Drug & supplement interaction

Lithium + Amitriptyline, Perphenazine

Amitriptyline, Perphenazine brand names: Triavil, Etrafon, Etrafon-A, Etrafon-Forte.

Major Interaction
Medically reviewed by · Updated September 2026
The bottom line Major

Amitriptyline, Perphenazine falls into 3 drug categories that Lithium can interact with; the most serious is rated major. Theoretically, taking lithium supplements with serotonergic drugs might both mask and increase the risk of serotonin syndrome.

Read the full interaction report
SeverityMajor
LikelihoodProbable
Interactions3
EvidenceD
What do Severity, Likelihood & Evidence mean?
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Interaction report

Lithium and Amitriptyline, Perphenazine

These two interact in 3 distinct ways. Each one is explained separately below.

Why Are There 3 Interactions?

Lithium interacts with whole categories of medication. Amitriptyline, Perphenazine falls into 3 of those categories, so it can interact with Lithium in 3 different ways. We’ve listed each one below — your overall risk is driven by the most serious of them (Major).

Major

SEROTONERGIC DRUGS

1 of 3

Why this applies to Amitriptyline, Perphenazine

Amitriptyline, Perphenazine falls under SEROTONERGIC DRUGS — the group Lithium interacts with.

Theoretically, taking lithium supplements with serotonergic drugs might both mask and increase the risk of serotonin syndrome.
In a case report, a 67-year-old female with depression and bipolar disorder using lithium in combination with selective serotonin reuptake inhibitors (SSRIs) and other medications developed serotonin syndrome with symptoms of deep tendon hyperreflexia, muscle rigidity, tremor, and hyperthermia. However, agitation, one classical symptom of serotonin syndrome, was lacking. This was thought to be due to masking by lithium toxicity. Lithium can increase serotonin levels, thus, combining serotonergic drugs with lithium might increase the risk of serotonergic side effects including serotonin syndrome and cerebral vasoconstrictive disorders. It is unclear if this interaction would occur with the smaller doses found in lithium supplements.
Severity Major Likelihood Probable Evidence D

Interaction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports..

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

This combination pill pairs amitriptyline, an antidepressant that raises serotonin, with perphenazine, an older antipsychotic. Lithium also nudges serotonin activity upward. So stacking a lithium supplement on top of amitriptyline could, in theory, push serotonin too high and raise the risk of serotonin syndrome, which can show up as tremor, muscle stiffness, overactive reflexes, sweating, fast heartbeat, and feeling overheated.

One tricky point: lithium can actually hide some warning signs (like agitation), so trouble may be harder to spot. This concern is largely theoretical and based on prescription-strength lithium, not the tiny doses in supplements, but it is rated as serious. Please don't add any lithium product without first checking with your pharmacist or doctor.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Martindale W. Martindale the Extra Pharmacopoeia. Pharmaceutical Press, 1999.
  2. McEvoy GK, ed. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists, 1998.
  3. Landa E, Wagner S, Makkar A, Liu A, Jung D. An atypical presentation of serotonin syndrome. Cureus. 2021;13(2):e13377. PubMed
Moderate

ANTIPSYCHOTIC DRUGS

2 of 3

Amitriptyline, Perphenazine also falls under ANTIPSYCHOTIC DRUGS.

Theoretically, taking lithium supplements with antipsychotic drugs might increase the risk of encephalopathic syndrome.
Encephalopathic syndrome has been reported in multiple patients taking prescription lithium and antipsychotics concomitantly. Symptoms have included weakness and lethargy, fever, confusion, and extrapyramidal symptoms. In some patients, resulting brain damage was irreversible. Although there is no established causal relationship between these symptoms and the combination of lithium and antipsychotic medications, there is a theoretical relationship. It is unclear if this interaction would occur with the smaller doses found in lithium supplements.
Severity Moderate Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the deal with this combo. Your medication is a two-in-one: amitriptyline (an older antidepressant) plus perphenazine, which is an antipsychotic. Because perphenazine sits in the antipsychotic family, it falls under a long-noted concern when paired with lithium. In some people taking prescription lithium alongside antipsychotics, doctors have reported a rare reaction called encephalopathic syndrome, with symptoms like unusual weakness, sluggishness, fever, confusion, and movement problems (stiffness, tremor, restlessness). In a few cases the effects didn't fully reverse.

I want to be honest about the evidence here: this is theoretical and based mostly on scattered case reports, not a proven cause-and-effect. It's also unclear whether the low amounts in lithium supplements (like lithium orotate) carry the same risk. Still, given the stakes, please don't pair these on your own. Talk with your pharmacist or doctor first.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017812s028,018421s027lbl.pdf. Accessed Nov. 21, 2018
Moderate

PHENOTHIAZINES

3 of 3

Amitriptyline, Perphenazine also falls under PHENOTHIAZINES.

Theoretically, taking lithium supplements with phenothiazines might decrease the levels and clinical effects of phenothiazines.
Concomitant use of lithium with phenothiazines might reduce lithium concentrations. Lithium might also reduce phenothiazine concentrations, making the pharmacokinetic effect unpredictable. It is unclear if these interactions would occur with the smaller doses found in lithium supplements.
Severity Moderate Likelihood Probable Evidence D

Interaction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports..

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Your medication is a combo pill: amitriptyline (an older antidepressant) plus perphenazine (a phenothiazine antipsychotic). When lithium and a phenothiazine are taken together, the theory is that each may lower the other's blood levels, so the effects become hard to predict. For the perphenazine part, that could mean less control of the symptoms it's meant to treat, and the lithium side could swing too.

I want to be honest with you: this is a theoretical concern based on how the drugs behave, not something proven in solid studies. It's also unclear whether the tiny amounts in lithium supplements like lithium orotate matter at all. Still, because both drugs are heavy hitters, please loop in your pharmacist or doctor before combining them rather than guessing.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Martindale W. Martindale the Extra Pharmacopoeia. Pharmaceutical Press, 1999.
  2. McEvoy GK, ed. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists, 1998.

What These Ratings Mean

Every interaction above is graded three ways — here’s the key to each label.

Severity how clinically significant the interaction is
Major

Clinically significant. Avoid the combination, or use only under close professional supervision.

Moderate

Usually worth avoiding or managing — may need monitoring, a dose change, or timing apart.

Minor

Generally not serious. Be aware of it and mention it to your pharmacist.

Likelihood how strong the evidence is that the interaction actually happens in people
  • LikelyWell-controlled human studies have demonstrated the likely existence of this interaction.
  • ProbableInteraction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports.
  • PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.
  • UnlikelyInteraction has been demonstrated in animal or in lab research but has been shown not to occur in humans.
Evidence the quality of the studies behind the rating (graded A–D)
  • AHigh-quality meta-analysis (quantitative systematic review).
  • BCase-control study.
  • CConsensus.
  • DAnecdotal evidence.

These ratings are for information only. Never start, stop, or otherwise change your therapy before speaking with your provider.

Keep it in perspective

Lithium Also Interacts With Other Medications

Lithium has 258 major, 256 moderate known drug interactions in our database — the Amitriptyline, Perphenazine one above is among them. If you take anything else, check it against the full list below.

Major 258 Moderate 256 No known interaction 2,316 (incl. Amitriptyline, Perphenazine)
Taking anything else?

Check Another of Your Medications Against Lithium

Covers the 2,830 medications we’ve checked against Lithium. Pick one to open its full report.

From our Q&A

Questions About Lithium or Amitriptyline, Perphenazine

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers Lithium or Amitriptyline, Perphenazine, not necessarily both, but if one is close to what you were about to ask it will usually go further than a database entry can:

Not quite your question? Ask our pharmacists directly — it is free, there is no account required, and answers usually come back within 24 hours.

Everything else you take

See Every Supplement That Interacts With Amitriptyline, Perphenazine

This page covers Lithium only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Amitriptyline, Perphenazine page lists 311 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: 1,4-butanediol (major), Activated Charcoal (major), American Hellebore (major), Arsenic (major) and Beer (major).

By severity: 19 major · 235 moderate · 57 minor.

From our pharmacist’s overview on the Amitriptyline, Perphenazine page

“Alcohol is the risk I'd flag first for anyone taking amitriptyline with perphenazine (Triavil, Etrafon). Beer and wine both carry major ratings here, and 78 of the 311 ingredients on file deepen the drowsiness this antidepressant and antipsychotic combination already causes, sometimes to the point of slowed breathing.”

Reviewed by 2 · Jul 18, 2026

Open the Amitriptyline, Perphenazine interaction page

One more smart check

Taking Lithium as Part of a Dietary Supplement Product? Check It for Interactions

We hold 330 real supplement products containing Lithium, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Lithium. Your product may carry other ingredients that interact with Amitriptyline, Perphenazine too, on top of Lithium — and those would not show on this page. Find your product and we’ll check every ingredient on its label:

How much people look this up

Where Lithium and Amitriptyline, Perphenazine Sit Against Everything Else

Out of every supplement and medication people look up on HelloPharmacist, here is where these two land this week — and which way each has been moving.

Supplement Lithium
Top 25%

#257 of 1,452 supplements looked up here in the last 7 days

29 days ago today
Medication Amitriptyline, Perphenazine
Top half

#1,295 of 2,830 medications looked up here in the last 7 days

29 days ago today

Position among everything looked up on this site, not a measure of how commonly either one is used or how important it is. A supplement can climb this list because of a news story. It counts every request to the page, automated ones included, and nothing here identifies anyone.

Supplement

About Lithium

What is Lithium?

Lithium
  • Mood support
  • Bipolar disorder (prescription)
  • Healthy mental function
  • Irritability or stress
  • Sleep support

Lithium is a naturally occurring metal that, in prescription form (lithium carbonate or citrate), is an FDA-approved, well-proven treatment for bipolar disorder. Low-dose supplement forms like lithium orotate are sold for mood support, but there is very little reliable evidence that they work, and even small amounts of lithium can be risky for some people. Always talk to a pharmacist or doctor before taking any lithium product.

Read the full Lithium monograph & all interactions
Keep checking

Other Drugs & Lithium

Browse every other medication we’ve checked against Lithium — both the ones with a known interaction and the ones without. Select any drug for the full detail.

258Major
256Moderate
0Minor
2,315No known interaction
258 Major 256 Moderate 2,315 No interaction
Major

258 interactions

Showing 60 of 258 major interactions — see all 258 on the Lithium page.

Moderate

256 interactions

Showing 60 of 256 moderate interactions — see all 256 on the Lithium page.

No interaction 2,315 drugs checked — show the list

We also checked Lithium against these medications and found no known interaction in our sources. Open any page to confirm.

Showing the 60 most looked-up of 2,315 medications checked with no known interaction — see the full Lithium list.

See the full Lithium interactions page
See every supplement checked against Amitriptyline, Perphenazine, ranked by severity
Sources

Sources & How We Checked

Interaction details are evidence-graded and sourced from the Natural Medicines database. The medication overview comes from MedlinePlus.

Content is written and reviewed by licensed HelloPharmacist pharmacists. See our data sources and editorial standards for how this information is built and checked.

Parts of this content are provided by the Therapeutic Research Center, LLC.

DISCLAIMER: Currently this does not check for drug-drug interactions. This is not an all-inclusive comprehensive list of potential interactions and is for informational purposes only. Not all interactions are known or well-reported in the scientific literature, and new interactions are continually being reported. Input is needed from a qualified healthcare provider including a pharmacist before starting any therapy. Application of clinical judgment is necessary.

© 2021 Therapeutic Research Center, LLC

Keep exploring
Lithium monograph › Uses, safety, and every drug interaction in one place Amitriptyline, Perphenazine supplement interactions › Every supplement checked against Amitriptyline, Perphenazine, ranked by severity Supplement interaction checker › Check any supplement or product against your medications Browse medications A–Z › Every drug we've checked against herbs & supplements Ask a pharmacist › Free, personal answer from our licensed team
Pharmacist Counseling Corner

Taking Lithium and Amitriptyline, Perphenazine Together: Common Questions

Can you take Lithium with Amitriptyline, Perphenazine?
This is rated a major interaction, so the combination is best avoided unless your doctor or pharmacist has specifically told you otherwise. Read the full details on this page and confirm with your pharmacist before combining them.
Why are there 3 interactions listed for Lithium and Amitriptyline, Perphenazine?
Amitriptyline, Perphenazine belongs to more than one drug category, and Lithium interacts with each of those categories a little differently. We list every one so nothing is missed — your overall risk is driven by the most serious of them.
How serious is the Lithium and Amitriptyline, Perphenazine interaction?
We rate it Major. This is a clinically significant combination that is generally best avoided, or used only under the direct supervision of your physician or pharmacist.

Written and reviewed by the HelloPharmacist editorial staff. Our editorial policy

Still Have a Question About Amitriptyline, Perphenazine and Lithium?

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This information is for education only and is not a substitute for professional medical advice. Always check with your pharmacist or doctor before starting, stopping, or combining supplements and medications.