Nortriptyline

Tricyclic antidepressants block the reuptake of serotonin and norepinephrine. Nortriptyline is a secondary amine, the group of tricyclics with the stronger effect on norepinephrine; tertiary amines such as amitriptyline act more on serotonin [2]. Its FDA label covers the relief of symptoms of depression and states that the mechanism of mood elevation is unknown [1].

The label's usual adult dose is 25 mg three or four times a day, or the same total once a day, and 30 to 50 mg a day for older adults and adolescents. Doses above 150 mg a day are not recommended. Above 100 mg a day, the label calls for measuring nortriptyline in the blood and keeping it between 50 and 150 ng/mL [1]. Because the label sets a target range, a blood test can show directly whether a person's level is too high or too low, whatever the cause.

CYP2D6 adds a hydroxyl group to nortriptyline, producing 10-hydroxynortriptyline [3]. CPIC describes the hydroxy metabolites of tricyclics as less active than the parent drug [2], though not inert: the label calls 10-hydroxynortriptyline active and notes that older adults can have higher levels of it [1]. Like other tricyclics, it can cause anticholinergic, nervous system and heart effects, and CPIC notes that tricyclic blood levels are linked to both toxicity and benefit [2].

A CYP2D6 result is an activity score: each copy of the gene gets a value (1 for normal function, 0.5 or 0.25 for decreased function, 0 for no function) and the two are added. A score of 0 means poor metabolizer, 0.25 to 1 intermediate, 1.25 to 2.25 normal and above 2.25 ultrarapid, which requires extra copies of the gene [5][6]. The amitriptyline page explains the scoring and the main alleles in more detail.

Nortriptyline shows the effect of CYP2D6 unusually clearly. In a 1998 study that gave single doses to people with 0, 1, 2, 3 and 13 working copies of the gene, the oral clearance of nortriptyline ran in the proportion 1:1:4:5:17 across those groups. The ratio of nortriptyline to its 10-hydroxy metabolite was 36 times higher in the group with no working copies than in the person with 13. The people with extra copies were given twice the dose (50 mg), yet showed no more drying of saliva than the others did at 25 mg [3].

For tricyclics in general, the FDA label says poor metabolizers have higher than expected blood levels at usual doses, and that the rise can be small or as large as an 8-fold increase in total exposure (AUC), depending on how much of the drug goes through CYP2D6 [1]. CPIC expects side effects to be more likely in poor metabolizers. Ultrarapid metabolizers are more likely to get no benefit because levels stay low; CPIC describes documented cases of ultrarapid metabolizers who needed very large nortriptyline doses to reach target levels and then had very high levels of the hydroxy metabolite, which may raise the risk of heart toxicity [2].

These results are common. In CPIC's frequency tables, about 6.5% of people of European ancestry are poor metabolizers, compared with 2% to 3% in most other groups and under 1% of people of East Asian ancestry. Intermediate metabolizers make up roughly 23% to 39% of most groups [7].

The Clinical Pharmacogenetics Implementation Consortium (CPIC) published its tricyclic guideline in 2013 and updated it in 2016. It uses amitriptyline and nortriptyline as its reference drugs because most pharmacogenetic studies were done with them [2]. Nortriptyline and CYP2D6 are CPIC level A, CPIC's highest level: genetic information should be used to change prescribing [4]. The recommendations are written for the higher doses used to treat depression, and the "starting dose" in them means the target steady-state dose, which a prescriber may reach over several days [2]. CPIC's current tables split the intermediate group: the 25% reduction is rated moderate for activity scores of 0.25 and 0.5 and optional for 0.75 and 1 [8].

An ultrarapid result requires extra copies of the gene, because every increased-function CYP2D6 allele is a gene duplication [6].

The FDA label gives no genotype-specific doses. Its precautions explain that poor metabolizers have higher than expected tricyclic levels and that drugs which block CYP2D6 can make normal metabolizers resemble poor metabolizers [1]. FDA's Table of Pharmacogenetic Associations lists nortriptyline and CYP2D6 in its section for effects on drug levels only [9].

The Dutch Pharmacogenetics Working Group (DPWG) published its own tricyclic guideline in 2026. For nortriptyline it advises 40% of the normal dose in CYP2D6 poor metabolizers, 60% in intermediate metabolizers and 1.7 times the normal dose in ultrarapid metabolizers, and notes that ultrarapid metabolizers may need a different drug [10]. Gene2Rx reports use the CPIC recommendations.

Bring the report to your prescriber or pharmacist with a list of everything you take, including over-the-counter products. CPIC considers genotype-guided dosing most useful when a tricyclic is started; after months on a steady dose, the dose may already have been adjusted to response, side effects or blood levels [2]. Do not start, stop or change nortriptyline because of a genetic result without talking to your prescriber.

Medicines that change the picture

Other drugs can make CYP2D6 behave differently from what the genes predict, which is called phenoconversion. FDA lists bupropion, fluoxetine, paroxetine, quinidine and terbinafine as strong CYP2D6 inhibitors [11]. The nortriptyline label reports that quinidine can lengthen nortriptyline's half-life and raise its exposure, that all SSRIs inhibit CYP2D6 to varying degrees, and that at least 5 weeks may be needed between stopping fluoxetine and starting a tricyclic. It also says a person who is stable on a tricyclic "may become abruptly toxic" when an inhibitor is added, and that it is desirable to check tricyclic blood levels when one is [1]. CPIC notes the suggestion that people taking strong CYP2D6 inhibitors be treated like poor metabolizers [2].

Other factors

Older age, liver disease and reduced kidney function may call for lower tricyclic doses whatever the genotype [2]. For older adults the label also advises monitoring heart rhythm and blood pressure and keeping to the smallest effective dose [1]. A normal result points to standard dosing, but it does not promise good tolerance or a good response.

Consumer arrays from 23andMe, AncestryDNA and MyHeritage are not clinical-grade tests, and their raw data is labeled as not for medical use. They read fixed positions and can miss rare variants. Array processing uses imputation to infer some variants that were not measured directly, but a variant at a position the data does not cover cannot be seen. A normal result therefore means none of the assessed variants was found among the positions your data covers. "Indeterminate" means the alleles found could not be assigned a function.

For nortriptyline, a blood level shows how much drug is in the body, whatever the reason.

Does this apply if I take a low dose for nerve pain?

Not directly. CPIC's tables are written for the higher doses used in depression, and its separate low-dose advice covers amitriptyline for nerve pain, not nortriptyline [2]. Your prescriber has to judge how a result applies at a low dose.

I take amitriptyline. Which page applies?

Both genes matter for amitriptyline, because CYP2C19 turns it into nortriptyline and CYP2D6 then clears both. The amitriptyline page covers the combined interpretation.

Can a blood test check my level?

Yes. The label recommends measuring nortriptyline above 100 mg a day, with a target of 50 to 150 ng/mL; see How nortriptyline works [1].

1. Pamelor (nortriptyline HCl) capsules (SpecGx): prescribing information. DailyMed, US National Library of Medicine. Indication, dosing, the labeled blood-level range, CYP2D6 precautions and interactions.
2. Hicks JK et al. Clinical Pharmacogenetics Implementation Consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther (2017). CPIC recommendations, tricyclic metabolism, dose scope and evidence summary.
3. Dalén P et al. 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin Pharmacol Ther (1998). Nortriptyline clearance by number of working CYP2D6 genes.
4. CPIC. Assignment of CPIC levels for genes/drugs (ClinPGx). What the CPIC levels mean.
5. Caudle KE et al. Standardizing CYP2D6 genotype to phenotype translation: consensus recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group. Clin Transl Sci (2020). The CYP2D6 activity score ranges used since 2019.
6. CPIC. CYP2D6 allele functionality table (spreadsheet). Function and activity value of each CYP2D6 allele, including the duplications.
7. CPIC. CYP2D6 frequency table (spreadsheet). Allele and phenotype frequencies by biogeographic group, with methods and caveats.
8. CPIC guideline for CYP2D6, CYP2C19 and tricyclic antidepressants (ClinPGx guideline page). Current recommendation tables, including updates since publication.
9. US Food and Drug Administration. Table of Pharmacogenetic Associations. FDA's summary of gene-drug interactions in labeling.
10. Kleine Schaars K et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6 and CYP2C19 and tricyclic antidepressants. Eur J Hum Genet (2026). The Dutch tricyclic recommendations.
11. US Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong and moderate CYP2D6 and CYP2C19 inhibitors and inducers.