Key takeaways:
Spravato (esketamine) is a nasal spray that’s FDA approved for certain types of depression. You’ll receive Spravato under medical supervision in a healthcare setting.
Combining Spravato with opioids, benzodiazepines, or alcohol may cause excessive drowsiness. This Spravato interaction can also occur with other medications that make you sleepy.
Spravato can also interact with stimulants and monoamine oxidase inhibitors (MAOIs). There’s an increased risk of high blood pressure with these combinations.
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 some risks, including drug interactions. Knowing about interactions in advance can help you avoid unwanted side effects and other issues during Spravato treatment.
Spravato interactions at a glance
Below is a list of possible Spravato interactions to be aware of. Keep in mind that other interactions are possible. So be sure to review the medications and supplements you take with your prescriber before starting Spravato.
Spravato interactions include:
Opioid pain medications
Benzodiazepines
Alcohol
Barbiturates
Other medications that cause drowsiness, such as some antihistamines and muscle relaxers
Stimulants, such as Ritalin (methylphenidate) or Provigil (modafinil)
Monoamine oxidase inhibitors (MAOIs)
Let’s take a closer look at six Spravato interactions to be aware of.
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, such as:
Drowsiness
Dizziness
Nausea
Constipation
Risk of dependence and misuse
Slowed breathing
Combining opioids and Spravato can make these side effects worse. So if you take opioids, make sure your healthcare team is aware. They’ll let you know whether it's safe to continue them while receiving Spravato based on your personal history.
2. Benzodiazepines
Benzodiazepines (“benzos”) are a group of medications used for conditions such as anxiety and insomnia (trouble sleeping). Examples include Valium (diazepam) and Ativan (lorazepam).
Like Spravato, benzos can make you feel sleepy and dizzy. Taking Spravato and benzos together might worsen these side effects. In rare cases, slowed breathing and injuries from falls can occur.
If you take benzos, talk with your prescriber before starting Spravato. How they manage this potential interaction will depend on many factors, including your dose and how often you take it.
Spravato tips: Learn what to expect during a Spravato treatment and how to get the most from your medication.
Another fast-acting antidepressant: Here’s how Spravato stacks up to Auvelity, an oral tablet that can begin working in about a week.
Spravato side effects: What to expect after a Spravato treatment, from common side effects to rare reactions.
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 may worsen your depression.
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. Other sedating medications
Combining Spravato with other medications that make you drowsy can raise the risk of excessive sleepiness or dizziness. In severe cases, it could also slow your breathing. Examples of medications that cause drowsiness include:
Some antihistamines, such as Benadryl (diphenhydramine)
Muscle relaxers, such as Flexeril (cyclobenzaprine)
Sleep medications, such as Ambien (zolpidem)
Barbiturates, such as phenobarbital
Some antidepressants, such as amitriptyline and trazodone
In some cases, your prescriber may OK Spravato treatment even if you’re taking a sedating medication. In others, they may want you to hold off on taking an interacting medication within a day or two before and after receiving Spravato. Your healthcare team can give you recommendations specific to your needs. Just be sure to let them know about all medications you’re taking — even over-the-counter products — before starting Spravato.
5. Stimulants
Stimulant medications are used to treat conditions such as ADHD (attention-deficit hyperactivity disorder) and narcolepsy. They’re also used for congestion and weight management. Examples include:
Adderall (mixed amphetamine salts)
Concerta (methylphenidate ER)
Vyvanse (lisdexamfetamine)
Ritalin
Provigil
Sudafed (pseudoephedrine)
Adipex-P (phentermine)
Qsymia (phentermine / topiramate ER)
Spravato carries a risk for increasing your blood pressure and heart rate. This is one reason you need to remain under medical supervision for at least 2 hours after receiving it. If you combine Spravato with a stimulant medication, the risk of increased blood pressure goes up.
As with other interactions, your prescriber will let you know if you need to make any changes to your stimulant medication(s) before starting Spravato. In some cases, they may just monitor your blood pressure more closely. In others, they may have you hold off on your medication before and after the day you receive Spravato.
6. Monoamine oxidase inhibitors (MAOIs)
Monoamine oxidase inhibitors (MAOIs), such as Nardil (phenelzine), are a group of older medications that treat depression and Parkinson’s disease.
Like stimulants, MAOIs can increase the risk of high blood pressure if you combine them with Spravato. In most cases, you can still receive these medications together. But your prescriber will likely keep a close eye on your blood pressure after each Spravato treatment.
Frequently asked questions
After receiving Spravato, you’ll remain under medical supervision for at least 2 hours. This helps your healthcare team keep an eye out for any side effects that may occur. It also gives time for Spravato’s dissociative effects to wear off. Bringing a book, tablet, or craft project can be a good way to help you pass the time. You may also feel dizzy or drowsy for the rest of the day, so plan to stay at home and take it easy once you leave the clinic.
There are two phases to Spravato’s effects. The initial dissociative effects of Spravato typically peak about 30 to 40 minutes after your dose and wear off within 2 hours. The antidepressant effects of Spravato typically start within 24 hours of your first dose and continue to improve over time. But unlike other antidepressants, you don’t need to keep consistent Spravato levels in your body in order for it to work. Many people only need 1 dose of Spravato once every 2 weeks. After the first 9 weeks of treatment, your doses may be even less frequent.
Spravato and intravenous (IV) ketamine are both effective options for treatment-resistant depression, according to clinical studies. But only Spravato is FDA approved for this use. This means it’s more likely to be covered by insurance and there’s clearer dosage and safety guidelines for Spravato when it comes to treating depression. That being said, some studies show that IV ketamine may be more effective and better tolerated than Spravato for some people. Your prescriber can answer any questions about Spravato versus IV ketamine based on your specific healthcare needs.
After receiving Spravato, you’ll remain under medical supervision for at least 2 hours. This helps your healthcare team keep an eye out for any side effects that may occur. It also gives time for Spravato’s dissociative effects to wear off. Bringing a book, tablet, or craft project can be a good way to help you pass the time. You may also feel dizzy or drowsy for the rest of the day, so plan to stay at home and take it easy once you leave the clinic.
There are two phases to Spravato’s effects. The initial dissociative effects of Spravato typically peak about 30 to 40 minutes after your dose and wear off within 2 hours. The antidepressant effects of Spravato typically start within 24 hours of your first dose and continue to improve over time. But unlike other antidepressants, you don’t need to keep consistent Spravato levels in your body in order for it to work. Many people only need 1 dose of Spravato once every 2 weeks. After the first 9 weeks of treatment, your doses may be even less frequent.
Spravato and intravenous (IV) ketamine are both effective options for treatment-resistant depression, according to clinical studies. But only Spravato is FDA approved for this use. This means it’s more likely to be covered by insurance and there’s clearer dosage and safety guidelines for Spravato when it comes to treating depression. That being said, some studies show that IV ketamine may be more effective and better tolerated than Spravato for some people. Your prescriber can answer any questions about Spravato versus IV ketamine based on your specific healthcare needs.
The bottom line
Spravato (esketamine) is a nasal spray that treats certain types of depression. Spravato interacts with substances such as opioids, benzodiazepines, and alcohol. It can also interact with other sedating medications, such as antihistamines and muscle relaxers. These combinations can cause excessive drowsiness or slowed breathing.
Other Spravato interactions include stimulant medications and monoamine oxidase inhibitors (MAOIs). Combining Spravato with these medications can raise the risk of high blood pressure.
The best way to prevent unwanted interactions is to review your complete medication list with your prescriber before you start Spravato treatment. They can let you know if any changes are needed to protect your safety.
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References
Bahji, A., et al. (2021). Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. Journal of Affective Disorders.
Bahr, R., et al. (2019). Intranasal esketamine (Spravato) for use in treatment-resistant depression in conjunction with an oral antidepressant. Pharmacy and Therapeutics.
Diekamp, B., et al. (2021). Effect of concomitant benzodiazepine use on efficacy and safety of esketamine nasal spray in patients with major depressive disorder and acute suicidal ideation or behavior: Pooled randomized, controlled trials. Neuropsychiatric Disease and Treatment.
Janssen Pharmaceuticals Inc. (2025). Spravato- esketamine hydrochloride solution [package insert].
MedlinePlus. (2025). Esketamine nasal spray.
Spravata. (2025). Patient brochure.
