What medications should you not take with Zoloft? (5+ interactions)

In this article, we will discuss medications that should not be taken with Zoloft (sertraline) – a selective serotonin reuptake inhibitor (SSRI) primarily used as an antidepressant.

What medications should you not take with Zoloft?

Medications that should not be taken with Zoloft (sertraline), a selective serotonin reuptake inhibitor (SSRI), include: (1)

Medications taken with sertralinePotential complications
Monoamine oxidase inhibitors (MAOIs)Risk of serotonin syndrome
Additive side effects
Non-steroidal anti-inflammatory drugs (NSAIDs)Risk of severe GI disturbances/ulceration 
Gastrointestinal bleeding
Blood thinners/anticoagulantsIncreased risk of bleeding
Other serotonergic antidepressants (SSRIs, trazodone, etc)Risk of serotonin syndrome
Risk of cardiac complications
Additive side effects
Certain antibiotics (such as clarithromycin) QTc prolongation
Inhibition of sertraline metabolism – risk of serotonin syndrome
Controlled drugs (opioids, stimulants, etc)Psychological side effects
Cardiological complications 
Serotonin syndrome
PimozideQTc prolongation/arrhythmia

Let’s discuss the medications mentioned above and their interactions with sertraline (Zoloft) in detail:

Monoamine oxidase inhibitors (MAOIs)

Monoamine oxidase inhibitors (MAOIs) should not be taken with Zoloft because of how these medications work. Taking these medications together can increase the risk of a rare but life-threatening condition called serotonin syndrome (2,3). 

This is because Zoloft is a serotonergic antidepressant that primarily works by inhibiting the reuptake of serotonin, a monoamine neurotransmitter involved in the pathophysiology of depression and related symptoms. 

MAOIs, such as selegiline, rasagiline, etc., work by inhibiting enzymes responsible for the breakdown of certain neurotransmitters, such as serotonin. When these medications are used together, serotonin levels are dangerously increased in the body, leading to the symptoms of serotonin syndrome, which include: (3)

  • Agitation or restlessness
  • Confusion
  • Rapid heart rate
  • Dilated pupils
  • Loss of muscle coordination or twitching muscles
  • Excessive sweating
  • Shivering or goosebumps
  • High blood pressure
  • Dilated pupils
  • Diarrhoea
  • Headache
  • High fever
  • Shivering or tremors
  • In severe cases, it can lead to seizures or unconsciousness.

Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs are contraindicated for use with Zoloft. NSAIDs are commonly used medications for fever, inflammation, and pain, and some of these meds are available over the counter – meaning you do not need a prescription to purchase them. 

The use of NSAIDs and Zoloft has two major concerns:

Severe gastrointestinal (GI) side effects

NSAIDs are well-known for causing GI side effects. This is because NSAIDs primarily inhibit prostaglandin synthesis, which are important mediators of inflammation and pain. However, these prostaglandins also make up the protective lining around your stomach, preventing its exposure to gastric acid (4). 

When NSAIDs block prostaglandins, the protective lining of your stomach is affected, leaving it exposed to the corrosive effects of gastric acid. This is the main reason why NSAIDs cause GI side effects. 

Zoloft, on the other hand, is also known for causing GI side effects, such as acid reflux, nausea, abdominal pain, etc. Using these meds together can significantly increase this risk.

Increased risk of GI bleeding

NSAIDs like aspirin are known for their blood-thinning effects. Zoloft, on the other hand, also has blood-thinning properties that could be dose-dependent. The combined use of NSAIDs and Zoloft, along with the GI disturbances these meds can cause, significantly increases the risk of gastrointestinal bleeding (4).

Blood thinners/anticoagulants

Zoloft is also contraindicated with blood thinners and anticoagulants, such as warfarin, apixaban, rivaroxaban, etc. These medications primarily inhibit platelet aggregation and cause blood thinning (5). 

As discussed earlier, Zoloft also has blood-thinning properties. Although Zoloft-induced blood thinning effects are not as prominent as actual blood thinners, the concomitant use of these medications can increase the risk of bleeding and cause complications.

Other serotonergic antidepressants 

Zoloft should not be taken with other serotonergic antidepressants, including other SSRIs like Celexa, Prozac, Lexapro, Paxil, and Trazodone. These antidepressants also increase serotonin levels primarily, so taking two of these can dangerously increase serotonergic activity in the brain, leading to serotonin syndrome (3). 

Since these drugs have similar side effect profiles, their combination can also cause terrible additive side effects. Furthermore, some serotonergic antidepressants such as Celexa can cause QTc prolongation and related cardiac effects. 

When combined with Zoloft, which can also cause this side effect in rare cases, it can increase the chances of cardiac complications.

Certain antibiotics 

Some antibiotics, such as clarithromycin, should not be taken with Zoloft. 

Clarithromycin and other antibiotics that can inhibit the cytochrome P450 enzyme system, particularly CYP450 3A4, involved in the metabolism or breakdown of Zoloft, can increase the concentration of Zoloft in the body, leading to an increased risk of serotonin syndrome (6). 

Research also states that clarithromycin, when paired with Zoloft, can cause hallucinations and other psychological side effects in susceptible individuals. This is why antibiotics should be carefully prescribed to people who are being treated with Zoloft or any other antidepressant.

Controlled drugs

Controlled drugs, or scheduled drugs, such as opioids (morphine, codeine, hydrocodone, etc.) and stimulants (amphetamines), should be avoided or taken cautiously with Zoloft. All of these medications can affect brain chemistry and may cause additive side effects (7). 

Psychological complications are also common with these medications, along with an increased risk of addiction and abuse. Some of these medications can also cause cardiac complications, such as QTc prolongation, and Zoloft can also rarely cause this side effect. 

When paired together, the chances of cardiac complications can be increased. If there is a need to take Zoloft with a controlled substance, the doses are always carefully adjusted. Dose adjustment is crucial when it comes to pairing two medications that can affect your brain chemistry. 

So, if you’re taking such meds together, it is important to stick to the prescribed doses and not take these medications more often than recommended. It is also important to closely monitor your side effects and report anything unusual to your provider.


Pimozide is also contraindicated with Zoloft. Pimozide is primarily used to manage the symptoms associated with Tourette’s syndrome. 

Zoloft and some antipsychotic medications can increase the gastric permeability of pimozide – meaning these drugs can increase the absorption and bioavailability of pimozide, which can elevate its activity (8). 

Pimozide is associated with cardiac complications and can cause QTc prolongation. When paired together with Zoloft, the risk of cardiac complications significantly increases, leading to life-threatening complications.

How to ensure the safe use of Zoloft with other medications?

The best way to ensure the safe and effective use of Zoloft with other medications is to make sure that the medications you are taking are compatible with Zoloft. 

Some medications might have mild interactions with the antidepressant, and dose adjustments can prevent any potential risk. However, some medications should be completely avoided with this antidepressant. 

That’s why it is crucial to discuss all the prescription and over-the-counter medications you are currently taking to prevent any potential drug-drug interactions. If you’re confused about anything, reach out to your doctor or pharmacist. 

As a pharmacist, I always try to educate my patients about drug-drug interactions and help them choose medications for common ailments that are safe to take with their current prescription medications. 

Patient education is vital in such cases, as even over-the-counter meds can potentially cause an interaction with medications like antidepressants. So, it’s best to seek professional advice to ensure the safety of your physical and mental health.


  1. Drug Interactions with Antidepressants. Available from: https://bpac.org.nz/bpj/2007/march/docs/bpjse_interactions_pages_20-23.pdf 
  1. Sub Laban T, Saadabadi A. Monoamine Oxidase Inhibitors (MAOI). 2023 Jul 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 30969670. https://www.ncbi.nlm.nih.gov/books/NBK539848 
  1. Simon LV, Keenaghan M. Serotonin Syndrome. 2023 Jul 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 29493999. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482377
  1. de Jong JC, van den Berg PB, Tobi H, de Jong-van den Berg LT. Combined use of SSRIs and NSAIDs increases the risk of gastrointestinal adverse effects. Br J Clin Pharmacol. 2003 Jun;55(6):591-5. doi: 10.1046/j.0306-5251.2002.01770.x. PMID: 12814454; PMCID: PMC1884264. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884264/ 
  1. Nochaiwong S, Ruengorn C, Awiphan R, Chai-Adisaksopha C, Tantraworasin A, Phosuya C, Kanjanarat P, Chongruksut W, Sood MM, Thavorn K. Use of serotonin reuptake inhibitor antidepressants and the risk of bleeding complications in patients on anticoagulant or antiplatelet agents: a systematic review and meta-analysis. Ann Med. 2022 Dec;54(1):80-97. doi: 10.1080/07853890.2021.2017474. PMID: 34955074; PMCID: PMC8725830. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8725830/ 
  1. Westphal JF. Macrolide-induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin. Br J Clin Pharmacol. 2000 Oct;50(4):285-95. doi: 10.1046/j.1365-2125.2000.00261.x. PMID: 11012550; PMCID: PMC2015000. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2015000/ 
  1. Shah K, Bradshaw CM, Szabadi E. Interaction between antidepressants and d-amphetamine on variable-interval performance. Psychopharmacology (Berl). 1990;100(4):548-54. doi: 10.1007/BF02244010. PMID: 2108453. https://pubmed.ncbi.nlm.nih.gov/2108453/
  1. Alderman J. Coadministration of sertraline with cisapride or pimozide: an open-label, nonrandomized examination of pharmacokinetics and corrected QT intervals in healthy adult volunteers. Clin Ther. 2005 Jul;27(7):1050-63. doi: 10.1016/j.clinthera.2005.07.013. PMID: 16154484. https://pubmed.ncbi.nlm.nih.gov/16154484/ 

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