Duloxetine

Is duloxetine safe?

For most adults it is a reasonable choice, with more trade-offs than the first-choice SSRIs. Duloxetine, sold as Cymbalta, is a serotonin and noradrenaline reuptake inhibitor (SNRI). It treats depression and anxiety, and unlike most antidepressants it is also approved for long-term pain: diabetic nerve pain, fibromyalgia and chronic musculoskeletal pain. It was filled about 17.9 million times in the US in 2024.

It is not addictive, and an overdose of duloxetine alone is rarely life-threatening. Its weak points are side effects that make about one in twelve people stop, withdrawal symptoms after stopping, rare but serious liver injuryDrug-induced liver injuryLiver damage caused by a medicine, herbal product or supplement. It is usually rare and unpredictable, but it can be serious.More in the glossary and a long list of interactions. We score it 66, below sertraline (72) and above venlafaxine.

What are the side effects of duloxetine?

Most side effects come early and fade. In the label's pooled placebo-controlled trials across all approved adult uses (8,100 people on duloxetine, 5,655 on placebo):

In the depression trials, 8.4% stopped because of side effects against 4.6% on placebo. Sexual side effects are common with all serotonin drugs. On 15 October 2026 the MHRA said UK leaflets for duloxetine and other antidepressants will add the term "post-SSRI sexual dysfunction" (PSSD), because for some people symptoms continue after stopping.

The rarer serious risks include serotonin syndromeSerotonin syndromeA reaction caused by too much serotonin in the body, usually from combining medicines that raise it. Symptoms range from shivering to high fever.More in the glossary, bleeding (especially with aspirin, NSAIDs or warfarin), low blood sodium in older people, falls from a drop in blood pressure on standing, urinary retention, severe skin reactions, seizures and triggering mania in undiagnosed bipolar disorder.

The liver warning

This is where duloxetine differs from SSRIs. The label reports hepatitis and liver failure, sometimes fatal, with liver enzymes above 20 times normal. In placebo-controlled trials 1.25% of people on duloxetine had an ALT rise above three times the upper limit, against 0.45% on placebo, usually around two months in. Liver problems led 0.3% of trial patients to stop.

Because duloxetine and alcohol may together injure the liver, the label says it should not be prescribed to people with substantial alcohol use or chronic liver disease. Yellow skin or eyes, dark urine, itching or pain under the right ribs are reasons to call your doctor the same day.

The boxed warning on suicidal thoughts

Duloxetine carries the antidepressant class boxed warningBoxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary. In pooled short-term trials across antidepressants, there were 14 extra cases of suicidal thinking or behaviour per 1,000 patients under 18, and 5 extra per 1,000 aged 18 to 24; there was no increase after 24 and a reduction from 65. Watch closely in the first months and after dose changes, and contact the prescriber the same day about agitation, worsening mood or thoughts of self-harm. In the UK, the Samaritans are on 116 123.

Stopping duloxetine and withdrawal

Duloxetine has a half-life of about 12 hours, much shorter than fluoxetine's, so levels fall fast after a missed dose or an abrupt stop. In the label's trials, dizziness, headache, nausea, diarrhoea, pins and needles, irritability, vomiting, insomnia, anxiety, sweating and fatigue were more common after stopping duloxetine than after stopping placebo. A 2024 meta-analysis of 79 studies found that about 31% of people had at least one discontinuation symptom after stopping an antidepressant, against 17% after placebo; severe symptoms affected about 3%.

The capsules cannot be opened or split, so tapering needs lower-strength capsules and a plan. Do not stop on your own.

Overdose and interactions

Duloxetine is much less dangerous in overdose than older tricyclic antidepressants. In a 2022 series from two toxicology units of 64 overdoses of duloxetine alone (median 840 mg), none needed intubation or had an arrhythmia. About half had a fast heart rate or mildly raised blood pressure, six had moderate serotonin toxicitySerotonin syndromeA reaction caused by too much serotonin in the body, usually from combining medicines that raise it. Symptoms range from shivering to high fever.More in the glossary and one had a seizure. The label does report deaths, including one at 1,000 mg alone. Any overdose needs hospital assessment: in the US call Poison Help on 1-800-222-1222, in the UK call 111, or 999 if someone is drowsy or fitting.

The interactions that matter most:

• MAOI antidepressants, linezolid and IV methylene blue: contraindicatedContraindicationA situation in which a medicine should not be used, because the risk clearly outweighs any benefit, such as a known allergy to it.More in the glossary.
• Fluvoxamine raised duloxetine levels about 6-fold; ciprofloxacin and cimetidine also block its breakdown.
• Duloxetine raises levels of drugs cleared by CYP2D6CYP450 enzymesA family of liver enzymes that break down many medicines. When another drug or supplement speeds them up or slows them down, drug levels change.More in the glossary, including tricyclics, flecainide and thioridazine (avoid).
• Other serotonin drugs, including tramadol, triptans, other antidepressants and St John's wort.

Who should be careful

Talk to your doctor or pharmacist before starting duloxetine if you drink heavily or have liver disease, have severe kidney disease, take blood thinners, other antidepressants or pain medicines, have glaucoma, epilepsy, bipolar disorder or high blood pressure, are over 65 and prone to falls, or are pregnant. A lower score is not a reason to stop a medicine that is working; any change should be planned with your prescriber.

How we scored it

Track record (88) and overdose marginOverdose marginHow far a normal dose is from a harmful one. A wide margin means an accidental extra dose is unlikely to cause serious harm.More in the glossary (75) are the strongest factors. Dependence (72) is lower than for long-acting SSRIs because withdrawal symptoms are common. Interactions (52) and regulatory warnings (48) reflect the CYP1A2CYP450 enzymesA family of liver enzymes that break down many medicines. When another drug or supplement speeds them up or slows them down, drug levels change.More in the glossary and CYP2D6 interactions, the liver warning and the class boxed warningBoxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary.