Amitriptyline is an antidepressant that can also help with insomnia, pain, irritable bowel syndrome (IBS), and many other disorders and diseases. However, it also causes many side effects that turn people away. These include sleepiness, weight gain, and impaired immune and sexual function. Read on to see whether or not this drug is right for you.

Disclaimer: By writing this post, we are not recommending this drug. Some of our readers who were already taking the drug requested that we commission a post on it and we are simply providing information that is available in the clinical and scientific literature. Please discuss your medications with your doctor.

What Is Amitriptyline?

Amitriptyline is a tricyclic antidepressant. It is otherwise known as Elavil or Endep [1, 2].

The tricyclic simply means that it contains three rings in its chemical structure [1].

This drug was at one point the most widely used antidepressant. In England, it was prescribed over 11 million times in 2013 [3, 1].

It is also among the most commonly used drugs against migraines [4].

Amitriptyline is converted to nortriptyline in the body, which is its active form. This drug works via many mechanisms hence the many benefits and side effects [5, 6].

Amitriptyline Mechanism of Action

  • It blocks the reuptake of both serotonin and noradrenaline. Therefore, both serotonin and noradrenaline stay in your system longer, which prolongs their effects [1].
  • It blocks the action of histamine in the brain, which results in drowsiness [7].
  • It blocks NMDA receptors and activates adenosine A1 and opioid receptors. All of these lead to pain relief [8, 9].

Uses of Amitriptyline

1) Depression

Two large meta-analyses of 186 and 194 studies compared amitriptyline against other tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). Both found that amitriptyline helped more people. However, it also produced more side effects than the other drugs [10, 11].

More people dropped out of the studies due to side effects compared to people taking other drugs [11].

With this drug, the antidepressant effects take a long time to take effect. Often, patients see improvements in other areas such as in insomnia or pain before noticing any antidepressant effects [12].

2) Migraines

A meta-analysis (12 studies, 1,006 participants) found that amitriptyline helped with migraines much better than placebo. The effects were better for those that took the drug for longer periods of time [4].

However, it causes more side effects than other drugs used to treat migraines, such as selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), or nortriptyline [4, 13].

Also, it doesn’t seem to help children with migraines [14, 15].

3) Pain Relief

Amitriptyline is mainly used to fight neuropathic pain, which is caused by damage to nerve tissue.

According to a meta-analysis (17 studies, 1,342 participants), this drug is beneficial for chronic neuropathic pain but only works in about 25% of people. It may help people with pain due to diabetes, shingles, spinal cord injury, or stroke [1].

However, many studies concluded that this drug was not any better for pain than other pain relievers/antidepressants such as nortriptyline, maprotiline, desipramine, pregabalin, or fluoxetine [16, 17, 18, 19, 18].

It is difficult to say if this drug will help as a pain reliever in a particular case because pain is caused by a variety of factors.

A good example is a study comparing amitriptyline to nortriptyline for pain caused by shingles. In the study (double-blind randomized controlled trial), 5 out of the 31 patients felt pain relief from amitriptyline, but not from nortriptyline. Four people felt pain relief from nortriptyline, but no effect from amitriptyline [16].

Amitriptyline applied to the skin can also relieve pain. Overall, 5% topical amitriptyline tends to have more local effects while 10% amitriptyline provides pain relief throughout the body [20].

In rats, this drug, unlike other pain relievers, was effective even when the nerves were damaged [21].

4) Fibromyalgia

Fibromyalgia is a continuous pain in “tender points” lasting over three months. It can lead to sleep loss, fatigue, and depression [22].

A meta-analysis (9 studies, 649 patients) showed that amitriptyline cured fibromyalgia in 36% of patients [22].

In two studies (double-blind randomized controlled trial) with 22 and 62 fibromyalgia patients, this drug improved sleep and decreased fatigue [23, 24].

However, one study (double-blind randomized controlled trial) found that it actually worsened fibromyalgia in 4 of the 19 patients [25].

5) Sleep Issues and Insomnia

In a study (double-blind randomized controlled trial) of 27 opiate withdrawal patients suffering from insomnia, amitriptyline induced sleep equally well as another hypnotic drug, lorazepam. However, amitriptyline caused less drowsiness after waking. This allowed patients to go about their mornings without feeling sluggish [26].

Amitriptyline increased total sleep by 15 minutes in a study (double-blind randomized controlled trial) of 14 patients. They also fell asleep faster. The study noted increases in slow-wave sleep, or deep sleep, which is when muscles recover and you re-energize. A week after going off of the drug, it was already harder to fall asleep, and the sleep was more restless [3].

This drug reduced rapid eye movement (REM) sleep in 30 patients (double-blind randomized controlled trial). REM sleep is abnormally long in patients with depression [27, 28, 29].

6) Anxiety

Amitriptyline decreased anxiety in a study (double-blind randomized controlled trial) of 55 patients awaiting surgery [30].

In a pilot study of 32 patients with anxiety and depression, this drug was effective in reducing anxiety [31].

Similarly, in two other studies, both with 30 patients, it reduced anxiety in insomnia patients [32, 33].

Anxiety is also common in people with migraines. Reducing migraines with amitriptyline can help rid people of their anxiety [34, 35].

This drug decreased anxiety in rats with migraines and under chronic stress [12, 36, 37].

Although useful for anxiety, it has a high dropout rate (30 to 50%) due to side effects. Patients tend to prefer selective serotonin reuptake inhibitors (SSRIs) and only move to tricyclic antidepressants when SSRIs fail [36].

7) Inflammation

Mast cells release inflammatory molecules, which can worsen disorders such as chronic fatigue syndrome. Amitriptyline decreased the release of inflammatory agents from mast cells by up to 98% [38, 39].

In rats, this drug also decreased levels of nitric oxide, IL1-beta, and TNF-alpha, which all increase inflammation [40, 41].

Amitriptyline decreased gut and kidney inflammation in rats [42, 43].

8) Gut Function

Functional dyspepsia is a disorder that causes pain in the upper stomach, discomfort, and fullness after meals. Fifty-one of the 96 patients with functional dyspepsia improved when given amitriptyline (double-blind randomized controlled trial) [44].

In a study (double-blind randomized controlled trial) of 28 volunteers, this drug increased gut transit time. This is important for gut function and better digestion. Amitriptyline also made it easier to drink large volumes of water without problems, which can be important for people suffering from diarrhea [45].

9) Irritable Bowel Syndrome (IBS)

There are three types of IBS: IBS with diarrhea (IBS-D), IBS with constipation, and mixed-stool pattern IBS. Tricyclic antidepressants work best against IBS-D [46].

Tricyclic antidepressants like amitriptyline increase the time that food stays in the gut, which allows for more solid defecations [46].

In 101 IBS patients given this drug, IBS improved in 66% of cases. The treatment decreased stomach pain, stomach discomfort, and stool frequency and improved the quality of life. However, side effects were frequent [46].

In a study (double-blind randomized controlled trial) of 54 patients, amitriptyline increased rates of full recovery (no more symptoms) [47].

A different study (double-blind randomized controlled trial) of 32 adolescents (12-18 years) showed similar results [48].

A meta-analysis and other studies all showed that this drug improved IBS [47, 49, 50].

10) Cystic Fibrosis Symptoms

Amitriptyline improved cystic fibrosis symptoms in a study (double-blind randomized controlled trial) of 19 patients. It also decreased levels of ceramides that tend to accumulate in the lungs of cystic fibrosis patients [51].

Another study double-blind randomized controlled trial) of 19 patients showed similar results [52].

11) Autism

In 50 children with autism, amitriptyline improved symptoms of [53]:

  • Excessive activity
  • Impulsivity
  • Aggression
  • Self-injury

Another study noted that amitriptyline could also help with irritability, gut problems, and insomnia possibly by increasing levels of BDNF, an important molecule for brain health [54].

12) Parkinson’s Disease

In rat models of Parkinson’s disease, amitriptyline decreased the loss of dopamine-sensitive neurons. It also protected neurons with tyrosine hydroxylase activity, which are decreased in patients with Parkinson’s disease [55, 56].

The drug also increased dopamine levels and improved movement in rats with Parkinson’s-like disease [57].

13) Chronic Cough

Amitriptyline was more effective in suppressing chronic cough than the cough-suppressant drug codeine/guaifenesin. In total, 14 of the 15 (randomized controlled trial) patients on amitriptyline saw some improvement. In fact, 11 of the 15 patients improved by 75 to 100% [58].

14) Vocal Cord Dysfunction

In a study of 62 patients with vocal cord dysfunction, amitriptyline improved symptoms in 90% of cases. People that have had the condition for less than 12 months showed greater and quicker results [59].

15) Cyclic Vomiting Syndrome

Cyclic vomiting syndrome is a disorder leading to constant nausea and vomiting. In a study (double-blind randomized controlled trial) of 64 children, 66% of patients given amitriptyline saw temporary recovery [60].

Animal and Cellular Studies

The following studies were done in animal models and on cells only.

16) Brain Health and Repair

The drug increased BDNF in rats with Alzheimer’s disease, which increased both their short and long-term memory [61].

Similarly, amitriptyline increased GDNF levels in brain cells. Increasing GDNF can improve neuron survival and protect neurons against stress [62, 63].

In cell studies, amitriptyline increased the production of brain-derived neurotrophic factor (BDNF) in brain cells (astrocytes and microglia). BDNF protects neurons and stimulates their growth. Increased BDNF is a potential mechanism by which amitriptyline produces antidepressant effects [64].

17) Cognitive Function

Amitriptyline improved cognitive function and decreased stress (HPA axis activity) in aged rats [65].

It slightly improved cognitive function in depressed rats [66].

The drug also improved cognitive function in rats with Alzheimer’s disease and in stressed baby rats [61, 67].

18) Stress

In rats, amitriptyline decreased the functioning of the hypothalamic-pituitary-adrenal (HPA) axis, which reacts to stress by releasing adrenocorticotropic (ACTH) hormone. Amitriptyline decreased stress-induced ACTH levels by 38% [68].

The HPA system also increases levels of corticosterone in response to stress. Rats stressed by separating them from their mothers saw no such increase when given amitriptyline [69].

19) Stomach Ulcers

In rats, amitriptyline reduced stomach ulcers caused by [70]:

The drug reduced the acidity of the stomach [70].

Another rat study found that this drug also decreased gut bleeding [71].

20) Cancer

Amitriptyline caused cancer cell death in rats with multiple myeloma tumors. Tumor growth decreased and the rats survived longer [72].

In cell studies, amitriptyline killed uterine leiomyosarcoma cancer cells [73].

It also damaged lung, cervical, and hepatoma cancer cells. The drug increased levels of reactive oxygen species (ROS), which caused damage to the cancer cells [74].

Cancer cells resist chemotherapeutic drugs using enzymes glutathione S-transferases pi (GST-π) and glutathione S-transferases alpha (GST-α). In cell studies, amitriptyline inhibited the effects of both GST-π and GST-α [75].

21) Histamine Regulation

It enhanced histamine-N-methyltransferase (HNMT) and diamine oxidase (DAO) activity in guinea pigs. Both of these enzymes degrade histamine [76].

This drug also caused mast cells to release less histamine, a potent allergy-inducing molecule [77].

22) Polycystic Ovary Syndrome (PCOS)

Amitriptyline improved the function of ovaries, increased the production of sex hormones (estradiol, testosterone, and progesterone), and restored the reproductive cycle of rats with polycystic ovaries, which might make it a potential treatment for PCOS [78].

Safety and Side Effects of Amitriptyline

Many users experience amitriptyline-related side effects. In one study (double-blind randomized controlled trial), 95% of patients receiving amitriptyline noted some adverse event [79].

The most serious side effect associated with amitriptyline is that it can increase the risk of suicidal thoughts and behavior, especially in children, adolescents, and young adults [80].

Common side effects are [1]:

  • Dry mouth
  • Drowsiness
  • Weight gain
  • Anticholinergic effects

Other side effects include:

  • Increased agitation [81, 82]
  • Stomach pain [79]
  • Constipation [46]
  • Rashes [79]
  • Nightmares [82]
  • Hyperpigmentation [83]
  • Confusion [84]
  • Delirium [84]
  • Seizures [84]
  • Irregular heartbeats [84]

1) Can Increase Weight Gain

Weight gain is especially common during the early stages of amitriptyline use. It can be seen as either an improvement for depressed patients who under-eat or as a symptom in people that eat when depressed [85].

Weight gain after discontinuing amitriptyline can occur as a side effect of the treatment [85].

2) Is Addictive

Antidepressants with sedative effects such as amitriptyline are vulnerable to abuse [84].

A meta-analysis of 14 case reports found that amitriptyline was the most abused among antidepressants. Abusers noted that taking this drug in large amounts produced a “high” feeling of euphoria and pleasantness [86].

This high can be especially addictive to narcotic users [84, 87].

A survey of 346 individuals in a methadone maintenance program found that 25% of the people were taking amitriptyline for the feelings of euphoria. Of those surveyed, 34% of the individuals had traces of it in their urine [87].

Even doses of 100 to 200 mg a day, which is not substantially high, can induce drug dependence [88].

Abusers may take amitriptyline because it can escape urine tests looking for narcotics [88].

Withdrawal symptoms can occur within days of discontinuing drug use. Withdrawing from amitriptyline can cause [89]:

  • Gut distress
  • Pain
  • Fatigue
  • Sleep disturbances
  • Mood changes
  • Movement disorders

Other side effects can include nightmares and worsen conditions such as [3]:

  • Irregular heartbeat and chest pain
  • Peptic ulcers

If withdrawal symptoms occur, it is advised to restart amitriptyline and wane off of the drug [89].

3) May Worsen Fibromyalgia

One study (double-blind randomized controlled trial) found that amitriptyline worsened fibromyalgia in 4 of the 19 patients [25].

4) Increases Sleepiness

A study (double-blind randomized controlled trial) of 14 male patients found that taking this drug produced drowsiness and sluggishness in the mornings [3].

Another study (double-blind randomized controlled trial) of 14 volunteers found that amitriptyline decreased next-day alertness and increased daytime sleepiness [90].

5) May Cause Coenzyme-Q Deficiency

Amitriptyline induced coenzyme-Q10 deficiency, oxidative stress, and damage to mitochondria (the energy-producing organelle in cells) in 40 depressed patients [91].

It strongly decreased coenzyme-Q10 levels in the lungs and liver of rats [92].

6) May Trigger Parkinson’s Disease

Studies report that a history of antidepressant use is strongly correlated with the occurrence of Parkinson’s disease [93].

In rats, amitriptyline increased neuron damage in the brain (substantia nigra). The drug caused movement dysfunction in the rats, a common symptom of Parkinson’s disease [93].

7) May Suppress the Immune System

This drug decreased levels of white blood cells in burned rats by 40%. White blood cells protect the body against foreign invaders [94].

8) May Impair Sexual Function and Decrease Libido

In 8 studies (randomized controlled trial), the average frequency of sexual dysfunction due to amitriptyline in men was 11.9% and 1.7% in women. Depressed patients were more likely to experience sexual dysfunction [95].

The drug impaired libido (sex drive), in both men and women, but the effect was more pronounced in women [95].

9) May Impair Driving

In a study (double-blind) of 17 volunteers, this drug decreased concentration while driving [96].

10) Amitriptyline and Fatal Overdoses

A study reviewing 112 cases of fatal self-ingested overdose (1983-1987) found that amitriptyline was the most common tricyclic antidepressants in a fatal overdose situation [97].

Contraindications of Amitriptyline

Amitriptyline should be taken with caution in pregnancy. Amitriptyline and nortriptyline can both cross the placenta and be toxic to the fetus [98, 99].

Newborns that have been exposed to tricyclic antidepressants may display withdrawal symptoms [100].

Complications such as pre-term delivery and increased blood pressure can also occur following tricyclic antidepressant use [100].

This drug can also be transferred via breast milk. A case study showed that breastfeeding while on amitriptyline can cause poor feeding and extreme sedation in the child [101].

Amitriptyline Use During Pregnancy and Breastfeeding

Taking amitriptyline while pregnant does not appear to pose a greater risk of overall birth defects, complications, or miscarriage during pregnancy. However, one cohort study found that it increased the occurrence of “certain organ-specific defects” by a small percentage [102].

The drug is found in small amounts in the breast milk, however, it is safe to take while breastfeeding and there are no reports of it affecting growth or development of the child [103].

Drug Interactions of Amitriptyline

Amitriptyline inhibits cytochrome P450 enzymes (CYP1A2, CYP2D6, and CYP2C9) at higher rates than other TCAs such as desipramine and nortriptyline. This causes more side effects and worse drug interactions [13].

This drug should not be taken with:

  • Antipsychotics, such as quetiapine (Seroquel) and chlorpromazine (Largactil, Thorazine) [104, 105]
  • Antifungals such as terbinafine (Lamisil) and fluconazole (Diflucan). They can increase levels of amitriptyline to toxic levels even 6 months after use [106, 107, 108]
  • Valproic acid (Depakote) [109]
  • Rifampicin (Rifadin, Rimactane), an antibiotic [110]
  • Phenprocoumon (Marcoumar), a drug that keeps blood from clumping [111]

Forms and Dosage of Amitriptyline

The drug is available in tablets (10, 25, and 50 mg) or as an oral solution [1].

The stronger tablets will have stronger effects but are also more likely to cause side effects. It is recommended to start off small and slowly increase the dosage until side effects start to occur.

Because it can cause drowsiness, the drug is often taken at night [1].

Overdose

Overtaking this drug can lead to confusion, delirium, and seizures. Overdosing can produce irregular heartbeats (heart arrhythmia) and can be fatal [84].

Deaths due to amitriptyline are fairly common. Most of these overdose deaths are suicidal, although in some cases it can be due to addiction [112].

Amitriptyline Compared to Other Medications

Amitriptyline vs. Nortriptyline

Both are equally effective in relieving pain, headaches, and migraines. However, amitriptyline had more side effects; thus, nortriptyline may be more useful [5, 1, 13, 13].

Amitriptyline vs. Benzodiazepines

Amitriptyline produced better antidepressive effects than adinazolam (Deracyn), a benzodiazepine. However, it also caused more side effects [113].

Amitriptyline was also more effective than diazepam (Valium) [113].

Both amitriptyline and Xanax (alprazolam) drugs were effective against depression in 80 patients (double-blind randomized controlled trial). Amitriptyline worked faster, but also caused more people to drop out of the study, even though the overall side effects were similar between the two drugs [114].

Another study (double-blind randomized controlled trial) of 130 patients found that Xanax was the quicker of the two and was better in curing anxiety [115].

Amitriptyline vs Selective Serotonin Reuptake Inhibitors (SSRIs)

In a study (double-blind randomized controlled trial) with 148 patients, paroxetine (Paxil, Pexeva) was better in relieving pain, improving quality of life, sleep, and emotional well-being [116].

Both drugs were effective in treating depression in a study (double-blind randomized controlled trial) of 40 patients. However, paroxetine produced a quicker response. Side effects were similar [117].

Amitriptyline vs. Opioids

A study (double-blind randomized controlled trial) of 45 patients found that tramadol (Ultram) and meperidine (Pethidine), stopped shivering quicker than amitriptyline. The response rate for amitriptyline was only 13% compared to 87% for tramadol and 93% for meperidine [118].

When used as an anesthetic, amitriptyline was more sedative than meperidine and produced fewer side effects [119].

Synergies with Other Drugs/Supplements

One study (double-blind randomized controlled trial) of 63 patients noted that amitriptyline with melatonin reduced pain better than amitriptyline alone [82].

Amitriptyline and fluoxetine (Prozac, Sarafem) work better when combined to improve pain, well-being, and sleep in fibromyalgia [25].

Combining amitriptyline with warfarin increases and prolongs the effects of warfarin (blood thinning) [120].

Amitriptyline increases the blood levels and effectiveness of oxycodone [121].

Chlordiazepoxide (Librium) increases the antidepressant effects of amitriptyline [122].

Genetics Related to Amitriptyline

CYP2D6

CYP2D6 ultrarapid metabolizers should avoid the use of tricyclic antidepressants due to the potential lack of effectiveness (the drug gets degraded too quickly). They should consider an alternative drug not metabolized (broken down) by CYP2D6 [123].

For CYP2D6 intermediate metabolizers, a 25% reduction of the starting dose is recommended [123].

CYP2D6 poor metabolizers have higher than expected blood concentrations of tricyclic antidepressants when given usual doses. They should avoid the use of this drug because of the potential for side effects. If the use of amitriptyline is warranted, it is recommended to take 50% of the starting dose to avoid side effects [123].

In a pilot study of 31 patients, patients with normal or ultrarapid metabolism of amitriptyline (CYP2D6) displayed fewer side effects [124].

However, a study of 100 patients with major depressive order found that those with CYP2D6 ultrarapid metabolism were more likely to drop out from the study when drug doses were low. This was most likely due to lack of effect [125].

CYP2C19

CYP2C19 ultrarapid metabolizers should avoid the use of this drug due to reduced effectiveness. They should consider an alternative drug not metabolized by CYP2C19, such as nortriptyline or desipramine [123].

CYP2C19 poor metabolizers, should avoid the drug or consider a 50% reduction of the starting dose while monitoring drug blood levels to avoid side effects [123].

Amitriptyline for Dogs and Cats

Interestingly, amitriptyline is prescribed for dogs with chronic or nerve pain after other painkillers fail [5, 126].

Injecting the drug straight into the bloodstream can induce side effects such as [127]:

  • Sedation
  • Lack of muscle coordination (ataxia)
  • Rapid heart rate (transient tachycardia)
  • Excessive hunger (polyphagia)
  • Vomiting

Oral dosing can cause vomiting if the dogs are fasted [5].

A recommended dose for dogs is 1-4 mg/kg [127].

In cats, this drug given orally is more effective than over the skin [128].

The drug cured inflammation of the bladder in 9 of 15 cats. However, some side effects included [129]:

About the Author

Biljana Novkovic - PHD (ECOLOGICAL GENETICS) - Writer at Selfhacked

Dr. Biljana Novkovic, PhD

PhD (Ecological Genetics)

Biljana received her PhD from Hokkaido University.

Before joining SelfHacked, she was a research scientist with extensive field and laboratory experience. She spent 4 years reviewing the scientific literature on supplements, lab tests and other areas of health sciences. She is passionate about releasing the most accurate science & health information available on topics, and she's meticulous when writing and reviewing articles to make sure the science is sound. She believes that SelfHacked has the best science that is also layperson-friendly on the web.

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