Antiseizure pill offers hope for people with alcohol use disorder

The antiseizure medication topiramate appears to reduce heavy drinking in individuals with alcohol use disorder (AUD) by attenuating alcohol cue-elicited brain activation and craving, as shown in a recent study.

A gamma-aminobutyric acid (GABA)/glutamate modulator, topiramate exerts multiple pharmacologic effects that inhibit neuronal activity. The drug is believed to help with alcohol dependence by inhibiting alcohol-induced dopamine release in the reward-related mesolimbic dopamine pathways. This can happen as a result of GABA neurotransmission enhancement and/or glutamatergic neurotransmission blockage, according to the investigators. [Int J Neuropsychopharmacol 2014;17:1541-1544; Curr Opin Psychiatry 2019;32:255-265]

“This suppression of alcohol-induced dopamine release could decrease the reinforcing effects of alcohol. Over time, repeated reductions in alcohol-induced reinforcement may devalue the rewarding properties of alcohol cues and attenuate the motivation (ie, craving) to consume alcohol,” they explained. [Lancet 2003;361:1677-1685]

In the study, the investigators looked at the functional magnetic resonance imaging (fMRI) data of 22 adult AUD patients with heavy alcohol consumption; 12 had been randomized to receive topiramate (maximal daily dosage of 200 mg/day) and the remaining eight to receive placebo for 6 weeks. These patients had sought treatment voluntarily to either quit drinking or reduce their consumption to safe levels (<3 standard drinks per day and 12 drinks per week for men; <2 drinks per day and 8 drinks per week for women).

Results of the fMRI alcohol cue-reactivity tasks showed that at treatment conclusion, topiramate led to a marked reduction in alcohol cue-elicited activation of the left ventral striatum (VS), bilateral orbitofrontal cortex (OFC), and medial OFC, alcohol cue-elicited craving, and heavy drinking days compared with placebo. [Neuropsychopharmacology 2021;46:1414-1420]

Interestingly, the reduction in alcohol cue-elicited activation in the medial OFC translated to decreased craving, whereas the diminished activation observed in the right VS, right OFC, and medial OFC correlated with a drop in heavy drinking days.

“Because our data are correlational, it is not possible to determine whether the attenuation of brain responses to alcohol cues in the VS and OFC is a cause or effect of the changes in heavy drinking,” the investigators noted.

“However, posthoc analyses examining whether changes in heavy drinking days were associated with changes in global resting cerebral blood flow from baseline to scan 2 showed no correlation (p=0.18). Although replication of these findings is needed, it is possible that topiramate reduces heavy drinking by reducing the value of alcohol cues and alcohol reward,” they added.

Even with the small sample size and the inability to correct for multiple regions of interests, the study was able to perform a baseline scan. This scan ensured that the medication groups did not have pre-existing differences in alcohol cue reactivity and cerebral blood flow.

“Topiramate has a long titration period, and consequently, patients were scanned after about 6 weeks of dosing, including a full week at maximum dosage. Although this approach allowed for a more accurate assessment of topiramate’s effects, the long interval between scans led to patient attrition,” they said.