Key takeaways

Esketamine, a derivative of ketamine, has been FDA-approved for treatment-resistant depression, offering a new option for those with severe depression.
Ketamine’s effectiveness in treating depression is believed to be linked to its impact on the neurotransmitter glutamate, differing from traditional antidepressants that target serotonin, norepinephrine, and dopamine.
While ketamine shows promise in rapidly alleviating symptoms of severe depression and suicidality, its long-term safety profile remains under-researched, with short-term use considered safe.
Access to ketamine treatment for depression is limited to medical settings due to its potential for abuse and significant side effects, and it comes with a high cost.

It seems unlikely that ketamine, an anesthetic and recreational party drug also known as Special K, would be used as a depression treatment—but a derivative of the drug, esketamine, has recently been approved by the U.S. Food and Drug Administration (FDA) for treatment-resistant depression. And research shows that ketamine can be an effective treatment for severe and prolonged depression.

Depression is one of the most common mental health disorders in this country, affecting some 17.3 million American adults, says the National Institute of Mental Health. Symptoms of depression may include:

Persistent feelings of sadness, hopelessness and emptiness
Decreased energy, or fatigue
Restlessness
Difficulty concentrating
Appetite and sleep changes

People with treatment-resistant depression, a type of depression that persists despite using at least two different standard antidepressants at an adequate dosage for an adequate time. In addition to helping with treatment-resistant depression, ketamine is being hailed by those in the psychiatric community as revolutionary in the treatment of depression and other mood disorders, such as anxiety, obsessive compulsive disorder (OCD), bipolar disorder, and post traumatic stress disorder (PTSD).

What is ketamine?

Ketamine is a dissociative anesthetic that is sometimes used off label as a pain reliever in low doses. It’s also abused as a tranquilizer and psychedelic club drug. A “dissociative” drug makes you feel disconnected from your body and your thoughts. Ketamine is in the same class of drugs as phencyclidine (PCP) and can have similar effects. It’s commonly used as an anesthetic in veterinary clinics and, sometimes, in hospital settings.

According to the National Institute on Drug Abuse, in high doses, ketamine produces dream-like states and hallucinations. In lower doses, it can impair your memory, attention, and your ability to function. Other side effects include high blood pressure and breathing problems.

When used medically, ketamine is generally injected into a muscle or given intravenously. It blocks NMDA receptors to induce loss of consciousness, which is why it’s often used during surgical procedures. When used recreationally, it’s usually snorted, smoked, or swallowed and generally makes a person feel “high,” happy, relaxed, and sometimes removed from their own bodies.

How is ketamine used for depression?

Studies have found that ketamine treatment is effective against cases of depression that have otherwise been resistant to traditional oral antidepressants, talk therapy, and even electroconvulsive therapy. According to recent research in the Journal of Managed Care & Specialty Pharmacy, one in three people with major depressive disorder (MDD), a severe depressive condition marked by unrelenting feelings of sadness, hopelessness, and suicidal ideation, have treatment-resistant depression.

When used to treat depression, very low doses of ketamine (lower than doses used for anesthesia) are generally delivered in one of two forms: by infusion or through a nasal spray. Both can only be administered at health clinics or doctor’s offices and both provide fast-acting relief from severe depression, although repeated treatments are needed.

Ketamine infusions

Racemic ketamine is most often used in infusions. Infused ketamine has been used off-label for persistent depression for a number of years. It’s given at a clinic via an IV in the arm. Some clinics have mental health professionals on staff; others don’t but will work in tandem with your doctor. Patients often start with three infusions per week and gradually decrease the number until they are down to one infusion per month. Small clinical trials have shown that infused ketamine can improve depression symptoms within two to four hours, with peak relief achieved in 24 hours.

Esketamine nasal sprays

In March 2019, the FDA approved the drug esketamine (a chemical found in ketamine) for treatment-resistant depression in adults. The drug, marketed under the name Spravato, is given through the nose via a spray and is used along with a daily oral antidepressant. Spravato is given twice weekly for the first four weeks, then once a week for the next month, then once a week or once every two weeks. Because of the addictive nature of ketamine and its potential for abuse—plus the sedation the drug causes—the medication is only used in a medical setting under a healthcare professional’s supervision. It’s not available for take-home use. Patients self-administer the nasal spray after instruction from a healthcare professional and then are monitored for at least two hours before leaving the clinic.

While Spravato uses low doses of esketamine, it’s still a powerful drug. It comes with a “Boxed Warning” noting side effects like impaired judgment and difficulty concentrating after administration. Patients and their prescribers are required to sign what is known as a “Patient Enrollment Form,” stating that all parties recognize the drug causes sedation and patients should not drive or operate heavy machinery on the day they receive treatment. In fact, patients must have a ride home from the clinic where the drug is given. Several short-term clinical trials have found the drug to be safe, yet it is not recommended for anyone with uncontrolled high blood pressure or vascular disorders, as these patients could be at higher risk for adverse events like heart attack and stroke. It should also not be used by children, people with a history of psychosis, pregnant women, women wanting to become pregnant, or women who are breastfeeding.

Besides being effective, Spravato, like infused ketamine, has proven to be fast-acting. Whereas traditional antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs) Prozac and Lexapro, can take weeks to work, Spravato works to relieve depression in a matter of hours to days. That’s a huge boon to anyone experiencing severe depression, but especially to those who may be experiencing suicidality.

“Approximately two thirds of patients with major depressive disorder experience a clinically significant improvement in symptoms within three hours,” says William Coryell, MD, an author for The Merck Manuals and a professor of psychiatry at the University of Iowa’s Carver College of Medicine. “For most, however, these effects decrease considerably over the following several days. For this reason, a series of treatments is often used and this yields sustained benefit for many patients.”

Dr. Corywell cautions against trying recreational ketamine for depression relief. “The antidepressant effects appear to operate only within a certain, sub-anesthetic dose range,” he notes. “Recreational use is likely to exceed this range and there is considerable risk for abuse.”

What makes ketamine effective?

Depression is a mood disorder influenced by neurotransmitters—chemical messengers in the brain that can regulate mood, sleep, and other functions. Experts aren’t entirely sure how ketamine or the esketamine in Spravato works to improve severe depression, but they suspect it may have something to do with how they block the neurotransmitter glutamate from attaching to a particular receptor (called N-methyl-D-aspartate, or NMDA) on the nerves. “Before esketamine became available, drugs approved for use as antidepressants had their effects through changes in the neurotransmitters serotonin, norepinephrine, and dopamine,” explains Dr. Coryell. “Esketamine, in contrast, appears to work chiefly through its effects on the neurotransmitter glutamate.” Researchers are taking what they know about ketamine and looking at ways they can develop glutamate inhibitors that don’t have the negative side effects of ketamine.

Is ketamine safe to use for depression and anxiety?

Long-term use of ketamine hasn’t been well researched, but the general consensus is that it’s safe to use in the short-term. Side effects, which usually last no more than a few hours, include:

Drowsiness
Dizziness
Nausea
Dissociation
Elevated blood pressure
Blurred vision
Body sensations, such as feeling strange or loopy

Where can I get ketamine?

If you’re experiencing chronic, major depression that isn’t improving with your current medications, talk to your healthcare provider. There are infusion clinics around the country that administer ketamine with a doctor’s order, but this is considered an off-label use. The nasal spray Spravato is the only FDA-approved ketamine-like drug available for treatment-resistant depression. It’s only available at health clinics and via doctor’s offices—and the cost is high, ranging between $600-$800 for a single dose of ketamine, says Dr. Coryell. Infusions are similar in price.

One last word of caution: Don’t attempt to get ketamine off the street. Ketamine is a controlled substance and a medical professional needs to determine the proper dose and monitor you for side effects, some of which can be very serious.