Spravato (Esketamine) - Nasal

Warning:

Spravato (esketamine) has a black box warning, which is the strongest warning required by the Food and Drug Administration (FDA).

Spravato may cause sedation, (a state of calmness and relaxation) and dissociation (a sense of feeling disconnected from yourself, your thoughts, feelings, and things around you). Due to these risks, each dose of Spravato is given in a healthcare setting. It cannot be given at home. After taking the medicine, you must be monitored by a healthcare provider for at least two hours.

As a controlled substance, Spravato has the potential for abuse and misuse. Certain people with a higher risk or history of abuse may be able to take Spravato. Those who take it should be monitored for potential abuse or misuse.

In some studies, antidepressants increased the risk of suicidal thoughts and behavior in children and young adults. Although Spravato is not approved for use in children, any individual who takes this drug must be closely monitored for depression symptoms and changes in thoughts and behaviors, especially early in treatment and after dosage changes.

Because of all of the serious risks, this drug is available only through a restricted program called the SPRAVATO REMS. The SPRAVATO REMS is a Risk Evaluation and Mitigation Strategy (REMS) program, which ensures healthcare providers, pharmacies, and patients fulfill certain requirements and are properly trained and educated on the medication.

What Is Spravato?

Spravato (esketamine) is a prescription nasal spray used for treatment-resistant depression (depression that does not initially respond to treatment) in adults or symptoms of depression in adults with major depressive disorder who have acute suicidal thoughts or behavior.

Spravato should be used in combination with an oral antidepressant. It is available as a nasal spray. Spravato is in a drug class called N-methyl-D-aspartate (NMDA) receptor antagonists. Its exact mechanism of action (the way it works) for depression is not fully understood, but it is thought to act on several molecular targets in the brain to produce its antidepressant effects.

Researchers suggest it targets the NDMA receptors to boost glutamate in the brain. Glutamate is a neurotransmitter that plays a role in sending signals between nerve cells. It helps regulate learning and memory.

This medication contains esketamine, which is considered a Schedule III controlled substance. Controlled substances have the potential for abuse and physical dependence, so they must be prescribed and used carefully.

Spravato is given intranasally (through the nose) with a nasal spray device.

Drug Facts

Generic Name: Esketamine

Brand Name(s): Spravato

Drug Availability: Prescription; under a restricted program called SPRAVATO REMS

Therapeutic Classification: Antidepressant

Available Generically: No

Controlled Substance: Yes

Administration Route: Intranasal (in the nose)

Active Ingredient: Esketamine hydrochloride

Dosage Form(s): Nasal spray

What Is Spravato Used For?

The Food and Drug Administration (FDA) approved Spravato to be used along with an oral antidepressant for:

  • Treatment-resistant depression in adults
  • Depression symptoms in adults with major depressive disorder who are having suicidal thoughts or behavior

Studies have not looked at Spravato for preventing suicide or reducing suicidal thoughts and behaviors; therefore, it is unknown whether Spravato is effective for this use. Moreover, hospitalization may still be required for those who need it, even if Spravato helps improve symptoms.

Although esketamine (the active ingredient in Spravato) is chemically related to the anesthetic medication ketamine, Spravato has not been studied as an anesthetic medicine and is not approved for use as such.

How to Take Spravato

Before taking Spravato, you must complete all education and requirements of the SPRAVATO REMS. Read the instructions given to you by your healthcare provider and discuss any questions or concerns with them.

Spravato is self-administered in a healthcare setting. Therefore, you will administer the medicine under the supervision of a healthcare provider.

Here's what you should know before using Spravato:

  • Spravato can make you feel nauseous or vomit. You can reduce these side effects by not eating for at least two hours before taking your dose and not drinking within 30 minutes of taking it.
  • Do not use any other nasal medicines within one hour before taking Spravato.
  • After taking Spravato, you will be monitored for at least two hours. Spravato can cause severe drowsiness. It may also cause dissociation, which involves feeling disconnected from yourself, your thoughts, feelings, and things around you.
  • Your healthcare providers will assess you and tell you when it is safe to go home. You will need someone to drive you home, a caregiver, friend, or family member. You will not be able to drive until the next day after getting a whole night of sleep.
  • You may still need treatment in the hospital, even if your symptoms start to improve with Spravato.

Your healthcare provider will tell you how often to use Spravato. Keep all appointments, as all doses of this drug must be given in a healthcare setting.

How Long Does Spravato Take to Work?

Spravato reaches its maximum levels in 20 to 40 minutes, but it can take several weeks to experience the full effects. You may still need treatment in a hospital and/or other treatment, even after taking Spravato. Your treatment will also consist of another medication (an oral antidepressant).

What Are the Side Effects of Spravato?

This is not a complete list of side effects, and others may occur. A healthcare provider can advise you on side effects. If you experience other effects, contact your healthcare provider. You may report side effects to the FDA at fda.gov/medwatch or 1-800-FDA-1088.

Like other medications, Spravato can cause side effects. Tell your healthcare provider about any side effects you experience while taking this medication.

Common Side Effects

The most common side effects of Spravato include:

  • Dissociation
  • Dizziness or vertigo
  • Dysgeusia (distorted sense of taste)
  • Nausea and vomiting
  • Sedation
  • Anxiety
  • Lethargy (feeling weary and lacking energy)
  • Increased blood pressure
  • Numbness
  • Urinary problems
  • Feeling drunk or abnormal

In clinical trials, dissociative symptoms occurred soon after dosing, peaking at 40 minutes. Mild to moderate side effects typically cleared up the same day of dosing.

Severe Side Effects

Call your healthcare provider immediately if you have serious side effects. Call 911 if your symptoms feel life-threatening or if you think you’re having a medical emergency. Serious side effects and symptoms can include the following:

  • Hypersensitivity reaction or anaphylaxis: Rash, hives, swelling around the lips, tongue, and face, and difficulty breathing
  • Central nervous system (CNS) depression, or a slowing down of brain activity, which can cause drowsiness and sedation
  • Unconsciousness
  • Cognitive impairment: Trouble with learning, thinking, memory, and decision-making
  • Dissociation
  • Abuse and dependence
  • Suicidal thoughts and behaviors: Patients, caregivers, and families should be alert to any changes in mood and behavior, such as irritability, agitation, aggression, restlessness, and depression.
  • Severely high blood pressure: Spravato can increase blood pressure for a few hours after each dose. Tell your healthcare provider if you have chest pain, difficulty breathing, headache, blurry vision, or pounding in the neck or ears. Your blood pressure will be monitored before and after dosing.

Long-Term Side Effects

Spravato was studied for long-term safety (one year) in a clinical trial called SUSTAIN-2. Most side effects were temporary and occurred on the day that Spravato was administered. According to the results, side effects may occur sometimes or every time Spravato is taken; however, the drug was found to be safe overall when used over a one-year period.

Aside from this particular study, there is little data on the long-term use of this medication. However, as Spravato continues to be used, its long-term safety will be studied. Discuss with your healthcare provider the risks and benefits of taking Spravato long-term.

Report Side Effects

Spravato may cause other side effects. Call your healthcare provider if you have any unusual problems while taking this medication.


If you experience a serious side effect, you or your healthcare provider may send a report to the FDA's MedWatch Adverse Event Reporting Program or by phone (800-332-1088).

Dosage: How Much Spravato Should I Take?

Drug Content Provided and Reviewed by IBM Micromedex®

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For nasal dosage form (solution):
    • For depressive symptoms in patients with major depressive disorder (MDD) with suicidal ideation or behavior:
      • Adults—84 milligrams (mg) 2 times per week for 4 weeks. Your doctor may adjust your dose as needed and tolerated.
      • Children—Use and dose must be determined by your doctor.
    • For treatment-resistant depression (TRD):
      • Adults—The starting dose is 56 milligrams (mg) on Day 1, followed by 56 or 84 mg taken 2 times per week on Weeks 1 to 4. Then, 56 or 84 mg taken once a week on Weeks 5 to 8, followed by 56 or 84 mg taken every 2 weeks or once a week on Week 9 and after. Your doctor may adjust your dose as needed and tolerated.
      • Children—Use and dose must be determined by your doctor.

Modifications

People with moderate liver problems may need close monitoring when taking this medication. It is not approved for use in those with severe liver problems.

If you are pregnant, you likely won't be prescribed Spravato, since it can harm the fetus. If you find out you're pregnant while taking Spravato, tell your healthcare provider immediately. People of childbearing potential should use effective contraception to reduce the chances of pregnancy while undergoing treatment. Additionally, you should not use Spravato while breastfeeding.

Missed Dose

Call your healthcare provider right away if you miss an appointment for a Spravato dose. They will tell you when to come in for your next dose.

Overdose: What Happens If I Take Too Much Spravato?

Spravato is given under the supervision of a healthcare provider; therefore, an overdose is unlikely. You will be monitored in a healthcare setting after your dose for any serious adverse reactions.

What Happens If I Overdose on Spravato?

If you think you or someone else may have overdosed on Spravato, call a healthcare provider or the Poison Control Center (800-222-1222).


If someone collapses or isn't breathing after taking Spravato, call 911 immediately.

Precautions

Drug Content Provided and Reviewed by IBM Micromedex®

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood tests may be needed to check for unwanted effects.

This medicine may cause prolonged drowsiness, mental changes (eg, confusion about identity, place, and time, feeling of unreality, sense of detachment from self or body), or high blood pressure. Your doctor will check for these effects for at least 2 hours after each treatment session.

Esketamine nasal spray may cause some people to be agitated, irritable, or display other abnormal behaviors. It may also cause some people to have suicidal thoughts and tendencies or to become more depressed. Also tell your doctor if you have sudden or strong feelings, such as feeling nervous, angry, restless, violent, or scared. If you or your caregiver notice any of these side effects, tell your doctor right away.

This medicine may make you drowsy, confused, or have problems with thinking clearly. Do not drive or do anything else that could be dangerous until the next day after a restful sleep or until you know how this medicine affects you. You may also need someone to drive you home after treatment with this medicine.

This medicine may cause bladder problems, including ulcerative or interstitial cystitis. Check with your doctor right away if you have bloody or cloudy urine, difficult, burning, or painful urination, or a frequent urge to urinate.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant during treatment with this medicine. If you think you have become pregnant while using this medicine, tell your doctor right away.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

What Are Reasons I Shouldn't Take Spravato?

Spravato is not appropriate for everyone. You should not take this medication if allergic to esketamine, ketamine, or any inactive ingredients in Spravato. 

Other reasons you should not take Spravato include:

  • Aneurysmal vascular disease (blood vessel disease)
  • Abnormal connection between arteries and veins
  • A history of bleeding in the brain
  • Severe liver problems
  • Pregnancy or breastfeeding

Spravato may be prescribed with caution in some people only if the healthcare provider determines it is safe. This includes those:

  • With moderate liver problems
  • Taking a medication that causes CNS depression, such as a muscle relaxant, antianxiety medication, or opioid pain medication
  • Who drink alcohol
  • With a blood pressure measure above 140/90 millimeters of mercury (mmHg)
  • With heart conditions
  • With conditions that affect blood flow to the brain
  • With a history of substance abuse
  • With psychosis (seeing, feeling, or hearing things that are not there or believing in things that are not true)
  • With a history of hypertensive encephalopathy (a high blood pressure emergency)
  • Of childbearing age and potential

What Other Medications May Interact With Spravato?

Tell your healthcare provider about your medications, including prescription and over-the-counter (OTC) products and vitamins or supplements. While taking Spravato, do not start any new medications without approval from your healthcare provider.

Be aware of the following drug interactions that can occur with Spravato:

CNS Depressants

Other drugs that cause CNS depression can have an additive effect with Spravato, leading to extreme sedation, unconsciousness, coma, or death.

Examples of these drugs include:

  • Alcohol
  • Benzodiazepines for anxiety such as Klonopin (clonazepam) or Xanax (alprazolam)
  • Muscle relaxers such as Flexeril (cyclobenzaprine) or Skelaxin (metaxalone)
  • Opioid pain medications such as oxycodone (brand names include Percoset), Ultram (tramadol), or Vicodin (hydrocodone/acetaminophen)

Stimulants

CNS stimulants may increase blood pressure when combined with Spravato. If the combination is unavoidable, your healthcare provider will monitor your blood pressure closely.

CNS stimulants include:

  • Adderall (amphetamine salts)
  • Ritalin (methylphenidate)
  • Narcolepsy medicine such as Provigil (modafinil)
  • Weight-loss drugs such as Adipex (phentermine)

Monoamine Oxidase Inhibitor (MAOI) Drugs

MAOIs such as Nardil (phenelzine) or Parnate (tranylcypromine) can increase blood pressure when taken with Spravato and require close blood pressure monitoring.

Other drug interactions may occur with Spravato. Consult your healthcare provider for a complete list of drug interactions.

What Medications Are Similar?

While ketamine is similar in name and chemical structure to Spravato, ketamine is a different drug. Ketamine, also known by the brand name Ketalar, is used to induce (start) and maintain anesthesia, for example, during surgery. Although that is currently the only FDA-approved use, some healthcare providers use it off-label (for a condition that is not FDA-approved) for a variety of conditions such as pain and depression, and the drug is currently being studied for various uses.

For people who have treatment-resistant depression, sometimes a higher dose of the medication being taken is required, or sometimes another antidepressant that works differently can be added on. Drugs specifically approved as an adjunctive (add-on) treatment for depression include:

Frequently Asked Questions

  • What is Spravato used for?

    Spravato contains the ingredient esketamine. It is a prescription nasal spray used for treatment-resistant depression in adults. It can also be used for symptoms of depression in adults who are having acute suicidal thoughts or behavior. Spravato should always be used in combination with an oral antidepressant.

  • How does Spravato work?

    The way Spravato works is not entirely understood, but its mechanism of action is thought to be similar to ketamine. It is thought to block glutamate N-methyl-D-aspartate (NMDA) receptors on gamma-aminobutyric acid (GABA) interneurons. This increases the release of glutamate, an excitatory neurotransmitter that plays a role in cognition and mood regulation.

  • What drugs should not be taken with Spravato?

    Avoid consuming alcohol when taking Spravato. Spravato also interacts with medications that cause central nervous system (CNS) depression, stimulants used to treat ADHD, narcolepsy medications, weight-loss drugs, and MAOIs.

    Review your medication list with your healthcare provider before taking Spravato.

  • How long does it take for Spravato to work?

    Although Spravato reaches its highest levels in 20 to 40 minutes, you may still need treatment in a hospital and/or adjunctive (add-on) treatment with an oral antidepressant. It may take a few weeks to see the full benefit of Spravato.

  • What are the side effects of Spravato?

    Because of its potential for serious side effects, Spravato is taken in a healthcare setting. You will be monitored for at least two hours after taking the medication. Some common side effects include feeling dissociated (or detached) from your body, sedation, weakness, anxiety, numbness, increased blood pressure, and feeling drunk. Before taking Spravato, discuss the side effects with your healthcare provider.

  • How do I stop taking Spravato?

    Your healthcare provider will tell you how long to take Spravato. Follow the instructions carefully and keep all appointments.

How Can I Stay Healthy While Taking Spravato?

While depression can seem overwhelming, there are many treatment options and places to turn for help. In addition to taking your medication, talking with a therapist can be helpful. Sometimes it may take a bit of trial and error to find the right therapist, the one you feel comfortable confiding in. Talk with your healthcare team about coping strategies for making your symptoms more manageable.

Finding the proper treatment regimen can take some trial and error too. Many medications differ in how they work and their side effect profile. So if you find that one does not work or has bothersome side effects, ask your healthcare provider if you can try another one.

If you are thinking about suicide, call 911, go to your nearest emergency room, or call 988 to reach the National Suicide Prevention Lifeline, 24 hours a day.

Medical Disclaimer

Verywell Health's drug information is meant for educational purposes only and is not intended to replace medical advice, diagnosis, or treatment from a healthcare provider. Consult your healthcare provider before taking any new medication(s). IBM Watson Micromedex provides some of the drug content, as indicated on the page.

9 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. DailyMed. Label: Spravato- esketamine spray.

  2. Pal MM. Glutamate: The master neurotransmitter and its implications in chronic stress and mood disorders. Front Hum Neurosci. 2021;15:722323. doi:10.3389/fnhum.2021.722323

  3. Bahr R, Lopez A, Rey JA. Intranasal esketamine (Spravato) for use in treatment-resistant depression in conjunction with an oral antidepressant. P T. 2019 Jun;44(6):340-375. PMID: 31160868; PMCID: PMC6534172.

  4. Sapkota A, Khurshid H, Qureshi IA, et al. Efficacy and safety of intranasal esketamine in treatment-resistant depression in adults: a systematic review. Cureus. 2021;13(8):e17352. doi:10.7759/cureus.17352

  5. Epocrates. Spravato.

  6. Wajs E, Aluisio L, Holder R, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J Clin Psychiatry. 2020;81(3):19m12891. doi:10.4088/JCP.19m12891

  7. Pai S, Gries JM. Off-label use of ketamine: a challenging drug treatment delivery model with an inherently unfavorable risk-benefit profile. The Journal of Clinical Pharmacology. 2022;62(1):10-13. doi:10.1002/jcph.1983

  8. Thase M, Connolly KR. Unipolar depression in adults: choosing treatment for resistant depression. UpToDate.

  9. Salahudeen MS, Wright CM, Peterson GM. Esketamine: new hope for the treatment of treatment-resistant depression? a narrative review. Ther Adv Drug Saf. 2020;11:2042098620937899. doi:10.1177/2042098620937899

By Karen Berger, PharmD
Karen Berger, PharmD, is a community pharmacist and medical writer/reviewer.