Can Ketamine Help with Depression?

Ketamine is a drug used in both human and animal medicine. It’s well known for being used to induce anesthesia or manage pain.

“Traditionally, ketamine was used as an anesthetic and has been used for this purpose for the last few decades,” says Dr. Carrie Lam, a board certified physician in family medicine and anti-aging and regenerative medicine from Tustin, California.

“But the doctors using it began to notice interesting unintended effects: the lifting of depression within a few hours, and the fact that it was so robust it could deter desperate suicidal cases quickly,” she adds.

As a dissociative anesthetic, the drug may make you feel detached from your thoughts or reality. It may also cause hallucinations, confusion, or a sense of euphoria.

Two primary forms of ketamine are commercially available:

• Racemic ketamine is the original form approved by the Food and Drug Administration (FDA). This fast-acting drug is usually administered as an infusion into the bloodstream for anesthesia. Most research involving ketamine use focuses on racemic ketamine infusions.
• Esketamine is a new form of ketamine, under the brand name Spravato. It emerged in 2019 as a nasal spray. This drug is specifically developed as an at-home treatment for major depression. Esketamine binds more tightly to receptors in the brain, meaning it can achieve clinical results at lower dosages.

Ketamine use without professional guidance can be dangerous. In some cases, the drug can cause seizures, loss of consciousness, and even be fatal.

When someone takes the drug recreationally, they may find they need more and more ketamine to achieve the desired effects. This increases the risk of a potentially fatal outcome.

Due to its potential for misuse, ketamine is considered a schedule 3 drug on the Drug Enforcement Administration (DEA)’s list of controlled substances.

Living with depression isn’t easy, and when your symptoms don’t respond to firstline treatments, you may feel like nothing will help.

When you’ve exhausted other options, your mental health team may recommend ketamine therapy.

Research from 2019 suggests ketamine therapy can significantly improve symptoms of severe depression.

Medical professionals may give ketamine in different forms, including infusions and nasal sprays.

It’s not yet clear if there’s a difference in results between different types of ketamine therapy — including esketamine nasal spray and infusions of racemic ketamine. Your doctor will help you decide which form of ketamine therapy might work best for your current situation.

While use of racemic ketamine for depression is off-label, most of the research supporting ketamine therapy has used this form of the drug.

For this reason, your doctor may prefer to use ketamine infusions instead of the nasal spray.

The exact way ketamine works for depression is still under investigation. Experts believe a neurotransmitter called glutamate is at the heart of ketamine’s effectiveness.

“So far, two main hypotheses have been presented to explain how ketamine acts on depression,” Lam says.

“On one hand, studies done by National Institutes of Health are looking at the metabolite that the body creates when it breaks down ketamine as the possible answer to how ketamine rapidly lifts depression, sometimes in hours, or even minutes,” she explains.

Another possible hypothesis, Lam says, is that ketamine blocks glutamate receptors. At a therapeutic dose, ketamine causes an increase of glutamate.

Glutamate is an important amino acid and neurotransmitter. It encourages “neuroplasticity” — the brain’s ability to form neuron connections, particularly in learning or after injury.

Glutamate also allows cells in the brain to communicate and can influence the strength of the signal between parts of the brain.

Living with depression can mean your neuroplasticity — the flexibility of your brain to create new connections — decreases over time. The fewer neuron connections your brain makes, the more your functioning may become impaired.

Ketamine may provide your brain with the glutamate boost it needs to help rebuild those important neuron connections.

In addition to improving your neuroplasticity through glutamate production, other benefits of ketamine are currently being studied.

To add even more complexity to the way ketamine may affect the brain, a 2020 study suggests it may also influence other neurotransmitters, such as serotonin, a chemical directly linked to mood regulation and inflammation.

Esketamine is approved by the FDA specifically as an option for treatment-resistant depression and major depressive disorder with suicidal thoughts or actions.

Racemic ketamine, on the other hand, is not currently approved for treating depression. It’s FDA-approved only for use as a short-acting anesthetic in humans and animals.

Any other uses, such as depression treatment, are considered “off-label.”

According to the FDA, off-label use means:

• using ketamine to treat a disease or medical condition other than what it’s been approved for
• giving ketamine through an unapproved route of administration (taking an injectable liquid orally, for example)
• prescribing a dose different from the recommended standard (taking half a tablet when the label says 1, for example)

Before a drug comes to market, it must submit scientific safety data to the FDA for approval. Once that medication has been used clinically for decades, however, alternative uses become widely recognized and accepted.

Off-label usage, when monitored by your treatment team, can be helpful for your overall treatment plan.

If your doctor is comfortable making off-label recommendations, the medication you’re using has likely been on the market for a long time and has independent research behind it.

“It was only very recently that the FDA gave a formulation of ketamine, called esketamine, designation to be used for major depression,” explains Lam.

“And, because those who suffer from treatment-resistant depression and suicidal ideation need relief very quickly, many doctors are using ketamine now, before the researchers and FDA can produce conclusive results and give their approval,” she adds.

Almost every medication has some side effects. When it comes to ketamine infusions, study results suggest you’re most likely to experience feeling “strange” or “weird.”

Other side effects may include:

• difficulty speaking
• numbness
• dissociation
• a sensation of floating
• visual distortions
• high blood pressure
• nausea or vomiting

Manufacturers of the esketamine product, Spravato, note similar side effects, but also state there may be potential for misuse as the product becomes more available for at-home use.

Ketamine misuse can cause a number of psychological and physical side effects, including:

• severe abdominal pain
• bladder abnormalities
• kidney issues
• hallucinations

You might think ketamine sounds like the perfect solution for depression, but it’s still not considered a firstline option for most people.

Ketamine shows promise as a treatment for depression, but its effects and long-term results are not yet well understood.

“Of course, the benefits of ketamine shouldn’t be seen as a magic bullet. At this time, its best used for short-term relief, just long enough to get you through a crisis and into a more holistic program that suits your needs,” Lam says.

If you’re not experiencing suicidal thoughts or behaviors, your mental health professional may want to explore more well-known treatment options with you at the start.

Firstline therapies have shown high rates of success in managing depression, with proven results and safety margins.

These treatments include:

• antidepressants
• cognitive behavioral therapy (CBT)
• interpersonal therapy (IPT)
• electroconvulsive therapy (ECT)
• transcranial magnetic stimulation (TMS)

If you’re considering self-harm or suicide, help is available right now:

• Call a crisis hotline, such as the National Suicide Prevention Lifeline at 800-273-8255.
• Text HOME to the Crisis Text Line at 741741.

Major depression affects an estimated 17.3 million U.S. adults.

You’re not alone if you’re living with depression, and especially if treatments have yet to make a big difference or have stopped working as effectively.

If your depression is considered treatment resistant, or you’re having suicidal thoughts and behaviors, ketamine therapy may be a fast-acting option to discuss with your treatment team.

A 2019 review reports that ketamine can have antidepressant effects that peak at 24 hours and last for 1–2 weeks after infusion.

Your medical team can help you explore the use of this drug as an alternative — or supplementary — option for depression relief.