Valproate's label: carbapenem antibiotics, topiramate, cannabidiol and lamotrigine each interact in a different way
Depakote's label calls for valproate level monitoring with aspirin, carbapenem antibiotics, estrogen contraceptives and methotrexate; warns of "Hyperammonemia and encephalopathy" with topiramate and raised liver enzymes with cannabidiol.
Reasonable evidence with real limitations. how we score evidence
Caveat on this rating: The cannabidiol finding comes from trials of prescription-strength cannabidiol; whether typical over-the-counter CBD doses reach the same effect is not stated in the label and was not read.
Valproate is a mood stabiliser with a boxed warning for liver failure, and its interaction list includes an antibiotic that can strip the drug from the blood in days.
Significant findings
DEPAKOTE (divalproex sodium) prescribing information (AbbVie, April 2026), Drug Interactions summary: "Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dosage adjustment are indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn". "Aspirin, carbapenem antibiotics, estrogen-containing hormonal contraceptives, methotrexate: Monitoring of valproate concentrations is recommended".
On what valproate does to others: "Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g., diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement". With amitriptyline, a single dose in volunteers on valproate showed "a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline."
Two psychiatric combinations get their own sections. 7.3: "Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy", and with hypothermia "in patients who have tolerated either drug alone." 7.4: "Concomitant administration of valproate and cannabidiol has been associated with an increased risk of ALT and/or AST elevation. This has been manageable by dose reduction or, in more severe cases, by discontinuation of one or both drugs. Liver function, including serum transaminase and total bilirubin levels, should be monitored during concomitant treatment".
Worth asking
The carbapenem interaction is the one to know by name: meropenem, imipenem and ertapenem are hospital antibiotics, and the Tobin 2009 row in this wave shows what happens to the valproate level when one is started. The cannabidiol interaction reaches beyond prescriptions to over-the-counter CBD products, which contain the same molecule. If you take valproate and use CBD, that is worth telling the prescriber, and asking whether liver enzymes are being checked.
Source
DEPAKOTE (divalproex sodium) delayed-release tablets: FDA-approved prescribing information, Drug Interactions 7.1 to 7.4 — AbbVie Inc.; US Food and Drug Administration (2026)
Regulator or national health body
How this was scored
- Study design
- Regulatory safety determination
- Funding
- Industry funded
- Published in
- Regulator or national health body
- Sample size
- not recorded
- Preregistered
- not recorded
- Conflicts disclosed
- not recorded
- Independent of proponent
- not recorded
- Retracted
- No
Read the full scoring rubric, including what it can't tell you.
Published September 21, 2026.
Questions
How strong is the evidence behind this?
veisund rates this source "moderate evidence". Reasonable evidence with real limitations. It scores 57 out of 100 on our published rubric. One caveat travels with that badge: The cannabidiol finding comes from trials of prescription-strength cannabidiol; whether typical over-the-counter CBD doses reach the same effect is not stated in the label and was not read. The score is calculated from recorded facts about the source — study design, funding, publication venue, sample size, preregistration — not typed in by an editor.
What is the source for this?
DEPAKOTE (divalproex sodium) delayed-release tablets: FDA-approved prescribing information, Drug Interactions 7.1 to 7.4 — AbbVie Inc.; US Food and Drug Administration (2026). Published in: Regulator or national health body. The full source is linked on this page so you can read it yourself.
Who paid for this research, and does that matter?
Study design: Regulatory safety determination. Funding: Industry funded. Independence from the proponent is not recorded. Industry sponsorship is one of the most reliably measured biases in medicine, which is why funding carries real weight in the score rather than sitting in a footnote.
Is this medical advice?
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.