Topiramate’s Emerging Role in Cocaine Use Disorder

In 2024, 4.3 million individuals aged 12 and older reported using cocaine.¹ Cocaine is a schedule II narcotic classified based on its high potential for misuse and abuse, while also having a medical use for treatment in the US.² Cocaine can be extracted from the coca plant, Erythroxylum coca, which is native to areas of South America. In its illicit form, cocaine exists as a white powder that can be snorted for a euphoric high effect or rubbed in the gums for a numbing effect, mimicking its indication for medical procedures. Additionally, cocaine powder can be manipulated for other administration modalities, such as injecting or smoking, to promote a quicker onset of effect.³ Cocaine use causes an increase in neurotransmitters, including dopamine, serotonin, and norepinephrine, which contribute to its stimulant nature, intense euphoric effect, and addictive nature.⁴

The adverse effects of cocaine use are primarily cardiovascular and include tachycardia, arrhythmias, and an increased risk of myocardial infarction.^3,4 Cocaine can also cause hyperthermia, diaphoresis, and seizures.⁴ With long-term use, cocaine-induced vasoconstriction can damage vital organs by reducing blood flow and forcing the heart to work harder to maintain circulation. This increased cardiovascular strain raises the risk of stroke, aortic aneurysm or rupture, and inflammation of the heart muscle.³ Overdosing from cocaine is also a relevant clinical concern. Between 2021 and 2023, cocaine was the third leading cause of mortality from illicit substances following fentanyl and methamphetamine.⁵ Given the severe and potentially life-threatening adverse effects associated with cocaine use, it is important to explore options that can serve as treatment for patients with cocaine use disorder as limited options exist.

Therapeutic Options

Despite the prevalence of cocaine use disorder, there is limited primary literature that explores potential pharmacotherapy agents for its treatment. The 2024 guidelines from the American Society of Addiction Medicine/American Academy of Psychiatry (ASAM/AAAP) conclude that the current evidence is insufficient to support a definitive recommendation for pharmacotherapy in the treatment of cocaine use disorder.⁶ While various options are listed for consideration such as bupropion, modafinil, and the combination of topiramate and extended-release amphetamine salts, not one pharmacotherapy agent is endorsed with a strong recommendation. The guidelines acknowledge that current pharmacotherapy use for stimulant use disorders falls under off-label indications, as there are currently no FDA-approved medications for this use.

Topiramate, an antiseizure medication, has an off-label indication for cocaine use disorder and it received a conditional recommendation with a low certainty of evidence.^7,8 The proposed mechanism by which topiramate may reduce cocaine use involves enhancing γ-aminobutyric acid (GABA)-mediated inhibitory neurotransmission while antagonizing glutamatergic excitatory signaling. These effects are thought to attenuate cocaine-induced dopamine release within the brain's reward pathways, thereby reducing craving and the reinforcing effects of cocaine.⁷

Literature Search

Studies evaluating the use of topiramate for cocaine use disorder have been limited. Article selection was made based on design, patient population, and comparison group. Meta-analyses were not included. Two randomized control trials were selected.

Literature Review

The first study evaluated was a randomized, controlled trial conducted by Johnson et al. comparing topiramate with placebo. Baseline characteristics were balanced between groups. As shown in Table 2, participants receiving topiramate had a significantly greater increase in cocaine non-use days than those receiving placebo (13.3% vs. 5.3%; mean difference 8%; 95% CI, 1.4–14.6%; P=0.02). When missed urine screens were counted as cocaine-use days, topiramate still resulted in significantly more cocaine non-use days than placebo (8.9% vs. 3.7%; 95% CI, 0.2–10.1%; P=0.04). Participants receiving topiramate were also more likely to achieve a cocaine-free week than those receiving placebo (16.6% vs. 5.8%; OR, 3.21; 95% CI, 1.24–8.32; P=0.02). Although the study was not powered to evaluate exploratory outcomes, the topiramate group demonstrated greater reductions in cocaine craving and improved clinician-rated global functioning (P<0.05). However, patient-rated improvement did not reach statistical significance. The authors concluded that topiramate may be efficacious for cocaine dependence. Limitations included the small sample size, declining retention and compliance over time, reliance on self-reported secondary outcomes, and the 12-week follow-up period.¹¹

Kampman et al. also compared topiramate with placebo in patients with co-occurring cocaine and alcohol dependence. Baseline characteristics were balanced between groups. Overall, topiramate did not significantly reduce self-reported cocaine or alcohol use. However, during the final 3 weeks of the study, participants receiving topiramate achieved higher rates of cocaine abstinence based on urine samples than those receiving placebo (20% vs. 7%; P=0.01). Among participants with more severe cocaine withdrawal symptoms (Cocaine Selective Severity Assessment score >18), topiramate also significantly increased cocaine abstinence. The authors concluded that topiramate may be more effective in patients with more severe withdrawal symptoms but that these findings may not be generalizable to patients unable to achieve an initial period of abstinence. Limitations included the small sample size, low retention rates, and lack of adjustment for variability in the time required to achieve abstinence.¹²

Critical Appraisal

Although both trials targeted a maintenance dose of 300 mg/day of topiramate, differences in study design may explain the variability in findings. Johnson et al. included patients with lower baseline alcohol use, whereas Kampman et al. enrolled patients with more extensive co-occurring alcohol use, which may have influenced the measured efficacy of topiramate for cocaine use disorder. Another key difference was the abstinence requirement before treatment initiation. Johnson et al. did not require patients to achieve cocaine abstinence before randomization and found that topiramate significantly increased cocaine non-use days, cocaine-free urine samples, and improved self- and clinician-reported outcomes. In contrast, Kampman et al. required participants to achieve abstinence before treatment and did not demonstrate a significant benefit for the primary outcome, although greater efficacy was observed among patients with more severe cocaine withdrawal symptoms. Treatment retention also differed between studies. Johnson et al. reported lower overall retention than Kampman et al., although completion rates were higher in the topiramate groups than the placebo groups in both trials.^11,12

Conclusion

The studies by Johnson et al. and Kampman et al. demonstrate the complexity that exists in identifying the role of topiramate in the management of cocaine use disorder. Differences regarding the extent of co-occurring substance use disorders, requirement of drug abstinence prior to enrollment, severity of withdrawal symptoms, and maintaining the retention of subjects in the study all represent challenges in discerning topiramate’s specific role in the treatment of cocaine use disorder. The results of both studies should be applied conservatively to patients.^11,12

It is imperative that individual assessment of a patient’s comorbidities, the presence of other mental health conditions, and concomitant medication use, such as with other psychotropic agents, all be carefully considered prior to topiramate initiation. The limited evidence discussed is suggestive that select subgroups, including patients who demonstrated greater signs of withdrawal symptoms, as in Kampman et al., might achieve greater abstinence from cocaine after several weeks of topiramate use.¹² When deciding if topiramate is an appropriate agent for the treatment of cocaine dependence, factors including a patient’s willingness to achieve abstinence as well as experience withdrawal symptoms must be taken into consideration.

For patients unable to achieve abstinence from cocaine use, the findings in Johnson et al. suggest that topiramate might still be beneficial for the reduction of cocaine use and related symptoms such as cravings. Finally, because both studies were designed using dose escalation and maintenance of an efficacy phase, topiramate might be a less appropriate pharmacotherapy option for patients who struggle with adherence, frequent changes to their medication regimen, and are not motivated to maintain consistency in use amidst a lack of immediate benefit.^11,12

Although preliminary evidence suggests that topiramate may reduce cocaine use and promote abstinence, the current body of literature remains limited by small sample sizes, heterogeneous study designs, and a lack of large-scale randomized controlled trials, precluding a strong recommendation for its routine use. Further well-powered studies are needed to clarify its efficacy, optimal dosing, and role within evidence-based treatment guidelines for cocaine use disorder.

REFERENCES

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2. Cocaine. Department of Justice. December 2024. Accessed August 14, 2026. https://www.dea.gov/sites/default/files/2025-01/Cocaine-2024-Drug-Fact-Sheet.pdf

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9. Topiramate capsule. DailyMed. Updated March 24, 2026. Accessed August 14, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d1588c37-9da9-4ccb-b78a-64234938a115

10. Topiramate. Drugs.com. Updated August 12, 2026. Accessed August 14, 2026. https://www.drugs.com/topiramate.html

11. Johnson BA, Air-Daoud N, Wang XQ, et al. Topiramate for the treatment of cocaine addiction: a randomized clinical trial. JAMA Psychiatry. 2013;70(12):1338-1346. doi:10.1001/jamapsychiatry.2013.2295

12. Kampman KM, Pettinati HM, Lunch KG, Spratt K, Wierzbicki MR, O’Brien CP. A double-blind, placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence. Drug Alcohol Depend. 2013;133(1):94-99. doi:10.1016/j.drugalcdep.2013.05.026