Topiramate and Naltrexone Reduce Alcohol Through Common Mechanism

Dr. Daniel Amen’s use of brain scans to diagnose mental disorders is controversial, but his image sure gets this point across

Two very different medications quiet alcohol cravings the same way in the brain

STUDY: Logge WB et al, Psychopharmacology 2025

STUDY TYPE: Randomized controlled trial

FUNDING: National Health and Medical Research Council of Australia; Medical Research Future Fund

Background

Topiramate and naltrexone reduce drinking through very different mechanisms:

• Topiramate modulates GABA and glutamate
• Naltrexone alters reward circuits by partially blocking opioid receptors

But this study of brain imaging suggests they arrive at a common place.

The Study

• 47 adults with alcohol use disorder randomized to topiramate (up to 200 mg/day) or naltrexone (50 mg/day) for 12 weeks.
• Brain scans taken at week 7, two hours after the morning dose.
• Alcohol cue reactivity (fMRI responses to alcohol images) and resting-state brain connectivity were compared between groups.

Results

No differences. Both drugs produced the same brain activation patterns in response to alcohol cues and the same resting-state connectivity. Across the whole sample, alcohol images triggered increased activity in visual processing regions, while reward- and salience-related areas — the insula, anterior cingulate, and prefrontal cortex — went quiet. These are exactly the regions where both drugs are expected to act. Neither drug showed an edge over the other, and brain responses didn’t predict subsequent heavy drinking days.

Limitations

No pre-treatment baseline scan was obtained, so the study can’t show whether either drug changed brain activity over time. The sample was small (47 for cue reactivity), and no formal power analysis was done. There was no placebo arm.

Practice Implications

1. Topiramate and naltrexone appear to target the same reward circuits through different routes, and both reduce heavy drinking. When choosing between them, the brain science won’t tell you much. Tolerability will.
2. Topiramate causes cognitive slowing and paresthesias and requires a slow titration; naltrexone is simpler to start.
3. For a patient who failed naltrexone, topiramate is a reasonable next step — and vice versa. Start with whichever your patient is more likely to tolerate and take.