Prescription ·Strong evidence ·Reviewed May 2026
Prescription mood stabilizer and anticonvulsant approved for maintenance treatment of bipolar I disorder to delay episodes of depression and mania, as well as for epilepsy. Particularly effective for bipolar depression prevention. Requires very slow dose titration over 6+ weeks to minimize the risk of life-threatening Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Dosage must be determined by your prescribing physician.
The bottom line
Evidence rating strong. Most-documented uses: bipolar depression prevention, bipolar episode delay, seizure control. 11 sources indexed (2009–2025), with 5 interaction records on file.
Core mechanism
Blocks voltage-sensitive sodium channels, stabilizing neuronal membranes and inhibiting the presynaptic release of glutamate and aspartate (excitatory amino acids). May also modulate calcium channels and serotonin reuptake. The reduction of glutamatergic excitotoxicity is thought to contribute to its mood-stabilizing effects.
Can be taken with or without food. Very slow dose titration required. Concurrent valproate significantly increases lamotrigine levels (reduce dose by half); carbamazepine and other enzyme inducers reduce levels.
Valproic acid inhibits the glucuronidation of lamotrigine, approximately doubling lamotrigine levels. This increases the risk of serious skin reactions including Stevens-Johnson syndrome, especially during lamotrigine titration.
Recommendation: When used together, lamotrigine dose must be reduced by 50% and titrated very slowly. Standard lamotrigine titration schedules have specific reduced-dose protocols for valproate co-administration.
Lamotrigine is a weak inhibitor of dihydrofolate reductase, though clinical studies show minimal effect on serum or RBC folate in most patients. However, folic acid supplementation may theoretically reduce lamotrigine's anticonvulsant efficacy by counteracting its antifolate mechanism. Paradoxically, animal studies suggest the combination of lamotrigine and folic acid may enhance antidepressant effects and seizure threshold. The clinical significance remains debated.
Recommendation: If folate supplementation is needed (particularly in women of childbearing age), use it under prescriber supervision while on lamotrigine. Monitor seizure frequency when starting or changing folate supplementation. Methylfolate may be preferable to folic acid as it bypasses the dihydrofolate reductase step. Do not discontinue lamotrigine or folate without medical guidance.
Unlike enzyme-inducing anticonvulsants (carbamazepine, phenytoin), lamotrigine has minimal effects on CYP-mediated vitamin D catabolism and does not appear to significantly impair bone mineral density. However, vitamin D deficiency is common in epilepsy patients regardless of specific anticonvulsant. Routine supplementation is recommended as a preventive measure, and lamotrigine does not interfere with vitamin D absorption or metabolism.
Recommendation: Vitamin D3 supplementation (1000-2000 IU/day) is recommended as general preventive care for patients on anticonvulsant therapy, including lamotrigine. No timing separation is needed. Periodic 25-OH vitamin D level monitoring is advisable.
St. John's Wort can induce UGT glucuronidation enzymes responsible for lamotrigine metabolism, potentially reducing lamotrigine blood levels and risking loss of seizure control or mood stabilization. Lamotrigine is primarily metabolized by UGT1A4 and UGT2B7 to its N2-glucuronide metabolite (approximately 90% of the excreted dose). Reduced lamotrigine levels can lead to breakthrough seizures or bipolar mood episodes.
Recommendation: Avoid St. John's Wort while taking lamotrigine. Loss of seizure control or mood stabilization can have severe consequences including status epilepticus. If already taking both, consult your prescriber immediately before making changes. Do not abruptly stop St. John's Wort as lamotrigine levels may rise.
Lamotrigine is a folate antagonist that inhibits dihydrofolate reductase. Long-term use may reduce folate levels. However, folate supplementation may reduce lamotrigine levels, potentially decreasing seizure control or mood stabilization.
Recommendation: If folate supplementation is needed (especially in pregnancy), monitor lamotrigine levels and seizure control closely. Low-dose folate (400-1000mcg) is generally safer than high doses. Discuss with your neurologist before starting.
Numbered references. Citations throughout the page link here.
Riva HR, Zheng S, Sohail N et al.. Rechallenge of Lamotrigine After Rash: A Systematic Review. The Journal of clinical psychiatry. 2025
Haenen N, Kamperman AM, Prodan A et al.. The efficacy of lamotrigine in bipolar disorder: A systematic review and meta-analysis. Bipolar disorders. 2024
Kumar R, Garzon J, Yuruk D et al.. Efficacy and safety of lamotrigine in pediatric mood disorders: A systematic review. Acta psychiatrica Scandinavica. 2023
Wilkowska A, Wiglusz MS, Jakuszkowiak-Wojten K et al.. Ketamine and Lamotrigine Combination in Psychopharmacology: Systematic Review. Cells. 2022
Methaneethorn J, Leelakanok N. Sources of lamotrigine pharmacokinetic variability: A systematic review of population pharmacokinetic analyses. Seizure. 2020
Egunsola O, Choonara I, Sammons HM. Safety of lamotrigine in paediatrics: a systematic review. BMJ open. 2015
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