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Sertraline interactions to avoid

Sertraline can have significant interactions with other drugs that have serotonergic characteristics, antiplatelet medications, and medications that are metabolized via common pathways
Marissa Walsh headshot
By | Oct. 30, 2023
Rx pill bottle and prescription pad: Sertraline interactions to avoid
In this article:

Sertraline, otherwise known under its brand name, Zoloft, is an antidepressant medication in the selective serotonin reuptake inhibitor (SSRI) class. Sertraline carries multiple Food and Drug Administration (FDA) approvals, including major depressive disorder (MDD), obsessive-compulsive disorder (OCD), panic disorder, posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), and social anxiety disorder. In addition, sertraline is prescribed for several other off-label indications, including binge eating disorder and body dysmorphic disorder, even sexual dysfunction conditions like premature ejaculation.

Mental health conditions are very common, with 1 in every 6 adults experiencing depression at some time in their life. Those who experience depression often experience other mental health conditions, including anxiety disorders. Sertraline, with its use for many indications, serves as an excellent option in the management of these conditions. However, awareness of drug interactions with other medications, both prescription drugs and those obtained over-the-counter, as well as foods that can affect sertraline’s effectiveness or cause adverse effects, is critical. 

Key takeaways:

  • Sertraline can seriously interact with other medications with serotonergic properties, products with antiplatelet properties, and medications metabolized by common pathways. 
  • Adverse effects that can result from these serious interactions include the development of serotonin syndrome and the enhancement of properties of other medications that can result in adverse effects. 
  • Sertraline and many medications may interact with one another on a less serious scale based on the way the body metabolizes medications; many medications are known to inhibit metabolism by one important hepatic pathway that sertraline is metabolized, resulting in increased circulating levels of serotonin the body. Similarly, medications that induce sertraline metabolism will decrease the circulating amount of sertraline. Depending on the degree of inhibition of this pathway, different severity of interactions and ultimately effects may occur. 

In the event of a sertraline interaction, it is important to seek advice from a healthcare professional as soon as possible. The levels of severity have a broad range, so any new signs and symptoms noticed should be discussed with a medical practitioner instead of brushed off, no matter how mild at first, as the level of interaction could intensify if not addressed immediately. 

Sertraline drug interactions

Sertraline can interfere with many medications. Still, those with the most serious potential include those that also enhance serotonergic activity, medications with antiplatelet effects, and any medication that alters the metabolism of sertraline—be it inhibiting or inducing the metabolism. While many interacting agents are other prescription medications, some over-the-counter products can cause concern. When taking sertraline, always discuss a complete list of medications-including supplements and herbals-with a healthcare professional to ensure no serious drug interactions exist. 

Pimozide

Pimozide is a type of antipsychotic known as a first-generation or typical antipsychotic. The use of pimozide concurrently with sertraline is contraindicated, as the combination increases the body’s overall exposure to pimozide significantly. This can result in serious cardiac side effects, including QT interval prolongation and arrhythmias, which can end in cardiac death if not corrected immediately. Never combine sertraline with pimozide. 

Monoamine oxidase inhibitors (MAOIs) 

Monoamine oxidase inhibitors, or MAOIs, were the first class of antidepressants developed. These medications work by blocking an enzyme, monoamine oxidase, which removes serotonin from the brain. By inhibiting this enzyme, increased serotonin levels remain available to regulate mood, allowing feelings of focus, emotional stability, and overall happiness. The use of these medications requires diet restrictions and comes with many drug interactions. Therefore, MAOI use has mostly been replaced by newer antidepressants, like sertraline, which are safer and cause fewer side effects. In some individuals, however, the MAOI class can relieve depression in treatment—refractory scenarios so that their use isn’t entirely defunct. Some MAOIs have additional indications, like selegiline used as adjunctive therapy for the management of Parkinson’s disease. 

Other medications exist that inhibit monoamine oxidase as a secondary mechanism to a primary, intended effect. Suppose any medication with the ability to inhibit monoamine oxidase is used in combination with SSRIs like sertraline. In that case, the serotonergic effect of MAOIs can be enhanced, which could result in a serious medical condition known as serotonin syndrome. Patients taking MAOIs should not concomitantly take SSRIs, and vice versa. A minimum of a 2-week washout period should be permitted between discontinuation of a medication in one of the drug classes and initiation of a drug in the other, with some longer recommendations for specific agents within these classes. If a patient experiences symptoms of serotonin syndrome, such as shivering, tremor, confusion, or low blood pressure, they should immediately seek emergency medical treatment. 

MAOIs include:

  • Isocarboxazid (Marplan)
  • Phenelzine (Nardil)
  • Selegiline (Emsam)
  • Tranylcypromine (Parnate)

Additional medications that inhibit monoamine oxidase but are not antidepressants include:

  • Methylene blue
  • Linezolid (Zyvox)

Serotonergic Agents

Many medications have the ability to enhance serotonin in the brain in multiple mechanisms. While MAOIs decrease serotonin metabolism, other mechanisms include inhibition of serotonin reuptake or direct serotonin receptor stimulation, which can be an intentional outcome but also a secondary mechanism. SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs) all intentionally increase the concentration of serotonin, and it isn’t recommended to take any combination of medications that do so concomitantly given the risk of serotonin syndrome and/or serotonin toxicity. It is important to note that individuals may develop serotonin syndrome and/or serotonin toxicity on only a single serotonergic agent. Therefore, any onset of symptoms should be managed by immediate communication with a healthcare professional. 

Selective serotonin reuptake inhibitors, in addition to sertraline, include: 

  • Citalopram (Celexa)
  • Escitalopram (Lexapro)
  • Paroxetine (Paxil)
  • Fluoxetine (Prozac)
  • Fluvoxamine
  • Vilazodone
  • Vortioxetine

Serotonin and norepinephrine reuptake inhibitors (SNRIs) include: 

  • Venlafaxine (Effexor)
  • Duloxetine (Cymbalta)
  • Desvenlafaxine succinate (Pristiq)

Tricyclic antidepressants (TCAs) include:

  • Amitriptyline
  • Clomipramine
  • Desipramine
  • Doxepin
  • Imipramine
  • Lofepramine
  • Nortriptyline
  • Trimipramine

Antiplatelets/Anticoagulants

Serotonin is transported by platelets and released upon platelet activation. Platelet activation induces constriction of injured blood vessels and enhancement of platelet aggregation to ultimately form clots. Medications that block the serotonin reuptake in the central nervous system inadvertently block the reuptake of serotonin in platelets. The result is reduced serotonin content in platelets, in some reports to as low as 1% as pre-treatment levels. An association between SSRIs and hemorrhage has been reported, but the overall risk of bleeding is considered to be quite low. It is therefore not entirely contraindicated, but the risks of therapy with sertraline may outweigh the benefits for certain patients taking antiplatelet medications—particularly those with a history of bleeding at baseline and those taking what is considered higher potency SSRIs, which includes sertraline. Any symptoms of an internal bleed while taking sertraline should be treated as a medical emergency, and emergency services should be contacted immediately.

Antiplatelet drugs include:

  • Aspirin
  • Cilostazol (Pletal)
  • Clopidogrel (Plavix)
  • Dipyridamole (Persantine)
  • Dipyridamole extended-release/aspirin (Aggrenox)
  • Prasugrel (Effient)
  • Ticagrelor (Brilinta)
  • Vorapaxar (Zontivity)

Anticoagulant drugs include:

  • Apixaban (Eliquis)
  • Dabigatran (Pradaxa)
  • Edoxaban (Savaysa)
  • Rivaroxaban (Xarelto)
  • Warfarin (Coumadin)

NSAIDs

Nonsteroidal anti-inflammatory agents (NSAIDs) can inhibit platelet aggregation and secretion by inhibiting the enzyme cyclooxygenase-1 (COX-1). Many reports have found an increase in both gastrointestinal and intracranial bleeding when NSAIDs are combined with SSRIs. Still, it is important to recognize the limitations in much of the published data. The analyses are retrospective and lack uniformity in definitions and study designs. However, the dual mechanism of platelet function should not be entirely dismissed. Some analyses suggest the highest risk with high potency SSRIs, which includes sertraline. Similarly, the use of COX-2 selective NSAIDs may reduce the risk. 

NSAIDs are a class of medications that include: 

  • Diclofenac
  • Etodolac
  • Ibuprofen
  • Indomethacin
  • Ketorolac
  • Meloxicam
  • Nabumetone
  • Naproxen
  • Sulindac

Amphetamines

Medications known as amphetamines, which are a type of central nervous system (CNS) stimulants that increase the levels of dopamine, norepinephrine, and serotonin in the body to improve focus and increase alertness. These medications may also enhance the serotonergic effects of sertraline, which could result in serotonin syndrome. Patients on both medications should be monitored closely, and a lower amphetamine dose should be considered if they need to be used in combination. 

Amphetamines include:

  • Amphetamine
  • Benzphetamine
  • Dextroamphetamine
  • Lisdexamfetamine
  • Phentermine

Metabolism interactions

Many sertraline drug interactions occur due to medications referred to as “CYP3A4 inducers,”—which are medications that increase the activity of a common enzyme (cytochrome P450)—involved in the metabolism of many medications, including sertraline. CYP3A4 inducers are ubiquitous and rev up the enzyme to varying degrees. Strong CYP3A4 inducers include anticonvulsant medications like phenobarbital, phenytoin, and carbamazepine. These medications will decrease the blood levels of sertraline, which may necessitate dose increases, but minimally close monitoring for reduced antidepressant effects. 

Other strong CYP3A4 inducers include: 

  • Rifampin
  • Ketoconazole

Moderate CYP3A4 inducers include:

  • Diltiazem
  • Erythromycin
  • Medications for fungal infections, such as fluconazole, isavuconazole, and posaconazole
  • Letermovir
  • Verapamil

Bupropion is another type of antidepressant in a slightly different class than sertraline, known as a dopamine-norepinephrine reuptake inhibitor. There have been cases describing toxic effects when combining SSRIs, like sertraline, with bupropion suggesting that using these agents together increases the risk of serious side effects like serotonin syndrome. The mechanism(s) for any possible interaction remains unclear; given bupropion’s mechanism of action, it is unlikely that its use would cause any direct increased serotonin activity that could account for the reported side effects. A more likely scenario is an interruption of the metabolism of sertraline, given bupropion’s tendency to inhibit another CYP enzyme known as CYP2D6, which is at least in part responsible for the clearance of the active form of sertraline from the body. 

It’s important to note that these lists are not all-inclusive. Always check with a healthcare professional for any drug-drug interactions.

Sertraline food interactions

Sertraline, and other SSRIs, have been associated with weight gain. It’s not entirely known if this is related to improvement in the symptoms of depression, allowing an appetite to return to a healthy level in those who had experienced weight loss, or due to its effects on serotonin receptor activity which may regulate appetite and weight. Incorporate a healthy diet full of nutritious foods and follow an exercise plan to fit your lifestyle. If weight gain becomes a problem, discuss your options with a healthcare professional or consult a registered dietitian.

Sertraline and grapefruit 

Grapefruit and its juice interact with many prescription drugs. It is known through scientific studies to inhibit an important enzyme in the metabolism of many medications, known as cytochrome P450 3A4 or CYP3A4. CYP3A4 plays a role in metabolizing more than 65% of all drugs. When grapefruit juice inhibits the action of the enzyme, more of the drug is available to remain in the blood and throughout the body. This interaction is present between methylprednisolone and grapefruit juice, with studies demonstrating that high amounts of grapefruit juice increase blood levels of sertraline. Persons who regularly consume grapefruit juice and go on to take sertraline should be aware of this interaction and monitor themselves for increased side effects related to the antidepressant. 

Other sertraline interactions

Sertraline has potentially serious side effects with many other consumables we may take for granted as “safe.” Always investigate by discussion with a knowledgeable healthcare professional, like a pharmacist, when starting anything new while on sertraline. 

Sertraline and alcohol 

Alcohol interacts with many prescription drugs, and sertraline is one of them. Some of the common side effects of sertraline include impairment of cognitive and/or motor performance, so there is great concern that combining this medication with alcohol may cause further enhancement of these potential side effects. In addition, alcohol can make the mental condition being managed with sertraline worse, such as anxiety, fatigue, and irritability. Similarly, it is important to understand that the oral solution formulation of sertraline contains 12% alcohol and, if taken with disulfiram, can cause a serious reaction. 

Sertraline and herbal supplements

Herbals, like Syrian Rue (also known as Ayahuasca) or St. John’s wort, can increase the risk of serotonin syndrome. Always discuss with a healthcare professional a complete list of products consumed, including vitamins and herbal supplements purchased over the counter. 

How to minimize sertraline interactions

Always carry a complete list of medications, including supplements, on your person. Any time you’re inquiring about medical advice, provide this list so that a thorough review and drug information assessment can be performed to minimize the risk of drug interactions. Anytime you start a new medication and new signs or symptoms arise, however mild they might be, it’s best to review them with your healthcare professional. 

When to talk to a healthcare provider about sertraline interactions

This article is not a complete list of sertraline interactions. Be mindful of the risk of additive side effects and direct drug interactions, which may occur when sertraline is used in combination with prescription and over-the-counter medications. Communicate directly with a healthcare professional anytime you begin taking sertraline so that a comprehensive review of interactions of both medications, diet, and conditions can occur to ensure a proper monitoring plan is put in place. Similarly, never abruptly discontinue serotonergic antidepressants like sertraline without being directly monitored by a provider, as withdrawal symptoms may occur. It is always preferable to slowly reduce the dose of sertraline over time rather than stopping immediately, whenever possible. Knowledge of other side effects associated with sertraline should also be taken into consideration, especially the increased risk of suicidal thoughts and behavior in pediatrics and young adults with major depression. 

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