RESEARCH MONOGRAPH · KDC-MN-216
Amitriptyline
Amitriptyline (Elavil) is one of the founding tricyclic antidepressants, approved in 1961 and still in heavy clinical use, though almost never for depression anymore. At antidepressant doses (150 to 300 mg) the side-effect burden is rough: heavy sedation, dry mouth, constipation, weight gain, and blood pressure drops on standing. At low doses (10 to 75 mg) it has become a workhorse for chronic pain, particularly neuropathic pain, tension headache, and migraine prevention, where its effects on serotonin and norepinephrine signaling in spinal pain pathways do useful work. It also blocks sodium channels in the heart, which makes overdose genuinely dangerous and limits its use in anyone with cardiac conduction disease. 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 Kodiac editorial, not peer-reviewed.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 (tertiary amine)
A foundational tertiary amine TCA with potent serotonergic, noradrenergic, anticholinergic, and antihistaminergic activity; widely repurposed for chronic pain.
Abstract
Amitriptyline (3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethylpropan-1-amine; CAS 50-48-6; molecular formula C20H23N; molecular weight 277.40) is a dibenzocycloheptene tertiary amine TCA developed at Merck and approved in the US in 1961 under the trade name Elavil. The parent compound exhibits balanced SERT and NET inhibition (SERT Ki approximately 4 nM, NET Ki approximately 35 nM); the active metabolite nortriptyline (formed by CYP-mediated demethylation) is a more selective NET inhibitor and contributes substantially to steady-state activity. Off-target activity is extensive: muscarinic M1-M5 antagonism (Ki approximately 18 nM at M1) produces strong anticholinergic effects, H1 antagonism (Ki approximately 1 nM) drives sedation and weight gain, alpha-1 adrenergic antagonism causes orthostatic hypotension, and sodium channel block contributes to cardiotoxicity in overdose. Plasma half-life is 10 to 28 hours; metabolism is via CYP2D6, CYP2C19, CYP3A4. Approved for major depressive disorder; widely used at lower doses (10 to 75 mg) for migraine prophylaxis, postherpetic neuralgia, diabetic neuropathy, fibromyalgia, and tension-type headache. Used as the canonical TCA reference compound in mechanism studies.
Mechanism of action
Balanced SERT/NET inhibition; potent anticholinergic, antihistaminergic, alpha-1 adrenergic, and sodium channel block. Active metabolite nortriptyline shifts selectivity toward NET.
Reported research dose ranges
Reported research dose ranges in the literature.
References
- Bryson HM, Wilde MI. Amitriptyline. A review of its pharmacological properties and therapeutic use in chronic pain states. Drugs Aging 1996.
- Coupland N, et al. The biochemistry of melancholia: TCA-class pharmacology. Br J Psychiatry 1992.
- Lawson K. Tricyclic antidepressants and fibromyalgia: what is the mechanism of action? Expert Opin Investig Drugs 2002.
Read the full monograph
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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.