What Are Serotonin Antagonist and Reuptake Inhibitors (SARIs)?

Serotonin antagonist and reuptake inhibitors (SARIs) are a class of antidepressants that work by blocking your serotonin receptors while also preventing serotonin reuptake. This dual action helps regulate your mood and treat conditions like major depressive disorder (MDD), anxiety, and insomnia.

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What Are SARI Medications?

Serotonin antagonists and reuptake inhibitors (SARIs) are mainly used to treat depression[1], anxiety, and insomnia. The most common reason for being prescribed a SARI would be for insomnia and depression.

The most common SARIs prescribed in the United States include:

  • Trazodone (Desyrel, Oleptro)
  • Nefazodone (Serzone, Dutonin, Nefadar)

What Do Serotonin Inhibitors Do?

Serotonin inhibitors are a broad range of medications that do different things, but they all work similarly by affecting how the brain creates, stores, and gets rid of serotonin in the brain. 

Some medications increase serotonin levels, while others may decrease them. Others may affect how your brain stores serotonin and how your brain gets rid of it.[1]

SARIs vs SSRIs

Both SARIs and selective serotonin reuptake inhibitors (SSRIs) are classified as antidepressants, but they work in different ways and have distinct effects from one another. 

SARIs inhibit serotonin reuptake, which promotes the serotonin in the brain to be active for longer. The second thing that SARIs do is block certain serotonin receptors such as (5-HT2A) to reduce side effects like sexual dysfunction and agitation.[2]

SRIs are a little different as they only have one effect that works by strongly inhibiting the serotonin reuptake process, which increases serotonin levels in the brain. SSRIs are usually first in line for depression and anxiety, while SARIs are usually best for things like Insomnia.

What are the Side Effects of SARIs?

Some of the most common side effects that users experience while on a prescription for SARIs:

  • Drowsiness/sedation: Very common, especially with trazodone (often used for insomnia).
  • Dizziness: May occur due to low blood pressure effects.
  • Dry Mouth: Common but mild.
  • Nausea/gastrointestinal issues: Less frequent than with SSRIs but still possible.
  • Headache: Occurs in some patients.

Less common but more significant side effects include:

  • Orthostatic Hypotension (dizziness when standing up): Can cause dizziness or fainting, especially in older adults.
  • Blurred Vision: Due to mild anticholinergic effects.
  • Weight Changes: Some SARIs (like trazodone) may cause weight gain.

Rare side effects that are more serious include: 

  • Priapism (prolonged, painful erection): Trazodone-specific
  • Liver toxicity (Hepatotoxicity): Nefazodone-specific
  • Serotonin syndrome: Rare but dangerous if combined with other serotonergic drugs
  • Suicidal thoughts: Common in young adults and adolescents

Withdrawal symptoms of SARIs?

Discontinuing SARIs, especially trazodone and nefazodone, can lead to withdrawal symptoms, though they are generally less severe than SSRI or SNRI withdrawal. 

The severity depends on the dose, duration of use, and how quickly the medication is stopped.[3]

Common Withdrawal Symptoms Include:

  • Insomnia and rebound sleep disturbances: Since SARIs (especially trazodone) are sedating, stopping suddenly can cause worsened insomnia.
  • Dizziness/lightheadedness: Due to the sudden drop in serotonin modulation, some may feel dizzy or off-balance.
  • Nausea and digestive issues: Stomach upset, nausea, or diarrhea may occur, though less common than with SSRIs.
  • Flu-like symptoms: Fatigue, muscle aches, and headaches can resemble mild flu symptoms.
  • Anxiety/irritability: Some may experience increased anxiety, mood swings, or agitation.
  • Brain zaps: Uncommon with SARIs but may occur, especially with trazodone.
  • Depression relapse: Stopping abruptly can cause a return of depressive symptoms.

Are These Medications Addictive?

No, SARIs (serotonin antagonist and reuptake inhibitors) like trazodone and nefazodone are not considered addictive in the way that substances like benzodiazepines or opioids are. They do not produce euphoria, cravings, or compulsive drug-seeking behavior, which are key characteristics of addiction.

However, they can cause dependence, meaning the body adapts to their presence, and stopping them abruptly may lead to withdrawal symptoms like insomnia, dizziness, or anxiety. This is why slowly tapering off SARIs is recommended instead of stopping suddenly.

Can You Overdose on SARIs?

Yes, you can overdose on SARIs. However, SARIs generally have a lower risk of fatal overdose compared to some other classes of antidepressants, such as tricyclic antidepressants (TCAs).

Prescription Drug Detox

Completing a detox program is the very first step to getting addiction treatment for prescription drugs. Going to a medically supervised detox center is the safest and most recommended plan of action when deciding to get off of a prescription medication that has addictive characteristics. 

When in a medically controlled environment during detoxification of drugs, you have access to the tools and medications that ensure you have the safest and best experience while your body re-aclimates.

The Next Level of Care for Prescription Drug Addiction

Following completion of a detox program, it is usually recommended that you attend either a partial hospitalization program (PHP) or an intensive outpatient program (IOP), depending on the severity of your addiction and the length of time you were using.

Intensive Outpatient Program (IOP) for Prescription Drugs

Tree House Recovery provides a 90-day intensive outpatient program (IOP) for substance use disorder in Portland, Oregon. The Tree House evening IOP allows you to maintain your professional and personal commitments while focusing on your recovery. Scheduled in the evenings during the workweek, this program lets you balance work and family responsibilities as you work on your sobriety. Address the root causes of addiction and lay the foundation for your new, sober life.

Partial Hospitalization Program (PHP) for Prescription Drugs

Our comprehensive partial hospitalization program in Portland, Oregon, is designed to help you achieve long-term health and sobriety. Explore the modality tabs above to discover how our holistic approach can help you get and stay sober. 

Together, we’ll help you create your best life! Call today to start building your personalized treatment plan.

Partial Hospitalization Program (PHP) for Prescription Drugs

If you or a loved one are struggling with prescription drug use, the first step to recovery is finding a treatment center that suits your needs. A great way to start is by speaking with a doctor, therapist, or addiction specialist. They can help direct you to treatment centers with a proven success rate for substance abuse recovery.

Tree House Recovery can also be a valuable resource for prescription drug addiction treatment. We specialize in helping individuals recover from prescription drug misuse and have an admissions team ready to guide you toward recovery as soon as possible. Feel free to call (503) 850-2474 to begin your journey to recovery.

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  1. Chu, A. (2023, May 1). Selective serotonin reuptake inhibitors. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK554406/

     

  2. Jarema M;Dudek D;Landowski J;Heitzman J;Rabe-Jabłońska J;Rybakowski J; (n.d.). [trazodon–the antidepressant: Mechanism of action and its position in the treatment of depression]. Psychiatria polska. https://pubmed.ncbi.nlm.nih.gov/22232986/

     

  3. Mayo Foundation for Medical Education and Research. (2024, September 11). The type of antidepressant prescribed most often. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/depression/in-depth/ssris/art-20044825