Can cannabis worsen the effects of Lamictal (lamotrigine)?

Cannabis and Lamotrigine (Lamictal) Interaction

Cannabis can worsen outcomes in patients taking lamotrigine through multiple mechanisms: it inhibits the enzymes that metabolize lamotrigine (potentially increasing drug levels and paradoxically raising seizure risk), may exacerbate underlying psychiatric conditions that lamotrigine treats, and compounds central nervous system side effects.

Pharmacokinetic Interaction Mechanisms

Cannabis inhibits cytochrome P450 enzymes (specifically CYP3A4 and CYP2C19) that are responsible for metabolizing lamotrigine, which can unpredictably increase lamotrigine blood levels. 1 This enzyme inhibition is particularly problematic because:

• Cannabis products have highly variable THC and CBD content, making the degree of enzyme inhibition unpredictable 1
• The interaction may require dose adjustments and close monitoring when both substances are used concurrently 1

Paradoxical Seizure Risk

Elevated lamotrigine levels from cannabis-mediated enzyme inhibition can paradoxically increase seizure risk, as documented in lamotrigine overdose cases. 1 This creates a dangerous situation where:

• Patients using lamotrigine for seizure control may experience breakthrough seizures despite therapeutic intent 1
• The seizure threshold may be lowered rather than raised when drug levels become excessive 1

Psychiatric Disorder Exacerbation

Cannabis may counteract lamotrigine's mood-stabilizing effects by exacerbating the underlying psychiatric disorders that lamotrigine is prescribed to treat. 1 Specifically:

• Cannabis use is associated with major depression, suicidal ideation, and elevated risk for psychotic disorders 1
• Patients with pre-existing psychiatric disorders face particular vulnerability, as cannabis may destabilize their conditions 1
• This is especially concerning given that lamotrigine is commonly prescribed for bipolar disorder and mood stabilization 1

Additive Central Nervous System Effects

Both cannabis and lamotrigine cause overlapping CNS side effects that compound when used together. Cannabis causes dizziness, confusion, dry mouth, fatigue, tachycardia, orthostatic hypotension, severe confusion, and paranoia 1, which overlap with lamotrigine's known adverse effects including dizziness, headache, back pain, and somnolence 2

Older adults face substantially higher risk of confusion, falls, and cardiovascular events (including myocardial ischemia/infarction) when combining these substances. 1

Critical Safety Considerations

Driving and Motor Function

Cannabis impairs reaction time and coordination for up to 12 hours depending on product type, and drivers testing positive for cannabis are more than twice as likely to be involved in motor vehicle crashes. 1 This risk is compounded by lamotrigine's CNS effects 1

Medication Adherence

Cannabis use is associated with poor medication adherence in patients with psychiatric conditions, which could lead to subtherapeutic lamotrigine levels and treatment failure. 3 Between 20-36% of adverse effects from continued cannabis use may be mediated through effects on medication adherence 3

Clinical Management Algorithm

If a patient on lamotrigine chooses to use cannabis despite these risks:

1. Start with the absolute lowest cannabis dose and titrate extremely slowly 1
2. Monitor closely for signs of lamotrigine toxicity (increased dizziness, ataxia, diplopia, nausea) and paradoxical seizure activity 1
3. Check liver function tests when using CBD products, especially at doses exceeding 300 mg/day 1
4. Avoid high-fat meals when taking oral cannabis products, as this significantly increases cannabinoid absorption and may exacerbate drug interactions 4
5. Consider lamotrigine level monitoring if cannabis use continues, though therapeutic ranges may not predict toxicity in this context 1

Absolute Contraindications

Patients should avoid cannabis entirely if they have:

• History of psychotic disorders, as cannabis may trigger psychotic episodes 1
• Pregnancy or breastfeeding status, due to fetal brain development risks 1
• History of substance use disorder, given higher risk of developing cannabis use disorder 1

Storage and Safety

Cannabis must be stored in locked, child-resistant containers away from children and pets, as pediatric cannabis exposures increased from 207 in 2017 to 3,054 in 2021, causing CNS depression, vomiting, and tachycardia 1

Common Pitfalls to Avoid

• Do not assume "natural" cannabis is safer than pharmaceutical medications - the drug interaction profile is significant and potentially dangerous 1
• Do not rely on patient self-reporting of cannabis use alone - maintain open, non-judgmental communication to ensure accurate medication history 4
• Do not ignore the variable potency of cannabis products - THC concentrations have nearly doubled from 9% in 2008 to 17% in 2017, with some concentrates reaching 70% THC 2