7 Spravato Interactions to Watch For, And How To Manage Them

Spravato (esketamine) is a nasal spray that’s FDA-approved for treatment-resistant depression (TRD). This is a type of depression that doesn’t improve after trying several antidepressants. Spravato is also prescribed for depression with suicidal thoughts or actions.

While most oral antidepressants take weeks to work, Spravato may start working within a day. But it comes with significant risks, too, including drug interactions. Here, we’ll cover seven Spravato interactions to watch for.

1. Opioids

Opioid medications treat moderate to severe pain. Oxycontin (oxycodone) and hydrocodone / acetaminophen are common examples. Spravato isn’t an opioid, but there are many similarities between opioid side effects and Spravato side effects. Examples include:

• Drowsiness

• Dizziness

• Nausea

• Constipation

• Risk of dependence and misuse

• Slowed breathing

If you take opioids, your healthcare team will let you know whether it's safe to continue them while receiving Spravato. They’ll consider how frequently you take opioids and at what dose. They'll also consider your individual risk for excessive drowsiness, slowed breathing, and misuse.

Good to know: Like opioids, Spravato is a controlled substance. It has risks for dependence and misuse. If you have a history of substance use disorder, let your healthcare professional know. A history of substance use can increase your risk of misuse with Spravato.

2. Benzodiazepines

Benzodiazepines (“benzos”) are a group of medications used for various conditions, such as anxiety and trouble sleeping. Examples of benzos include Valium (diazepam) and Ativan (lorazepam).

Like Spravato, benzos can make you feel sleepy and dizzy. So taking Spravato with benzos might worsen these effects. In rare cases, slowed breathing and injuries from falls can occur.

Benzos may have interactions with ketamine (Ketalar), an injectable anesthetic that’s used off-label for depression. Some small studies show that high doses of benzos may delay how quickly ketamine starts working and make it less effective for depression. Spravato is related to ketamine, but they're not exactly the same. In Spravato studies, benzos didn’t seem to lessen effectiveness, but they were associated with increased sedation.

If you take benzos, talk with your doctor’s office. Let them know how often you take benzos and when your last dose was. How they manage this potential interaction will depend on many factors, including what benzo you're taking and why you're taking it.

3. Alcohol

Alcohol also increases your risk of drowsiness, slowed breathing, and injuries from falls. Combining alcohol with Spravato may worsen these side effects. Additionally, alcohol might make your depression worse.

To be safe, it’s best to avoid alcohol while you’re receiving Spravato. This is especially important in the day or two before and after your Spravato treatment. If you think alcohol might still be in your system on the day you receive Spravato, let your healthcare team know. They'll advise you on how to proceed.

4. Barbiturates

Barbiturates such as phenobarbital are used to treat seizures and can cause sedation. If you take barbiturates with Spravato, you may experience excessive drowsiness. This can increase your risk for slowed breathing and falls.

Your doctor’s office will let you know if you need to make any changes to your barbiturate medication. But don’t adjust your dose without talking to them first. Stopping barbiturates abruptly can be dangerous.

5. Stimulants

Stimulant medications are used to treat health conditions including ADHD (attention-deficit hyperactivity disorder). Adderall (mixed amphetamine salts), Concerta (methylphenidate ER), and Vyvanse (lisdexamfetamine) are common examples. Other stimulant medications include Sudafed (pseudoephedrine) for congestion and Adipex-P (phentermine) for weight loss. 

Both stimulants and Spravato may increase blood pressure and heart rate. So the risk of high blood pressure is increased if you receive both of these medications. 

However, most blood pressure increases resolve within 2 hours of receiving Spravato. But if your blood pressure remains high for more than 2 hours after your dose, you may need additional support. This might include blood pressure medications or other measures. Your healthcare team will give you guidance for how to proceed.

If you experience severe headache, chest pain, or shortness of breath at any point after your Spravato dose, seek emergency care.

Good to know: Several medications can increase your blood pressure. Give your pharmacist and prescriber a list of all the medications you take. This will help them check for possible Spravato interactions and let you know if any medications need to be avoided.

6. Monoamine oxidase inhibitors (MAOIs)

Monoamine oxidase inhibitors (MAOIs), such as selegiline (Emsam, Zelapar), are a group of older medications that treat depression and Parkinson’s disease. They aren’t commonly used, but they may be prescribed when other medications haven’t worked.

Like Spravato, MAOIs can increase your blood pressure. Even if you take an MAOI, your healthcare team may say it’s OK to receive Spravato, since your blood pressure will be closely monitored by your doctor’s office. They might also recommend that you check your blood pressure at home.

Good to know: Oral antidepressants are typically prescribed alongside Spravato. Most commonly used depression medications are safe to take with Spravato. But always check with your prescriber to make sure.

7. Lamotrigine

Lamotrigine (Lamictal) is an oral medication used for seizures and bipolar disorder. Concerns have been raised about a potential interaction between Spravto and lamotrigine.

This interaction may occur due to opposite effects on glutamate, a chemical in the brain. Lamotrigine reduces glutamate release, whereas Spravato boosts glutamate levels. So lamotrigine might interfere with Spravato’s effects. But interestingly, research in animals suggests that using lamotrigine and intravenous ketamine together may boost ketamine’s antidepressant effects. So far, human studies haven’t been conclusive.

More research is needed to know whether lamotrigine and Spravato interact. If you take lamotrigine, don’t stop without talking to your healthcare professional. This could lead to withdrawal seizures.

When should you contact your prescriber about a ketamine interaction?

Before starting Spravato, and any time you start a new medication, let your healthcare team know. This will help them check for Spravato interactions. 

On the days you receive your Spravato dose and into the following day, pay close attention to how you feel. If you have any bothersome concerns, it’s best to let your healthcare team know.

If you notice any of the following symptoms, get medical help right away:

• Feeling like you’re going to pass out

• Severe dizziness or headache

• Shortness of breath/trouble breathing

• Change in skin coloring

• Chest pain

• Slowed or racing heart

• Thoughts of self-harm

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Written by:

Daphne Berryhill, RPh

Daphne Berryhill, RPh, has two decades of experience as a clinical pharmacist. She spent most of her career in the Chicago area practicing in-home infusion.

Edited by:

Amy B. Gragnolati, PharmD, BCPS

Amy Gragnolati, PharmD, BCPS, is a pharmacy editor for GoodRx. Amy currently holds her pharmacist license in Georgia and California.

Reviewed by:

Alyssa Billingsley, PharmD

Alyssa Billingsley, PharmD, is the director of pharmacy content for GoodRx. She has over a decade of experience as a pharmacist and has worked in clinical, academic, and administrative roles.

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