A Guide to Ketamine for Depression: Science, Safety, and Patient Experience

Traditional antidepressants don’t work for everyone—and when they do work, they can take weeks to kick in. That’s where ketamine, a fast-acting option that works differently than traditional antidepressants, comes in. But when it comes to ketamine for depression, it’s normal to have questions around how this medication works and if it’s the right treatment for you.

You’ve tried everything for depression—antidepressant medications, talk therapy, and lifestyle interventions. But somehow, nothing seems to stick. This frustration is quite common, since traditional depression medications don’t work for 30-50% of people with major depressive disorder (MDD), and we sometimes need something in addition to therapy and self-care strategies to overcome depression. In your search for that “something extra,” ketamine for depression might have popped up.

Ketamine therapy can offer fast-acting hope for depression. While the drug is FDA-approved as an anesthetic, its antidepressant properties mean it’s sometimes used off-label for MDD. What’s more, esketamine, a similar medication, is FDA-approved for treatment-resistatant depression or MDD with suicidal ideation or behaviors. In this guide, we’ll look at both of these treatments, determining who is a good candidate for each and what to realistically expect when it comes to ketamine and depression. 

What is ketamine?

Ketamine has been around since the 1960s. Originally, it was used as an anesthetic for surgery, but researchers started noticing that when someone received ketamine, it also impacted their mood. As scientists studied that effect, it became clear that ketamine had mood boosting properties and a faster onset of effect compared to other antidepressants. 

The cool thing was, ketamine worked faster (more on this below) and offered fewer long term side effects than traditional depression medications, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs). To this day, ketamine is used off-label for depression. 

In the 1990s, emergency rooms started using esketamine as an anesthetic too. The two terms sound similar, but they are not the same thing. “This is a really unique situation compared to other drugs,” says Ahmed Tahseen, MD, clinical advisor at Radial, medical director at Biohaven Therapeutics, and clinical instructor of psychiatry at Yale University, “and I think this is why it is so confusing for people.”

Fortunately, we’re here to dispel that confusion. To start, ketamine and esketamine have slightly different chemical makeups. Ketamine consists of two molecules (R- and S-ketamine), which are mirror images of each other, while esketamine only contains S-ketamine. This is easy to remember since when you say esketamine and S-ketamine out loud, they sound the same. 

That small chemical change impacts how they work, which is reflected in their FDA statuses. Ketamine is only approved as general anesthetic, though it’s sometimes used off-label for depression. Esketamine, under the brand name Spravato, is FDA-approved for treatment-resistant depression and MDD with suicidal ideation. 

How does ketamine work to treat depression?

While there’s good evidence supporting ketamine therapy for depression, researchers are still unsure how exactly it works. What we do know is that it operates differently than other antidepressant medications. 

Traditional antidepressants, such as SSRIs and SNRIs, block reuptake pumps that clear mood-regulating neurotransmitters. When these neurotransmitters are cleared more slowly, as is the case when on these medications,your brain regulates moods better, although the full effects take weeks to show up. 

SSRIs, SNRIs, and bupropion (Wellbutrin) primarily affect the neurotransmitters dopamine, norepinephrine, or serotonin. Ketamine and esketamine, on the other hand, appear to impact the brain’s glutamate system. A leading theory is that they block NMDA receptors, which leads to increased glutamate signaling. This possibly promotes rapid synaptic growth and flexibility in brain circuits involved in mood and emotion. 

Rapid is an important word here. Ketamine and esketamine are considered fast-acting treatments for depression, meaning they may reduce symptoms of depression more quickly than other medications.

Types of ketamine treatment for depression

When discussing ketamine treatment for depression, there are two main medications to consider: IV ketamine and esketamine, which goes by the brand name Spravato. While the two are similar, they have distinct differences.

IV ketamine infusion

While IV ketamine infusions offer clear  mood-boosting effects, ketamine for treatment-resistant depression is not FDA-approved. Instead, it’s prescribed off-label which usually means self-pay. Typically, it’s prescribed as an intravenous infusion, though it can also come in the form of an intramuscular injection or lozenge.

IV ketamine infusions are provided at ketamine clinics by licensed healthcare providers. On paper, this sounds solid, but that provider is not always a psychiatrist—and there are huge variations in how these clinics operate, notes Dr. Tahseen. 

“When people have negative experiences, it's usually at a place that just isn't psychotherapeutically oriented,” he explains, “Having a place where you feel safe and comfortable and where you do see a psychiatrist or therapist before, and someone who checks in with you during it makes a big difference.”

Esketamine (Spravato) nasal spray

When people talk about ketamine therapy for depression, they may be referring to esketamine. Unlike ketamine, esketamine it’s almost always prescribed by a psychiatrist, and treatment is administered via a nasal spray.  

Esketamine is FDA-approved for those with major depressive disorder with suicidal ideation (MDSI) and “treatment-resistant depression” (TRD). That second term is a bit misleading, since it just means that the depression didn’t respond to traditional antidepressants. It’s almost like saying physical pain is “treatment-resistant” if it doesn’t respond to Tylenol. 

Those FDA-approvals mean esketamine is much more likely to be covered by insurance. The treatment-resistant part, however, means that someone must try a few different medications before insurance will cover esketamine–or be acutely suicidal at the time of the initial evaluation in the outpatient setting, if the doctor is submitting to insurance based on the “MDSI” indication. That can lead to a slightly longer recovery timeline than if someone can self-pay for esketamine or IV ketamine.

How effective is ketamine for depression?

Both ketamine and esketamine have antidepressant effects that can last up to a week after treatment. According to a 2022 review of studies, ketamine is effective for bipolar depression and major depressive disorder. However, we don’t know as much about ketamine and depression as we do about esketamine and depression. 

As part of the FDA approval process, esketamine went through rigorous trials to determine its effect on depression specifically. A 2023 review of 14 studies demonstrated that esketamine works fast, with some patients experiencing fewer depressive symptoms within two hours., With esketamine,  55.4%  of MDD cases show a reduction in symptoms, while 27.1% of MDD cases go into remission.

While effective in the short-term, researchers are still exploring the long-term impacts. Early research suggests using the drug for up to a year may lead to sustained improvements in depression, but there isn’t enough evidence to conclusively state ketamine works for years on end, which is why it’s best used alongside therapy, other psychiatric treatments, and lifestyle changes that support mental health. 

Who is a good candidate for ketamine treatment for depression?

Our minds all work differently, and that means no treatment, including ketamine or esketamine, is right for everyone. These treatments tend to work best for those with depression that hasn’t responded to other medications or to talk therapy alone. It’s also an option for those who have major depressive disorder with suicidal ideation or behaviors. 

Moreover, ketamine and esketamine are most effective if you feel safe and comfortable trying them. Dr. Tahseen has talked to many patients about their experiences on these medications, and feeling mentally secure is a commonality among those who have a good experience. 

Who should not use ketamine for depression?

Someone might not be a good candidate for ketamine or esketamine if they:

• Are pregnant or breastfeeding
• Are under the age of 18
• Have uncontrolled heart problems
• Have a history of psychosis 
• Have a history of schizophrenia 
• Have a hypersensitivity to ketamine or esketamine 

What does ketamine treatment for depression feel like?

There’s no denying that ketamine has a reputation as a “party drug,” which may lead to questions about what ketamine sessions actually feel like. Turns out, ketamine treatment for depression is more similar to a breakthrough therapy session than an episode of “Euphoria.” 

Before treatment

When someone receives esketamine (or ketamine in a psychotherapeutic oriented clinic), treatment starts with a check-in with a psychiatrist or therapist. Dr. Tahseen mentions that this is an important step. It’s a chance for you to ask any questions and for a licensed mental health provider to set expectations and to integrate the experience you’re about to have into a larger depression treatment plan. 

During treatment

After a pre-treatment check-in, a clinic will either administer intravenous ketamine or provide esketamine nasal spray. This isn’t similar to a nasal spray for allergies; you don’t pick it up from a pharmacy and use it every night. Instead, an esketamine nasal spray is administered in-office.

Unlike that allergy nasal spray, esketamine and ketamine have psychoactive properties that can leave someone feeling detached from reality. We might refer to this sensation as “feeling high.” 

With ketamine and esketamine, “you are showing your brain a different way of being,” says Dr. Tahseen. He points out that when you’re depressed for a long time, it can be hard to imagine feeling good, much less actually experiencing happier emotions. Ketamine can provide that experience, as well as the hope that things can improve. “Sometimes people talk about depression as a constraint or heaviness,” explains Dr. Tahseen, “and ketamine kind of shakes you loose to where you can mentally or emotionally walk forward.”

After treatment

Immediately after a session, you may feel a little disoriented. If clinics are administering Spravato, the FDA requires observing  a patient for two hours after treatment. This may include a post-treatment “reorientation” to discuss what you experienced and how it relates to your depression, but this additional psychological support wasn’t included in any of the clinical trials for esketamine.

“The next day you just don't feel the burden or heaviness of the depression,” says Dr. Tahseen, “Sometimes people describe it as coming back to themselves.” That antidepressant effect typically lasts about one week. That’s why, similar to most other antidepressants, you take ketamine or esketamine more than once. 

Beyond the tangible antidepressant effects, the experience of taking either of these medications can change your perspective on depression. “So often, people who have been experiencing depression or have been treated for depression for a while, don't feel like they can get better,” explains Dr. Tahseen. “Quite a number of people who receive an intervention like TMS or ketamine come out with the newfound belief that they can get better, which is a big deal.”

Side effects and safety considerations

When starting any new depression medication, it’s normal to feel anxious about what the side effects might be. Both ketamine and antidepressants have side effects, but the difference is that many of ketamine side effects occur during the in-clinic experience, while other antidepressants impact you in the long-term, according to Dr. Tahseen. 

“With ketamine, there’s sometimes nausea,” he says, “Or sometimes you have a pretty intense experience, which is really hard to describe, but I'm not worried about any of the long term effects like I am with other medications.” That intense experience is sometimes referred to as dissociation. 

In rare cases, someone may feel dizzy or like they’re about to pass out while on the drug. Since ketamine and esketamine are delivered in-clinic, tell the administering healthcare provider if you feel  light-headed.

Ketamine and eseketamine also increase blood pressure, which can be dangerous for individuals with an uncontrolled heart condition. Additionally, the disassociative effect can negatively impact those with psychosis or schizophrenia, which is why neither treatment is recommended for these patient populations. 

Ketamine vs. other depression treatments

Ketamine isn’t the only depression treatment out there. Here’s how it stacks up against SSRIs, TMS, ECT, and talk therapy. 

Ketamine vs. SSRIs

When it comes to ketamine vs antidepressants, there’s a clear winner in terms of which one acts faster (ketamine).  However, most insurance providers only cover esketamine after someone tries SSRIs first, meaning SSRIs are often more accessible.  SSRIs can also be taken at home while ketamine and esketamine require close monitoring in a clinic.  

Ketamine vs. TMS

Transcranial magnetic stimulation (TMS) is a FDA-cleared treatment for depression. Like ketamine, it requires in-clinic sessions. “TMS and ketamine both are great options for depression,” says Dr. Tahseen, “They have favorable side effect profiles and high remission/response rates.” 

That said, certain TMS protocols, including the ones offered at Radial, have higher remission rates than esketamine. TMS is also non-invasive and doesn’t require medication. Where ketamine edges ahead is in terms of speed: ketamine may work in a matter of hours, while the fastest TMS protocols take about five days to kick-in.  

Ketamine vs. ECT

Electroconvulsive therapy (ECT) is one of the oldest depression treatments. It’s sometimes stigmatized as “shock therapy” because it uses electric stimulus to induce controlled seizures. But that stereotype doesn’t reflect the experience of ECT. Today, ECT is done under anesthesia which makes the treatment safe and humane. 

It’s also pretty effective for MDD, boasting a much higher remission rate than ketamine. The effects of ECT, however, take two to four weeks to appear, and it requires anesthesia and is invasive. Cognitive side effects are common in patients undergoing ECT treatment.

Ketamine vs. psychotherapy

When it comes to ketamine and psychotherapy (talk therapy), it shouldn’t be an either-or situation. “Ketamine plus psychotherapy is a must,” says Dr. Tahseen, “If I was going to refer anyone to a ketamine clinic or if I was going to do it myself, it would always be within a psychotherapeutic framework.”

Cost, insurance, and access

Most insurance providers cover esketamine for depression. Usually, the prescribing psychiatrist must submit documentation on the severity and persistence of the patient's depression and any other treatments they’ve tried. Most insurance companies only approve esketamine when someone has a MDD diagnosis and failed other medications.

When esketamine treatment is approved by the insurance, the patient usually pays their in-office copay, about $30-$50 per clinic visit. If opting for self-pay, each esketamine dose can cost up to $1,365. The most affordable price point (as little as $10 per dose) comes from the Spravato withMe Savings program, which is for people with commercial insurance (i..e not through Medicare, Medicaid, or another government program) who meet specific eligibility criteria.

Ketamine IV therapy costs vary by clinic. Northwell Health, for example, charges $650 per infusion. Since ketamine isn’t FDA-approved for depression like esketamine, any costs will likely be out-of-pocket.

How to decide if ketamine is right for you

The benefits of ketamine may be life-changing. It can help shake off the heaviness of depression and provide hope that things can change. However, it’s not a “cure” for depression. Rather, it’s a tool that can be used alongside lifestyle changes, talk therapy, and other interventions.

If you’re curious about whether ketamine should be part of your depression treatment plan, talk to a psychiatrist with experience administering esketamine or ketamine, such as the team at Radial. Questions to ask may include:

• Am I a good candidate for ketamine or esketamine?
• Which option would you recommend for me: esketamine or ketamine?
• Do you administer ketamine or esketamine at your clinic? If so, what is the experience like?
• Are there any other treatments I should consider alongside ketamine or esketamine?
• What are my payment options? Does my insurance plan cover esketamine for depression?

The bottom line

Ketamine and esketamine are depression treatments worth considering. Both work fast, have a safer side effect profile than some other medications, and have higher remission rates than SSRIs and SNRIs. The key to a positive experience, however, is taking ketamine or esketamine in a psychotherapeutically-minded clinic, such as Radial. 

Key takeaways

• Ketamine and esketamine are two medications with antidepressant effects. They typically work faster than other antidepressant medications with fewer side effects.
• Esketamine is FDA-approved for depression, meaning insurance is more likely to cover it than ketamine. It also means there are more clinical trials backing the efficacy of esketamine for depression than ketamine. 
• For a good experience, it’s important to work with a psychiatry clinic, not a general ketamine clinic. When administered by a mental health provider, ideally in tandem with talk therapy, you can  more effectively and safely integrate ketamine or esketamine into a larger depression treatment plan. 
• Ketamine and esketamine are potential tools, not a “cure” for depression. The most effective way to overcome depression is to work with a clinic like Radial that can help you explore all the potential tools and design a tailored treatment plan. 

Frequently asked questions (FAQs) 

How long does ketamine treatment last for depression?

The antidepressant effect of ketamine typically lasts about one week. Esketamine’s effect on depression lasts a similar amount of time, and both of these treatments are intended to be administered in-clinic multiple times, as opposed to a one-time treatment or a medication taken at home. 

How is ketamine administered?

Ketamine is usually administered via an IV infusion. Some clinics may also administer it as an intramuscular injection or a lozenge. Esketamine, which is a similar medication that’s FDA-approved for depression, is delivered via a nasal spray. Both esketamine and ketamine must be administered in a clinic where a healthcare provider monitors the experience. The FDA has specific guidance advising against compounded ketamine, such as is sometimes prescribed for sublingual or subcutaneous administration.

Is ketamine addictive?

Regularly using high doses of ketamine can lead to addiction. That’s why it’s important to only take ketamine in a qualified clinic where someone can monitor the dose and any symptoms. 

Deep dive recommendations 

• American Journal of Therapeutics. Psychedelic Therapy: A Primer for Primary Care Clinicians—Ketamine.
• MedCity News. Combining Ketamine and Deep TMS: A New Frontier in Treating Depression.
• The Frontier Psychiatrists. Why ketamine clinics keep closing. 
• The Psychiatrist  Podcast. Ketamine/Esketamine (Spravato) with Dr. Joshua Rosenblat.
• Huberman Lab Podcast. Ketamine: Benefits and Risks for Depression, PTSD & Neuroplasticity.
• The KevinMD Podcast. Ketamine, What PCPs Need to Know with Carlene MacMillan, M.D., FCTMSS, DFAACAP.