Amitriptyline and Valproic Acid: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 2, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Amitriptyline
Valproic Acid
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
You've been prescribed amitriptyline (Elavil) along with valproic acid (Depakote or Depakene). Here's what that combination means. Valproic acid can slow down how your body clears amitriptyline, so more of the drug and its active form (nortriptyline) can build up in your blood. In one study, the combined levels went up by about 88%.
Higher levels can mean stronger side effects like drowsiness, dry mouth, constipation, dizziness, or a faster heartbeat. The good news is that this is very manageable. Your care team can check your amitriptyline levels and adjust your dose to keep you safe. If you notice new or stronger side effects, just let your doctor or pharmacist know.
Effect: Valproic acid increases exposure to amitriptyline and its active metabolite nortriptyline via reduced clearance (probable partial inhibition of CYP2D6-mediated metabolism). Neither drug is a prodrug, so this is a straightforward increase in tricyclic exposure and effect.
- Magnitude: Sum amitriptyline + nortriptyline serum concentration rose ~88% in a retrospective study; single-dose data showed ~21% decrease in amitriptyline clearance and ~34% decrease in nortriptyline net clearance.
- Evidence/onset: Probable; onset unspecified.
- Risk: Additive anticholinergic and cardiac (QT/conduction) TCA toxicity.
- Management: Dose cautiously, monitor amitriptyline/nortriptyline levels, and consider lowering the amitriptyline dose.
What happens
Increased amitriptyline exposure
Interaction Deep Dive
Taking amitriptyline together with valproic acid can markedly raise exposure to both amitriptyline and nortriptyline. A retrospective analysis found that adding valproic acid to amitriptyline produced an 88% rise in the mean combined serum concentration of amitriptyline plus nortriptyline compared with amitriptyline given by itself1. A separate study showed that a single 50 mg oral dose of amitriptyline given alongside valproate 500 mg twice daily led to a 21% reduction in the plasma clearance of amitriptyline and a 34% reduction in the net clearance of nortriptyline. During postmarketing experience, elevated amitriptyline concentrations have been reported on rare occasions when valproate was used with amitriptyline. Toxicity has rarely been linked to the combined use of valproate and amitriptyline2. When the two must be used together, dose with caution1. Track amitriptyline levels and think about reducing the amitriptyline dose when valproate is present2.
Why it happens (mechanism)
Reduced amitriptyline clearance; possible inhibition of CYP2D6-mediated metabolism by valproate
How to manage this interaction
Keep taking both medications exactly as prescribed unless your prescriber tells you otherwise. This combination is used, but it needs a little extra attention.
- Your care team may check your amitriptyline (and nortriptyline) blood levels to see how much has built up.
- Your amitriptyline dose may need to be adjusted and individualized by your team, often lowered, based on those levels and how you feel.
- Watch for stronger side effects: excess drowsiness, dry mouth, constipation, blurred vision, dizziness, or a racing heartbeat.
Tell your pharmacist or prescriber about any new or worsening symptoms so they can fine-tune your treatment.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) When a single 50 mg oral dose of amitriptyline was given to 15 healthy volunteers (10 men and 5 women) who were taking valproate (500 mg twice daily), the plasma clearance of amitriptyline fell by 21% and the net clearance of nortriptyline fell by 34%. Elevated amitriptyline concentrations have been reported infrequently during postmarketing experience when valproate was used together with amitriptyline. The combined use of valproate and amitriptyline has been rarely linked to toxicity 2.
b) In a retrospective analysis of therapeutic drug monitoring data, giving valproic acid together with amitriptyline, compared with matched controls receiving amitriptyline alone, significantly raised both amitriptyline and nortriptyline concentrations, by 59% (mean, 110.5 vs 69.7 nanograms(ng)/mL) and 123% (mean, 126.6 vs 56.7 ng/mL), respectively. With concurrent valproic acid, the mean combined serum concentration of amitriptyline plus nortriptyline rose by 88% (237.1 vs 126.4 ng/mL). After adjusting for dose, the differences in serum levels of amitriptyline, nortriptyline, and the combined total of nortriptyline and amitriptyline were also significantly higher with concurrent valproic acid. The metabolite to parent drug ratio (nortriptyline/amitriptyline) was lower during concurrent valproic acid use (0.865 vs 1.3), which is consistent with a possible mechanism of valproic acid inhibiting CYP2D6 1.
c) An open-label study of 15 healthy volunteers examined the pharmacokinetic interactions between divalproex sodium and amitriptyline. Participants received amitriptyline 50 mg alone and again two hours after taking nine doses of divalproex sodium 500 mg administered every 12 hours. Giving amitriptyline together with divalproex sodium produced a 17% rise in amitriptyline maximum concentration (Cmax) and a 31% rise in the amitriptyline area under the concentration-time curve (AUC). The time to maximum concentration (Tmax) for amitriptyline did not change during coadministration with divalproex sodium. For nortriptyline, the metabolite of amitriptyline, AUC rose by 55%, Cmax rose by 28%, and Tmax was unchanged. The authors proposed that divalproex sodium significantly alters the disposition of amitriptyline and nortriptyline, possibly by inhibiting hepatic metabolism 3.
d) Adding valpromide to a stable amitriptyline regimen may lead to a rise in antidepressant plasma levels. Twenty patients with major depressive illness (DSM - III criteria) were separated into two groups, one receiving amitriptyline alone and the other receiving both amitriptyline and valpromide. All patients took oral amitriptyline 125 mg once daily in the evening for 20 days. Only benzodiazepines (diazepam, lorazepam, bromazepam, clorazepate dipotassium), 5 to 30 mg/day, were also given. Ten patients additionally received 600 mg valpromide daily after 10 days of amitriptyline in order to prevent relapses and/or to reduce irritability and agitation. No statistically significant difference in amitriptyline and nortriptyline plasma levels was found on days 10 and 20, respectively, in the ten patients treated with amitriptyline 125 mg daily. In the 10 patients who received valpromide 600 mg, amitriptyline and nortriptyline plasma levels rose. The mean amitriptyline level rose significantly from 70.5 to 105.5 nanograms(ng)/mL, and the mean nortriptyline level rose significantly from 61 to 100.5 ng/mL. No significant relationship was found between the percentage increase in amitriptyline levels and the plasma level of valproic acid, the principal metabolite of valpromide. There was a significant linear relationship between the plasma levels of amitriptyline before and after valpromide (r equal to 0.94) and between the nortriptyline plasma levels before and after valpromide (r equal to 0.87). Tricyclic antidepressant plasma levels may rise above the therapeutic window after valpromide is added. Monitoring of tricyclic antidepressant plasma levels is advisable to manage this interaction 4.
Common questions
Can I take Amitriptyline and Valproic Acid together?
Valproic acid can raise amitriptyline levels (by roughly 88% in one study), so expect your care team to monitor levels and possibly lower your amitriptyline dose. Keep taking both as prescribed and report any stronger side effects. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Valproic Acid interaction?
It is rated moderate. Can be significant — usually manageable with monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Amitriptyline and Valproic Acid interaction managed?
Keep taking both medications exactly as prescribed unless your prescriber tells you otherwise. This combination is used, but it needs a little extra attention. Your care team may check your amitriptyline (and nortriptyline) blood levels to see how much has built up. Your amitriptyline dose may need to be adjusted and individualized by your team, often lowered, based on those levels and how you fee… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Amitriptyline or Valproic Acid need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there anything you'd monitor while I'm on both?
References (4)
- Unterecker S, Burger R, Hohage A, et al: Interaction of valproic acid and amitriptyline: analysis of therapeutic drug monitoring data under naturalistic conditions. J Clin Psychopharmacol 2013; 33(4):561-564. PubMed
- Product Information: Depakote oral delayed-release tablets, divalproex sodium oral delayed-release tablets. AbbVie Inc (per manufacturer), North Chicago, IL, 2023. DailyMed
- Wong SL, Cavanaugh J, Shi H, et al: Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics. Clin Pharmacol Ther 1996; 60:48-53. PubMed
- Vandel S, Bertschy G, Jounet J, et al: Valpromide increases the plasma concentrations of amitriptyline and its metabolite nortriptyline in depressive patients. Ther Drug Monit 1988; 10(4):386-389.
Keep reading about Amitriptyline
Keep reading about Valproic Acid
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