DangerousContraindicated
5-HTP
5-HTP can raise serotonin synthesis and add to levomilnacipran's serotonergic activity.
Recommendation: Avoid 5-HTP while taking levomilnacipran.
Levomilnacipran
Prescription ·Strong evidence ·Reviewed May 2026
Levomilnacipran is an extended-release SNRI approved for major depressive disorder in adults. Compared with many SNRIs it has prominent norepinephrine reuptake inhibition, so blood pressure, heart rate, urinary hesitation, and activation symptoms require attention. It carries the antidepressant boxed warning for suicidal thoughts and behaviors in pediatric and young adult patients.
What it's good for
The bottom line
Evidence rating strong. Most-documented uses: treatment of major depressive disorder in adults, improvement in depressed mood and low motivation, once-daily extended-release administration. 3 sources indexed (2005–2024), with 4 interaction records on file.
The science
How it works, mechanistically.
Core mechanism
Levomilnacipran inhibits reuptake of norepinephrine and serotonin, increasing monoaminergic signaling in CNS pathways involved in mood and motivation. It has greater norepinephrine than serotonin reuptake inhibition in vitro. It is metabolized partly by CYP3A4 and eliminated substantially by the kidney, so severe renal impairment and strong CYP3A4 inhibitors require dose limits.1,2
Class
Serotonin-norepinephrine reuptake inhibitor antidepressant
Dosing
Dosing & protocol.
Common range
Start 20 mg once daily for 2 days, then 40 mg once daily. Usual range is 40-120 mg once daily; do not exceed 80 mg once daily with strong CYP3A4 inhibitors.
Recommended form
Extended-release oral capsule swallowed whole once daily
Can be taken with or without food. Capsules should be swallowed whole and not opened, crushed, or chewed.3
Safety
Full safety detail.
Side effects
- Nausea
- Constipation
- Hyperhidrosis
- Increased heart rate
- Increased blood pressure
- Urinary hesitation or retention
- Erectile dysfunction or delayed ejaculation
- Serotonin syndrome with serotonergic agents
- Hyponatremia
- Bleeding risk
- Activation of mania or hypomania
Contraindications
Interactions
Interaction records.
DangerousContraindicated
L-Tryptophan
Supplemental L-Tryptophan increases serotonin precursor availability and may increase serotonin syndrome risk with levomilnacipran.
Recommendation: Avoid L-Tryptophan supplements during therapy.
DangerousContraindicated
St. John's Wort
St. John's Wort can increase serotonergic activity and can induce drug-metabolizing pathways.
Recommendation: Do not combine St. John's Wort with levomilnacipran.
ModerateCaution
Ginkgo Biloba
Levomilnacipran may increase bleeding risk, and ginkgo may add mild antiplatelet effects.
Recommendation: Use cautiously, particularly with anticoagulants, antiplatelet therapy, frequent NSAIDs, bleeding disorders, or upcoming procedures.
Sources
Sources, by evidence tier.
Numbered references. Citations throughout the page link here.
Reviews & position papers
2- 1Levomilnacipran extended release for the treatment of major depressive disorderNeeds reviewNo linkAsnis GM, D'Arcy J · Drugs of Today · 2015
Review summarizes pharmacology, efficacy, and noradrenergic adverse effects such as increased pulse and blood pressure.
- 2The serotonin syndromeNeeds reviewNo linkBoyer EW, Shannon M · New England Journal of Medicine · 2005
The review supports avoiding combinations of serotonergic drugs and supplements that increase serotonin production or signaling.
Reference material
1- 3FETZIMA (levomilnacipran) extended-release capsules, US Prescribing InformationNeeds reviewURLAllergan USA Inc. · DailyMed · 2024
Labeling describes MDD indication, titration, dose limits with strong CYP3A4 inhibitors, blood pressure and heart rate warnings, and MAOI contraindications.
Keep exploring
Deep dives & adjacent profiles.
This page is educational. Do not start, stop, or change a supplement or medication based on it without checking with a qualified healthcare professional.
Use this with your stack
Levomilnacipran in NutriStack.
Add it to your stack, see how it interacts with everything else you take, and get a Stack Score that updates the moment it does.