RESEARCH MONOGRAPH · KDC-MN-217
Nortriptyline
Nortriptyline (Pamelor, Aventyl) is the active leftover of amitriptyline, sold separately after FDA approval in 1964. The body strips one methyl group off amitriptyline to produce nortriptyline, and that small change shifts the drug toward blocking the norepinephrine pump preferentially with much less serotonin activity. It also drops the muscarinic and antihistamine load somewhat, which makes it more tolerable than the parent compound. Among older tricyclics it has the cleanest defined therapeutic blood-level window (50 to 150 ng/mL), which means clinicians can dose it precisely with a blood test rather than guessing. Used for depression, neuropathic pain, and migraine prevention. Not stocked by Kodiac. This monograph is provided for research and educational reference.
Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.
Tricyclic antidepressant (secondary amine)
The N-desmethyl active metabolite of amitriptyline; a NET-preferring TCA with a more favorable side effect profile.
Abstract
Nortriptyline (3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methylpropan-1-amine; CAS 72-69-5; molecular formula C19H21N; molecular weight 263.38) is the N-desmethyl active metabolite of amitriptyline, marketed independently as Pamelor and Aventyl after FDA approval in 1964. As a secondary amine TCA, the compound exhibits substantially greater NET selectivity than amitriptyline (NET Ki approximately 4 nM, SERT Ki approximately 18 nM) and reduced muscarinic antagonism (M1 Ki approximately 150 nM versus 18 nM for amitriptyline), producing a cleaner side effect profile. H1 antagonism remains significant (Ki approximately 10 nM) and contributes to residual sedation, but the anticholinergic burden is meaningfully lower. Plasma half-life is 18 to 35 hours; metabolism is via CYP2D6 (primary). Approved for major depressive disorder; widely used at low dose (10 to 75 mg) for chronic pain, neuropathy, and as a smoking cessation aid (off-label). Therapeutic plasma concentrations are well-defined (50 to 150 ng/mL) and routinely monitored, distinguishing nortriptyline from most modern antidepressants. Used as the canonical secondary amine TCA in mechanism studies.
Mechanism of action
NET-preferring TCA with reduced muscarinic burden compared to amitriptyline. Active metabolite of amitriptyline; defined therapeutic plasma window.
Reported research dose ranges
Reported research dose ranges in the literature.
References
- Roose SP, et al. Comparison of nortriptyline and SSRIs in elderly depressed patients. Am J Geriatr Psychiatry 1998.
- Watson CP, et al. Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial. Neurology 1998.
- Mavissakalian MR, Perel JM. Long-term maintenance and discontinuation of imipramine therapy. Arch Gen Psychiatry 1999.
Read the full monograph
Available as a research-use-only PDF download. Note: PDFs for newly added compounds may take a few hours to propagate after this article was published.
The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.
FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.