What Is Ketamine and How Is It Used To Treat Depression?

Ketamine is a medication that’s been used for over 50 years as an anesthetic and pain killer. It’s also used illegally to get high. 

But recently, ketamine — and its close cousin, esketamine (Spravato) — have gained attention for their use in treating depression and other mental health conditions. Ketamine seems to work very quickly, sometimes providing relief after just one dose. It may also help suicidal thoughts go away.

This is why ketamine may be a promising option for people with certain types of depression. Let’s learn how it works.

What is ketamine?

Ketamine was first created in the 1960s. It was approved for use during surgery as a part of anesthesia. At low doses, ketamine produces psychedelic effects similar to substances like LSD and psilocybin (the active ingredient in “magic mushrooms''). Ketamine can also make people feel disconnected or separated from their body.

Ketamine is classified as a Schedule III controlled substance. This means it has a potential for abuse or misuse. But it’s considered less harmful or addictive than Schedule I or II substances, like heroin or oxycodone. 

Over time, ketamine use during surgery became less common. But more healthcare providers began using it off-label to treat pain. And with more widespread use, providers started noticing that ketamine also seemed to have antidepressant effects.

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What is esketamine?

Esketamine (Spravato) is a nasal spray that’s FDA approved to treat:

• Treatment-resistant depression

• Depression with suicidal thoughts or actions

So how’s it different from ketamine? Ketamine is made up of two molecules that are mirror images of each other: (S)-ketamine and (R)-ketamine. But esketamine is only the (S)-ketamine molecule (hence the name). This molecule seems to be more potent than ketamine, with fewer side effects.

How do ketamine and esketamine work?

We don’t know exactly how ketamine and esketamine help with depression. They seem to act on many different parts of the brain, but experts still aren’t exactly sure which matters the most for depression.

Ketamine has effects on the following:

• Glutamate: Ketamine affects glutamate activity in the brain. Glutamate is a chemical messenger that influences your mood, emotions, and the way you think.

• Opioid receptors: Ketamine is not an opioid, but it affects the opioid system. The opioid system controls mood, reward/pleasure, and pain.

• Neuroplasticity: Ketamine increases neuroplasticity. This is the brain’s ability to adapt to changes like learning, stress, or injury. Research shows connections between depression and lower neuroplasticity.

• Default mode network (DMN): The DMN refers to parts of your brain that kick in when you’re awake but not active — like when you daydream. It may also be responsible for negative thoughts, especially about yourself. People with depression may have too much activity in their DMN. Ketamine has the ability to lower DMN activity in depressed people.

Esketamine works similarly to ketamine in the body. But it seems to do a better job of binding to glutamate receptors in your brain. 

What is ketamine used to treat, and what does the research say?

Though ketamine is only FDA approved for use as an anesthetic, it’s also used off-label for treatment-resistant depression. Experts are also exploring the potential of ketamine therapy for several other mental health conditions, including:

• Anxiety

• Post-traumatic stress disorder (PTSD)

• Substance use disorders

Depression

Ketamine’s quick antidepressant effects have been researched for decades. In 2000, the first human trial was conducted on ketamine for major depressive disorder. The results showed that ketamine infusions led to a significant improvement in symptoms.

In a study of over 500 people treated with ketamine for depression, more than 53% responded to treatment and 73% had a reduction in suicidal thoughts. Of those who responded, the improvements lasted up to 4 weeks for 80% of participants and up to 8 weeks for 60% of participants.

A benefit of ketamine treatment for depression is that it’s safe to keep taking most other antidepressant medications with it. Also, most FDA-approved antidepressant medications can take several weeks to start working. Ketamine seems to work much faster (within hours to days). But again, there’s still a lot about it we don’t know. 

For example, we don’t know if ketamine’s psychedelic effects are necessary for its use as an antidepressant. More research is needed to find out exactly how ketamine works for depression.

Anxiety

Ketamine may cause anxiety for some people. But there’s also research on ketamine’s anti-anxiety effects. This could be an added benefit of ketamine, as many people with depression also have an anxiety disorder.

A review of the research concluded that ketamine may improve anxiety that hasn’t improved with other treatments. But more studies are needed to know for sure.

Post Traumatic Stress Disorder (PTSD)

PTSD is an illness that’s often caused by a traumatic or stressful event. It has many of the same symptoms as depression and anxiety. PTSD has also been linked to glutamate activity, reduced neuroplasticity, and abnormalities in the DMN. Experts believe that ketamine’s effects on these things could make it a helpful treatment option for PTSD.

But so far, studies on ketamine for PTSD symptoms have had mixed results. Ketamine may be more effective at treating chronic PTSD symptoms. One study showed that 67% of people with chronic PTSD responded to ketamine treatment.

Substance Use Disorders

Substance use disorders are one of the most pressing public health issues today, affecting over 20 million Americans over the age of 12. Ketamine has been studied for the treatment of certain substance use disorders.

People with alcohol use disorder saw 66% abstinence rates for up to 1 year after ketamine treatment. Research also showed a 67% reduction in cocaine use and up to 50% reduction in heroin use after three ketamine sessions. Much of the research found success when combining ketamine with psychotherapy.

Research also suggested that multiple ketamine treatment sessions may be more beneficial than a single treatment. The group treated for heroin use disorder saw a 22% reduction in use and cravings after one ketamine treatment session compared to a 50% reduction after three sessions.

What is esketamine used to treat?

Esketamine (Spravato) is FDA approved to treat treatment-resistant depression as well as depression with suicidal thoughts and behavior. So far, it doesn’t seem to be as effective as ketamine infusions for depression. But the nasal spray is easier to use and seems to have fewer side effects, which may make it a more attractive treatment option for some people.

How is ketamine administered for depression?

A healthcare provider can administer ketamine in several different ways. The different forms of ketamine include:

• Intravenous infusion (IV)

• Injection into the muscle (IM)

• Injection under the skin

• Oral or sublingual tablet

• Nasal spray

Ketamine given as an IV has the most research behind it. The IM injection is often reserved for emergency situations involving suicidal actions. Oral ketamine isn’t absorbed well, so the effects are more subtle. It’s usually prescribed to take at home between infusion treatments. 

What is microdosing — and how is it different?

Microdosing refers to the practice of taking very small doses of a psychedelic substance. These doses are meant to be small enough to avoid severe psychedelic effects but still offer some potential benefits. But more research is needed, as most microdosing “evidence” is self-reported, and many of these claims have not been proven in human studies. 

It isn’t considered microdosing when you receive ketamine treatment for depression. Depression treatment requires a lower dose than anesthesia, but it’s still high enough to cause psychedelic effects. More research is being done to see if microdoses of ketamine may be effective for depression.

What are the side effects of ketamine and esketamine?

The risk and severity of ketamine and esketamine side effects might depend on the dose and how often you take it. But it’s hard to say for sure, especially since ketamine is used off-label — meaning side effects aren’t as closely monitored as with an FDA-approved medication like Spravato.

More serious ketamine side effects can also occur, but they’re more common with higher doses of ketamine or an IV infusion that’s given too fast. These include:

• Difficulty breathing

• Slow heart rate

• Seizures

• Coma

Is it safe to use ketamine or esketamine over a long period of time?

We don’t know yet. There’s not enough evidence to say whether it’s safe to use ketamine or esketamine long-term for depression. 

So far, there’s evidence that esketamine is safe to use for up to 1 year. But the long-term risks aren’t as clear with ketamine. There’s some evidence ketamine use over time could damage your kidneys, bladder, or brain. More research is needed to know for sure.

Do ketamine or esketamine interact with other medications?

Yes. Ketamine and esketamine have possible drug interactions to consider.

Esketamine can interact with the following medications:

• Central nervous system (CNS) depressants, such as benzodiazepines, opioids, and alcohol. If they’re combined with esketamine, your breathing could become dangerously slow.

• Stimulants, such as methylphenidate (Ritalin) or modafinil (Provigil). If these medications are combined with esketamine, it could cause a severe increase in blood pressure or heart rate, which could be life-threatening. 

• Monoamine Oxidase Inhibitors (MAOIs). MAOIs are a class of medications that treat depression. Most antidepressant medications are safe to take with esketamine. But combining it with MAOIs can increase blood pressure and heart rate.

There’s less information available on ketamine drug interactions. CNS depressants and stimulants likely interact with ketamine the same way as esketamine. Benzodiazepines, lamotrigine (Lamictal), and certain antipsychotic medications may make ketamine less effective, but the evidence isn’t strong.

The lack of good information on drug interactions highlights the importance of taking ketamine while under the care of a medical professional. They’re able to monitor for any signs of an interaction and help manage it. Be sure to keep a medication list and show it to your provider prior to starting ketamine or esketamine treatment.

How do I know if ketamine or esketamine are right for me?

In most cases, ketamine and esketamine are not the first choice to treat depression or other mental health conditions. But if your depression symptoms are severe, or if you’ve tried and failed with other treatments, ketamine or esketamine may be an option for you.

Keep in mind that you shouldn’t try to self-treat with ketamine or esketamine. There are health conditions and medications that could make these medications unsafe for you. Ketamine or esketamine should only be used under the guidance of a healthcare professional. 

The best first step is to talk to your mental healthcare provider about whether ketamine or esketamine are an option for you. 

Who should not take ketamine or esketamine?

Ketamine may not be safe to take if you have certain conditions, such as:

• Pregnant or nursing

• High or unstable blood pressure 

• Liver problems

• Schizophrenia

• Alcohol intoxication

You should not take esketamine if you:

• Have a history or bleeding in the brain

• Have arteriovenous malformation

• Have an aneurysm or blood vessel disease

Why trust our experts?

Written by:

Arielle Tandowski, MPH

Arielle Tandowski, MPH, is a freelance writer for GoodRx. She holds a master's degree in public health from the University of Haifa, where she focused on mental health, substance use, and harm reduction.

Edited by:

Stacia Woodcock, PharmD

Stacia Woodcock, PharmD, is a pharmacy editor for GoodRx. She earned her Doctor of Pharmacy degree from the University of Kentucky and is licensed in New York and Massachusetts.

Reviewed by:

Sarah Gupta, MD

Sarah Gupta, MD, is a licensed physician with a special interest in mental health, sex and gender, eating disorders, and the human microbiome. She is currently board certified by the American Board of Psychiatry and Neurology.

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