Amitriptyline

Amitriptyline is a pharmacologically diverse drug. Like other TCAs, it inhibits the reuptake of serotonin and noradrenaline, boosting the levels of these neurotransmitters in the brain. It also blocks several types of receptors, including adrenergic, muscarinic, and histaminic receptors (8, 9).

Interestingly, amitriptyline and related TCAs also show anti-inflammatory properties, which may contribute to their use in neuropathic pain and pain sensitisation. These properties are even being explored in conditions such as atherosclerosis (16, 1).

However, this complex pharmacology comes at a cost: a wide range of side effects, particularly affecting the heart and cognitive function—especially in older adults (8, 9).

Anticholinergic Effects and Brain Health

Many of amitriptyline’s side effects stem from its anticholinergic activity, which disrupts brain signalling and metabolism. This can lead to symptoms such as:

• Memory loss

• Confusion

• Delirium

• Increased risk of falls

• Higher likelihood of triggering or worsening dementia

The total effect of such medications on the body and brain is known as the anticholinergic burden (11, 12, 13).

Amitriptyline and Serotonin Syndrome Risk

Because it increases serotonin levels, amitriptyline can interact with other medications and supplements that raise serotonin—such as SSRIs, MAO inhibitors, tramadol, certain opioids, St. John’s Wort, and tryptophan—potentially leading to serotonin syndrome (17).

Why Anticholinergic Burden Matters—Especially in Older Adults

Anticholinergic burden is a critical consideration in geriatric medicine, as many older patients take multiple medications with anticholinergic properties. Healthcare professionals should be especially mindful of this when prescribing or reviewing medications.

Important insights about anticholinergic burden (12, 13, 11, 10, 14, 6):

• Multiple drugs contribute—even those with weaker effects or limited ability to cross the blood–brain barrier (e.g., some medications for urinary incontinence or IBS).

• Inflammatory stressors amplify the impact—hospitalisation, frailty, stress, and polypharmacy can all make symptoms worse.

• Duration matters—the longer the exposure, the more harmful the cumulative effect.

• Aging increases vulnerability—what may seem like “normal ageing” could actually be a masked side effect of medication.

• Even low doses of amitriptyline significantly contribute to the overall anticholinergic burden.

• Neuroprotective mechanisms in the brain are disrupted, potentially accelerating inflammation and neurodegeneration.

• Misdiagnosis risk is high—anticholinergic symptoms are sometimes mistaken for ageing or treated with additional drugs, creating a prescribing cascade.

Amitriptyline has very strong anticholinergic activity and is classified as Class 3 on the Anticholinergic Burden Scale—indicating a high risk of these effects (10).

Serotonin Syndrome

Serotonin syndrome is a potentially serious condition that can occur rapidly—often within 1 hour of a medication change or interaction (in about 30% of cases) or within 6 hours (in about 60% of cases) (17).

Symptoms may involve:

• Mental state changes: agitation, confusion, anxiety, hypomania, hypervigilance, seizures, or coma

• Muscle effects: tremors, poor coordination, rhythmic muscle jerks (myoclonus)

• Autonomic disturbances: fever (>40°C), sweating, diarrhoea, fast heart rate (tachycardia)

Not all symptoms are required for diagnosis. Serotonin syndrome may be mild but can be life-threatening—urgent medical attention is required.

Prolonged QT Interval

Among TCAs, amitriptyline carries the highest risk for causing a prolonged QT interval—a change in the heart's electrical rhythm that can lead to serious arrhythmias. TCAs are more likely to cause this than SSRIs (7).

Common Symptoms (15):

• Palpitations

• Light-headedness or fainting

• Weakness

• Seizures (in some cases)

Risk Factors (15):

• Female sex

• Older age

• Electrolyte imbalances (e.g., low potassium, magnesium, calcium)

• Use of multiple QT-prolonging drugs

• Diuretic use

• Heart disease or arrhythmias

• Liver or kidney dysfunction

• Underlying genetic predisposition (e.g., Long QT Syndrome)

If you experience symptoms of prolonged QT interval, seek immediate medical help.

Amitriptyline Overdose and Toxicity

Overdosing on amitriptyline can be dangerous and carries a relatively high risk of fatality (17). Symptoms may include:

• Dry mouth

• Coma (with varying severity)

• Low blood pressure

• Seizures

• Serious heart arrhythmias

• Dilated pupils

• Urinary retention

Amitriptyline vs. Other TCAs

Amitriptyline is one of the most potent TCAs in terms of:

• Muscarinic receptor blockade, contributing to its strong anticholinergic effects and higher risk of prolonged QT interval

• Histamine receptor blockade, which is associated with increased appetite and weight gain

Amitriptyline Side Effects

Amitriptyline’s side effects reflect its broad pharmacological activity. Below, we group the most common and clinically relevant side effects according to the drug’s mechanism of action (8).

Most Common Side Effects

These are frequently reported, especially at the beginning of treatment:

• Weight gain

• Constipation

• Dry mouth

• Dizziness

• Headache

• Drowsiness (somnolence)

Effects from Alpha-Adrenergic Receptor Blockade

Blocking alpha-adrenergic receptors can reduce blood pressure and increase sedation:

• Orthostatic hypotension (feeling faint when standing up)

• Dizziness

• Sedation

Anticholinergic Side Effects

Amitriptyline strongly blocks muscarinic (cholinergic) receptors, leading to symptoms often seen in medications with high anticholinergic burden:

• Blurred vision

• Dry mouth

• Urinary retention

• Fast heart rate (tachycardia)

• Acute angle-closure glaucoma

• Confusion

• Delirium

Histamine Receptor Blockade

This action contributes to increased appetite and sedation, especially at lower doses:

• Sedation

• Increased appetite

• Weight gain

• Confusion

• Delirium

Other Reported Side Effects

Amitriptyline may also cause:

• Suicidal thoughts or ideation (especially in younger patients)

• Increased risk of seizures

• Abnormal liver function tests

The activity of CYP2C19 and CYP2D6 enzymes varies between individuals due to genetic differences. These differences can significantly affect how your body responds to the drug:

• Poor metabolisers: If your genetic test shows reduced activity in either CYP2C19 or CYP2D6, you're at increased risk of side effects and drug accumulation. In such cases, clinical guidelines recommend:

  • Starting at 50% of the usual starting dose

  • Close therapeutic monitoring for adverse effects

• Ultrarapid metabolisers: If your body breaks down amitriptyline too quickly, the drug may not reach effective levels. In this case, switching to a different medication that is not metabolised by these enzymes may be recommended.

Related Medications:

Pharmacogenetic factors can influence the safety and effectiveness of other tricyclic antidepressants (TCAs), not just amitriptyline. Similar genetic considerations—especially involving CYP2C19 and CYP2D6—may apply to:

• Clomipramine

• Imipramine

• Nortriptyline

• Protriptyline

• Desipramine

If you're taking or considering one of these medications, a pharmacogenomic (PGx) test can help identify whether a different dose or alternative drug may be more suitable for your genetic profile.