Using DNA testing to guide epilepsy treatment and reduce side effects

For most people with epilepsy, medication is the first treatment. There are many anti-seizure medications, and the right choice depends on the type of epilepsy and seizures, your age, other health conditions, other medications and, for some people, pregnancy plans. About one in three people with epilepsy continues to have seizures despite trying several medications, and side effects are a common reason people stop or skip doses. Your genes can affect how quickly your body clears some of these medications. This article explains how pharmacogenetic testing can help guide the choice and dose of anti-seizure medications and reduce side effects.

How do genes affect anti-seizure medications?

Many anti-seizure medications are broken down in the liver by enzymes such as CYP2C9, CYP2C19 and CYP3A4, or by UGT enzymes. Variations in the genes for these enzymes change how quickly a medication is cleared. If it is cleared too slowly, it can build up and cause sleepiness, dizziness, poor balance, trouble concentrating or "brain fog". If it is cleared too quickly, it may not control seizures at the usual dose. Pharmacogenetic testing shows whether you are a poor, intermediate, normal, rapid or ultrarapid metabolizer for these enzymes, which helps your doctor choose the medication and dose.

Some medications are not affected by these enzymes. Levetiracetam (Keppra), for example, is mostly removed by the kidneys, which makes it easier to combine with other medications.

Which anti-seizure medications are affected by genes and interactions?

Medication (brand)	Common uses	Genes and enzymes	Key cautions
phenytoin (Dilantin)	Focal and tonic-clonic seizures	CYP2C9	Lower dose for CYP2C9 poor and intermediate metabolizers. Many interactions.
carbamazepine (Tegretol)	Focal seizures	CYP3A4	Can worsen absence and myoclonic seizures. Speeds up the breakdown of many medications, including birth control.
oxcarbazepine (Trileptal)	Focal seizures	Not a major CYP drug	Can lower sodium levels.
valproate (Epival, Depakene)	Absence, generalized and focal seizures	UGT and other enzymes	Serious risk in pregnancy. Not for people with POLG mitochondrial disease.
ethosuximide (Zarontin)	Absence seizures	CYP3A4	Levels change with CYP3A4 inducers and inhibitors.
lamotrigine (Lamictal)	Focal and generalized seizures	UGT1A4	Must be started slowly to lower rash risk. Valproate raises its levels. Estrogen birth control lowers them.
clobazam (Frisium)	Add-on treatment for many seizure types	CYP2C19	Lower dose for CYP2C19 poor metabolizers.
brivaracetam (Brivlera)	Focal seizures	CYP2C19	A lower dose may be needed for CYP2C19 poor metabolizers.
lacosamide (Vimpat)	Focal seizures	CYP2C19 (partly)	Can affect heart rhythm.
levetiracetam (Keppra)	Focal and generalized seizures	Kidneys	Can cause irritability and mood changes. Lower dose for kidney problems.
topiramate (Topamax)	Focal and generalized seizures, migraine	Mostly kidneys	Rarely causes sudden glaucoma. Risk in pregnancy.
vigabatrin (Sabril)	Infantile spasms, focal seizures	Kidneys	Can cause permanent loss of side vision. Needs regular eye tests.
cannabidiol (Epidiolex)	Lennox-Gastaut syndrome, Dravet syndrome, tuberous sclerosis complex	CYP3A4, CYP2C19	Raises clobazam levels. Liver problems with valproate.

This table lists common examples. It is not a complete list of medications, uses or cautions.

How does CYP2C9 affect phenytoin?

Phenytoin has a narrow safe range: a small change in blood level can cause side effects such as dizziness, unsteadiness, double vision and confusion. CYP2C9 clears most of it. The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends a lower starting dose for people who are CYP2C9 intermediate or poor metabolizers, followed by blood level monitoring. The same applies to fosphenytoin, which the body turns into phenytoin.

How does CYP2C19 affect clobazam, brivaracetam and other medications?

CYP2C19 breaks down clobazam's active form, brivaracetam and diazepam, and partly lacosamide. In CYP2C19 poor metabolizers, levels of these medications can be much higher than usual, so drug labels recommend a lower starting dose of clobazam and suggest a lower dose of brivaracetam. About 2% to 5% of people of European or African ancestry and about 15% of people of East Asian ancestry are CYP2C19 poor metabolizers.

Why do drug interactions matter so much in epilepsy?

Many people with epilepsy take two or more anti-seizure medications, and these medications often affect each other:

• Carbamazepine and phenytoin speed up liver enzymes and can lower the levels of many other medications, including hormonal birth control, some antidepressants and blood thinners.
• Valproate slows the breakdown of lamotrigine and roughly doubles its levels, so lamotrigine must be started at a lower dose.
• Estrogen-containing birth control lowers lamotrigine levels, which can lead to breakthrough seizures.
• Cannabidiol blocks CYP2C19 and raises the levels of clobazam's active form, which can cause sleepiness. Combined with valproate, it can raise liver enzymes.

An interacting medication can have the same effect as a gene variant. This is why your genes and your full medication list, including over-the-counter products and cannabis, should be reviewed together.

What should women know about anti-seizure medications?

Valproate taken during pregnancy can cause serious birth defects and problems with learning and development. Drug labels warn that it should not be used by women who can become pregnant unless other treatments have not worked and effective birth control is used. Topiramate has also been linked to birth defects. Some anti-seizure medications reduce the effectiveness of hormonal birth control. If you are planning a pregnancy, talk to your neurologist before stopping or changing any medication.

What about cannabidiol (CBD)?

Prescription cannabidiol (Epidiolex) is approved in the United States for seizures caused by Lennox-Gastaut syndrome, Dravet syndrome and tuberous sclerosis complex. In Canada, ask your neurologist about access. Unlike CBD oils and gummies sold without a prescription, it has a precise, consistent dose. CBD is broken down by CYP3A4 and CYP2C19 and interacts with other anti-seizure medications. Do not add any CBD or cannabis product without talking to your doctor and pharmacist.

Why does taking seizure medication consistently matter?

Missed doses and poorly controlled seizures raise the risk of injuries and of sudden unexpected death in epilepsy (SUDEP). In a Swedish nationwide study, people whose medical records mentioned not taking their medication as prescribed had almost three times the risk of SUDEP. Taking three or more anti-seizure medications, often needed for hard-to-control seizures, was linked to a much lower risk, and no single medication increased the risk. Finding medications and doses you can tolerate makes it easier to take them every day.

For seizure emergencies, such as a seizure lasting more than five minutes, fast-acting benzodiazepines are used. Midazolam given in the nose or cheek or rectal diazepam can be given by family members or paramedics, and lorazepam is often given in hospital. Ask your doctor about a seizure action plan.

How can a pharmacogenetic test help?

A Pillcheck test reports CYP2C9, CYP2C19, CYP3A4 and other genes that affect many anti-seizure medications, as well as antidepressants, pain relievers and other medications often used by people with epilepsy. Pillcheck reports on 24 genes, increasing coverage with new guidelines and drug labels (see the genes tab), and covers 355 medications, which account for over 70% of dispensed prescriptions. A Pillcheck pharmacist reviews your results together with all your medications, checks for interactions and gives written recommendations on medication choice and dose to discuss with your neurologist or doctor.

Summary

• The choice of anti-seizure medication depends on the type of epilepsy, your health, your other medications and, for some medications, your genes.
• CYP2C9 guides phenytoin dosing, and CYP2C19 affects clobazam, brivaracetam and diazepam.
• Drug interactions between anti-seizure medications, birth control and cannabidiol are common and can change medication levels.
• Valproate and topiramate carry risks in pregnancy, so women should plan treatment with their neurologist.
• Taking medication consistently lowers the risk of seizures and SUDEP. Pharmacogenetic testing with a pharmacist review can help find medications and doses you can tolerate.

Frequently asked questions

Does Pillcheck report HLA genes?

No. HLA genes are linked to rare but serious allergic reactions to some medications, such as severe skin reactions (Stevens-Johnson syndrome, or SJS) and DRESS. Clinical guidelines (CPIC) recommend avoiding certain drugs in people who carry specific HLA variants. Examples are abacavir (HLA-B*57:01), carbamazepine, oxcarbazepine and phenytoin (HLA-B*15:02), carbamazepine (HLA-A*31:01) and allopurinol (HLA-B*58:01).

We don't include HLA results in Pillcheck reports because these results can easily be misread:

• Carrying a risk variant doesn't mean you will react. Most people who carry one take the medication without problems.
• Not carrying a known variant doesn't mean you're safe. People without any known risk variant can still have a severe reaction. A 2025 US study found that more than one-third of people with severe allopurinol reactions did not carry HLA-B*58:01, the variant usually tested for. Among Black patients in the study, the figure was 45%. Many risk variants haven't been discovered yet, especially in populations that have been studied less.
• Most tests check only a few variants. HLA genes are among the most variable in the body, with thousands of known versions. A test for one variant can miss closely related ones that also carry risk.

A negative HLA result could therefore give false reassurance. Whatever your genetic results, watch for early warning signs after starting a new medication, such as a rash, fever, blistering or sores in the mouth. Contact a healthcare provider right away if they appear.

If your doctor recommends HLA testing before you start a specific medication, they can order it through a clinical lab. If you've had a reaction before, an allergist or dermatologist can advise whether tests such as patch testing could help identify the cause.

Can a genetic test tell me which seizure medication will work?

No test can predict whether a medication will control your seizures. A pharmacogenetic test shows how your body processes many medications, which helps your doctor choose a safer dose and avoid some side effects and interactions.

Should I change my seizure medication based on my results?

No. Never stop or change an anti-seizure medication on your own, because this can trigger seizures. Share your results with your neurologist or pharmacist, who can decide whether a change is needed.

Can I use CBD oil for my seizures?

Talk to your doctor first. Over-the-counter CBD products vary in strength and can interact with anti-seizure medications. Prescription cannabidiol is used only for specific epilepsy syndromes.

References

Karnes JH, Rettie AE, Somogyi AA, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update. Clin Pharmacol Ther. 2021;109(2):302-309.

Phillips EJ, Sukasem C, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update. Clin Pharmacol Ther. 2018;103(4):574-581.

Balestrini S, Sisodiya SM. Pharmacogenomics in epilepsy. Neurosci Lett. 2018;667:27-39.

Sveinsson O, Andersson T, Mattsson P, et al. Pharmacologic treatment and SUDEP risk: A nationwide, population-based, case-control study. Neurology. 2020;95(18):e2509-e2518.

Ortega-Vázquez A, et al. Influence of genetic variants and antiepileptic drug co-treatment on lamotrigine plasma concentration in Mexican Mestizo patients with epilepsy. Pharmacogenomics J. 2020;20:845-856.

EPIDIOLEX (cannabidiol) US prescribing information. FDA drug label.

Alsherbiny MA, Li CG. Medicinal Cannabis—Potential Drug Interactions. Medicines (Basel). 2019;6(1):3.