Nortriptyline

What it is

Nortriptyline is a secondary-amine tricyclic antidepressant and the active breakdown product of amitriptyline. It is taken by mouth as a capsule or solution. It is cleared largely by the liver enzyme CYP2D6, so people who are genetically poor metabolisers, or who take a CYP2D6-inhibiting drug such as an SSRI, can reach much higher blood levels on an ordinary dose. Unusually for an antidepressant, it has a defined therapeutic plasma range, 50 to 150 ng/mL.

What the research says

Approved only for depression, nortriptyline is used far more widely than that. For depression, a Cochrane review of primary-care trials found tricyclics beat placebo with a median number needed to treat of 9, and a placebo-controlled trial in people over 59 found maintenance nortriptyline cut three-year recurrence from 90% to 43%. For neuropathic pain, the use many people actually take it for, a Cochrane review found only very low quality evidence and concluded against it as a first-line choice. For smoking cessation, also off-label, a Cochrane review found it roughly doubled quit rates. The harms are the classic tricyclic ones: anticholinergic effects, a boxed warning about suicidality in people under 25, and — the one that distinguishes TCAs from newer antidepressants — overdose toxicity, with a case fatality roughly 28 times that of SSRIs as a class.

Evidence grade: Well established.

How it works

Drug class: Tricyclic antidepressant (secondary amine; noradrenaline reuptake inhibitor with antihistaminic and anticholinergic activity)

Nortriptyline blocks the reuptake of noradrenaline (and to a lesser extent serotonin) back into nerve endings, leaving more of it in the synapse. It also blocks histamine and acetylcholine receptors, which is where the dry mouth, constipation, blurred vision and drowsiness come from. The label states plainly that how any of this lifts mood is not actually known. (Source 1)

Boxed warning

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of nortriptyline hydrochloride or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Nortriptyline hydrochloride is not approved for use in pediatric patients (

(Source 2)

What it is used for

• A Cochrane review of 14 primary-care trials, mostly of tricyclics, found a response relative risk of 1.24 (95% CI 1.11-1.38) against placebo with a median number needed to treat of 9, and a number needed to harm for withdrawal due to side effects as low as 4. A placebo-controlled maintenance trial in people over 59 found nortriptyline cut three-year recurrence from 90% to 43%. Evidence: established. (Source 3)
• In a 2x2 randomised, double-blind, placebo-controlled trial of 107 recovered patients averaging 67 years old, three-year recurrence was 43% on nortriptyline with medication clinic visits versus 90% on placebo with medication clinic visits. Evidence: established. (Source 4)
• A 2015 Cochrane review of six studies found no study provided first or second tier evidence for any outcome, that all studies had one or more sources of potential major bias, and that the evidence did not support nortriptyline as a first-line treatment. More participants reported adverse events on nortriptyline than on placebo. It is nonetheless recommended in European, UK and US guidelines. Evidence: not-supported. (Source 5)
• A 2023 Cochrane review found nortriptyline aided smoking cessation versus placebo (RR 2.03, 95% CI 1.48 to 2.78; 6 studies, 975 participants), with some evidence that bupropion does better, although that comparison was imprecise. Evidence: limited. (Source 6)

Interactions

• Monoamine oxidase inhibitors, linezolid and intravenous methylene blue (label): Combining nortriptyline with an MAOI risks serotonin syndrome; the combination is contraindicated and the label requires at least 14 days between stopping one and starting the other. (Source 7)
• CYP2D6 inhibitors, including the SSRIs fluoxetine, sertraline and paroxetine, plus quinidine and cimetidine (label): These block the enzyme that clears nortriptyline, so a person stable on a dose can become abruptly toxic when one is added. (Source 8)
• St John's wort (Hypericum perforatum) (pharmacokinetic study): St John's wort induces CYP enzymes and P-glycoprotein. In 12 patients taking amitriptyline, adding 900 mg/day of hypericum extract LI160 cut the area under the curve for nortriptyline, the active metabolite, by 41%. (Source 9)
• Alcohol (label): The label states the response to alcohol may be exaggerated in people taking nortriptyline. We found no pharmacokinetic or psychomotor study of nortriptyline with alcohol in the searches we ran; this interaction rests on the label rather than on a trial. (Source 10)
• Other anticholinergic and sympathomimetic drugs (label): Taking nortriptyline alongside other drugs with anticholinergic activity compounds dry mouth, constipation, urinary retention and confusion, and raises the cumulative anticholinergic burden linked in observational work to later dementia. (Source 10)
• Cimetidine (label): Cimetidine raises plasma concentrations of tricyclic antidepressants to a clinically significant degree. (Source 10)
• Chlorpropamide (and, by extension, blood-glucose-lowering drugs) (case reports): The label records a case of significant hypoglycaemia in a person with type 2 diabetes on chlorpropamide after nortriptyline was added. This is a single case report, not a trial. (Source 10)

Stopping it

• Abrupt cessation after prolonged therapy can produce nausea, headache and malaise. The label is explicit that these symptoms are not a sign of addiction. (Source 11)
• Across 79 studies and 21,002 patients, roughly 31% reported at least one discontinuation symptom after stopping an antidepressant against 17% after stopping placebo. The review's INTERPRETATION calls the drug-attributable incidence approximately 15%, one in six to seven patients, while its own pooled difference within the randomised trials was 0.08. (Source 12)
• Severe discontinuation symptoms were uncommon in the same meta-analysis: 2.8% after stopping an antidepressant versus 0.6% after stopping placebo. (Source 13)
• Stopping is not risk-free in the other direction either: in older adults with recurrent depression, three-year recurrence on placebo with medication clinic visits was 90% against 43% on maintenance nortriptyline. (Source 4)
• The label asks for dose reduction rather than abrupt stopping if minor side effects appear, but prompt discontinuation if serious or allergic reactions occur. (Source 14)

What goes wrong

In pooled short-term placebo-controlled trials, antidepressants produced 14 extra cases of suicidality per 1000 patients treated in those under 18 and 5 extra per 1000 at ages 18-24, while reducing cases at ages 25 and over. (Source 15)

• Meta-analysis, Moderate certainty.
• Size: 24 short-term pediatric trials of 9 drugs in over 4,400 patients; 295 short-term adult trials of 11 drugs in over 77,000 patients.
• Who: Children, adolescents and adults with major depressive disorder and other psychiatric disorders.
• How long: Short-term trials, median duration about 2 months in adults.
• Result: Drug-placebo difference in cases of suicidality per 1000 treated: under 18, 14 additional cases; 18-24, 5 additional cases; 25-64, 1 fewer case; 65 and over, 6 fewer cases. No suicides occurred in any pediatric trial.
• Funding: FDA pooled analyses of sponsor trials.

These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases

Tricyclic antidepressants are far more lethal in overdose than SSRIs: their case fatality rate ratio was about 28 times higher. (Source 16)

• Cohort study, Moderate certainty.
• Size: National prescribing data (UK), poisoning deaths with coroners' verdicts of suicide or undetermined intent (England and Wales) and non-fatal self-poisoning presentations to six general hospitals, 2000-2006.
• Who: People in England and Wales prescribed or self-poisoning with antidepressants.
• How long: 7 years.
• Result: Case fatality rate ratios: TCAs 13.8 (95% CI 13.0-14.7); venlafaxine 2.5 (2.0-3.1); mirtazapine 1.9 (1.1-2.9); SSRIs 0.5 (0.4-0.7)
• Funding: not stated in the abstract.

Limit of this finding: The paper describes citalopram as having a higher case fatality than the other SSRIs, but citalopram's own index, 1.1 (95% CI 0.8-1.4), includes 1. The comparison holds only because citalopram's interval and the other SSRIs' interval, 0.3 (0.2-0.4), do not overlap. Read it as citalopram being less safe in overdose than other SSRIs, not as citalopram being shown dangerous in absolute terms. The tricyclic figure, 13.8 (13.0-14.7), is the precise one and is the one that bears on nortriptyline.

Case fatality rate ratios showed greater toxicity for TCAs (13.8, 95% CI 13.0-14.7) than the SNRI venlafaxine (2.5, 95% CI 2.0-3.1) and the NaSSA mirtazapine (1.9, 95% CI 1.1-2.9), both of which had greater toxicity than the SSRIs (0.5, 95% CI 0.4-0.7).

Cumulative exposure to strongly anticholinergic antidepressants was associated with higher odds of later dementia in a very large nested case-control study. (Source 17)

• Case-control study, Low certainty.
• Size: 284,343 case patients and matched controls; 63.1% women, mean age 82.2 years.
• Who: Older adults in UK primary care records.
• How long: Exposure window 1 to 11 years before diagnosis, with sensitivity windows out to 20 years.
• Result: Anticholinergic antidepressants above 1095 total standardised daily doses: adjusted OR 1.29 (95% CI 1.24-1.34). Overall anticholinergic exposure: OR 1.06 (1.03-1.09) at the lowest category rising to 1.49 (1.44-1.54) at the highest. Population-attributable fraction 10.3%.
• Funding: not stated in the abstract.

There were significant increases in dementia risk for the anticholinergic antidepressants (adjusted OR [AOR], 1.29; 95% CI, 1.24-1.34), antiparkinson drugs (AOR, 1.52; 95% CI, 1.16-2.00), antipsychotics (AOR, 1.70; 95% CI, 1.53-1.90), bladder antimuscarinic drugs (AOR, 1.65; 95% CI, 1.56-1.75), and antiepileptic drugs (AOR, 1.39; 95% CI, 1.22-1.57) all for more than 1095 TSDDs.

About one in three people who stop an antidepressant report at least one discontinuation symptom, against about one in six who stop placebo; inside the randomised trials the pooled between-group difference was 0.08, so the share attributable to the drug is smaller than the raw gap suggests. (Source 13)

• Meta-analysis, Moderate certainty.
• Size: 79 studies (44 RCTs, 35 observational), 21,002 patients; 16,532 discontinued an antidepressant and 4,470 discontinued placebo.
• Who: Adults discontinuing antidepressants; 72% female, mean age 45 years.
• How long: Varied.
• Result: Incidence of at least one discontinuation symptom 0.31 (95% CI 0.27-0.35) after antidepressants versus 0.17 (0.14-0.21) after placebo; summary difference in RCTs 0.08 (0.04-0.12); severe symptoms 0.028 (0.014-0.057) versus 0.006 (0.002-0.013). Imipramine was among the drugs with higher frequency and severity.
• Funding: None.

Limit of this finding: This review's summary and its own numbers do not match. It reports at least one discontinuation symptom in 31% of people who stopped an antidepressant and 17% of people who stopped placebo, and a pooled difference between arms inside the randomised trials of 0.08, that is about 8 percentage points. The INTERPRETATION section then states the incidence is "approximately 15%", which is the 31 minus 17 subtraction rather than the pooled randomised estimate. Take the share of symptoms attributable to the drug as somewhere between roughly 8 and 15 percent depending on which comparison is used, and do not treat 15% as a settled figure.

Incidence of at least one antidepressant discontinuation symptom was 0·31 (95% CI 0·27-0·35) in 62 study groups after discontinuation of antidepressants, and 0·17 (0·14-0·21) in 22 study groups after discontinuation of placebo.

In overdose, cardiac dysrhythmias, severe hypotension, convulsions and coma are the critical manifestations, and widening of the QRS complex on the ECG is the key marker of tricyclic toxicity. (Source 18)

• Official position, Certainty not rated.
• Size: Not applicable: regulator-approved labelling.
• Who: People who overdose on nortriptyline.
• How long: Acute.
• Result: No rate given; the label notes reports of recovery from overdoses of up to 525 mg.
• Funding: not applicable.

Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, shock, congestive heart failure, pulmonary edema, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity.

Anticholinergic effects are a defining harm of the drug: dry mouth, blurred vision, impaired accommodation, constipation, paralytic ileus and urinary retention. (Source 19)

• Official position, Certainty not rated.
• Size: Not applicable: regulator-approved labelling.
• Who: People taking nortriptyline.
• How long: Not stated.
• Result: No frequencies given in the label.
• Funding: not applicable.

Dry mouth and, rarely, associated sublingual adenitis, blurred vision, disturbance of accommodation, mydriasis; constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract.

At analgesic doses, tricyclics including nortriptyline did prolong the QTc interval slightly, though no case exceeded 500 ms and none had a fatal arrhythmia. (Source 20)

• Cohort study, Very low certainty.
• Size: 87 patients (65 amitriptyline, 22 nortriptyline)
• Who: Patients given a tricyclic for herpes zoster pain or postherpetic neuralgia at a single centre, 2007-2012.
• How long: Median medication period 62 days.
• Result: QTc before 413.2 +/-17.0 ms, after 419.9 +/- 18.9 ms, p < 0.01; median nortriptyline dose 10 mg/day; left ventricular hypertrophy was the only risk factor for abnormal prolongation, adjusted OR 4.09 (95% CI, 1.01-16.55, p < 0.05)
• Funding: not stated in the abstract.

TCAs significantly prolonged the QTc interval (before, 413.2 +/-17.0 ms; after, 419.9 +/- 18.9 ms, p < 0.01). Three patients showed marked QTc prolongation, but it did not exceed 500 ms, or deltaQTc of 60 ms, and none had an episode of fatal arrhythmia.

Abruptly stopping nortriptyline after prolonged therapy can produce nausea, headache and malaise; the label states these are not indicative of addiction. (Source 11)

• Official position, Certainty not rated.
• Size: Not applicable: regulator-approved labelling.
• Who: People stopping nortriptyline after prolonged therapy.
• How long: Not stated.
• Result: No rate given.
• Funding: not applicable.

Though these are not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise.

Poor CYP2D6 metabolisers, and people taking a CYP2D6 inhibitor, can reach much higher tricyclic blood levels on an ordinary dose and may become abruptly toxic. (Source 21)

• Official position, Certainty not rated.
• Size: Not applicable: regulator-approved labelling.
• Who: People taking tricyclic antidepressants; about 7% to 10% of Caucasians are poor metabolisers.
• How long: Any.
• Result: Up to an 8-fold increase in plasma AUC of the TCA.
• Funding: not applicable.

Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA).

What the evidence supports

Tricyclic antidepressants outperformed placebo for depression in primary care, with a median number needed to treat of 9 and a number needed to harm for withdrawal as low as 4. (Source 3)

• Systematic review, Moderate certainty.
• Size: 14 studies (16 comparisons); 1,364 participants on active drug and 919 on placebo.
• Who: Adults under 65 with depression recruited in primary care.
• How long: Nearly all studies short, typically 6-8 weeks.
• Result: TCAs versus placebo RR 1.24, 95% CI 1.11-1.38; NNT for TCAs 7 to 16, median 9; NNH for withdrawal due to side effects 4 to 30.
• Funding: not stated in the abstract.

Limit of this finding: The numbers-needed-to-treat sentence is garbled in the published Cochrane record itself: it opens a brace and closes a parenthesis that was never opened, and it quotes a "patient expected event rate" falling from 63% to 26% without saying which group that describes. The text is reproduced exactly as published rather than tidied. The relative risks either side of it are clean. Treat the median numbers needed to treat, 9 for tricyclics and 7 for SSRIs, as approximate, and do not try to read the event rates out of that sentence.

Pooled estimates of efficacy data showed an RR of 1.24, 95% CI 1.11-1.38 in favour of TCAs against placebo. For SSRIs this was 1.28, 95% CI 1.15 to 1.43..

Maintenance nortriptyline roughly halved three-year recurrence of major depression in people over 59 compared with placebo. (Source 4)

• Randomized trial, Moderate certainty.
• Size: 107 fully recovered patients randomised into 4 maintenance conditions (nortriptyline + medication clinic n=24; placebo + medication clinic n=29; IPT + placebo n=21; IPT + nortriptyline n=22)
• Who: Patients older than 59 with recurrent nonpsychotic unipolar major depression, average age 67, one third aged 70 or over.
• How long: 3 years.
• Result: Recurrence over 3 years: nortriptyline and IPT 20% (95% CI 4%-36%); nortriptyline and medication clinic visits 43% (25%-61%); IPT and placebo 64% (45%-83%); placebo and medication clinic visits 90% (79%-100%)
• Funding: not stated in the abstract.

Recurrence rates over 3 years were as follows: nortriptyline and IPT, 20% (95% confidence interval [CI], 4%-36%); nortriptyline and medication clinic visits, 43 % (95% CI, 25%-61%); IPT and placebo, 64% (95% CI, 45%-83%); and placebo and medication clinic visits, 90% (95% CI, 79%-100%).

Nortriptyline roughly doubled smoking quit rates compared with placebo; the review also reports bupropion doing better than nortriptyline, but that comparison was imprecise and its confidence interval includes no difference. (Source 6)

• Systematic review, Moderate certainty.
• Size: 6 studies, 975 participants for the nortriptyline versus placebo comparison.
• Who: People trying to stop smoking.
• How long: Long-term abstinence outcomes (typically 6 months or more)
• Result: RR 2.03, 95% CI 1.48 to 2.78; I2 = 16%.
• Funding: not stated in the abstract.

Limit of this finding: The review calls bupropion's quit rates "superior" to nortriptyline's on a relative risk of 1.30 with a 95% confidence interval of 0.93 to 1.82. That interval includes 1, which means no difference at all remains compatible with the data, and the review itself adds that the result was subject to imprecision. Read it as "bupropion may be better, on three small trials totalling 417 people", not as a demonstrated advantage over nortriptyline. The nortriptyline-versus-placebo figure beside it, 2.03 (1.48 to 2.78), does not include 1 and is the solid one.

We also found evidence that nortriptyline aided smoking cessation when compared with placebo (RR 2.03, 95% CI 1.48 to 2.78; I2 = 16%; 6 studies, 975 participants)

What the evidence does not support

For neuropathic pain, no study of nortriptyline reached first or second tier evidence quality, and the Cochrane authors found little to support its use. (Source 5)

• Systematic review, Very low certainty.
• Size: Six studies; 272 participants randomised to nortriptyline and 145 to placebo, with further arms on gabapentin, morphine, chlorimipramine and amitriptyline.
• Who: Adults with chronic neuropathic pain, chiefly postherpetic neuralgia and painful diabetic neuropathy.
• How long: Treatment periods of three to eight weeks.
• Result: No pooled effect estimate was possible; third tier evidence indicated similar efficacy to other active drugs and to placebo (very low quality evidence); more participants reported adverse events on nortriptyline than on placebo.
• Funding: not stated in the abstract.

Limit of this finding: The published abstract has a missing space and prints "much or very much improved.We could not pool data". That is a typesetting fault in the source record, left exactly as published rather than silently edited inside a quotation. It does not change the meaning.

No study provided first or second tier evidence for any outcome. Only one study reported our primary outcome of people with at least 50% reduction in pain. There was no indication that either nortriptyline or gabapentin was more effective in postherpetic neuralgia (very low quality evidence).

The Cochrane review concluded the evidence does not support nortriptyline as a first-line treatment for neuropathic pain, and that better-supported alternatives exist. (Source 22)

• Systematic review, Very low certainty.
• Size: Six studies.
• Who: Adults with chronic neuropathic pain; no studies at all in trigeminal neuralgia.
• How long: Three to eight weeks.
• Result: No usable pooled effect; authors cite small size and potential major bias.
• Funding: not stated in the abstract.

We found little evidence to support the use of nortriptyline to treat the neuropathic pain conditions included in this review. There were no studies in the treatment of trigeminal neuralgia. The studies were methodologically flawed, largely due to small size, and potentially subject to major bias. The results of this review do not support the use of nortriptyline as a first line treatment.

In a large electronic health record study, nortriptyline showed no dose-response QTc prolongation, unlike its parent drug amitriptyline. (Source 23)

• Survey study, Low certainty.
• Size: 38,397 adults with an electrocardiogram after an antidepressant or methadone prescription; 1,978 (5.2%) on nortriptyline.
• Who: Adults in a large New England healthcare system, 1990-2011.
• How long: Cross-sectional, with a within-subject paired subset.
• Result: Adjusted beta for nortriptyline -0.01 (SE 0.04) and 0.04 (0.04) in the two models, neither significant; amitriptyline 0.11 (0.03), P<0.001.
• Funding: not stated in the abstract.

Also of note, we observe significant QTc prolongation with amitriptyline but not with its metabolite nortriptyline, consistent with a recent preclinical study which identified minimal QTc effects with nortriptyline.

Where the research disagrees

Whether nortriptyline should be used for neuropathic pain

• European, UK and USA clinical guidelines, as summarised by the Cochrane review authors, guideline recommendation, reported in the Cochrane review as background: There were no studies in the treatment of trigeminal neuralgia. The studies were methodologically flawed, largely due to small size, and potentially subject to major bias. (Source 22)
• Derry and colleagues, Cochrane Review (2015), systematic review of six randomised double-blind studies: The results of this review do not support the use of nortriptyline as a first line treatment. Effective medicines with much greater supportive evidence are available, such as duloxetine and pregabalin. (Source 22)

Whether nortriptyline prolongs the QT interval

• Castro and colleagues, cross-sectional electronic health record study of 38,397 adults (BMJ 2013), cross-sectional study with within-subject paired subset: Also of note, we observe significant QTc prolongation with amitriptyline but not with its metabolite nortriptyline, consistent with a recent preclinical study which identified minimal QTc effects with nortriptyline. (Source 23)
• Retrospective single-centre observational study of 87 patients on analgesic-dose tricyclics (Osaka City Medical Journal 2014), retrospective observational study with before-and-after ECGs: TCAs significantly prolonged the QTc interval (before, 413.2 +/-17.0 ms; after, 419.9 +/- 18.9 ms, p < 0.01). Three patients showed marked QTc prolongation, but it did not exceed 500 ms, or deltaQTc of 60 ms, and none had an episode of fatal arrhythmia. (Source 20)

How much

• Reference intake: There is no reference intake for a prescription medicine. The dose is set by the prescriber. The US label (Sun Pharmaceutical nortriptyline hydrochloride capsules, SPL dated 15 July 2026) gives, as a position, a usual adult dose of 25 mg three or four times daily started low and increased as required, and 30 to 50 mg/day for elderly and adolescent patients. (Source 14)
• Upper limit: The label states, as a position, that doses above 150 mg/day are not recommended, and that above 100 mg/day plasma levels should be monitored and kept in the optimum range of 50 to 150 ng/mL. (Source 14)
• Studied: In the three-year maintenance trial in people over 59, nortriptyline was dosed to steady-state plasma levels of 80-120 ng/mL rather than to a fixed milligram dose. (Source 24)
• Studied: In the analgesic-dose QTc study, the median daily dose was 10 mg/day for nortriptyline (and 25 mg/day for amitriptyline) given for herpes zoster pain or postherpetic neuralgia. (Source 20)

A common belief, and what the research shows

The belief: Nortriptyline is a well-established treatment for nerve pain — that is what it is mostly prescribed for now.

What the research shows: It is widely prescribed for nerve pain and recommended in guidelines, but the Cochrane review that looked for the trials found almost nothing to stand on. "No study provided first or second tier evidence for any outcome." Its conclusion was blunt: "The results of this review do not support the use of nortriptyline as a first line treatment." The use is off-label, and the approved use — depression — is the one with the stronger evidence base.

Questions and answers

What is it?

Nortriptyline is a tricyclic antidepressant, one of the older generation of antidepressants, sold as Pamelor and Aventyl among other names. It is also what the body turns amitriptyline into, so the two drugs overlap. It is approved in the United States only for depression, though it is widely used off-label for nerve pain and for stopping smoking. (Source 25)

What does it do in the body?

It keeps more noradrenaline in the gaps between nerve cells by blocking its reuptake, and it also blocks histamine and acetylcholine signalling. Those extra blockades are not incidental: they produce the dry mouth, blurred vision, constipation and drowsiness that limit how much people can take. The label does not claim to know how any of this lifts mood. (Source 1)

Is it good or bad for you?

For depression, the randomised evidence supports it, with a number needed to treat around 9 in primary care and a strong maintenance effect in older adults. For nerve pain, the Cochrane evidence is very low quality and does not support it as first line. The harms that matter most are overdose lethality — tricyclics have a case fatality roughly 28 times that of SSRIs — the anticholinergic burden in older people, and the boxed warning about suicidality in people under 25. (Source 16)

How do you get more of it?

Nortriptyline is prescription-only; no food or supplement supplies it. What changes the level in your blood is how fast your liver clears it. Roughly 7% to 10% of people of European descent carry a low-activity CYP2D6 enzyme and run much higher levels on an ordinary dose, and many common drugs — including SSRIs, quinidine and cimetidine — turn a normal metaboliser into a functional poor one. (Source 21)

If it is harmful, what reduces it?

Levels fall when the drug is stopped or reduced, and St John's wort lowers them substantially by inducing the enzymes that clear it — in a 12-patient study, nortriptyline exposure fell 41%, which is an unwanted loss of treatment rather than a remedy. For overdose, the label's management is supportive with cardiac monitoring; there is no simple antidote and widening of the QRS complex is the warning sign. (Source 9)

Why might someone be low in it or missing it?

Nortriptyline is not a nutrient, so no one is deficient in it. People do end up with blood levels below the therapeutic 50 to 150 ng/mL range while still taking it — most often because they are fast metabolisers, because a drug or supplement such as St John's wort is inducing the clearing enzymes, or because the dose was kept low to avoid side effects. A subtherapeutic level is a common reason it appears not to work. (Source 14)

Which whole foods contain it or feed it?

No whole food contains nortriptyline. The food and supplement that matter are the ones that change how it is handled: St John's wort cuts exposure by about 41%, and alcohol's effects may be exaggerated in people taking it. There is no dietary way to supply or substitute for the drug. (Source 10)

What happens if you do not have it?

Nothing, if you have never needed it. If you are on it for recurrent depression and it is withdrawn, relapse is the main risk: in the three-year trial in people over 59, recurrence was 90% on placebo versus 43% on nortriptyline. Stopping abruptly after prolonged therapy can also produce nausea, headache and malaise, and across antidepressants somewhere between roughly 8 and 15 percent of people get discontinuation symptoms attributable to the drug rather than to stopping as such. (Source 12)

How can you test for it?

Unlike most antidepressants, nortriptyline has a defined plasma therapeutic range and a blood test to go with it: the label asks for plasma levels to be monitored and kept between 50 and 150 ng/mL when doses go above 100 mg daily. The test measures the drug, not whether it is working, and interpretation depends on the sample being taken at a consistent time relative to the dose. An ECG is the other relevant test, since QRS widening is the marker of tricyclic cardiac toxicity. (Source 14)

References

1. DailyMed, US National Library of Medicine (FDA Structured Product Label). NORTRIPTYLINE HYDROCHLORIDE CAPSULE [SUN PHARMACEUTICAL INDUSTRIES, INC.] - CLINICAL PHARMACOLOGY. 2026. Read the source
2. DailyMed, US National Library of Medicine (FDA Structured Product Label). NORTRIPTYLINE HYDROCHLORIDE CAPSULE [SUN PHARMACEUTICAL INDUSTRIES, INC.] - BOXED WARNING: Suicidality and Antidepressant Drugs. 2026. Read the source
3. The Cochrane database of systematic reviews. Antidepressants versus placebo for depression in primary care.. 2009. PMID 19588448, DOI 10.1002/14651858.CD007954. Read the source
4. JAMA. Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years.. 1999. PMID 9892449. Read the source
5. The Cochrane database of systematic reviews. Nortriptyline for neuropathic pain in adults.. 2015. PMID 25569864, DOI 10.1002/14651858.CD011209.pub2. Read the source
6. The Cochrane database of systematic reviews. Antidepressants for smoking cessation.. 2023. PMID 37230961, DOI 10.1002/14651858.CD000031.pub6. Read the source
7. DailyMed, US National Library of Medicine (FDA Structured Product Label). NORTRIPTYLINE HYDROCHLORIDE CAPSULE [SUN PHARMACEUTICAL INDUSTRIES, INC.] - CONTRAINDICATIONS: Monoamine Oxidase Inhibitors (MAOIs). 2026. Read the source
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