Trazodone is an FDA-approved treatment for depression, anxiety, and some forms of insomnia. It is also sometimes used “off-label” to relieve certain symptoms of bulimia, dementia, and alcoholism. Read on to learn more about the various medical uses, mechanisms, and potential side-effects of this drug.
Disclaimer: This post is not a recommendation or endorsement for trazodone. This medication is only approved for the treatment of certain specific medical disorders, and can only be taken by prescription and with oversight from a licensed medical professional. We have written this post for informational purposes only, and our goal is solely to inform people about the science behind trazodone’s effects, mechanisms, and current medical uses.
What is Trazodone?
Trazodone is a sedative and antidepressant medication belonging to the class of serotonin receptor antagonists and reuptake inhibitors (SARIs). In simpler words, this means it has two main effects. For one, it prevents serotonin from being taken back up into neurons after it is released, which increases the total amount of serotonin available to the brain. Secondly, it also inhibits the activity of certain specific types of serotonin receptors (such as 5HT2a and 5HT2c) [1].
This medication has been approved for the treatment of depression, anxiety, and insomnia, which are its primary medical uses. It also has numerous “off-label” uses to treat conditions such as bulimia nervosa, aggressive behaviors, and sexual dysfunctions (“off-label” refers to when doctors use a drug to treat a health condition that a drug hasn’t been officially approved for).
Trazodone works rapidly, and the effects are often evident within the first week of treatment [2].
Not only is trazodone effective, but it also shows some key advantages over other antidepressants regarding therapeutic efficacy, due to its multifunctional properties (more on this below) [3, 4].
Data suggests that trazodone has less potential for short-term abuse than other drugs like triazolam and zolpidem [5].
Mechanism Of Action
Trazodone is a dose-dependent multifunctional drug, meaning that it has more than one therapeutic mechanism. At low doses (50-100 mg) it acts as a hypnotic, while at higher doses (150-600 mg) it has antidepressant properties [6].
At low doses it:
- Blocks serotonin 5HT2 (5-HT2A and 5-HT2C), thus decreasing the arousing effect of serotonin and leading to an increase in slow-wave sleep / EEG slow-wave activity [1, 7].
- Blocks α-adrenergic receptors, decreasing the arousing effect of noradrenaline [8, 9].
- Blocks histamine H1 receptors, decreasing the arousing effect of histamine [10].
At high doses it:
- Blocks the serotonin reuptake transporter (SERT), which increases serotonin that stimulates 5-HT1A receptors exerting its antidepressant effects [11, 12].
- Its active metabolite, methyl-chlorophenylpiperazine (mCPP), also stimulates 5-HT1A receptors, leading to wakefulness-promoting effects However, these effects might be variable due to genetic variability in mCPP-related genes which are relatively common in the general population [9, 13].
Official Medical Uses of Trazodone
Trazodone has a number of primary medical uses, which have been fully approved by the FDA. Although this means that the evidence for its efficacy is very strong, always keep in mind that this is a prescription medication that must only be used under the direction and supervision of a qualified medical professional.
1) Helps Treat Depression
Major depressive disorder (MDD) is the leading cause of disability, affecting approximately 6.7% of the population in the US and over 350 million people worldwide. As an atypical antidepressant, trazodone is FDA-approved and frequently used to treat depression [14, 15].
In various short-term trials, trazodone and mirtazapine were reported to be beneficial in treating patients with moderate-to-severe depression [16].
In a double-blind randomized controlled (DBRC) study of 108 patients between 20-28 years old, trazodone was found to be effective in reducing common symptoms of depression such as lack of sleep and motivation, and promoting recovery [17].
Another DBRC study of 127 patients with depression compared trazodone to amitriptyline and placebo. Trazodone outperformed the placebo in the treatment of depression and anxiety. Trazodone also produced fewer side effects than amitriptyline [18, 19].
In another DBRC study comparing bupropion and trazodone, 124 patients were randomly assigned to receive one of these two medications. While the overall efficacy of the drugs was similar, the group that received trazodone had a significant improvement after only 7 days, most likely due to trazodone’s ability to promote better sleep [20].
2) Improves Insomnia
Prolonged insomnia increases the risk for depression, and insomnia is often treated with low-dose antidepressants like trazodone [21, 22].
At low doses (50-100 mg), trazodone acts as a hypnotic, which helps treat sleep disorders [23, 22].
Due to its sedative properties, it is the second-most commonly-prescribed medication for the treatment of insomnia [24].
Patients with Alzheimer’s disease also often suffer from sleep disorders. In a double-blind randomized controlled study, Alzheimer’s patients received either trazodone or placebo, and the results showed that trazodone significantly improved their sleep [25].
Trazodone also improved sleep quality in patients with other conditions, such as fibromyalgia and various mood disorders [26, 27].
In a double-blind study of 6 men between 18-32 years old, trazodone significantly enhanced deep sleep [28].
3) Improves Anxiety and PTSD Symptoms
Anxiety disorder is characterized by worried or panicked feelings that are frequent, excessive, and difficult-to-control. It is often accompanied by depression, and is commonly treated in a similar manner [29].
Due to its hypnotic and sedative effects, trazodone has been used to treat various anxiety disorders [10].
In a study of 6 patients, trazodone reduced the intensity of PTSD symptoms including agitation, insomnia, severe anxiety, fear, and self-destructive behavior in 66% of the patients [10].
According to a survey of 60 PTSD patients, trazodone decreased nightmares and improved overall sleep in ~75% of patients [30].
Interestingly, trazodone also treats anxiety symptoms in animals and is, therefore, used in various veterinary practices. For example, according to one study, trazodone significantly improved anxiety in cats during transportation [31].
Off-Label Medical Uses of Trazodone
Occasionally, doctors will prescribe medications to help treat conditions that fall outside of the official uses approved by the FDA — also known as “off-label” drug use [32]. Usually this is done because there is actually decent evidence that the drug may help, although this evidence might not be quite strong enough to get full FDA approval (which generally has very strict requirements).
As always, however, always remember that the decision to use medications in this way can only be made by a licensed medical professional.
1) Treating Alcoholism
When treating alcohol addiction with oral medication, the treatment primarily focuses on alleviating the withdrawal symptoms — which in the case of alcohol abuse and many other drugs can be quite severe [33].
Trazodone has shown to be effective in decreasing depressive and anxious symptoms as well as cravings for alcohol in patients with alcohol withdrawal symptoms for more than 35 years [34].
Trazodone was effective in treating 17 alcoholic patients’ withdrawal symptoms by blocking norepinephrine receptors [34].
One double-blind randomized controlled study of 16 patients with alcoholism suggested that trazodone is an option to treat post-withdrawal symptoms and prevent alcohol relapses [35].
In a study where both the researchers and the patients knew which medication was being administered, trazodone was reported to reduce relapse rates and helped maintain alcohol abstinence in 60% of the patients [36].
2) Treating Bulimia Nervosa
In a double-blind randomized controlled study of 42 women with bulimia nervosa, trazodone was reported to significantly decrease the frequency of binge eating and vomiting [37].
In 4 out of 10 patients, episodes of binge eating and vomiting completely disappeared, while in 2 of the patients, the episodes were decreased by 55-99%. Trazodone was also the preferred medication due to its relatively low toxicity compared to other drugs used to treat eating disorders [38].
Trazodone also contributed to the improvement of dental abnormalities and damaged throat, which are consequences of bulimia nervosa [39, 40].
3) Treating Adjustment Disorders
An adjustment disorder is characterized by stress, sadness, hopelessness, and physical symptoms following an overreaction to a stressful event, probably due to an inability to cope.
The symptoms of adjustment disorders often overlap with those of major depressive disorder, and include prolonged feelings of hopelessness, lack of motivation, anxiety, sleep problems, and lack of energy. Due to these overlapping symptoms, antidepressants such as trazodone may have potential for treating adjustment disorders [41, 42].
One prospective cohort study reported that after 56 days of trazodone therapy, 34 out of 52 patients showed improvements in symptoms of anxiety, self-esteem, insomnia, and aggressive behaviors [42].
Similarly, a double-blind randomized controlled study of 18 cancer patients diagnosed with adjustment disorder reported that trazodone was more successful in reducing stress, sleep disorders, and lack of appetite compared to clorazepate (another sedative) [43].
4) Treating Aggressive Behavior
Despite being a normal human behavior when in moderation, excessively emotional or impulsive forms of aggression are often treated with medications such as antidepressants, mood stabilizers, or antipsychotics to prevent self-harm [44].
Aggressive behaviors are thought to be at least partially caused by a deficiency of serotonin. By blocking serotonin reuptake, trazodone increases the amount of serotonin in the brain, thereby reducing aggression [45].
A study of 3 individual patients (with different levels of aggression) concluded that trazodone was effective for decreasing aggressive behavior in children. In each of the 3 cases studied, aggressive behaviors relapsed after treatment discontinuation, further demonstrating that trazodone was responsible for their improvement [45].
Aggressive and impulsive behaviors significantly improved in 13 out of 22 hospitalized children who were unresponsive to several other types of antidepressants [46].
Trazodone has long-term effects, and is used to control behavioral disturbances in children [46].
5) Canceling Out Sexual Side-Effects From SSRIs
Sexual dysfunction is one of the potential side-effects of antidepressant therapy. For example, selective serotonin reuptake inhibitors (SSRIs) have been reported to cause sexual dysfunctions in up to 70% of the users [47, 48].
One of trazodone’s potential strengths is that, unlike many other common antidepressant medications, it doesn’t appear to cause these types of side-effects in the first place, making it a potentially superior treatment option for people who experience SSRI-related sexual dysfunction [1].
Additionally, a study in depression patients who were currently experiencing sexual dysfunction due to treatment with SSRIs reported that adding trazodone to their treatment caused these sexual side-effects to resolve, leading to a recovery of their normal sexual function [49].
6) Treating Symptoms of Dementia
Dementia causes a long progressive decline in cognition and overall functioning, and can be quite difficult to treat. Hence, other common symptoms of dementia — such as insomnia and aggression — are often treated instead [50].
In one randomized controlled trial of 26 dementia patients, trazodone significantly decreased irritability, agitation, depressive symptoms, and eating disorders in 10 of the patients [51].
In another study, 18 out of 22 dementia patients with behavioral complications showed significant improvement with trazodone. The authors of this study concluded that trazodone may have potential as an alternative to other common medications, such as neuroleptics or benzodiazepines [52].
Side-Effects, Contraindications, and Potential Drug Interactions
Side-Effects
While trazodone is one of the more tolerable antidepressants, like any drug it is not without its share of potential side-effects.
As always, the only responsible way to minimize the risk of adverse side-effects is to discuss all treatment options with your doctor, and to take any medications they prescribe you exactly as directed.
Some common side-effects of trazodone include drowsiness, dizziness, stomach upset, vomiting, weakness, decreased alertness, weight loss, tremor, dry mouth, blurred vision, bowel movement disturbances, and delayed urine flow [53, 54].
Less frequently, trazodone can cause the following severe side effects:
- Cardiovascular issues / heart disorders [24]
- Priapism (uncontrollable, painful, and long-lasting erections) [55, 56, 57]
- Auditory hallucinations [58]
- Headaches [59]
Trazodone Withdrawal
Like many antidepressants, people who are prescribed trazodone but later decide to stop taking it are generally advised to taper off gradually, rather than stopping all medication suddenly. This is done to minimize the potential of withdrawal symptoms, and is always done under the supervision of a doctor. Nonetheless, there have been some reported cases of withdrawal-like symptoms in patients who tapered off their use of trazodone [60, 61, 62, 63]. Although this generally rare, it is nevertheless something to be aware of if you are prescribed it.
Contraindications
As with many medications, there are some other factors that can interfere with taking trazodone, and which could cause potentially severe side-effects if not taken into account. For this reason, there are a few indicators that a person should actively avoid taking trazodone.
As always, the best way to avoid complications from trazodone is to use it only as directed by your doctor, who will take these potential factors into account when deciding whether or not to prescribe it for you.
Some of the known contraindications include [64]:
- People taking monoamine oxidase inhibitors (MAOIs), such as linezolid and intravenous (IV) methylene blue should not take trazodone, due to an increased risk of serotonin syndrome (dangerously elevated levels of serotonin in the brain / nervous system).
- Caution should be used in those who have kidney and liver function impairment.
Use in Pregnancy and Breastfeeding
Trazodone has been reported to be safe during pregnancy and has not been found to increase the occurrence of birth defects. Although the exposure of babies to trazodone via breast milk is minimal, you should tell your doctor if you’re breastfeeding before starting the treatment [65, 66].
Drug Interactions
There are a few known interactions between trazodone and other medications that may potentially cause issues [67].
As always, the best way to minimize your risk is to keep your doctor up-to-date about any ongoing medications you are taking.
Some of these interactions include:
- Fluconazole (for fungal infection) can cause prednisone toxicity because both drugs are metabolized by the CYP3A4 enzyme [68].
- Clonidine (for blood pressure) excessively decreased blood pressure in a 12-year-old boy, which caused a syncopal episode associated with hypotension, bradycardia, and sedation [69].
- Warfarin (blood thinners) affected the blood clotting effect of warfarin in 3 clinically relevant cases [70].
Other drug interactions have also been documented. For example, consuming alcohol while on trazodone has been reported to significantly impair performance on manual (dexterity-based) tasks — significantly more than just alcohol alone — suggesting that these drugs may interact with other and potentially exaggerate their negative effects. For this reason, it is often advised that people who are currently on antidepressant medications should avoid consuming alcohol altogether [71].
Forms and Dosage of Trazodone
Note: the information below is presented strictly for educational purposes, and should under no circumstances be used to replace the guidance or advice of your personal doctor. Dosing any psychoactive medication is a complicated issue — and only a fully licensed medical expert is qualified to decide what the optimal dose for each patient is, based on their particular symptoms and individual medical history.
Trazodone is available in both immediate- and extended-release formulations, which typically come in doses of 50, 100, 150, or 300mg. In general, the daily dosages used for treating depression tend to be higher than those used for “off-label” uses, such as treating insomnia [9].
In all cases, however, the particular dosage used is something that should always be left to the discretion of the attending physician.
In most cases, doctors will advise against taking trazodone in the evening, as it can interfere with sleep onset and daytime wakefulness levels when taken too close to a person’s normal bedtime [9].
