Spravato Drug Interactions: What to Avoid and What to Tell Your Doctor

Spravato (esketamine) interacts with several important medication classes. Because it causes sedation and dissociation as part of its normal action, combining it with other drugs that affect the central nervous system can significantly increase the risk of serious adverse effects. Before starting Spravato, it's essential to give your healthcare provider a complete list of every medication, supplement, and substance you take.

Most Important Spravato Drug Interactions to Know

1. CNS Depressants — Major Interaction (Increased Sedation and Respiratory Risk)

The most clinically significant category of Spravato interactions is with central nervous system (CNS) depressants. These drugs all slow down brain activity, and combining them with Spravato — which already causes significant sedation — can create dangerously excessive drowsiness and respiratory depression.

CNS depressants to be cautious with include:

Benzodiazepines (alprazolam/Xanax, diazepam/Valium, lorazepam/Ativan, clonazepam/Klonopin): Very common in TRD patients for anxiety; significant sedation risk with esketamine. If you take a benzodiazepine, discuss with your provider whether to hold it on treatment days.

Opioid pain medications (oxycodone, hydrocodone, fentanyl, buprenorphine): Increased sedation and respiratory depression risk. Avoid or use with extreme caution. Buprenorphine (for opioid use disorder) is a particularly important interaction to discuss with your psychiatrist.

Alcohol: Do not drink alcohol on treatment days or combine with Spravato. Significant additive CNS depression.

Antihistamines (diphenhydramine/Benadryl, hydroxyzine/Vistaril): Additive sedation.

Muscle relaxers (cyclobenzaprine, methocarbamol): Additive CNS depression.

Sleeping medications (zolpidem/Ambien, eszopiclone/Lunesta): Additive sedation.

2. MAOIs (Monoamine Oxidase Inhibitors) — Major Interaction (Blood Pressure Risk)

Combining Spravato with MAOIs significantly increases the risk of dangerous blood pressure elevation (hypertensive crisis). MAOIs include:

Phenelzine (Nardil)

Tranylcypromine (Parnate)

Selegiline (Emsam patch)

Isocarboxazid (Marplan)

MAOIs are sometimes still used for severe TRD. If you are currently taking an MAOI, inform your prescriber immediately. Switching to Spravato typically requires a washout period.

3. Stimulant Medications — Moderate Interaction (Blood Pressure Risk)

Stimulant medications — used for ADHD, narcolepsy, or depression augmentation — can increase blood pressure and heart rate. Since Spravato also elevates blood pressure, combining the two increases the risk of hypertensive episodes. Stimulants to discuss with your provider include:

Amphetamine salts (Adderall, Vyvanse)

Methylphenidate (Ritalin, Concerta)

Pseudoephedrine (Sudafed) — decongestant with stimulant properties

Caffeine (high doses) — modest blood pressure interaction; monitor

4. Rifampin and Ticlopidine — Pharmacokinetic Interactions

These are less common but pharmacologically documented interactions:

Rifampin/rifampicin (antibiotic used for tuberculosis): Reduces esketamine plasma concentrations by 10–25%, potentially decreasing effectiveness

Ticlopidine (antiplatelet agent): Inhibits CYP2B6, increasing esketamine plasma levels and potentially increasing side effects

5. Nasal Medications — Timing Interaction

Because Spravato is a nasal spray, using other nasal medications at the same time can affect absorption. If you use nasal corticosteroids (like Flonase) or nasal decongestants, administer them at least 1 hour before your Spravato session to avoid reduced drug absorption.

What to Tell Your Doctor Before Starting Spravato

Before starting Spravato, provide your full medication list to your prescriber and treatment center. Be sure to include:

All prescription medications (psychiatric, pain, cardiovascular, etc.)

Over-the-counter medications (sleep aids, antihistamines, cold medicines, decongestants)

Supplements and herbal products (especially St. John's Wort, which affects CYP enzymes)

Recreational drug use — especially alcohol, cannabis, or illicit stimulants

Any history of substance use disorder

A Note on False Positive Drug Tests

Esketamine can trigger false-positive methadone results on urine immunoassay drug screens. If you are tested for drugs (for employment, legal, or medical purposes) while receiving Spravato treatment, inform the testing facility in advance. Confirmatory testing (GC/MS) is recommended for any positive immunoassay screen.

Managing Your Full Medication Regimen

Managing multiple medications for treatment-resistant depression can be complex — especially when some are hard to find at local pharmacies. medfinder calls pharmacies near you to find which ones have your prescriptions in stock, making it easier to stay consistent with your full medication regimen.

Also read: Spravato Side Effects: What to Expect and When to Call Your Doctor.