Can Ketamine Therapy Help Treat Depression and Other Mental Health Disorders?

Jacqueline had gone through therapy and been on antidepressants for years, yet she still felt numb, stuck, and disengaged. She was struggling to move past childhood trauma and had become disconnected from her emotions.

She wasn’t quite sure how to regain that connection, but she knew antidepressants weren’t doing the trick. “I need something different,” she told me.

After nearly a decade practicing traditional talk therapy, I began integrating ketamine into my practice in 2023. Ketamine was first synthesized in 1962; it’s since been used as a surgical anesthetic and at times misused as a recreational psychedelic drug. But it turns out that this molecule offers much in the way of mental health treatment. It has shown enormous promise in treating both acute and chronic depression, as well as addiction, PTSD, and other mental health disorders.

Though ketamine isn’t for everyone and is not a silver bullet — beware of anyone who claims otherwise — I’ve seen some pretty astonishing results.

Jacqueline (who asked we use only her first name to preserve her privacy) seemed wary when she arrived in my office; she had never used psychedelics before. But she had researched the science behind ketamine-assisted psychotherapy (KAP) and decided it wouldn’t hurt to try. The explanation and preparation put her at ease. “There was so much thought put into the process,” she recalls.

She settled into a zero-gravity armchair with an eye mask blocking external light. Ambient electronica music played in her headphones. She says she felt comfortable and safe. The nurse took her blood pressure, reviewed dosage options, and, after receiving a final confirmation, injected 50 mg of ketamine into Jacqueline’s right biceps.

“There’s no good way to describe what happened next,” Jacqueline says. For the next hour or so, Jacqueline was immersed in colorful imagery, stimulating all five senses. “I felt like I was in a happy daydream. It was the first time I’d felt joy in years.”

The real impact came afterward.

That night, Jacqueline slept better than she had in years. “I have always had trouble sleeping due to nightmares and anxiety: I was having them two to three times a week,” she says.

During the summer months following the KAP, she had just three nightmares. “So, it [was] the summer of good sleep for me — which has impacted both my mood during the day and my relationships. I think having such a consistent effect from the treatment is important; and once I started talking with other adults, I discovered this issue is more common than I thought.”

The day after her first KAP therapy, Jacqueline found herself opening up to her husband in ways she’d never felt able to before. It was as though the emotional blockage in her life was finally melting away.

How Does Ketamine Work to Support Depression?

To appreciate how and why ketamine works, it’s helpful to understand how and why traditional antidepressants work — and why they often don’t.

Ketamine works differently from traditional antidepressants, says John Lichtsinn, MD, a board-certified psychiatrist who offers KAP in his outpatient practice. He explains the difference with an analogy: Imagine the brain is a series of interconnected roads and highways. Traditional antidepressants are like gas stations along the road; for people who don’t produce enough feel-good “fuel” naturally, these medications top off the neurotransmitters dopamine, serotonin, or norepinephrine at certain signaling pathways in the brain.

If someone doesn’t have healthy neuropathways to begin with, the effect of the antidepressants can be limited, he says.

Ketamine enhances those neural networks — it maintains, rebuilds, and improves those roadways in the brain. This not only makes travel easier but also expands the ways one can get from point A to point B.

This is because ketamine acts on a different neurotransmitter: glutamate. The brain’s most abundant excitatory neurotransmitter, glutamate is critical to neurological changes involved in learning and memory. Studies have found that ketamine helps stimulate the brain to regrow synapses that may have been lost due to chronic stress, as well as to form new synapses. This effect, called synaptogenesis, seems especially profound in areas of the brain associated with depression and chronic stress.

Speed of impact is another benefit. Antidepressants can take weeks to begin working, while ketamine’s effects are nearly immediate. That makes it effective in treating acute conditions, such as suicidal ideation. It can also enable brief but intense transcendent experiences when administered via certain routes and doses (more on that later).

While it remains unclear just how long the newly formed synapses survive, it appears that the cognitive and behavioral benefits — new ways of seeing things, new ways of reacting to things — can sustain over time. With more routes to choose from, the brain can break out of ingrained mental habits to form new ways of thinking and reacting, a process known as neuroplasticity.

How long that neuroplasticity lasts remains a complicated question. Some effects, like synaptogenesis — the formation of new connections between neurons — seem to peak within a day, while the enhanced learning and processing enabled by increased neural connectivity may last for several weeks.

“Because the effects diminish over time, people generally benefit from additional treatment,” says Lichtsinn, noting that this often entails psychotherapy or other healing modalities — not just more ketamine. “I see the most change in clients who view the medicine as a catalyst rather than the ‘main event.’”

How Is Ketamine Administered?

Ketamine can be administered in various ways, each offering distinct amounts of bioavailability — the amount of the medicine absorbed into the system. This allows for flexibility in treatment. What follows are the three most common methods of delivery.

1) Sublingual ketamine lozenges that dissolve beneath the tongue generate mild enough side effects that they can be taken at home. Available via online prescribers at a relatively low cost, this is perhaps the most accessible form of ketamine on the market.

Efficacy rates are on par with infusions — in one study, about half of patients logged significant decreases in anxiety and depression scores after just three doses of sublingual ketamine — and may further improve with extended use.

2) Intranasal ketamine spray is based on a more potent form of ketamine called esketamine and is extremely fast-acting, capable of relieving depression symptoms in under an hour.

Esketamine is still under patent and quite expensive for patients, says Lichtsinn, so its use is currently limited. “Once it becomes available as less-expensive generic drugs, I think it will be more broadly used, including for ketamine-assisted therapy,” he explains. “It checks a lot of boxes and has advantages — no needle, no bad taste like with oral form, good absorption into the bloodstream. Given this relative ease of drug delivery, some people have discussed whether it has [a] potential role in acute care (like in emergency rooms) for acute relief of severe depression or for people who are suicidal.”

Because it can distort perception for up to two hours, esketamine is administered in a medical setting where patients are monitored until the side effects pass.

3) Intravenous ketamine infusions can provide rapid relief from depression as well as long-term improvements. Under supervision, patients receive a subanesthetic dosage but may still feel disoriented and euphoric for up to two hours.

Patients often undergo a series of infusions spread out over several weeks or months. One study found that 55 percent of patients who underwent ketamine infusions experienced long-term improvements in depression symptoms.

What Is Ketamine-Assisted Psychotherapy?

In ketamine-assisted psychotherapy (KAP), form — how the ketamine is administered — matters less than function: The intention is to bring patients into either a psycholytic or psychedelic state.

In a psycholytic state (achieved through lower doses like lozenges), the patient experiences an altered state of consciousness yet remains in touch with the present moment. They can still interact with their therapist, but with a “looser” state of mind.

Typically achieved via intramuscular injection, a psychedelic state is much deeper and transcendent — an out-of-body experience that can give rise to powerful memories, images, or sensations.

In either case, it’s the unique combination of neuroplasticity and psychotherapy that makes KAP so beneficial. A therapist can help the client make meaning of their experience and translate new perspectives into long-term healthy mental habits. For example, clients often tell me they “never thought of things that way” until undergoing a ketamine session. We use this realization — that there are many ways of perceiving a situation — to establish and reinforce cognitive restructuring skills, such as reframing assumptions or challenging all-or-nothing thinking.

I tell clients that ketamine is like adding motor oil to the brain, greasing the wheels of rigid thoughts, beliefs, and behaviors that have been contributing to their depression.

Who Should Avoid Ketamine, and What Are the Risks?

Ketamine is not a good fit for everyone. People with a history of or genetic risk for psychosis may want to avoid it; so might those who have certain medical conditions, including uncontrolled hypertension or cardiovascular disease.

Though ketamine is not recommended for individuals who are actively abusing drugs or alcohol, it can be a helpful component of substance-use treatment. But this poses another conundrum: the risk of addiction to ketamine itself.

Using ketamine — at least in certain doses — feels good. After all, it is a drug, and some people may abuse it.

“Clinics are popping up quickly and the regulatory agencies can’t keep up,” Lichtsinn warns. “So do your research before you choose a provider.”

Then there’s ketamine’s murky legal status. Esketamine nasal spray is the only form currently approved by the U.S. Food and Drug Administration for treatment of depression. But because ketamine has long been approved for surgical use, medical providers can legally access and administer the off-label version.

It’s a convenient loophole that presents some challenges. Insurance rarely covers treatment, and out-of-pocket costs can reach hundreds of dollars. With the actual cost of ketamine amounting to little more than pocket change, the profit margin can be enormous, hence the booming market.

“Clinics are popping up quickly and the regulatory agencies can’t keep up,” Lichtsinn warns. “So do your research before you choose a provider.”

According to Lichtsinn, reputable clinics conduct a full medical assessment prior to treatment and ensure that patients have access to immediate medical support while taking ketamine, especially if they’re taking it remotely.

“We’re seeing the best and worst of ketamine’s potential,” he adds. “Navigate cautiously.”

How Ketamine and Therapy Can Transform Mental Health

Jacqueline and I met a few days after her initial ketamine treatment in an integration session to explore ways she could build on her newfound mental flexibility. She committed to spending more time outdoors, taking a chance on new friendships, and really being present with her young daughter — all things that seemed unattainable beforehand.

“Trauma and depression trick you into thinking that’s all you’ll ever feel; ketamine woke me up from that,” Jacqueline says. “I remembered that I’ve felt joy before, and more importantly, I realized that I could feel it again.

“Rediscovering joy has improved everything in my life, but especially my relationships. I had always kind of assumed the worst with people, but now I don’t carry that negative perspective. As my daughter put it: ‘Mom, you don’t have a sad face anymore!’”

While crediting the ketamine for loosening her mental joints, Jacqueline considers the psychotherapy component equally important. “It helped me clarify what I wanted to get from the experience so I could go in with a clear intention. And more importantly, having built that therapeutic relationship allowed me to trust that I could surrender to whatever happened.”

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