fibrosis are less well studied and whether they affect liverrelated outcomes, including progression to cirrhosis and hepatocellular cancer, is unknown. The glucagon-like peptide-1 receptor agonists, liraglutide and semaglutide, appear to represent a first-line option in obese patients with NAFLD and type 2 diabetes mellitus (T2DM) since they induce considerable weight loss and have been extensively studied in patients with T2DM. However, more studies are needed to evaluated their effects on liverrelated and cardiovascular outcomes in patients with NAFLD, particularly in those without T2DM. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease and affects a considerable proportion of the general population worldwide. Obesity is a major risk factor for development and progression of NAFLD and weight loss is an effective intervention for the management of NAFLD. However, few patients achieve substantial and sustained weight loss with lifestyle measures. Therefore, antiobesity agents are frequently considered in patients with NAFLD but there are limited data on their safety and efficacy. In the present review, we discuss the role of antiobesity agents in the management of NAFLD. All approved antiobesity agents appear to reduce transaminase levels and to improve steatosis in patients with NAFLD. However, their effects on fibrosis are less well studied and whether they affect liver-related outcomes, including progression to cirrhosis and hepatocellular cancer, is unknown. The glucagon-like peptide-1 receptor agonists, liraglutide and semaglutide, appear to represent a first-line option in obese patients with NAFLD and type 2 diabetes mellitus (T2DM) since they induce considerable weight loss and have been extensively studied in patients with T2DM. However, more studies are needed to evaluated their effects on liver-related and cardiovascular outcomes in patients with NAFLD, particularly in those without T2DM.

The prolonged exposure to obesogenic diets disrupts the mesocortical dopaminergic input to the prefrontal cortex (PFC). This leads to suboptimal dopamine levels in this brain region, which affects cognition and control of food intake. Treatments that restore mesocortical dopaminergic neurotransmission may improve obesity-associated cognitive dysfunction and modulate food intake to induce weight loss. Given the complexity and multifactorial nature of obesity, combination treatments would likely achieve sizeable and sustained body weight loss and improve obesity-linked outcomes, such as cognitive dysfunction. Given this background, we hypothesize that concomitant activation of serotonin 5-HT2C and histamine H1 receptors, coupled with antagonism of histamine H3 receptors, synergistically modulates mesocortical dopamine neurotransmission and ameliorates obesity-induced cognitive dysfunction. We propose to test the hypothesis in a diet-induced obesity (DIO) rat model by treating animals with the 5-HT2C agonist lorcaserin and the H1 agonist and H3 antagonist betahistine. Consistent with our hypothesis, both lorcaserin and betahistine have been shown to reduce body weight in humans with obesity and animals. Both drugs have been demonstrated to improve cognitive functions by influencing dopaminergic signaling in the PFC. The proposed combination treatment addresses the paucity of studies on obesity treatments that improve cognitive function. This research may also help identify a potential targetable mechanism connecting obesity and neurocognitive outcomes. [ABSTRACT FROM AUTHOR]

As a chronic and relapsing disease, obesity negatiⓇvely impacts the health of men to a greater extent than that of women, with a higher risk of cardiovascular disease. Since lifestyle modifications alone are often challenging and limited for the maintenance of weight reduction, pharmacotherapy should be considered in a timely manner for obese men or overweight patients with weight-related comorbidities. Recent advances in anti-obesity drugs have enabled the potential of achieving clinically significant weight loss. Increasing evidence has shown that behavior-based interventions with one of these medications can result in greater weight loss than that elicited by usual care conditions. Data from most recent meta-analyses showed that the overall placebo-subtracted weight reduction (%) with the use of anti-obesity drugs for at least 12 months ranges from 2.9% to 6.8%; phentermine/topiramate (-6.8%) liraglutide (-5.4%), naltrexone/bupropion (-4.0%), lorcaserin (-3.1%), and orlistat (-2.9%). However, they have a high cost and may cause adverse outcomes depending on the individual. Very recently, on February 13, 2020, the US Food and Drug Administration requested withdrawal of lorcaserin from the market because a safety clinical trial showed an increased occurrence of cancer. Therefore the decision to initiate drug therapy in obese individuals should be made after the benefits and risks are considered. Thereafter, treatment should be tailored to specific patient subpopulations depending on their chronic conditions, comorbidities, and preferences. Herein, we provide an overview of the latest developments in weight loss medications, which may serve as one of the strategies for long-term obesity control.

Abstract The prolonged exposure to obesogenic diets disrupts the mesocortical dopaminergic input to the prefrontal cortex (PFC). This leads to suboptimal dopamine levels in this brain region, which affects cognition and control of food intake. Treatments that restore mesocortical dopaminergic neurotransmission may improve obesity‐associated cognitive dysfunction and modulate food intake to induce weight loss. Given the complexity and multifactorial nature of obesity, combination treatments would likely achieve sizeable and sustained body weight loss and improve obesity‐linked outcomes, such as cognitive dysfunction. Given this background, we hypothesize that concomitant activation of serotonin 5‐HT2C and histamine H1 receptors, coupled with antagonism of histamine H3 receptors, synergistically modulates mesocortical dopamine neurotransmission and ameliorates obesity‐induced cognitive dysfunction. We propose to test the hypothesis in a diet‐induced obesity (DIO) rat model by treating animals with the 5‐HT2C agonist lorcaserin and the H1 agonist and H3 antagonist betahistine. Consistent with our hypothesis, both lorcaserin and betahistine have been shown to reduce body weight in humans with obesity and animals. Both drugs have been demonstrated to improve cognitive functions by influencing dopaminergic signaling in the PFC. The proposed combination treatment addresses the paucity of studies on obesity treatments that improve cognitive function. This research may also help identify a potential targetable mechanism connecting obesity and neurocognitive outcomes.

Repurposing regulatory agency-approved molecules, with proven safety in humans, is an attractive option for developing new treatments for disease. We identified and assessed the efficacy of 3 drugs predicted by an in silico screen as having the potential to treat l -DOPA-induced dyskinesia (LID) in Parkinson's disease. We analysed ∼1.3 million Medline abstracts using natural language processing and ranked 3539 existing drugs based on predicted ability to reduce LID. 3 drugs from the top 5% of the 3539 candidates; lorcaserin, acamprosate and ganaxolone, were prioritized for preclinical testing based on i) having a novel mechanism of action, ii) having not been previously validated for the treatment of LID, iii) being blood-brain-barrier penetrant and orally bioavailable and iv) being clinical trial ready. We assessed the efficacy of acamprosate, ganaxolone and lorcaserin in a rodent model of l -DOPA-induced hyperactivity, with lorcaserin affording a 58% reduction in rotational asymmetry (P < 0.05) compared to vehicle. Acamprosate and ganaxolone failed to demonstrate efficacy. Lorcaserin, a 5HT2C agonist, was then further tested in MPTP lesioned dyskinetic macaques where it afforded an 82% reduction in LID (P < 0.05), unfortunately accompanied by a significant increase in parkinsonian disability. In conclusion, although our data do not support the repurposing of lorcaserin, acamprosate or ganaxolone per se for LID, we demonstrate value of an in silico approach to identify candidate molecules which, in combination with an in vivo screen, can facilitate clinical development decisions. The present study adds to a growing literature in support of this paradigm shifting approach in the repurposing pipeline. • Novel treatments are needed for l -DOPA-induced dyskinesia in Parkinson's disease. • Natural language processing of published abstracts to identify drugs to repurpose. • 5HT2C agonism is a potential novel mechanism to reduce l -DOPA-induced dyskinesia. • Study supports use of in silico methods in identification of drugs to repurpose. [ABSTRACT FROM AUTHOR]

Obesity is an important problem both nationally and worldwide, this is related to the increase in cases of systemic arterial hypertension and diabetes mellitus with the consequent increase in morbidity and mortality and health costs, which emphasizes the need for health policies for an early diagnosis and effective and safe treatment. Recently, the use of lorcaserin for the pharmacological treatment of obesity was approved. The objective of this article is to review the available and updated scientific literature on lorcaserin and be a reference framework for decision-making regarding the prescription of this drug. For the preparation of this guide specialists in internal medicine, endocrinology, a librarian and an expert in methodology were involved. An extensive search was conducted on PubMed and other specialized websites. It is concluded that lorcaserin is a well tolerated drug with mild adverse effects and a good safety profile at a dose of 10 mg twice a day, it has also presented benefits in glycemic control in patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Lorcaserin is a serotonergic agonist specific to the 5-hydroxytryptamine 2c receptor (5-HT2CR) that is FDA approved for the long-term management of obesity with or without at least one weight-related comorbidity. Lorcaserin can restrain patients’ appetite and improve insulin sensitivity and hyperinsulinemia mainly through activating 5-HT2CR in the hypothalamus. It is known that the mCPP, a kind of 5-HT2CR agonist, decreases plasma insulin concentration in mice and previous research in our laboratory found that mCPP inhibited glucose-stimulated insulin secretion (GSIS) by activating 5-HT2CR on the β cells. However, the effect of lorcaserin on GSIS of pancreatic β cell has not been studied so far. The present study found that 5-HT2CR was expressed in both mouse pancreatic β cells and β-cell–derived MIN6 cells. Dose-dependent activation of 5-HT2CR by lorcaserin suppressed GSIS and SB242084 or knockdown of 5-HT2CR abolished lorcaserin’s effect in vitro. Additionally, lorcaserin also suppressed GSIS in high-fat diet (HFD)-fed mice in dose-dependent manner. Lorcaserin did not change insulin synthesis ATP content, but lorcaserin decrease cytosolic free calcium level [(Ca2+)i] in MIN6 cells stimulated with glucose and also inhibit insulin secretion and (Ca2+)i in MIN6 treated with potassium chloride. Furthermore, stimulation with the L-type channel agonist, Bay K8644 did not restore GSIS in MIN6 exposed to lorcaserin. Lorcaserin inhibits the cAMP generation of MIN6 cells and pretreatment with the Gα i/o inhibitor pertussis toxin (PTX), abolished lorcaserin-induced suppression of GSIS in β cells, while membrane-permeable cAMP analogue db-cAMP had same effect as PTX. These date indicated lorcaserin coupled to PTX-sensitive Gα i/o proteins in β cells reduced intracellular cAMP level and Ca2+ influx, thereby causing GSIS dysfunction of β cell. These results highlight a novel signaling mechanism of lorcaserin and provide valuable insights into the further investigation of 5-HT2CR functions in β-cell biology and it also provides guidance for the clinical application of lorcaserin. [ABSTRACT FROM AUTHOR]

Obesity is a serious and growing worldwide health challenge associated with type 2 diabetes mellitus, cardiovascular disease, osteoarthritis, some cancers, sleep apnea, asthma, and nonalcoholic fatty liver. The Korean Society for the Study of Obesity recommends that pharmacotherapy should be considered when intensive lifestyle modifications fail to achieve a weight reduction in obese patients with a body mass index ≥25 kg/m². Long-term medications for obesity have traditionally fallen into two major categories: centrally acting anorexiant medications and peripherally acting medications, such as orlistat. In this paper, we provide an overview of the anti-obesity medications currently available for the long-term and individualized treatment of obesity.

Summary: The anorexigenic effect of serotonergic compounds has largely been attributed to activation of serotonin 2C receptors (Htr2cs). Using mouse genetic models in which Htr2c can be selectively deleted or restored (in Htr2c-null mice), we investigate the role of Htr2c in forebrain Sim1 neurons. Unexpectedly, we find that Htr2c acts in these neurons to promote food intake and counteract the anorectic effect of serotonergic appetite suppressants. Furthermore, Htr2c marks a subset of Sim1 neurons in the paraventricular nucleus of the hypothalamus (PVH). Chemogenetic activation of these neurons in adult mice suppresses hunger, whereas their silencing promotes feeding. In support of an orexigenic role of PVH Htr2c, whole-cell patch-clamp experiments demonstrate that activation of Htr2c inhibits PVH neurons. Intriguingly, this inhibition is due to Gαi/o-dependent activation of ATP-sensitive K+ conductance, a mechanism of action not identified previously in the mammalian nervous system.

The metabolic syndrome (MetS) encompasses medical conditions such as obesity, hyperglycemia, high blood pressure, and dyslipidemia that are major drivers for the ever-increasing prevalence of type 2 diabetes, cardiovascular diseases, and certain types of cancer. At the core of clinical strategies against the MetS is weight loss, induced by bariatric surgery, lifestyle changes based on calorie reduction and exercise, or pharmacology. This Review summarizes the past, current, and future efforts of targeting the MetS by pharmacological agents. Major emphasis is given to drugs that target the CNS as a key denominator for obesity and its comorbid sequelae., Introduction The metabolic syndrome (MetS) encompasses a cluster of pernicious metabolic diseases that include visceral obesity, dyslipidemia, hyperglycemia, and hypertension (1). It is considered to be a silent killer owing [...]

The serotonin (5‐HT) system has been implicated in the pathophysiology of alcohol (ethanol; EtOH) use disorders. Lorcaserin, a 5‐HT2C receptor agonist, attenuates drug self‐administration in animal models. We investigated the effects of lorcaserin on EtOH intake using the drinking‐in‐the‐dark (DID) procedure, an animal model of binge‐like drinking. We compared the effects of lorcaserin to those of the Food and Drug Administration (FDA)‐approved drug naltrexone and examined the effects of combining lorcaserin and naltrexone. To examine whether effects were specific for EtOH, we examined the effects of lorcaserin and naltrexone, administered alone and in combination, on saccharin intake. Adult male C57BL/6J mice received EtOH access (20% v/v) for 2 h in the home‐cage during the first 3 days of the DID procedure, beginning 3 h into the dark cycle. On day 4, mice were injected with lorcaserin, naltrexone, or a combination of lorcaserin and naltrexone prior to a 4‐h EtOH access. Intake was measured at 2 and 4 h. Lorcaserin reduced EtOH intake in a dose‐dependent fashion over the 2‐ and 4‐h measurement periods. Naltrexone also reduced EtOH intake when administered alone, with dose‐dependent effects being more pronounced over 2 h rather than the full 4‐h session. Combining lorcaserin and naltrexone reduced binge‐like EtOH drinking to a greater extent than either drug alone. A similar pattern of results was obtained for saccharin intake. These results suggest that lorcaserin and naltrexone can have additive effects on binge‐like EtOH drinking. They also support continued research into the therapeutic potential of lorcaserin for alcohol use disorders. [ABSTRACT FROM AUTHOR]

The 5-hydroxytryptamine 2C receptor (5-HTR2C) is a class G protein-coupled receptor (GPCR) enriched in the hypothalamus and the brain stem, where it has been shown to regulate energy homeostasis, including feeding and glucose metabolism. Accordingly, 5-HTR2C has been the target of several anti-obesity drugs, though the associated side effects greatly curbed their clinical applications. Dissecting the specific neural circuits of 5-HTR2C-expressing neurons and the detailed molecular pathways of 5-HTR2C signaling in metabolic regulation will help to develop better therapeutic strategies towards metabolic disorders. In this review, we introduced the regulatory role of 5-HTR2C in feeding behavior and glucose metabolism, with particular focus on the molecular pathways, neural network, and its interaction with other metabolic hormones, such as leptin, ghrelin, insulin, and estrogens. Moreover, the latest progress in the clinical research on 5-HTR2C agonists was also discussed. [ABSTRACT FROM AUTHOR]

There are no FDA‐approved treatments for cannabis use disorder (CUD). Preclinical research has shown that the 5HT‐2C agonist lorcaserin attenuates cue‐induced reinstatement of THC seeking and self‐administration. The goal of this placebo‐controlled, counterbalanced, within‐subject human laboratory study was to examine lorcaserin's effects on cannabis intoxication and self‐administration. Lorcaserin (10 mg BID) was administered during one of two 13‐day inpatient phases and placebo during the other; each phase was separated by ≥7 days of washout. Inpatient phases comprised (1) standardized cannabis administration (7.0% THC) at no financial cost (intoxication), counterbalanced with (2) the option to self‐administer cannabis following either 0 or 3 days of abstinence. Cognitive task performance, food intake, subjective ratings of drug effects, objective/subjective sleep measures, and tobacco cigarette use were also assessed. Fifteen normal‐weight, daily cannabis users (4F, 11M) not seeking treatment for CUD completed the study. Lorcaserin significantly reduced cannabis self‐administration following 0 and 3 days of cannabis abstinence and also reduced craving for cannabis during abstinence. Lorcaserin produced small but significant increases in positive cannabis ratings and body weight relative to placebo. Lorcaserin also reduced tobacco cigarette smoking on days of cannabis administration relative to placebo. During abstinence, subjective but not objective measures of sleep quality worsened during lorcaserin maintenance. Overall, lorcaserin's ability to decrease drug taking and cannabis craving in nontreatment‐seeking cannabis users supports further investigation of 5HT‐2C agonists as potential pharmacotherapies for CUD. [ABSTRACT FROM AUTHOR]

Background and Objectives: Preclinical studies show serotonin (5-HT) 5-HT2C receptor (5-HT2CR) agonists reduce cocaine-seeking and cocaine intake. This study examined safety of the 5-HT2CR agonist lorcaserin administered with cocaine in participants with cocaine use disorder (CocUD). Secondarily, subjective response to cocaine and choice of cocaine vs. money were examined. Methods: A double-blind, randomized, placebo-controlled trial of 25 inpatient non-treatment seeking participants with CocUD. Participants were randomized to either lorcaserin (n = 17) or placebo (n = 8). Primary outcome measures included cardiovascular measures and plasma cocaine levels. Secondary measures of subjective response to cocaine were assessed using a visual analog scale (VAS) and cocaine vs. money progressive ratio choice sessions. Results: Thirteen randomized participants were included in the final analysis. No serious or unexpected adverse events were related to lorcaserin. There were no significant interactions between cocaine and lorcaserin on cardiovascular measures, plasma cocaine, or subjective ratings. After multiple comparisons correction, cocaine significantly increased blood pressure, heart rate, and QTc. Lorcaserin significantly decreased VAS ratings of "feel irritable," "feel hungry," and "I am craving." For the cocaine vs. money choice procedure, there was a significant interaction between choice (cocaine vs. money) and lorcaserin. Participants treated with lorcaserin were more likely to choose cocaine. Discussion and Conclusions: This study showed safety of lorcaserin administered with cocaine but lack of efficacy to reduce the reinforcing effects of cocaine. Scientific Significance: This study is the first to show a disconnect between effects of 5-HT2CR agonists on craving and cocaine choice in human cocaine users. [ABSTRACT FROM AUTHOR]

Background and Objectives: Preclinical studies show serotonin (5-HT) 5-HT2C receptor (5-HT2CR) agonists reduce cocaine-seeking and cocaine intake. This study examined safety of the 5-HT2CR agonist lorcaserin administered with cocaine in participants with cocaine use disorder (CocUD). Secondarily, subjective response to cocaine and choice of cocaine vs. money were examined.Methods: A double-blind, randomized, placebo-controlled trial of 25 inpatient non-treatment seeking participants with CocUD. Participants were randomized to either lorcaserin (n = 17) or placebo (n = 8). Primary outcome measures included cardiovascular measures and plasma cocaine levels. Secondary measures of subjective response to cocaine were assessed using a visual analog scale (VAS) and cocaine vs. money progressive ratio choice sessions.Results: Thirteen randomized participants were included in the final analysis. No serious or unexpected adverse events were related to lorcaserin. There were no significant interactions between cocaine and lorcaserin on cardiovascular measures, plasma cocaine, or subjective ratings. After multiple comparisons correction, cocaine significantly increased blood pressure, heart rate, and QTc. Lorcaserin significantly decreased VAS ratings of “feel irritable,” “feel hungry,” and “I am craving.” For the cocaine vs. money choice procedure, there was a significant interaction between choice (cocaine vs. money) and lorcaserin. Participants treated with lorcaserin were more likely to choose cocaine.Discussion and Conclusions: This study showed safety of lorcaserin administered with cocaine but lack of efficacy to reduce the reinforcing effects of cocaine.Scientific Significance: This study is the first to show a disconnect between effects of 5-HT2CR agonists on craving and cocaine choice in human cocaine users.

Abstract Alcohol use disorder (AUD) and methamphetamine use disorder (MUD) are prevalent and have high adverse impacts on both the individual and society. Current treatment strategies for these disorders are ineffective at a population level. Lorcaserin, a 5‐HT2C receptor agonist, has shown potential at reducing the symptoms of substance use disorder. This pilot study (initiated prior to market withdrawal) examined feasibility and safety of lorcaserin treatment in people undergoing residential detoxification and treatment for AUD and MUD. This was an open label pilot study of lorcaserin where participants (n = 10 AUD; n = 8 MUD) received 10‐mg lorcaserin daily for 4 days then twice daily for 1 month. Primary outcome measures included recruitment and retention rate, incidence of treatment‐emergent events, incidence of methamphetamine or alcohol withdrawal‐related events, heart rate, and blood pressure. Secondary measures included pharmacokinetic data and self‐reported alcohol or methamphetamine use, craving, and psychological distress. AUD participants were recruited faster and had a greater retention rate compared with MUD participants. Lorcaserin did not alter vital signs, was well tolerated, and had a similar pharmacokinetic profile to individuals with obesity. Lorcaserin reduced self‐reported alcohol and amphetamine‐type substance use and craving in AUD and MUD participants, respectively. Self‐reported psychological health also improved over the treatment period for all participants. Despite the pilot nature of this study, our data support the notion of 5‐HT2C receptors as a therapeutic target for drug and alcohol abuse.

Alcohol use disorder (AUD) and methamphetamine use disorder (MUD) are prevalent and have high adverse impacts on both the individual and society. Current treatment strategies for these disorders are ineffective at a population level. Lorcaserin, a 5‐HT2C receptor agonist, has shown potential at reducing the symptoms of substance use disorder. This pilot study (initiated prior to market withdrawal) examined feasibility and safety of lorcaserin treatment in people undergoing residential detoxification and treatment for AUD and MUD. This was an open label pilot study of lorcaserin where participants (n = 10 AUD; n = 8 MUD) received 10‐mg lorcaserin daily for 4 days then twice daily for 1 month. Primary outcome measures included recruitment and retention rate, incidence of treatment‐emergent events, incidence of methamphetamine or alcohol withdrawal‐related events, heart rate, and blood pressure. Secondary measures included pharmacokinetic data and self‐reported alcohol or methamphetamine use, craving, and psychological distress. AUD participants were recruited faster and had a greater retention rate compared with MUD participants. Lorcaserin did not alter vital signs, was well tolerated, and had a similar pharmacokinetic profile to individuals with obesity. Lorcaserin reduced self‐reported alcohol and amphetamine‐type substance use and craving in AUD and MUD participants, respectively. Self‐reported psychological health also improved over the treatment period for all participants. Despite the pilot nature of this study, our data support the notion of 5‐HT2C receptors as a therapeutic target for drug and alcohol abuse. [ABSTRACT FROM AUTHOR]

As a chronic and relapsing disease, obesity negatiⓇvely impacts the health of men to a greater extent than that of women, with a higher risk of cardiovascular disease. Since lifestyle modifications alone are often challenging and limited for the maintenance of weight reduction, pharmacotherapy should be considered in a timely manner for obese men or overweight patients with weight-related comorbidities. Recent advances in anti-obesity drugs have enabled the potential of achieving clinically significant weight loss. Increasing evidence has shown that behavior-based interventions with one of these medications can result in greater weight loss than that elicited by usual care conditions. Data from most recent meta-analyses showed that the overall placebo-subtracted weight reduction (%) with the use of anti-obesity drugs for at least 12 months ranges from 2.9% to 6.8%; phentermine/topiramate (-6.8%) liraglutide (-5.4%), naltrexone/bupropion (-4.0%), lorcaserin (-3.1%), and orlistat (-2.9%). However, they have a high cost and may cause adverse outcomes depending on the individual. Very recently, on February 13, 2020, the US Food and Drug Administration requested withdrawal of lorcaserin from the market because a safety clinical trial showed an increased occurrence of cancer. Therefore the decision to initiate drug therapy in obese individuals should be made after the benefits and risks are considered. Thereafter, treatment should be tailored to specific patient subpopulations depending on their chronic conditions, comorbidities, and preferences. Herein, we provide an overview of the latest developments in weight loss medications, which may serve as one of the strategies for long-term obesity control. [ABSTRACT FROM AUTHOR]

Cocaine use disorder (CUD) is a major public health problem for which there is no approved pharmacotherapy. The primary purpose of this study was to evaluate the ability of lorcaserin, a 5-hydroxytryptamine 2 C (5-HT 2 C) receptor agonist, to facilitate abstinence in individuals seeking treatment for CUD. This was a 12-site, randomized, parallel arm study with a 13-week Treatment Phase that included a 1-week, single-blind run-in period when all participants received twice daily 15 mg acetazolamide capsules (a medication adherence marker), followed by randomization to either twice daily 10 mg lorcaserin or placebo capsules for the remaining 12 weeks. Pre-randomization data were utilized in an enrichment strategy aimed at achieving high levels of medication adherence and low placebo response rates in a subgroup of participants that qualified for the "efficacy population." For lorcaserin vs. placebo, the primary efficacy endpoint was the proportion of participants in the efficacy population achieving abstinence during the last three weeks of treatment, as evidenced by self-report of no cocaine use, confirmed by urine testing. Results: Within the efficacy population, 1.1% of 91 participants receiving lorcaserin and 4.3% of 92 receiving placebo achieved abstinence during the last 3 weeks of treatment. Among all randomized participants, 2.5% of 118 receiving lorcaserin and 5.6% of 124 receiving placebo achieved similar abstinence. Study participants receiving lorcaserin exhibited significantly greater reductions in body weight and BMI, indicating that medication adherence was sufficient to produce a pharmacological effect. Conclusions: Twice daily 10 mg lorcaserin failed to demonstrate efficacy in the treatment of CUD. • Lorcaserin (10 mg twice daily) lacked efficacy in cocaine use disorder treatment • Lorcaserin lacked efficacy in alcohol use disorder treatment in cocaine users • Significant lorcaserin-induced weight loss indicated adequate medication adherence [ABSTRACT FROM AUTHOR]

Lorcaserin, a selective serotonin 2C (5-HT 2C) receptor agonist, was approved for treating obesity and has been investigated for treating substance use disorders including those involving opioids. Although lorcaserin was withdrawn from the market, interest in the therapeutic potential of drugs acting at 5-HT 2C receptors continues, supporting the need to further characterize potential adverse effects especially when combined with drugs of abuse. This study examined acute effects of lorcaserin on opioid-induced ventilatory depression, which is the primary cause of overdose, and opioid self-administration, which models factors contributing to opioid abuse, in male and female rhesus monkeys. In one group (n = 4), effects of morphine (0.178 to 5.6 mg/kg, s.c.), fentanyl (0.0032 to 0.1 mg/kg, s.c.), and lorcaserin (0.1 to 1.78 mg/kg, s.c.) alone as well as effects of lorcaserin with each opioid on ventilation were determined using head plethysmography. Another group (n = 5) responded under a food versus fentanyl (0.1 to 3.2 μg/kg/infusion, i.v.) choice procedure, and lorcaserin (0.32 to 1.78 mg/kg, i.v.) was given as a pretreatment. Lorcaserin dose-dependently decreased minute volume to below 70 % of baseline when administered alone and increased the potency of morphine and fentanyl. Consistent with previous studies, lorcaserin failed to alter choice of fentanyl over food. This study demonstrates the novel finding that lorcaserin alone decreases ventilation and enhances the ventilatory-depressant effects of opioids. Taken together with previous studies, these results suggest that combining a 5-HT 2C receptor agonist such as lorcaserin with an opioid could increase the risk of ventilatory depression without the benefit of decreasing abuse. • Lorcaserin is a serotonin receptor agonist investigated for treatment of drug abuse. • Ventilatory effects of lorcaserin alone or with opioids are not well characterized. • Lorcaserin alone decreased ventilation and enhanced the potency of opioids. • Lorcaserin did not alter the positive reinforcing effects of fentanyl. [ABSTRACT FROM AUTHOR]

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

Summary: The US Food and Drug Administration (FDA) reported in February 2020 an increased risk of cancer with lorcaserin in the follow‐up of the CAMELLIA‐TIMI 61 trial. This systematic review and meta‐analysis addresses whether lorcaserin is associated with higher incidence of cancer compared with other interventions or no treatment. We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) for randomized controlled trials that compared lorcaserin with other interventions or no treatment in adults. We performed descriptive synthesis of all included studies and conducted meta‐analysis of trials that reported new cases of cancer. From 11 trials, comprising 21,299 individuals, four studies were included in the meta‐analysis and reported 476 cases of cancer in 10,342 subjects in the lorcaserin group and 438 among 9429 individuals randomized to placebo (relative risk [RR]: 1.08; 95% confidence interval [95% CI]: 0.96–1.23). The result was heavily influenced by the CAMELLIA‐TIMI 61 trial. In this study, the lorcaserin group had a higher risk of lung and pancreatic but not colon cancer. Overall risk of bias was low, and quality of evidence was moderate. The current evidence does not confirm the increased risk of cancer with lorcaserin but suggests a trend in this direction, with a greater incidence of some subtypes such as lung and pancreas. [ABSTRACT FROM AUTHOR]

The U.S. military has witnessed rising obesity among active component service members. The Department of Defense authorized coverage of weight loss medications in 2018, but no study has evaluated prescription prevalence within the active component. This descriptive retrospective cohort study analyzed data from active component U.S. military service members from January 2018 through June 2023. The study used data from the Defense Medical Surveillance System to determine prescription period prevalence of weight loss medication. Data on demographics, body mass index, and history of diabetes were considered. The study revealed a 100-fold increase in the prescription period prevalence of weight loss agents in the active component from their initial authorization date. Demographics associated with higher prescription period prevalence were non-Hispanic Black race and ethnicity, female sex, and older age. Service members in the health care occupations and the Navy had higher prevalence compared to other service branches and occupations. The findings indicate a significant rise in the period prevalence of weight loss prescriptions over time. Further research is recommended to assess the effectiveness, safety, and use in austere military environments.