Nortriptyline

What Does Nortriptyline Do?

Nortriptyline is an antidepressant primarily prescribed for major depressive disorder. It also has off-label applications for conditions such as chronic pain, irritable bowel syndrome, post-herpetic neuralgia, panic disorders, and smoking cessation. 

How Does Nortriptyline Work? (the complicated stuff!)

Nortriptyline works by inhibiting the reuptake of serotonin and norepinephrine at neuronal cell membranes, leading to increased levels of these neurotransmitters in the synaptic cleft. This enhanced neurotransmission contributes to its antidepressant effects, alleviating symptoms of major depressive disorder. Additionally, nortriptyline exhibits antimuscarinic effects through its interaction with acetylcholine receptors, which can result in side effects such as dry mouth and constipation.

Drug Type and Category of Nortriptyline

Drug Type:

• Antidepressant

Category:

• Tricyclic Antidepressant (TCA)

What dosage of Nortriptyline should you be taking?

NICE Guidelines ¹

For Depression:

• Adults: The typical starting dose is 25 mg taken three to four times daily. Alternatively, the total daily dose may be administered once daily. The dosage may be gradually increased as needed, but it usually does not exceed 150 mg per day.
• Elderly Patients: Due to increased sensitivity, older adults often start at lower doses, with a typical range of 30 to 50 mg per day, either in divided doses or as a single daily dose.

For Neuropathic Pain:

• Adults: Treatment typically begins with 10 mg once daily, usually taken at night to minimise potential drowsiness. If necessary, the dose can be gradually increased up to a maximum of 75 mg daily, under the supervision of a healthcare professional.

What are the side-effects of Nortriptyline?

Common Side Effects (May affect up to 1 in 10 people):

• Dry mouth
• Drowsiness or fatigue
• Dizziness or lightheadedness
• Constipation
• Blurred vision
• Increased appetite or weight gain
• Sweating
• Nausea

Less Common Side Effects (May affect fewer people):

• Difficulty urinating
• Heart palpitations or irregular heartbeat (e.g., tachycardia)
• Low blood pressure upon standing (postural hypotension)
• Mood changes, such as anxiety or irritability
• Confusion, especially in older adults
• Tremors or shakiness
• Sensitivity to sunlight

Serious Side Effects (Require immediate medical attention):

• Severe allergic reaction:
• Rash, itching, swelling (especially of the face or throat)
• Difficulty breathing
• Signs of serotonin syndrome (rare but serious):
• Agitation or restlessness
• Hallucinations
• Rapid heart rate
• High blood pressure
• Muscle rigidity
• Seizures
• Jaundice (yellowing of the skin or eyes)
• Worsening depression or suicidal thoughts
• Severe confusion or hallucinations

Long-Term Risks:

• Cardiovascular effects: Prolonged use may lead to arrhythmias, especially in individuals with pre-existing heart conditions.
• Dependence or withdrawal symptoms: Discontinuing abruptly can cause withdrawal effects like nausea, headache, or mood disturbances.

Interactions

1. Medications That May Interact with Nortriptyline

Antidepressants:

• Other Tricyclic Antidepressants (TCAs): Increased risk of side effects like drowsiness and heart rhythm problems.
• Monoamine Oxidase Inhibitors (MAOIs): Severe interactions, including serotonin syndrome, high blood pressure, or hyperthermia. Avoid using within 14 days of each other.
• Selective Serotonin Reuptake Inhibitors (SSRIs): Increased risk of serotonin syndrome or side effects. Examples: fluoxetine, sertraline.
• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Similar risks to SSRIs.

Central Nervous System Depressants:

• Alcohol: Enhances drowsiness and dizziness, increasing the risk of accidents.
• Benzodiazepines or Sedatives: Potentiates sedative effects, leading to excessive drowsiness or respiratory depression.

Anticholinergic Drugs:

• Medications for Overactive Bladder (e.g., oxybutynin) or Parkinson’s Disease (e.g., benztropine): Exacerbates side effects like dry mouth, constipation, or urinary retention.

 Medications Affecting Heart Rhythm:

• Antiarrhythmic drugs (e.g., quinidine): Increased risk of heart arrhythmias.
• Drugs that prolong QT interval (e.g., amiodarone, sotalol): Potentially dangerous heart rhythm abnormalities.

Blood Pressure Medications:

• Clonidine or Methyldopa: Decreased effectiveness of these drugs.
• Beta-blockers: Increased risk of blood pressure irregularities.

2. Substances That May Interact with Nortriptyline

 Alcohol:

• Enhances sedative effects, leading to increased drowsiness, dizziness, and risk of overdose.

Tobacco or Smoking:

• May reduce the effectiveness of nortriptyline by increasing its metabolism in the liver.

St. John’s Wort (Herbal Supplement):

• Increased risk of serotonin syndrome.

3. Diseases/Conditions That Interact with Nortriptyline

• Heart Conditions: Increases the risk of arrhythmias, tachycardia, or prolonged QT interval.
• Liver Disease: Slower metabolism, leading to higher drug levels and toxicity.
• Glaucoma: Worsens symptoms due to its anticholinergic effects.
• Urinary Retention or Prostate Enlargement: Exacerbates urinary issues.
• Seizure Disorders: Lowers seizure threshold, increasing risk.

4. Enzyme Interactions (CYP450 System)

Nortriptyline is metabolised primarily by the CYP2D6 enzyme. Drugs that inhibit or induce this enzyme can affect nortriptyline levels:

• CYP2D6 Inhibitors (e.g., fluoxetine, paroxetine): Increase nortriptyline levels, heightening side effects.
• CYP2D6 Inducers (e.g., rifampin): Decrease effectiveness of nortriptyline.

5. Avoid Combining with:

• Amphetamines or Stimulants: Increased risk of cardiovascular effects.
• Ephedrine or Pseudoephedrine (in cold medicines): Exacerbates blood pressure and heart rhythm issues.

Natural Alternatives to Nortriptyline

Do not swap your medication for alternative treatment options without thoroughly discussing the pro’s and con’s with your GP or consultant. 

1. St. John’s Wort

• Use: A herbal remedy often used for mild to moderate depression.
• Mechanism: Contains hypericin and hyperforin, which may affect serotonin, dopamine, and norepinephrine levels².
• Note: May interact with other medications (e.g., antidepressants, birth control)².

2. Omega-3 Fatty Acids

• Use: Effective in managing depression and reducing inflammation associated with chronic pain.
• Mechanism: Regulates neurotransmitters like serotonin and supports brain health³.
• Sources: Fish oil, flaxseed, and walnuts³.

3. Saffron (Crocus sativus)

• Use: Shown to improve mood and reduce symptoms of depression.
• Mechanism: May modulate serotonin activity in the brain⁴.
• Note: Studies suggest doses of 30 mg per day are effective⁴.

4. SAMe (S-Adenosyl-L-Methionine)

• Use: A naturally occurring compound that supports neurotransmitter metabolism.
• Mechanism: Enhances serotonin, norepinephrine, and dopamine levels⁵.
• Note: May be especially helpful for depression⁵.

5. Turmeric (Curcumin)

• Use: Reduces symptoms of depression and chronic pain.
• Mechanism: Anti-inflammatory properties and modulation of serotonin and dopamine⁶.
• Note: Best absorbed when combined with black pepper (piperine)⁶.

6. Lavender

• Use: Reduces anxiety, depression, and pain.
• Mechanism: Acts on the nervous system to promote relaxation and balance mood⁷.
• Forms: Essential oil (aromatherapy), oral supplements⁷.

7. Magnesium

• Use: Helps with anxiety, depression, and nerve pain.
• Mechanism: Regulates the hypothalamic-pituitary-adrenal (HPA) axis and neurotransmitter activity⁸.
• Sources: Leafy greens, nuts, seeds, and supplements⁸.

8. Valerian Root

• Use: Supports sleep and reduces anxiety, which may indirectly improve mood.
• Mechanism: Enhances GABA (gamma-aminobutyric acid) activity in the brain⁹.
• Note: Often used in combination with other natural remedies⁹.

9. Acupuncture

• Use: Proven to alleviate chronic pain and some symptoms of depression.
• Mechanism: Stimulates endorphin release and modulates serotonin levels¹⁰.

10. Yoga and Mindfulness-Based Stress Reduction (MBSR)

• Use: Improves symptoms of anxiety, depression, and pain.
• Mechanism: Balances stress hormones and increases relaxation¹¹.
• Evidence: Studies show consistent mood improvement with regular practice¹¹.

Interesting facts about Nortriptyline

Studies have shown that nortriptyline can help people quit smoking, especially in combination with nicotine replacement therapy. It reduces withdrawal symptoms and cravings.

It is considered a "cleaner" tricyclic antidepressant with less sedative and anticholinergic activity than amitriptyline, making it better tolerated in some patients, especially the elderly.

Nortriptyline is the active metabolite of amitriptyline, another tricyclic antidepressant. This means the body metabolises amitriptyline into nortriptyline to exert its therapeutic effects.

Disclaimer

This article is generated for informational purposes only. It was created in January 2025. Medications and medical guidance can change over time. Therefore, it is essential to consult with your general practitioner or healthcare provider before making any decisions regarding medications or treatment plans. Your GP can provide personalised advice based on your specific health needs and conditions.

References

1. https://bnf.nice.org.uk/drugs/nortriptyline
2. National Center for Complementary and Integrative Health, St. John’s Wort and Depression, 2023, https://www.nccih.nih.gov [accessed 27 January 2025].
3. American Psychiatric Association, Omega-3s and Mental Health, 2022, https://www.psychiatry.org [accessed 27 January 2025].
4. Phytotherapy Research, ‘Saffron for Depression: A Review of Clinical Evidence’, Phytotherapy Research, 36.5 (2022), 1201-1210, doi:10.1002/ptr.7345.
5. Cochrane Database of Systematic Reviews, ‘SAMe for Depression’, Cochrane Database of Systematic Reviews, 2021, doi:10.1002/14651858.CD000366.
6. Journal of Affective Disorders, ‘Curcumin in Mental Health: Potential Mechanisms’, Journal of Affective Disorders, 278 (2021), 164-171, doi:10.1016/j.jad.2020.07.051.
7. Frontiers in Psychology, ‘Lavender in Anxiety and Depression’, Frontiers in Psychology, 12 (2023), 1842, doi:10.3389/fpsyg.2023.01074.
8. Nutrition Neuroscience, ‘Magnesium in Depression’, Nutrition Neuroscience, 24.3 (2020), 163-172, doi:10.1080/1028415X.2019.1685052.
9. Complementary Therapies in Medicine, ‘Valerian Root: Efficacy in Sleep and Anxiety Disorders’, Complementary Therapies in Medicine, 55 (2022), 102573, doi:10.1016/j.ctim.2022.102573.
10.  Pain Management Research, ‘Acupuncture and Pain Relief’, Pain Management Research, 9.4 (2022), 215-225, doi:10.1177/2050324521103056.
11.  JAMA Psychiatry, ‘Yoga and MBSR for Mental Health’, JAMA Psychiatry, 79.1 (2022), 14-20, doi:10.1001/jamapsychiatry.2021.2683.