Naltrexone, a long-acting opioid receptor antagonist, is commonly utilized to avert relapse in individuals with opioid or alcohol dependence. While its efficacy in modifying cue-reactivity and lowering desire is well documented, less is known regarding its ability to elicit negative sensory-emotional reactions, particularly in response to olfactory stimulation. We present a rare case of a 16-year-old male with a history of cannabis usage who experienced acute episodes of respiratory distress after starting oral naltrexone (50 mg/day). These episodes were consistently triggered by the smell of opium or cannabis smoke, despite the patient’s abstinence. The reactions were severe enough to necessitate multiple emergency medical procedures. The patient had a prior adverse reaction to morphine and a history of multiple drug allergies, suggesting a possible underlying sensitivity to opioid system modulation. The symptoms resolved after discontinuation of naltrexone. This case raises significant clinical and neurobiological concerns about the role of opioid antagonism in modifying olfactory and emotional processing. We propose that naltrexone-induced disinhibition in olfactory-limbic circuits may have contributed to heightened sensory gain and conditioned unpleasant reactions in a sensitized individual. More research is needed to understand the mechanisms driving this unusual yet important reaction.