Nortriptyline: Independent Evidence on Depression, Nerve Pain, Smoking & Risks

Table of contents

• Evidence summary
• What nortriptyline is
• How it works
• What it is prescribed for
• What works and what does not
• Benefits by claim
• Risks and all side effects
• All interactions
• Who should avoid nortriptyline
• Dosage and how to take it
• Follow the money: who makes it and who funded the evidence
• Related research
• Frequently asked questions
• Sources and funding notes

Evidence summary

Independent evidence and credibility scorecard

Independence tier: 1 = no money from anyone selling the product; 4 = seller-funded. Credibility: A (highest) to D.

What nortriptyline is

Nortriptyline is a tricyclic antidepressant (TCA), ATC code N06AA10. The UK product information describes it as "a tricyclic antidepressant with actions and uses similar to these of amitriptyline. It is the principal active metabolite of amitriptyline" (UK SmPC). In other words, when someone takes amitriptyline, their liver turns part of it into nortriptyline. Chemically it is a "secondary amine" tricyclic, while amitriptyline is a "tertiary amine". This difference matters for side effects and metabolism (CPIC).

History and brands: the first US approvals were Eli Lilly's Aventyl Hydrochloride capsules (NDA 014684) and an Aventyl oral solution (NDA 014685, now in Ranbaxy's name), both dated 6 November 1964 in FDA records. Pamelor capsules and solution followed in 1977 (NDA 018013 and 018012), now held by SpecGx LLC. All of these brand applications are listed as discontinued (Drugs@FDA; openFDA Drugs@FDA data, queried 26 September 2026). We could not verify from a primary source which company first discovered the molecule.

Status today: fully generic and prescription-only in both countries. In the UK it comes as 10 mg, 25 mg and 50 mg tablets and as a liquid (10 mg or 25 mg per 5 ml) (NHS). The UK medicines database lists tablets from several generic companies, including Blackrock, Brown & Burk, Flamingo, Glenmark, Viatris and Wockhardt (emc). In the US, openFDA lists five generic (ANDA) applications with active prescription status, from Teva, Taro, Dr. Reddy's, Rubicon Research and Pharmaceutical Associates (openFDA).

How it works

The US label is frank: "The mechanism of mood elevation by tricyclic antidepressants is at present unknown". It adds that nortriptyline "inhibits the activity of such diverse agents as histamine, 5-hydroxytryptamine, and acetylcholine" and "interferes with the transport, release, and storage of catecholamines" (FDA label). In practice, tricyclics block the reuptake of noradrenaline and serotonin. Secondary amines such as nortriptyline have "a greater noradrenergic effect", while tertiary amines such as amitriptyline have "a more pronounced serotonergic effect" (CPIC). The NHS explains the pain effect in plain terms: it changes "the way your nerves receive pain signals" (NHS).

Why it is gentler than amitriptyline: much of a tricyclic's everyday side-effect burden comes from blocking acetylcholine (muscarinic) receptors, which causes dry mouth, constipation, blurred vision, urinary retention and confusion. In human brain tissue studies, amitriptyline was the most potent muscarinic blocker among 22 antidepressant compounds tested (El-Fakahany & Richelson, Br J Pharmacol 1983). The Canadian CANMAT guideline states that "nortriptyline has the fewest anticholinergic and hypotensive adverse effects" among tricyclics (CANMAT 2023). "Fewest" is relative, though. Nortriptyline is still on the Beers list of strongly anticholinergic drugs (AGS Beers 2023).

How the body handles it: nortriptyline is broken down mainly by the liver enzyme CYP2D6. Amitriptyline also relies on CYP2C19 (CPIC). Blood levels vary widely between people. About 7–10% of white people are CYP2D6 "poor metabolisers", who can reach up to 8-fold higher blood exposure to a tricyclic on usual doses (FDA label). This is why nortriptyline, unlike most modern antidepressants, has a recognised therapeutic blood-level range of 50–150 ng/mL (UK SmPC). CANMAT notes that, unlike with newer antidepressants, blood levels "can be informative" for tricyclics (CANMAT 2023).

What it is prescribed for

Off-label means the prescriber takes responsibility for using the medicine outside its licence. It does not mean the use is unsafe or unsupported, but no regulator has formally judged the evidence for that use. The UK product information and the NHS page differ on use under 18, and we report both as published.

What works and what does not

Benefits by claim

Stopping smoking: the clearest independent evidence

The 2023 Cochrane review of antidepressants for smoking cessation included 124 studies (48,832 participants). It counted only trials with at least six months of follow-up and used the strictest abstinence measure each trial reported. Pooling six placebo-controlled trials gave a risk ratio of 2.03 (95% CI 1.48 to 2.78; 975 participants). In other words, people on nortriptyline were about twice as likely to have quit at six months or more. Removing the two trials at high risk of bias did not change the result. Bupropion, a licensed stop-smoking medicine, may be more effective (RR 1.30, 95% CI 0.93 to 1.82, in favour of bupropion), but that comparison is imprecise. The review describes nortriptyline as "the second most commonly tested medication for smoking cessation" and notes that it "is licensed for smoking cessation in New Zealand" (Hajizadeh et al., Cochrane 2023; full text).

The picture is less clear when nortriptyline is added to nicotine replacement therapy (NRT). Four trials gave RR 1.21 (95% CI 0.94 to 1.55; 1,644 participants) (Cochrane 2023). The largest was a pragmatic trial in 901 people at NHS stop-smoking clinics. At six months, 16% on nortriptyline plus NRT had stopped smoking, compared with 12% on placebo plus NRT (RR 1.34, 95% CI 0.97 to 1.86). Nortriptyline caused noticeably more dry mouth and constipation, but it also reduced depression and anxiety during the quit attempt (Aveyard et al., BMJ 2008). NICE's tobacco guideline lists cytisinicline, NRT, varenicline, bupropion and e-cigarettes, and does not mention nortriptyline (NICE NG209). In the UK, then, it is an off-label fallback rather than a standard option. For the licensed alternative, see our bupropion review.

Depression in later life: an NIH-funded landmark

Nortriptyline has been studied most closely in older adults. In a US National Institute of Mental Health-funded trial, 107 people aged over 59 who had recovered from recurrent major depression were randomised to four maintenance treatments. Nortriptyline was dosed to steady blood levels of 80–120 ng/mL. Over three years, depression returned in 20% on nortriptyline plus monthly interpersonal psychotherapy (IPT), 43% on nortriptyline alone, 64% on IPT plus placebo and 90% on placebo. All three active treatments beat placebo. The authors concluded that combined treatment "appears to be the optimal clinical strategy" (Reynolds et al., JAMA 1999). CANMAT's 2023 guideline still says that nortriptyline "has a good safety and efficacy profile in elderly and post-stroke depression populations". It also notes that lithium combined with nortriptyline was superior for preventing relapse after electroconvulsive therapy (CANMAT 2023).

Honest reading: this was a small single-centre trial, and people who had already done well on nortriptyline were selected to continue. It shows that nortriptyline can keep a responder well. It does not show that nortriptyline is better than modern alternatives. The Beers Criteria's advice to avoid it in older adults (below) has to be weighed against this evidence, and that is a decision for a specialist.

Depression in adults: works, but not in the big network analysis

Nortriptyline was not among the 21 drugs in the Cipriani 2018 network meta-analysis. That analysis included only the two tricyclics on the WHO essential medicines list, amitriptyline and clomipramine (Cipriani et al., Lancet 2018). The best modern head-to-head evidence is GENDEP, a European study of 811 adults with moderate-to-severe depression allocated to escitalopram or nortriptyline for 12 weeks. There was "no difference between escitalopram and nortriptyline on the three original scales". On symptom sub-dimensions, mood and cognitive symptoms improved more with escitalopram, and sleep, appetite and energy symptoms improved more with nortriptyline (Uher et al., BJPsych 2009). For tricyclics as a class in primary care, a Cochrane review found a response risk ratio of 1.24 (95% CI 1.11 to 1.38) against placebo, with a median NNT of 9. The number needed to harm, measured as stopping because of side effects, ranged from 4 to 30 for tricyclics and from 20 to 90 for SSRIs (Arroll et al., Cochrane 2009). The NHS summary is simple: nortriptyline "does not work any better or worse than other antidepressants" (NHS). A 2026 UK pilot trial in Parkinson's disease found a larger fall in PHQ-9 depression scores than with placebo (−3.4, 95% CI −5.75 to −0.95), but no difference on the BDI-II scale. It was too small to be conclusive (Schrag et al., 2026).

Nerve pain: common practice, thin evidence

The Cochrane review of nortriptyline for neuropathic pain found six studies with 310 participants, most of them small crossover trials lasting three to eight weeks. "No study provided first or second tier evidence for any outcome." The authors concluded that "we found little evidence to support the use of nortriptyline" and that "effective medicines with much greater supportive evidence are available, such as duloxetine and pregabalin" (Derry et al., Cochrane 2015). The 2025 NeuPSIG meta-analysis (313 trials) estimated a number needed to treat of 4.6 (95% CI 3.2–7.7) for tricyclics as a class, compared with 7.4 for SNRIs and 8.9 for gabapentinoids, and made a strong first-line recommendation for all three classes. It described treatment outcomes as "modest" (Soliman et al., Lancet Neurol 2025). Most of that class evidence comes from amitriptyline, not nortriptyline. An unconflicted 2024 meta-analysis of 14 studies found a pooled standardised mean difference of 0.43 (0.23–0.64) against placebo across pain types. Nortriptyline was not superior to placebo in fibromyalgia or knee osteoarthritis (Hashemzadeh et al., BMJ Open 2024). The NHS says nortriptyline "does not work any better or worse than other medicines for nerve pain" (NHS). For the more heavily studied alternatives, see our amitriptyline, duloxetine and pregabalin reviews.

Risks and all side effects

At pain doses, "side effects are usually milder and go away within a few days" (NHS). At depression doses, anticholinergic effects are common. In the smoking trials, dropouts because of treatment were about twice as common as on placebo (RR 1.99, 95% CI 1.18 to 3.36; 4 studies) (Cochrane 2023).

Boxed warning (FDA)

The Pamelor label carries the class boxed warning. Antidepressants "increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults" in short-term trials. There was no increase in adults over 24 and a reduction in those aged 65 and over. Compared with placebo, there were 14 additional cases per 1,000 patients under 18 and 5 additional per 1,000 aged 18–24. There was 1 fewer per 1,000 aged 25–64 and 6 fewer per 1,000 aged 65 and over. The label also says prescriptions "should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose" (FDA label).

Withdrawal (discontinuation) symptoms

The NHS says nortriptyline "is not addictive", but stopping suddenly can cause withdrawal effects: "sweating, feeling or being sick, feeling anxious, feeling weak, headache and difficulty falling asleep" (NHS). The US label lists nausea, headache and malaise after abrupt stopping and says these "are not indicative of addiction" (FDA label). CANMAT rates tricyclics as having a "moderate" risk of discontinuation symptoms, higher than fluoxetine and lower than paroxetine or venlafaxine (CANMAT 2023).

Overdose: why this drug needs extra care

The US label says: "Deaths may occur from overdosage with this class of drugs." Signs "develop rapidly", including "cardiac dysrhythmias, severe hypotension, shock… convulsions, and CNS depression, including coma". Hospital monitoring with ECG for at least six hours is required (FDA label). According to the UK product information, among people who are alive when they reach hospital, reported mortality is 0–15% (UK SmPC). In England and Wales from 2000 to 2006, the case-fatality rate ratio for tricyclics as a group was 13.8, against 0.5 for SSRIs. Nortriptyline was involved in only 5 deaths. Its own case-fatality estimate, 11.0 (95% CI 3.6–25.5), is too imprecise to say whether it is safer or more dangerous than amitriptyline (Hawton et al., BJPsych 2010). NICE advises against routinely starting any tricyclic except lofepramine in people at significant risk of suicide (NICE NG222). This applies whatever the reason for the prescription. A supply meant for nerve pain or smoking is just as dangerous in overdose.

All interactions

Interaction sources: UK SmPC section 4.5, FDA Pamelor label, NHS interactions page and NHS common questions. Paracetamol and ibuprofen are fine for short periods (NHS). See our St John's wort review for that herb's interactions.

Who should avoid nortriptyline

Must not take it (UK contraindications): people allergic to nortriptyline; anyone taking MAOIs; and people with a recent heart attack, any degree of heart block, heart rhythm disorders or coronary artery insufficiency (UK SmPC). The US label contraindicates it during "the acute recovery period after myocardial infarction", with MAOIs (including linezolid and IV methylene blue), and warns of possible cross-sensitivity with other tricyclics (FDA label). It "should generally be avoided" in people with, or suspected of having, Brugada syndrome (UK SmPC).

Needs extra caution: heart problems; liver or kidney problems; epilepsy or ECT; glaucoma; difficulty passing urine or an enlarged prostate; diabetes; an overactive thyroid or thyroid medication; bipolar disorder or schizophrenia; and thoughts of self-harm (NHS, UK SmPC). NICE advises against routinely starting tricyclics, other than lofepramine, in people at significant risk of suicide (NICE NG222).

Older adults (65+): the 2023 AGS Beers Criteria list nortriptyline among "antidepressants with strong anticholinergic activity". They describe these drugs as "highly anticholinergic, sedating, and cause orthostatic hypotension" and recommend "Avoid" (high quality of evidence, strong recommendation). Beers' separate warning about fainting names only the tertiary tricyclics (amitriptyline, clomipramine, doxepin and imipramine), not nortriptyline (AGS Beers 2023). In a small study of depressed patients with heart failure, orthostatic hypotension developed in only 1 of 21 people on nortriptyline. The authors noted that it causes "significantly less orthostatic hypotension than imipramine" (Roose et al., JAMA 1986). The UK product information advises 30–50 mg a day in older people, starting at 10–20 mg. It recommends an ECG and blood-level checks if higher doses are needed, and warns that older people are "particularly liable" to agitation, confusion and postural hypotension. It also notes one case of apparent heart toxicity from the metabolite 10-hydroxynortriptyline despite "therapeutic" nortriptyline levels (UK SmPC). Beers is a US tool for shared decision-making, not a ban. CANMAT still regards nortriptyline as a reasonable tricyclic in older adults when one is needed (CANMAT 2023).

Pregnancy and breastfeeding: the NHS says you "may be advised to continue taking nortriptyline during pregnancy, especially if you take it to treat depression". Do not stop without advice (NHS). The UK product information is more cautious. It says there is "a moderate amount of data" and advises use only if the benefits clearly outweigh the risks. It lists possible newborn withdrawal signs after use late in pregnancy, including irritability, tremors, breathing irregularity and poor feeding. Only 0.6–1% of the mother's dose passes into breast milk, and no infant effects have been reported (UK SmPC). The NHS says a healthy baby can be breastfed, but advises not sharing a bed with the baby because of drowsiness (NHS).

Children and young people: the UK SmPC says it "should not be used" for depression under 18. The NHS lists specialist-supervised use from 12 to 17. The US label says it is "not recommended for children" (UK SmPC, NHS, FDA label).

Liver, kidneys and genetics: kidney failure "does not affect kinetics of nortriptyline", so usual doses can be used. In liver impairment, careful dosing and, if possible, blood-level checks are advised (UK SmPC). For people whose CYP2D6 genotype is known, the NIH-funded CPIC guideline advises the following for depression doses. Poor metabolisers should avoid tricyclics, or start at 50% of the usual dose with blood-level monitoring if one is needed. Intermediate metabolisers should consider a 25% reduction. Ultrarapid metabolisers should avoid it because it may not work. These rules apply to depression doses rather than low pain doses (Hicks et al., CPIC 2017).

Dosage and how to take it

How to take it: for nerve pain it is usually taken once a day. For depression it may be taken three to four times a day or once a day. If taken once a day, bedtime is best because it can cause sleepiness. Swallow tablets whole, because they taste bitter if chewed, and measure the liquid with the syringe or spoon provided. It can be taken with or without food. Never take two doses to make up for a missed one (NHS).

How long before it works: for nerve pain, "it usually takes a week or so for pain to begin to get better", and sleep may improve within a few days. For depression, people may feel better after a couple of weeks, with full benefit at 4 to 6 weeks. The NHS advises giving it "at least 6 weeks" (NHS). The UK product information says the antidepressant effect "usually sets in after 2 – 4 weeks". Treatment usually continues for up to 6 months after recovery (UK SmPC). The NHS says 6 months to a year (NHS).

How to stop: only with your prescriber. The UK product information says it "should be gradually withdrawn over several weeks" (UK SmPC). The NHS says the reduction may take longer after long-term use (NHS). NICE recommends step-wise tapering, reducing each time to a proportion of the previous dose (for example 50%). Smaller steps, such as 25%, are used as the dose gets lower, and liquid forms can help (NICE NG222).

Follow the money: who makes it and who funded the evidence

Who made it and who sells it now

• First US approval: Eli Lilly's Aventyl Hydrochloride (NDA 014684) on 6 November 1964 (Eli Lilly and Company, USA). The application is now listed as discontinued (Drugs@FDA). The Pamelor brand (1977) is held by SpecGx LLC, and its applications are also listed as discontinued (openFDA). We could not confirm from a primary source who discovered nortriptyline or the original UK brand holder.
• Generic makers: in the US, active generic applications belong to Teva, Taro, Dr. Reddy's, Rubicon Research and Pharmaceutical Associates (openFDA). In the UK, tablets are listed from Blackrock, Brown & Burk, Flamingo, Glenmark, Viatris and Wockhardt (emc). The UK SmPC cited here belongs to Glenmark Pharmaceuticals Europe Ltd, revised 8 February 2024 (UK SmPC).
• Revenue: we found no documented sales figure for nortriptyline from any company. As a decades-old generic with many makers, no single company has a large financial stake in it.

Who funded the evidence

• Most of the high-quality modern evidence is publicly funded. The late-life maintenance trial was funded by US NIMH grants (Reynolds 1999). The Cochrane smoking review receives UK NIHR infrastructure funding (Hajizadeh 2023). The largest UK smoking trial was funded by Cancer Research UK and the Economic and Social Research Council (Aveyard 2008). The Cochrane pain review was NIHR-supported (Derry 2015). The Parkinson's pilot trial was funded through the NIHR Health Technology Assessment programme (ADepT-PD). The overdose study had NIHR funding (Hawton 2010), and the CPIC guideline has NIH funding (CPIC).
• GENDEP lists a UK Medical Research Council grant in Europe PMC. We did not verify its full funding list or whether any company supplied study drugs (Uher 2009).
• Industry ties mostly point elsewhere. Aveyard's lead author declared consultancy for companies making smoking-cessation treatments, including nicotine replacement therapy, which competes with nortriptyline. His trial still found only a modest, non-significant added benefit (Aveyard 2008). CANMAT authors report fees from makers of newer patented antidepressants (CANMAT 2023). NeuPSIG authors report fees from pain-drug makers (Soliman 2025). None of these conflicts involve nortriptyline itself.
• What generic status means. No company has a financial reason to fund large new nortriptyline trials. That is why the Cochrane pain review found only six small studies (Derry 2015), and why it was left out of the Cipriani network (Cipriani 2018). The lack of evidence for some uses reflects this lack of commercial interest as well as the drug's merits.
• Documented integrity events: we found no fraud settlements, data-integrity cases or regulatory safety communications specific to nortriptyline in the sources we searched.

Related research

• Stress, anxiety and depression: prevention and treatment guide
• Supplements for stress, anxiety and depression: the evidence
• Sleep: evidence-based prevention guide and sleep supplements evidence
• St John's wort: do not combine it with nortriptyline
• Melatonin, magnesium, L-theanine, saffron for depression and ashwagandha
• Sibling medicine reviews: amitriptyline (its parent drug), bupropion (licensed for smoking cessation), duloxetine, pregabalin, escitalopram, sertraline and agomelatine

Frequently asked questions

Sources and funding notes

• NHS: Nortriptyline (about, who can take it, how to take it, side effects, pregnancy, interactions and common-questions pages; reviewed 2 April 2025) — UK government health service; no commercial funding.
• UK SmPC: Nortriptyline 10 mg film-coated tablets (Glenmark Pharmaceuticals Europe Ltd), revised 08/02/2024 — licence holder text, MHRA-approved.
• emc product search: nortriptyline — UK medicines database.
• US FDA label: Pamelor (SpecGx LLC; DailyMed, effective 4 December 2024) — manufacturer text reviewed and approved by the FDA (USA).
• Drugs@FDA: Aventyl NDA 014684 (Lilly) and openFDA Drugs@FDA dataset — US regulator databases.
• NICE NG222: Depression in adults (2022) — UK government-funded.
• NICE NG209: Tobacco (last updated February 2025) — UK government-funded.
• NICE CG173: Neuropathic pain in adults — UK government-funded.
• Hajizadeh et al., Antidepressants for smoking cessation, Cochrane 2023 (full text) — UK/USA; NIHR grant NIHR132114 and infrastructure; most authors declare no interests.
• Aveyard et al., BMJ 2008 — UK; Cancer Research UK and ESRC; lead author reports consultancy for makers of smoking-cessation treatments.
• Reynolds et al., JAMA 1999 — USA; NIMH grants (P30 MH30915, R37 MH43832, P30 MH52247).
• Uher et al. (GENDEP), Br J Psychiatry 2009 — UK/Europe; UK Medical Research Council grant listed; full funding not verified.
• Arroll et al., Antidepressants versus placebo in primary care, Cochrane 2009 — New Zealand/international; author declarations not re-checked for this article.
• Schrag et al. (ADepT-PD), J Neural Transm 2026 — UK; NIHR HTA 16/145/01; no competing interests declared.
• Cipriani et al., Lancet 2018 — UK/Japan/international; NIHR and JSPS; nortriptyline not included.
• Derry et al., Nortriptyline for neuropathic pain in adults, Cochrane 2015 — UK; NIHR grant 13/89/29.
• Soliman et al. (NeuPSIG), Lancet Neurol 2025 — international; NeuPSIG and ERA-NET Neuron; several authors declare pharmaceutical fees.
• Hashemzadeh et al., BMJ Open 2024 — Iran; competing interests "none declared".
• CANMAT 2023 depression guideline (Lam et al., 2024) — Canada; internal funds; many authors declare pharmaceutical fees.
• American Geriatrics Society 2023 Beers Criteria — USA; "no sponsor".
• Hicks et al., CPIC guideline for CYP2D6/CYP2C19 and tricyclic antidepressants, 2017 — USA/international; NIH-funded; some authors consult for genetic-testing firms or report pharmaceutical research support.
• Hawton et al., Br J Psychiatry 2010 — UK; NIHR Programme Grant RP-PG-0606-1247; one author sits on an MHRA advisory group.
• Roose et al., JAMA 1986 — USA; funding not shown in the abstract.
• El-Fakahany & Richelson, Br J Pharmacol 1983 — USA; laboratory receptor study; funding not shown in the abstract.
• NHS: Antidepressants overview — UK government health service.

Last reviewed: 26 September 2026. Educational information from Pure City Research, not medical advice. Medicine decisions belong with a qualified prescriber.