What is the role of lamotrigine in treating ketamine abuse?

Lamotrigine for Ketamine Use Disorder

Lamotrigine shows promising preliminary evidence for reducing ketamine craving and preventing relapse in ketamine use disorder, though the evidence base remains limited to preclinical studies and case reports. 1, 2

Mechanism of Action

Lamotrigine may help manage ketamine use disorder through its effects on glutamate neurotransmission:

• Lamotrigine inhibits glutamate release, which appears to counteract the neuroadaptations caused by chronic ketamine abuse 2, 3
• Chronic ketamine abuse induces delayed and persistent upregulation of the dopamine system, and lamotrigine may help normalize this dysregulation 2
• The drug's glutamate-modulating properties are thought to reduce both craving and relapse risk 4

Evidence for Efficacy

Preclinical Data

• In rat models, lamotrigine significantly decreased the motivation to self-administer ketamine as measured by breakpoint testing under progressive ratio schedules 4
• Lamotrigine prevented both cue-induced and ketamine priming-induced reinstatement of drug-seeking behavior in rats 4
• Importantly, lamotrigine did not affect food-seeking behavior or spontaneous locomotor activity, suggesting specificity for ketamine reinforcement rather than general behavioral suppression 4

Clinical Evidence

• A case report documented significant reduction in craving and ketamine use in a patient with ketamine use disorder treated with lamotrigine 2
• A systematic review identified lamotrigine as one of only three agents (along with naltrexone and paliperidone palmitate plus bupropion) with potential utility for craving/relapse prevention in ketamine use disorder 1
• All available clinical evidence is of very low quality, consisting only of case reports and descriptive outcomes 1

Clinical Considerations

Current Evidence Limitations

• No controlled trials exist examining lamotrigine for ketamine use disorder 1
• The entire clinical evidence base consists of a single case report and inclusion in one systematic review 1, 2
• All evidence quality is rated as "very low" using GRADE criteria 1

Potential Concerns

• Lamotrigine may reduce ketamine's therapeutic effects when ketamine is used clinically for depression, as it inhibits the glutamatergic signaling thought to mediate ketamine's antidepressant benefits 3
• One case report documented complete failure of ketamine anesthesia in a patient with lamotrigine overdose, demonstrating that lamotrigine can block ketamine's dissociative effects 5
• This interaction occurs because lamotrigine reduces the cortical glutamate release needed to mediate ketamine's effects 5

Practical Approach

For patients with ketamine use disorder seeking treatment, lamotrigine represents a reasonable pharmacological option to consider, particularly for managing craving and preventing relapse, given the absence of established effective treatments 1, 2:

• Consider lamotrigine specifically for the craving/relapse prevention phase of treatment rather than acute intoxication or withdrawal 1
• For acute ketamine intoxication or withdrawal, benzodiazepine regimens show more evidence of utility 1
• Titrate lamotrigine slowly according to standard protocols to minimize risk of serious rash 2
• Monitor for reduction in subjective craving and objective ketamine use 2

Critical Caveat

Clinical trials are urgently needed to determine whether the promising preclinical findings and single case report translate to broader clinical efficacy 2, 4. Until such data exist, lamotrigine should be considered experimental for this indication, though it may be justified given the lack of alternative evidence-based treatments for ketamine use disorder 1.