Ketamine for Depression: 7 Ketamine Interactions to Know About
Key takeaways:
Ketamine (Ketalar) is an anesthetic medication. It’s also used off-label for severe or hard-to-treat depression.
Opioids, benzodiazepines, and alcohol might cause excessive drowsiness or breathing problems when combined with ketamine. And stimulants like amphetamine salts (Adderall) and methylphenidate (Ritalin) can cause high blood pressure when used with ketamine.
Give your healthcare provider and pharmacist a list of the medications and over-the-counter products you take. And be honest with them about how much alcohol you drink. This will help them evaluate whether you’re at risk of any ketamine interactions.
Table of contents
Ketamine (Ketalar) is an injectable medication that’s FDA approved for surgical anesthesia. But ketamine has gained attention in recent years for helping with mental health conditions like depression.
Ketamine should only be given for depression under medical supervision. Even ketamine-based nasal spray Spravato (esketamine) isn’t meant for home use. That’s because serious side effects are possible, including drug interactions. Here, we’ll cover eight important ketamine interactions to watch for.
Good to know: We don’t have a lot of research on ketamine interactions when it’s used for depression. Ketamine doses used in depression are lower than doses used for anesthesia. So it’s likely that ketamine side effects and interactions are less of a risk than they would be with higher doses.
Search and compare options
1. Opioids
Ketamine and opioids are different types of medications. But they both:
Can treat pain, though ketamine isn’t FDA approved for pain
Are controlled substances and have risks for misuse
Share some of the same side effects, like drowsiness and dizziness
In hospital intensive care units, ketamine may be used to reduce the need for opioids. But combining ketamine and opioids can lead to worse nausea, drowsiness, and dizziness. More seriously, slowed breathing leading to death is also possible.
Methadone (Methadose) is a unique opioid used to treat pain and opioid use disorder. Besides the risk of slowed breathing, combining methadone and ketamine can increase the risk of hallucinations and other psychotic symptoms. This is because ketamine and methadone both block a receptor (binding site) called the N-methyl D-aspartate receptor. Blocking this receptor can lead to pain relief. But it can also cause psychosis, including hallucinations.
Let your healthcare provider know if you take opioids. If they think it’s safe for you to receive ketamine, they’ll monitor your vital signs closely.
Good to know: The risk for misuse is lower with ketamine than most opioids. But ketamine misuse is a growing concern, especially with home use of ketamine. The FDA recently warned that it’s not safe to use compounded ketamine oral pills or nasal sprays at home.
2. Benzodiazepines
If you have anxiety, your healthcare provider may have prescribed benzodiazepines for you. They’re not a first-choice medication for anxiety, but they can be useful in some cases. Examples include alprazolam (Xanax), lorazepam (Ativan), and diazepam (Valium).
Benzodiazepines interact with ketamine in several ways. This interaction may lead to:
Increased drowsiness and a higher risk for slowed breathing.
Reduced effectiveness of ketamine’s antidepressant effects.
High ketamine levels in the body when used with some benzodiazepines like diazepam, which blocks the breakdown of ketamine. Higher ketamine levels can mean more (or worse) side effects.
While some benzodiazepines don’t last long in the body, some stay in your system for days. If you take benzodiazepines — even sporadically — let your provider know. They may want you to adjust how you take your benzodiazepine or they may ask you to stop taking it altogether.
Good to know: Ketamine can interfere with your ability to perform daily tasks like driving. To be safe, avoid activities that require alertness for the rest of the day after your ketamine treatment. This is especially important if you take benzodiazepines, which can have the same effect.
3. Alcohol
Mixing alcohol with ketamine can lead to excessive drowsiness and breathing problems. At the very least, you should avoid drinking alcohol on your ketamine treatment day.
However, your healthcare provider may recommend avoiding alcohol altogether if you’re receiving ketamine. Not only do ketamine and alcohol cause similar side effects like drowsiness and dizziness, but alcohol can make depression worse.
Before starting ketamine, be honest with your healthcare provider about how much alcohol you drink. They’ll go over the risks versus benefits of starting ketamine treatment.
4. Barbiturates
Along with benzodiazepines, barbiturates are a type of sedative medication. Sedatives slow down the brain. This can make you feel off-balance or sleepy. Barbiturates aren’t prescribed often, but the most common example is phenobarbital, which is used for sedation and to treat seizures.
Ketamine has similar side effects to sedatives. So receiving ketamine while taking a barbiturate can make those side effects worse. This includes drowsiness and slowed breathing. Your healthcare provider can weigh the risks versus benefits for this potential interaction.
It’s possible you’ll need to take phenobarbital for seizures while using ketamine. Receiving your ketamine treatment in a medical setting will help keep you safe. And make sure to follow any home instructions from your healthcare provider.
5. Medications that affect ketamine levels
Ketamine is metabolized (broken down) in your liver. Some medications can speed up or slow down this process. In some cases this can make ketamine less effective. In other cases, ketamine may build up in the body and cause side effects. But we don’t have much research on how significant these interactions are.
A few examples of medications that might make ketamine less effective include rifampin (Rifadin) and St. John’s wort. Medications and substances that can increase ketamine side effects include ketoconazole, clopidogrel (Plavix), and grapefruit juice.
Share a list of medications and over-the-counter products you take with your provider and pharmacist. This will help them check for ketamine interactions. If these interactions can’t be avoided, your healthcare provider can tell you how best to manage them.
6. Stimulants
Stimulant medications include medications like amphetamine salts (Adderall) and methylphenidate (Ritalin). They're the most commonly prescribed medications for attention-deficit hyperactivity disorder (ADHD).
Both ketamine and stimulants can raise blood pressure. You’re most likely to notice a change within the first hour after receiving ketamine. After 2 to 4 hours, your blood pressure should return to baseline. But it’s possible that your blood pressure might increase more if you’re taking stimulant medication.
Good to know: If you already have high blood pressure or an existing heart problem, ketamine-induced blood pressure changes may be more dangerous. Make sure your healthcare provider knows your medical history before starting ketamine treatments.
7. Monoamine oxidase inhibitors
Monoamine oxidase inhibitors (MAOIs) are a group of older medications that treat depression and Parkinson’s disease. Examples include selegiline (Eldepryl, Emsam, Zelapar) and rasagiline (Azilect). MAOIs and ketamine can both increase blood pressure. If you take them together, your blood pressure might get too high.
If you take an MAOI, your healthcare provider can talk to you about the risks versus benefits of continuing to take it with ketamine. They may recommend closer monitoring of your blood pressure, which may include checking it at home.
Good to know: Oral antidepressants are first-choice treatments for depression. Your healthcare provider will likely prescribe IV ketamine alongside an oral depression medication. Most commonly used antidepressants are safe to use with ketamine.
When should you contact your healthcare provider about a ketamine interaction?
A few hours after receiving your ketamine treatment for depression, any side effects you felt will most likely resolve. Still, be mindful of how you’re feeling. If you notice anything that feels “off,” let your provider know. Certain symptoms might suggest something more serious is going on.
Get immediate medical help if you experience any of the following:
Excessive drowsiness
Trouble breathing
Severe headache
Suicidal behaviors or thoughts
Change in skin color
Slowed or racing heart
Chest pain
Very high blood pressure (over 180 mmHg systolic or 120 mmHg diastolic)
The bottom line
Ketamine (Ketalar) is an intravenous (IV) treatment that’s used off-label to treat severe depression. Ketamine has risks, including drug reactions.
We don’t have a lot of research on ketamine interactions, especially when it’s used as an antidepressant. But certain medications that have similar side effects to ketamine are worth knowing about. These medications can increase drowsiness and dizziness when taken with ketamine. More seriously, they can slow your breathing. Examples include opioids, benzodiazepines, and barbiturates. Alcohol may also cause similar problems.
Ketamine can also increase your blood pressure. Spikes in blood pressure may be more likely with stimulants and monoamine oxidase inhibitors (MAOIs). Medications and supplements like rifampin (Rifadin) and St. John’s wort can make ketamine less effective. Clopidogrel (Plavix), clarithromycin, and grapefruit juice could increase ketamine side effects.
Why trust our experts?
References
Andrashko, V., et al. (2020). The antidepressant effect of ketamine is dampened by concomitant benzodiazepine medication. Frontiers in Psychiatry.
Ballard, E. D., et al. (2020). The role of dissociation in ketamine’s antidepressant effects. Nature Communications.
Centers for Disease Control and Prevention. (2022). Alcohol and other substance use.
Devlin, J. W., et al. (2018). Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Critical Care Medicine.
Dinis-Oliveira, R. J. (2017). Metabolism and metabolomics of ketamine: A toxicological approach. Forensic Sciences Research.
Henry Schein, Inc. (2023). Ketamine hydrochloride injection, solution, concentrate [package insert].
Jewett, B. E., et al. (2022). Physiology, NMDA receptor. StatPearls.
Krystal, J. H., et al. (2023). Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments. Proceedings of the National Academy of Sciences of the United States of America.
Langmia, I. M., et al. (2022). Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant - implications for precision dosing in a global perspective. British Journal of Clinical Pharmacology.
McIntyre, R. S., et al. (2021). Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: An international expert opinion on the available evidence and implementation. American Journal of Psychiatry.
Moore, T. J., et al. (2022). Safety and effectiveness of NMDA receptor antagonists for depression: A multidisciplinary review. Pharmacotherapy.
Noguchi, K. (2002). NMDA antagonist-induced neurotoxicity and psychosis. Handbook of Neurotoxicology.
Pai, S. M., et al. (2021). Off-label use of ketamine: A challenging drug treatment delivery model with an inherently unfavorable risk-benefit profile. The Journal of Clinical Pharmacology.
Palamar, J. J., et al. (2021). Trends in ketamine use, exposures, and seizures in the United States up to 2019. American Journal of Public Health.
Riccardi, A., et al. (2023). Narrative review: Low-dose ketamine for pain management. Journal of Clinical Medicine.
Silva, A., et al. (2023). New perspective for drug–drug interaction in perioperative period. Journal of Clinical Medicine.
U.S. Food and Drug Administration. (2022). FDA alerts health care professionals of potential risks associated with compounded ketamine nasal spray.
U.S. Food and Drug Administration. (2023). FDA warns patients and health care providers about potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders.
Veraart, J. K. E., et al. (2021). Pharmacodynamic interactions between ketamine and psychiatric medications used in the treatment of depression: A systematic review. International Journal of Neuropsychopharmacology.
Yip, R., et al. (2022). Intravenous ketamine for depression: A clinical discussion reconsidering best practices in acute hypertension management. Frontiers in Psychiatry.
For additional resources or to connect with mental health services in your area, call SAMHSA’s National Helpline at 1-800-662-4357. For immediate assistance, call the National Suicide Prevention Lifeline at 988, or text HOME to 741-741 to reach the Crisis Text Line.
