TOPLINE:

Opioid antagonism with naltrexone reduced subjective distress and altered brain activity during automatic but not explicit threat processing in healthy volunteers. Naltrexone attenuated ventromedial prefrontal cortex (vmPFC), thalamus, and caudate activation when viewing negative images, suggesting that endogenous opioids might "fine-tune" automatic emotional responses.

METHODOLOGY:

• Researchers conducted a randomised, double-blind, placebo-controlled crossover study with 38 healthy participants (mean age, 24.38 years; 24 women) recruited from the University of Southampton campus and local community.
• Participants received either single-dose naltrexone 50 mg or a matched placebo capsule in a counterbalanced order, waiting 1 hour for peak plasma concentration before undergoing functional MRI (fMRI).
• The following two tasks were completed during fMRI: a cognitive emotional reappraisal task, with fearful/happy (regulate/attend) and neutral (attend) conditions probing explicit regulation; and a face-viewing task, with fearful, happy, or neutral facial expressions probing implicit processing.
• Primary outcomes included subjective distress ratings on a visual analog scale ranging from very distressed to very happy (scored from -50 to +50) and neural activation patterns measured via fMRI during emotional processing.
• Sessions were scheduled at least 7 days apart to reduce carry-over effects, with a total task duration of approximately 16 minutes.

TAKEAWAY:

• Naltrexone was associated with reduced distress compared with placebo across both attend and regulate blocks in the emotional reappraisal task (mean, -11.24; 95% CI, -15.70 to -6.76 for placebo vs mean, -9.08; 95% CI, -13.20 to -4.98 for naltrexone; P = .044).
• In the attend negative > neutral contrast, placebo was associated with increased activity in the bilateral medial thalamus extending to the left caudate and left vmPFC compared with naltrexone (P = .00278 for the left vmPFC; P = .0491 for the thalamus/caudate).
• In the fearful > happy faces contrast, naltrexone was associated with increased activity in the bilateral supramarginal gyrus, right middle temporal gyrus, and right superior frontal gyrus, and placebo showed increased activity in the vmPFC (P = .00459).
• No significant differences were observed between drug conditions in terms of activity in lateral prefrontal regions during explicit regulation in the reappraisal task.

IN PRACTICE:

"We found that endogenous opioid antagonism with naltrexone alters neural responses to emotional stimuli, reducing subjective distress without impairing explicit emotion regulation," the authors wrote.

"These findings highlight the complexity of the endogenous opioid system with regard to 'fine-tuning' automatic appraisal and regulation of emotional salience, and that blocking this system may blunt affective intensity rather than simply increasing distress," they added.

SOURCE:

This study was led by Nathan T.M. Huneke, University of Southampton, Southampton, England. It was published online on April 16, 2026, in The British Journal of Psychiatry.

LIMITATIONS:

The study was powered to detect changes in neural activation due to naltrexone, limiting its statistical power to detect subtle drug effects or interactions on behaviour. Residual carry-over effects cannot be completely excluded due to the short washout period of 7 days. The study examined a single dose of naltrexone and a single timepoint, preventing the assessment of dose-response relationships and temporal dynamics. Although fMRI provides valuable insights into functional activation, it cannot directly measure neurotransmitter activity. The study did not collect physiologic measures such as cortisol or blood pressure, limiting the ability to link neural changes to broader stress-response systems.

DISCLOSURES:

This study received support through a grant from the Medical Research Council. Several authors disclosed receiving honorarium, speaker honorarium, research funding, and department funding support from several organisations, including the National Institute for Health and Care Research (NIHR), Office of Life Sciences, NIHR South Central, and Focus Gulf Conferences. One author reported serving as a deputy director of education for the British Association for Psychopharmacology and being a clinical lecturer for the NIHR.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.