Amitriptyline

Is amitriptyline safe?

At the low doses most people now take it for, yes, for most adults: drowsiness and a dry mouth are the usual price. The real danger is overdose. Amitriptyline is a tricyclic antidepressant first approved in the US in 1961. It is now used less often for depression, and many people take 10 to 50 mg a night for nerve pain, migraine prevention, tension headaches or irritable bowel syndrome. It is not addictive.

What sets it apart from modern antidepressants is how little it takes to cause serious poisoning. The UK label puts severe toxicity at 750 mg in an adult, which is 30 tablets of 25 mg. We score it 52, well below duloxetine (66) and mirtazapine (65), mostly because of that narrow margin and its effect on the heart. For someone on 10 mg for headaches with no heart problems, the day-to-day risk is much lower than the score suggests.

Low dose for pain and migraine vs depression doses

The same drug is used in two very different ways:

The pain-relieving effect does not depend on the antidepressant effect, and the UK label says it normally appears after two to four weeks. The 2023 ATLANTIS trial, with 463 patients in English general practice, found that low, self-titrated doses improved irritable bowel symptoms over six months; 13% stopped for side effects against 9% on placebo. At these doses serious harm is uncommon. At depression doses, side effects and heart effects become much more likely, which is one reason sertraline and other SSRIs replaced it.

Side effects

Amitriptyline blocks the reuptake of serotonin and noradrenaline, and the UK label describes marked anticholinergic and sedative effects from its action on acetylcholine and histamine receptors. That explains the side effects the UK label lists as very common (more than 1 in 10): drowsiness, dry mouth, constipation, nausea, blurred near vision, a fast heart rate or palpitations, dizziness when standing up, sweating, weight gain, tremor and headache.

Most ease after a few weeks, and taking it in the evening turns the drowsiness into a benefit for some. The atropine-like effects matter more in some people: it can trigger urinary retention in men with an enlarged prostate and acute glaucoma in people with narrow angles. Older people are more prone to confusion, falls and delirium. Rare serious reactions include seizures, 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 the skin reaction DRESS.

Overdose: the main danger

Tricyclic antidepressants are the most dangerous common antidepressants in overdose. They cause seizures, coma, low blood pressure and heart rhythm problems that can develop quickly, and children are especially vulnerable. In a study of England and Wales from 2000 to 2006, tricyclics had a case fatality ratio of 13.8, against 0.5 for SSRIs and 2.5 for venlafaxine. Within the tricyclics, dosulepin and doxepin were each about 2.7 and 2.6 times as toxic as amitriptyline.

In 2024 amitriptyline was mentioned on 171 drug-poisoning death certificates in England and Wales, and 38 of those involved no other drug, more than any other antidepressant. Alcohol was involved in 40. A month's supply of 25 mg tablets is close to the toxic range for an adult, which is why prescribers often give small quantities.

Treat any overdose as an emergency, even if the person seems well, because symptoms can appear suddenly. In the US call 911 and Poison Help on 1-800-222-1222; in the UK call 999.

Interactions

Amitriptyline is 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 and CYP2C19. The US label says tricyclic levels can be up to eight times higher in people whose CYP2D6 works poorly, and that CYP2D6 blockers have a similar effect, which can turn a stable dose toxic; fluoxetine, paroxetine, bupropion and quinidine are strong examples. It is 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 with MAOIs. The UK label warns against combining it with other QT-prolongingQT prolongationA delay in the heart's electrical recovery between beats, seen on an ECG. Some medicines cause it, and in rare cases it leads to a serious heart rhythm problem.More in the glossary drugs, anticholinergic medicines, fluconazole, decongestants such as phenylephrine, and tramadol, which raises seizure and 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 risk. Alcohol and other sedatives add to drowsiness.

Who should be careful

Talk to your doctor or pharmacist before starting amitriptyline, or adding anything to it, if you:

• have heart disease, a recent heart attack, heart block or a long QT intervalQT prolongationA delay in the heart's electrical recovery between beats, seen on an ECG. Some medicines cause it, and in rare cases it leads to a serious heart rhythm problem.More in the glossary
• are over 65 or have had falls or confusion
• have epilepsy, glaucoma, an enlarged prostate or severe liver disease
• take another antidepressant, tramadol, an antipsychotic or a QT-prolonging drug
• drink heavily, or have had thoughts of self-harm
• have children in the home (store it locked away)

Stopping suddenly after long use can cause headache, malaise and poor sleep, so it is reduced over several weeks.

How we scored it

Track record (95) and dependence (82) are strong. The 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 (28) is the weakest factor and the main reason for the low score, followed by interactions (40) and the anticholinergic and heart side effects (48). A low score is not a reason to stop a medicine that is working; any change should be planned with your prescriber.