Safety and tolerability of topiramate and N-acetyl cysteine combination in individuals with alcohol use disorder: a 12 week, randomized, double-blind, pilot study.

2023-12-07
Alcohol and alcoholism (Oxford, Oxfordshire) 59(2)
- Nassima A-D Tiouririne
- Tevfik Kalelioglu
- Chamindi Seneviratne
- Xin-Qun Wang

PubMed: 38069498
DOI: 10.1093/alcalc/agad082

Study Design

Type: Randomized Controlled Trial (RCT)
Population: 17 participants (nine received TPM+NAC and eight matching TPM+Placebo)
Methods: 12-week, double-blind randomized trial assessing the effects of combining NAC (1200 mg/day) with TPM (200 mg/day) vs TPM alone
Blinding: Double-blind
Duration: 12 weeks

Topiramate (TPM), a GABA/glutamate modulator, has shown positive results for treating alcohol use disorder (AUD), but causes significant cognitive adverse effects. TPM causes cognitive side effects by reducing glutathione levels in the frontal lobe. N-acetyl cysteine (NAC) increases level of intracellular glutathione. We hypothesized that combining NAC with TPM may mitigate the possible cognitive side effects of TPM, as well as working synergistically in reducing alcohol consumption more efficaciously than using TPM alone. A 12-week, double-blind randomized trial assessing the effects of combining NAC (1200 mg/day) with TPM (200 mg/day) vs TPM alone (i) cognitive side effects caused by TPM, (ii) percentage of heavy drinking days (PHDD) and percentage of days abstinent (PDA) using weekly calendar, and (iii) craving outcomes using the obsessive-compulsive drinking scale. Seventeen participants were randomized into the study (nine received TPM + NAC and eight matching TPM + Placebo). Cognitive adverse events were not significantly different between the treatment arms (P = 0.581). There was no difference in PHDD (P = 0.536) and in PDA over the entire study period (P = 0.892). However, both treatment groups at study end, compared with the baseline, significantly reduced their PHDD and increased their PDA. As for cravings: TPM + NAC group has shown higher level in automaticity of drinking (P = 0.029) and interference due to drinking (P = 0.014) subscales compared with the TPM + Placebo group. No difference was observed between groups in terms of Drinking Obsessions and Alcohol Consumption subscales. This pilot study indicates that combining NAC with TPM is overall safe, but the addition of NAC has no significant benefit over placebo in the incidence of TPM-related cognitive impairment, and alcohol drinking. Furthermore, craving outcomes may become worse with the addition of NAC.

Research Insights

N-Acetyl Cysteine→Increased Days Abstinent
There was no difference in PHDD (P = 0.536) and in PDA over the entire study period (P = 0.892).
Effect
Neutral
Effect size
Small
Dose
1200 mg/day
N-Acetyl Cysteine→Reduced Alcohol Consumption
No difference was observed between groups in terms of Drinking Obsessions and Alcohol Consumption subscales.
Effect
Neutral
Effect size
Small
Dose
1200 mg/day
N-Acetyl Cysteine→Reduced Automaticity of Drinking
TPM+NAC group has shown higher level in automaticity of drinking (P = 0.029)
Effect
Harmful
Effect size
Small
Dose
1200 mg/day
N-Acetyl Cysteine→Reduced Drinking Obsessions
No difference was observed between groups in terms of Drinking Obsessions and Alcohol Consumption subscales.
Effect
Neutral
Effect size
Small
Dose
1200 mg/day
N-Acetyl Cysteine→Reduced Heavy Drinking Day
There was no difference in PHDD (P = 0.536) and in PDA over the entire study period (P = 0.892).
Effect
Neutral
Effect size
Small
Dose
1200 mg/day
N-Acetyl Cysteine→Reduced Interference Due to Drinking
TPM+NAC group has shown higher level in ... interference due to drinking (P = 0.014)
Effect
Harmful
Effect size
Small
Dose
1200 mg/day

Adverse Events Reported

N-Acetyl Cysteine→cognitive adverse events
Cognitive adverse events were not significantly different between the treatment arms (P = 0.581).
Finding
No significant difference
Significant
No
N-Acetyl Cysteine→Overall tolerability
This pilot study indicates that combining NAC with TPM is overall safe, but the addition of NAC has no significant benefit over placebo in the incidence of TPM-related cognitive impairment, and alcohol drinking.
Finding
Reported