Review ArticlesBiphasic reward effects are characteristic of both lorcaserin and drugs of abuse: implications for treatment of substance use disordersGrasing, Ken W.a,b; Burnell, Kima; De, Aloka Author Information aSubstance Use Research Laboratory, Research Service, Kansas City Veterans Affairs Medical Center, Kansas City, Missouri bDivision of Clinical Pharmacology, Department of Medicine, University of Kansas School of Medicine, Kansas City, Kansas, USA Received 27 August 2021 Accepted as revised 29 January 2022 Correspondence to Ken W. Grasing, MD, Substance Use Research Laboratory, Kansas City Veterans Affairs Medical Center, 151, Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128, USA, E-mail: [email protected] Behavioural Pharmacology: June 2022 - Volume 33 - Issue 4 - p 238-248 doi: 10.1097/FBP.0000000000000672 Buy Metrics Abstract Lorcaserin is a modestly selective agonist for 2C serotonin receptors (5-HT2CR). Despite early promising data, it recently failed to facilitate cocaine abstinence in patients and has been compared with dopamine antagonist medications (antipsychotics). Here, we review the effects of both classes on drug reinforcement. In addition to not being effective treatments for cocaine use disorder, both dopamine antagonists and lorcaserin can have biphasic effects on dopamine and reward behavior. Lower doses can cause enhanced drug taking with higher doses causing reductions. This biphasic pattern is shared with certain stimulants, opioids, and sedative-hypnotics, as well as compounds without abuse potential that include agonists for muscarinic and melatonin receptors. Additional factors associated with decreased drug taking include intermittent dosing for dopamine antagonists and use of progressive-ratio schedules for lorcaserin. Clinically relevant doses of lorcaserin were much lower than those that inhibited cocaine-reinforced behavior and can also augment this same behavior in different species. Diminished drug-reinforced behavior only occurred in animals after higher doses that are not suitable for use in patients. In conclusion, drugs of abuse and related compounds often act as biphasic modifiers of reward behavior, especially when evaluated over a broad range of doses. This property may reflect the underlying physiology of the reward system, allowing homeostatic influences on behavior. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.