INTRODUCTION: Central neurochemical systems including the monoamine, opioid, and 
cannabinoid systems have been promising targets for antiobesity drugs that 
modify behavioral components of obesity. In addition to modulating eating 
behavior, centrally acting antiobesity drugs are also likely to alter emotional 
behavior and cognitive function due to the high expression of receptors for the 
neurochemical systems targeted by these drugs within the fronto-striatal and 
limbic circuitry.
METHODS: This paper reviewed the neuropsychiatric adverse effects of past and 
current antiobesity drugs, with a central mechanism of action, linking the 
adverse effects to their underlying neural substrates and neurochemistry.
RESULTS: Antiobesity drugs were found to have varying neuropsychiatric adverse 
event profiles. Insomnia was the most common adverse effect with drugs targeting 
monoamine systems (sibutramine, bupropion and tesofensine). These drugs had some 
positive effects on mood and anxiety and may have added therapeutic benefits in 
obese patients with comorbid depression and anxiety symptoms. Sedation and 
tiredness were the most common adverse effects reported with drugs targeting the 
m-opioid receptors (i.e., naltrexone) and combination therapies targeting the 
opioid and monoamine systems (i.e., Contrave™). Cognitive impairments were most 
frequently associated with the antiepileptic drugs, topiramate and zonisamide, 
consistent with their sedative properties. Drugs targeting the cannabinoid 
system (rimonabant and taranabant) were consistently associated with symptoms of 
anxiety and depression, including reports of suicidal ideation. Similar adverse 
events have also been noted for the D₁/D₅ antagonist ecopipam.
CONCLUSION: These findings highlight the need to assess neuropsychiatric adverse 
events comprehensively using sensitive and validated methods early in the 
clinical development of candidate antiobesity drugs with a central mechanism of 
action.