If you were to compare esketamine vs. ketamine, what would you find? These two medications have a lot in common: They’re different forms of a drug that has been shown to improve symptoms of depression.
Although minimal research directly compares the effects of esketamine vs. ketamine, clinical trials indicate that the difference between esketamine and ketamine is significant.
This article will look at what these drugs are, how they differ, and what they have in common. Plus, we’ll look at what this information means for ketamine therapy and what to ask your healthcare provider.
What Is Ketamine?
Ketamine (R-ketamine) is a dissociative anesthetic. “Dissociative” means it makes a person feel detached from their body and environment. The FDA approved the surgical use of ketamine in 1970, and it remains in use throughout the world today.
Ketamine produces psychoactive effects at subanesthetic doses, which in other words means taking lower-than-anesthetic doses makes people trip. Those psychoactive effects include euphoria, hallucinations, and an out-of-body experience called the K-Hole.
In recent years, a growing number of providers have prescribed ketamine to help with treatment-resistant depression and other mood disorders. 1This is an off-label use, which means the medicine is used for a condition it wasn’t approved to treat.
As of the time this was published, ketamine may only be prescribed and administered by a licensed clinician. (Ketamine is a Schedule III controlled drug in the United States, so possession without a prescription is illegal.)
So, how does it work? Ketamine simultaneously affects many parts of the brain at once, but the most studied way is its effect on a neurotransmitter called glutamate.
Your brain uses chemical messengers called neurotransmitters to send signals. Neurotransmitters bind to specific receptors in your brain, like a lock fitting into a key. Ketamine temporarily blocks NMDA receptors, which causes levels of glutamate to increase. 2
The buildup of glutamate has ripple effects throughout the brain. Although scientists aren’t entirely sure how ketamine works in humans, one prevailing theory is that higher levels of glutamate activate pathways in the brain that support neuroplasticity and healthy cell growth. This activity results in rapid antidepressant effects. 3
What Is Esketamine?
Esketamine (S-ketamine) is a derivative of ketamine. In chemical terms, ketamine is a racemic mixture. That means ketamine’s molecular structure is like your left and right hands. They look pretty similar, right? Now, isolate one hand. Similarly, esketamine is one-half of the ketamine molecule.
Like ketamine, esketamine can cause dissociation, dizziness, hallucinations, and sedation. It also has antidepressant effects. In 2019, the FDA approved esketamine (brand name Spravato®) for treatment-resistant depression when combined with an oral antidepressant. 4
Esketamine vs. ketamine might seem like an empty comparison because they have so much in common. However, emerging research shows that these drugs work differently in the brain.
Esketamine has a higher affinity for the NMDA receptor (up to four times more potent than R-ketamine). 5 So, esketamine’s primary antidepressant effects come from its ability to temporarily block NMDA receptors and allow glutamate to increase in the brain.
If that process sounds familiar, it’s because that’s one of the primary ways that ketamine works, too. However, research shows that ketamine’s effects extend beyond glutamate. It may also act on other neurotransmitters and messenger pathways to spur neuroplasticity and cell growth. 6
In other words, esketamine works on just one part of the brain. Ketamine potentially works on many parts.
What are the Key Differences Between Esketamine and Ketamine?
Esketamine is only available as a nasal spray, which patients administer themselves under a licensed provider’s supervision. Spravato contains 28 milligrams of esketamine, and the patient uses two to three devices per treatment.
Ketamine can be administered as:
- An intravenous (IV) injection
- Intramuscular (IM) injection
- Sublingual (under the tongue) liquid
- Oral dose in pill form
Generally, ketamine therapy uses IV injections.
Some experts consider intranasal esketamine a more practical option because it’s cheaper and easier to administer than IV infusions. 6 However, an IV ketamine infusion is 100 percent bioavailable; in comparison, intranasal ketamine is 25–50 percent bioavailable. 7
Esketamine’s effects peak after about 40 minutes, and sessions take about two hours from start to finish. Treatment usually lasts for eight weeks, one to two times per week.
Ketamine lasts a bit longer. Treatment lasts about an hour, and the psychedelic effects subside within three hours. 2 Ketamine therapy usually involves six infusions spaced out over two to three weeks, but the frequency can vary depending on what your provider recommends. 8
Esketamine is FDA-approved, which opens up options for health insurance coverage. Eligible, commercially insured patients pay $10 per Spravato treatment. 9
Ketamine is not FDA-approved, and using ketamine for depression is an off-label use. As such, it’s usually not covered by insurance. Some clinics offer financing plans, but generally, the price can be prohibitive.
Esketamine and ketamine are effective antidepressants. However, emerging research indicates that ketamine may be the more effective option for reducing depression. 6
In 2022, a report published in JAMA Psychiatry found that intravenous ketamine may improve depressive symptoms more rapidly than intranasal esketamine. 10 The researchers reviewed two groups of people with major depressive disorder (MDD) who received esketamine or ketamine therapy. Although both treatments reduced symptoms, depressive symptoms were lower in the ketamine group.
Minimal clinical research specifically compares the efficacy of esketamine vs. ketamine for treatment-resistant depression. However, in a 2020 review of randomized controlled trials, ketamine demonstrated more significant overall improvements in depressive symptoms (over double that of esketamine). 6
Further clinical research is needed, but ketamine might be more effective than esketamine in reducing depressive symptoms for short-term use. The review authors note that how esketamine vs. ketamine compare among populations with treatment-resistant depression, MDD, or bipolar disorder is less clear.
What are the Key Similarities Between Esketamine and Ketamine?
Ketamine and esketamine both produce similar effects, such as:
- Calmness and relaxation
- Changes in perception of time and place
- High blood pressure
Ketamine side effects and risks include:
- Blurred vision
- Confusion, insomnia
Additionally, these drugs risk bladder problems, particularly if they’re abused. Therefore, it’s essential to only take esketamine and ketamine under the guidance of a medical professional.
Ketamine and esketamine may potentially lead to addiction and tolerance. If you or someone you know are struggling with substance use or addiction, reach out to the Substance Abuse and Mental Health Services Administration (SAMHSA) National Helpline at 1-800-662-4357 for information about support and treatment facilities in your area.
Both drugs work quickly. Antidepressant medications can take weeks to make a difference in how a person feels. In comparison, esketamine and ketamine have improved depressive symptoms within hours. 11,12
Although esketamine is FDA-approved, it’s only available at a certified doctor’s office or clinic. Similarly, ketamine can only be prescribed and administered by a licensed medical professional.
It’s important to note that some medical providers have been able to prescribe ketamine virtually due to the COVID-19 pandemic, leading to the rise of the ketamine telehealth industry. 14 At the time this was published, ketamine telehealth is allowed due to the ongoing public health emergency.
Esketamine vs. Ketamine: Which One is Better for You?
So, is one drug better than the other? As with most things in life, there isn’t a clear answer. Preclinical studies suggest that ketamine has better antidepressant effects than esketamine. However, more randomized controlled trials are needed to understand whether those effects apply to people with specific conditions.
We know that esketamine and ketamine are fast and effective ways to reduce depressive symptoms. And if you don’t like needles, you might prefer esketamine treatment because it’s available as a nasal spray. Additionally, esketamine may be more affordable than ketamine therapy if you have health insurance.
If you’re struggling with treatment-resistant depression, work with your doctor to determine whether esketemine or ketamine are better options.
Frequently Asked Questions
Does insurance cover Spravato?
You may be able to get coverage for Spravato (esketamine) through your insurance. Unlike ketamine, Spravato is more commonly covered because it’s an FDA-approved for treatment-resistant depression when combined with an oral antidepressant.
How do you get esketamine nasal spray?
You can get esketamine nasal spray if you’re eligible for treatment and receive a prescription from a health care professional. Spravato (esketamine) is reserved for treatment-resistant depression, which means at least two other therapies haven’t improved your symptoms.
How do I find a ketamine treatment center?
You can find a ketamine treatment center by working with a healthcare professional at a ketamine clinic. The following directories can help you find clinics in your area:
- American Society of Ketamine Physicians, Psychotherapists, and Practitioners
- Ketamine Clinics Directory
- Ketamine Directory
Ketamine has been around for decades, but we’re still discovering how it works in the brain. Both esketamine and ketamine can help people with treatment-resistant depression, and they work far more quickly than conventional antidepressant medications. Preclinical research suggests that ketamine infusion therapy is more effective in reducing symptoms of depression, but more clinical trials are needed. If you haven’t found success with other forms of treatment, talk to your doctor to see if you’re eligible for esketamine or ketamine therapy.
3. Matveychuk D, Thomas RK, Swainson J, et al. Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers. Ther Adv Psychopharmacol. 2020;10:2045125320916657. doi:10.1177/2045125320916657
4. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA. Accessed April 22, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified
5. Moaddel R, Abdrakhmanova G, Kozak J, et al. Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in ?7 nicotinic acetylcholine receptors. Eur J Pharmacol. 2013;698(1-3):228-234. doi:10.1016/j.ejphar.2012.11.023
6. Bahji A, Vazquez GH, Zarate CA. Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. J Affect Disord. 2021;278:542-555. doi:10.1016/j.jad.2020.09.071
8. Shiroma PR, Thuras P, Wels J, et al. A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression. Transl Psychiatry. 2020;10(1):206. doi:10.1038/s41398-020-00897-0
10. Nikayin S, Rhee TG, Cunningham ME, et al. Evaluation of the trajectory of depression severity with ketamine and esketamine treatment in a clinical setting. JAMA Psychiatry. Published online May 11, 2022. doi:10.1001/jamapsychiatry.2022.1074
11. 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
13. McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation. Am J Psychiatry. 2021;178(5):383-399. doi:10.1176/appi.ajp.2020.20081251