If you are considering Spravato® (esketamine) for treatment-resistant depression, it is understandable to have questions about safety.
You may be wondering whether dissociation will feel frightening, whether your blood pressure could rise too much, or why you cannot simply take the medication at home.
These are thoughtful and important questions. Spravato can be helpful for carefully selected adults, but it is not an ordinary nasal spray. Because it can temporarily affect consciousness, perception, breathing, blood pressure, and coordination, it must be administered under direct medical supervision.
At Light-tunnel Behavioral Health Services Inc. in New Haven, safety screening and individualized monitoring are essential parts of responsible psychiatric care. Dr. Omolola Aragbada, PMHNP, and the psychiatric care team can help you understand whether esketamine fits your medical history, current medications, and treatment goals.
What is Spravato, and why does it require monitoring?
Spravato contains esketamine, the S-enantiomer of ketamine. It acts primarily as a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, a receptor involved in glutamatergic neurotransmission and synaptic signaling.
A simple way to think about this is that depression can sometimes involve brain networks operating like communication systems with stuck gears. Esketamine may temporarily alter glutamate signaling and help those networks become more flexible. The precise antidepressant mechanism remains under investigation, and individual responses vary.
The same neurobiological effects that may support rapid symptom improvement can also briefly change how you experience your body and surroundings. That is why treatment takes place in a certified healthcare setting rather than at home.
Common Spravato side effects
Most side effects occur during or shortly after dosing and are temporary. In pivotal clinical trials and the FDA-approved prescribing information, commonly reported effects include:
- Dissociation: feeling detached from yourself, your thoughts, your body, or the surrounding environment
- Sedation or sleepiness
- Dizziness or vertigo
- Nausea and occasional vomiting
- Temporary blood-pressure increases
- Headache
- Anxiety or feeling uneasy
- Numbness or reduced sensation
- Lethargy or reduced energy
- Feeling intoxicated or “drunk”
Dissociation does not necessarily mean you are losing control. It may feel like time, space, sound, or body sensations seem different for a short period. Your clinician can help you remain grounded and comfortable while the effect passes.
In the TRANSFORM-1 randomized controlled trial, the most common adverse events included nausea, dissociation, dizziness, vertigo, and headache (Fedgchin et al., 2019). In TRANSFORM-2, the pattern was similarly dominated by transient dissociation, dizziness, nausea, sedation, and blood-pressure changes (Popova et al., 2019).
Why blood pressure is checked before and after treatment
Spravato can stimulate the sympathetic nervous system: the body’s short-term “fight-or-flight” response. You may picture this as temporarily pressing the accelerator on your cardiovascular system. Blood pressure and heart rate can rise before gradually returning toward baseline.
The FDA prescribing information reports that blood-pressure increases generally peak approximately 40 minutes after dosing and may last for about four hours. In the cardiac safety analysis by Doherty et al. (2020), blood pressure typically returned toward the predose range by approximately 1.5 hours.
In the double-blind clinical trials reviewed by Doherty and colleagues, blood-pressure-related adverse events occurred in 11.6% of patients receiving esketamine plus an antidepressant compared with 3.9% receiving placebo nasal spray plus an antidepressant. Serious cardiovascular events were uncommon, but the study excluded people with uncontrolled hypertension and certain significant cardiovascular conditions. Therefore, these results should not be interpreted as proof that Spravato is safe for every patient.
Your care team may:
- Check your blood pressure before dosing
- Recheck it around 40 minutes after dosing
- Continue monitoring as clinically necessary
- Delay treatment if your blood pressure is too high
- Evaluate chest pain, severe headache, shortness of breath, vision changes, seizure, or other concerning symptoms urgently
Why the two-hour observation period matters
Spravato treatment includes at least two hours of supervised monitoring after administration. This is not an arbitrary waiting period. It allows the healthcare team to observe the time when sedation, dissociation, respiratory changes, and blood-pressure elevations are most likely to occur.
Monitoring may include:
- Blood-pressure checks
- Assessment of alertness and orientation
- Observation for dissociation or severe anxiety
- Respiratory-status monitoring, including pulse oximetry
- Evaluation of dizziness, nausea, or vomiting
- A final assessment to determine whether you are clinically stable and ready to leave
You should not drive, operate machinery, or make safety-sensitive decisions until the next day after a restful sleep. Arrange for a responsible adult to drive you home.
Who should not use Spravato?
Spravato is contraindicated in people with:
- Aneurysmal vascular disease, including certain aneurysms affecting the brain, aorta, or peripheral arteries
- An arteriovenous malformation
- A history of intracerebral hemorrhage
- A known allergy to esketamine, ketamine, or an ingredient in the medication
Uncontrolled or significantly elevated blood pressure may require treatment to be delayed or avoided. The FDA label directs clinicians not to administer Spravato when a blood-pressure increase or increase in intracranial pressure would pose a serious risk.
Tell your psychiatric provider if you have:
- Hypertension or a history of hypertensive crisis
- Heart attack, stroke, heart failure, or significant heart-valve disease
- Abnormal heart rhythms
- A history of brain injury or increased intracranial pressure
- Liver disease
- Psychosis or psychotic symptoms
- A history of substance use disorder
Spravato is not recommended during pregnancy because it may cause fetal harm. Breastfeeding is also not recommended during treatment. If you are pregnant, planning pregnancy, breastfeeding, or considering pregnancy, discuss alternatives and reproductive planning with your healthcare provider before treatment.
Certain medications and substances also require careful review. Alcohol, opioids, benzodiazepines, and other central nervous system depressants may increase sedation. Psychostimulants and monoamine oxidase inhibitors may increase blood pressure. Never stop or change a prescribed medication without speaking with your clinician.
The Spravato REMS safeguards
Because of the risks of sedation, dissociation, respiratory depression, abuse, and misuse, Spravato is available only through the SPRAVATO Risk Evaluation and Mitigation Strategy (REMS).
Key safeguards include:
- Treatment must occur in a healthcare setting certified under the REMS program
- Spravato must be dispensed to and administered in an approved healthcare setting
- You administer the nasal spray under direct observation
- You remain under healthcare-provider supervision for at least two hours
- The team assesses whether you are clinically stable before discharge
- Clinicians screen for risks related to misuse, medical conditions, medications, and pregnancy
If you are considering treatment at Light-tunnel Behavioral Health Services Inc., ask the team to explain the site’s current REMS status, monitoring process, transportation expectations, and emergency procedures.
What to do: and what to avoid: on treatment days
Do:
- Follow your prescribed dosing schedule
- Tell the care team about every medication, supplement, and substance you use
- Report new or worsening symptoms immediately
- Follow instructions about fasting before treatment
- Arrange transportation home
- Keep follow-up appointments so your response and side effects can be evaluated
Avoid:
- Driving or operating machinery after treatment
- Alcohol, unless your prescriber specifically advises otherwise
- Taking extra medication to counteract sleepiness or anxiety
- Eating within two hours or drinking liquids within 30 minutes before treatment unless your clinician gives different instructions
- Using a nasal steroid or decongestant within the hour before Spravato unless directed otherwise
- Assuming that a mild reaction during one session guarantees the same reaction during the next session
What does the research say about safety?
Randomized controlled trials support the use of esketamine in selected adults with treatment-resistant depression, but the studies were conducted with medical screening and supervised administration.
- TRANSFORM-1 found that fixed-dose esketamine plus a newly initiated oral antidepressant improved depressive symptoms, with transient dissociation, dizziness, nausea, vertigo, and sedation among the most common adverse events (Fedgchin et al., 2019).
- TRANSFORM-2 evaluated flexible dosing and reported a similar tolerability profile, with monitoring built into every treatment session (Popova et al., 2019).
- SUSTAIN-1 examined relapse prevention after response or remission and provided longer-term randomized withdrawal data (Daly et al., 2019).
- Doherty et al. analyzed cardiovascular safety across the clinical development program and found that blood-pressure elevations were generally short-lived and serious cardiovascular events were uncommon in the screened study population (Doherty et al., 2020).
This evidence supports cautious hope, not a guarantee. Treatment-resistant depression can be debilitating, but it is not necessarily permanent. A carefully monitored treatment plan may open another path when previous approaches have not provided enough relief.
Learn more in New Haven
Light-tunnel Behavioral Health Services Inc. provides personalized psychiatric evaluation, medication management, therapy, and other behavioral health services. You can learn more about medication management, psychiatric evaluation, insurance options, or schedule an appointment.
Important medical and emergency disclaimer
This article is for general education and does not replace an evaluation, diagnosis, or treatment plan from a licensed healthcare professional. Spravato is a prescription medication with serious risks and should only be used exactly as prescribed in an appropriately certified healthcare setting. Do not begin, stop, or change psychiatric medication without consulting your prescriber.
If you experience chest pain, severe shortness of breath, sudden severe headache, vision changes, seizure, loss of consciousness, severe confusion, or another medical emergency, call 911 or go to the nearest emergency department.
If you or someone you know is experiencing suicidal thoughts or feels unable to stay safe, call or text 988 in the United States for the Suicide & Crisis Lifeline. If there is immediate danger, call 911.
References
Doherty T, Wajs E, Melkote R, et al. Cardiac Safety of Esketamine Nasal Spray in Treatment-Resistant Depression: Results from the Clinical Development Program. CNS Drugs. 2020;34:299–310. doi:10.1007/s40263-020-00699-4
Fedgchin M, Trivedi MH, Daly EJ, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: TRANSFORM-1. International Journal of Neuropsychopharmacology. 2019;22(10):616–630. doi:10.1093/ijnp/pyz039
Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: TRANSFORM-2. American Journal of Psychiatry. 2019;176(6):428–438. doi:10.1176/appi.ajp.2019.19020172
Daly EJ, Trivedi MH, Janik A, et al. A double-blind, randomized withdrawal, multicenter study of esketamine nasal spray plus an oral antidepressant for relapse prevention in treatment-resistant depression: SUSTAIN-1. JAMA Psychiatry. 2019;76(9):893–903. doi:10.1001/jamapsychiatry.2019.1189
U.S. Food and Drug Administration. SPRAVATO® (esketamine) nasal spray prescribing information, revised January 2025.
Next in the series: Read What to Expect During Spravato Treatment: A Step-by-Step Guide to Esketamine Therapy in New Haven.