[12] Due to the frequency and prominence of side effects, amitriptyline is generally considered a second-line therapy for these indications.

[21][22] Amitriptyline is indicated for the treatment of major depressive disorder, neuropathic pain, and for the prevention of migraine and chronic tension headache.

[12] Amitriptyline is effective for depression,[23] but it is rarely used as a first-line antidepressant due to its higher toxicity in overdose and generally poorer tolerability.

Low doses of amitriptyline moderately improve sleep disturbances and reduce pain and fatigue associated with fibromyalgia.

[39] Amitriptyline may reduce the frequency and duration of chronic tension headache, but it is associated with worse adverse effects than mirtazapine.

Overall, amitriptyline is recommended for tension headache prophylaxis, along with lifestyle advice, which should include avoidance of analgesia and caffeine.

[44] Tricyclic antidepressants decrease the frequency, severity, and duration of cyclic vomiting syndrome episodes.

[48] In the US, amitriptyline is commonly used in children with ADHD as an adjunct to stimulant medications without any evidence or guideline supporting this practice.

[49] Many physicians in the UK (and the US also) commonly prescribe amitriptyline for insomnia;[50] however, Cochrane reviewers were not able to find any randomized controlled studies that would support or refute this practice.

[59] The most frequent side effects, occurring in 20% or more of users, are dry mouth, drowsiness, dizziness, constipation, and weight gain (on average 1.8 kg[60]).

[23] Other common side effects are headache problems (amblyopia, blurred vision), tachycardia, increased appetite, tremor, fatigue/asthenia/feeling slowed down, and dyspepsia.

[23] Amitriptyline can increase suicidal thoughts and behavior in people under the age of 24 and the US FDA required a boxed warning to be added to the prescription label.

The rate of sexual dysfunction in males treated for indications other than depression and in females is not significantly different from placebo.

[69] The symptoms and the treatment of an overdose are largely the same as for the other TCAs, including the presentation of serotonin syndrome and adverse cardiac effects.

The British National Formulary notes that amitriptyline can be particularly dangerous in overdose,[70] thus it and other TCAs are no longer recommended as first-line therapy for depression.

If the affected person is unconscious or has an impaired gag reflex, a nasogastric tube may be used to deliver the activated charcoal into the stomach.

[74] Similar changes occur with a moderate inhibitor of CYP2C19 and other cytochromes cimetidine: amitriptyline level increases by about 70%, while nortriptyline decreases by 50%.

[78] The prescribing information warns that the combination of amitriptyline with monoamine oxidase inhibitors may cause potentially lethal serotonin syndrome;[12] however, this has been disputed.

[79] The prescribing information cautions that some patients may experience a large increase in amitriptyline concentration in the presence of topiramate.

[7][82] Amitriptyline causes an unusual type of interaction with the anticoagulant phenprocoumon during which great fluctuations of the prothrombin time have been observed.

Amitriptyline additionally acts as a potent inhibitor of the serotonin 5-HT2A, 5-HT2C, the α1A-adrenergic, the histamine H1 and the M1-M5 muscarinic acetylcholine receptors (see table in this section).

[120] Variability of the area under the curve in steady state is also high, which makes a slow upward titration of the dose necessary.

[127][128][58][130] The Clinical Pharmacogenetics Implementation Consortium recommends avoiding amitriptyline in patients who are CYP2D6 ultrarapid or poor metabolizers, due to the risk of a lack of efficacy and side effects, respectively.

[58] The Dutch Pharmacogenetics Working Group also recommends selecting an alternative drug or monitoring plasma concentrations of amitriptyline in patients who are CYP2D6 poor or ultrarapid metabolizers, and selecting an alternative drug or reducing initial dose in patients who are CYP2D6 intermediate metabolizers.

[131] Amitriptyline is a highly lipophilic molecule having an octanol-water partition coefficient (pH 7.4) of 3.0,[132] while the log P of the free base was reported as 4.92.

[134] Amitriptyline is prepared by reacting dibenzosuberane with 3-(dimethylamino)propylmagnesium chloride and then heating the resulting intermediate product with hydrochloric acid to eliminate water.

[136] According to research by a historian of psychopharmacology David Healy, amitriptyline became a much bigger selling drug than its precursor imipramine because of two factors.

[136][135] In the 2021 film The Many Saints of Newark, amitriptyline (referred to by the brand name Elavil) is part of the plot line of the movie.

[137] Amitriptyline is the English and French generic name of the drug and its INNTooltip International Nonproprietary Name, BANTooltip British Approved Name, and DCFTooltip Dénomination Commune Française, while amitriptyline hydrochloride is its USANTooltip United States Adopted Name, USPTooltip United States Pharmacopeia, BANMTooltip British Approved Name, and JANTooltip Japanese Accepted Name.

[138][139][140][141] Its generic name in Spanish and Italian and its DCITTooltip Denominazione Comune Italiana are amitriptilina, in German is Amitriptylin, and in Latin is amitriptylinum.