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.