Ketamine Therapy: A Medical Doctor Explains Its Use for Treatment-Resistant Depression

About the expert

Stephen Ferber, MD, is a board-certified psychiatrist and the Assistant Director of the Psychiatric Treatment-Resistance Program at Cleveland Clinic. He completed a fellowship in Interventional Neuropsychiatry and Neuromodulation at Massachusetts General Hospital, bringing extensive expertise to the management of treatment-resistant mental health conditions. Dr. Ferber specializes in interventional psychiatry, with a particular focus on Transcranial Magnetic Stimulation (TMS), Ketamine therapy, and Electroconvulsive Therapy (ECT). His research has centered on optimizing targeting strategies in TMS, and he is an active member of both the International Society for ECT and Neurostimulation and the Clinical TMS Society.

Highlights

• Ketamine therapy offers a new option for treatment-resistant depression.
• Unlike traditional antidepressants, ketamine acts fast in controlled settings.
• Generally safe but requires monitoring for short-term effects.
• Wellness retreats and at-home use raise safety concerns.

Interest in ketamine therapy has surged in recent years, with online searches for the treatment steadily increasing. Once known primarily as a surgical anesthetic—and as a party drug that’s made concerning headlines for its use among some high-profile figures—some consider ketamine to be at the forefront of a major shift in mental health care. Researchers and clinicians are exploring its potential for individuals with treatment-resistant depression (TRD), a severe form of depression that does not respond to traditional medications.

In 2019, the U.S. Food and Drug Administration (FDA) approved a nasal spray version of ketamine, called esketamine (Spravato), specifically for TRD. This approval marked a turning point, offering new hope to patients who had exhausted other treatment options. Since then, ketamine therapy has gained traction in controlled clinical settings, with ongoing research investigating its broader therapeutic benefits.

For those concerned about ketamine’s reputation as a recreational drug, Stephen Ferber, MD, a board-certified psychiatrist and the assistant director of The Psychiatric Treatment-Resistance Program at Cleveland Clinic, clarifies that the doses used in TRD treatment are significantly lower than those used in anesthesia or when abused recreationally. This controlled medical approach is key to its effectiveness and safety.

Ahead, Dr. Ferber explains everything you need to know about ketamine therapy and its role in treating resistant depression.

What is ketamine?

Ketamine is a dissociative anesthetic that has been used in medical settings since the 1960s. Initially developed as a surgical anesthetic, it works by blocking NMDA receptors in the brain, which disrupts pain perception and induces a trance-like state. As Dr. Ferber says, “More recently, it’s been investigated at much lower doses in the treatment or the management of treatment-resistant depression.”

While ketamine’s antidepressant effects are known, researchers are still working to understand the exact reasons behind them. The leading theory suggests that ketamine promotes neuronal growth, synaptic plasticity, and neurogenesis—processes believed to play a key role in alleviating depressive symptoms.

As for what patients experience during ketamine therapy, “it’s highly variable,” says Dr. Ferber. Unlike the higher doses used in anesthesia or recreational use, the amounts administered for depression treatment are significantly lower. As a result, “people aren’t going to have a full-blown psychedelic experience,” he explains. Instead, many describe a dreamlike distortion of reality, with some feeling groggy or drowsy. Patients often wear an eye mask and drift in and out of sleep while the medication takes effect.

What is ketamine used for?

According to Dr. Ferber, ketamine is primarily used in three key areas of medicine: anesthesia, psychiatry, and chronic pain management. As an anesthetic, it serves as an induction agent, helping to sedate patients for medical procedures. In psychiatry, ketamine has emerged as a promising treatment for individuals with TRD.

Ketamine is also used in pain management, with many pain centers incorporating IV ketamine therapy into their treatment protocols. While the specific protocols may vary, the medication itself remains the same.

How does ketamine therapy work?

Ketamine therapy follows a structured process, but the specifics can vary depending on the institution. Dr. Ferber outlines the typical course of treatment:

Step 1: Initial consultation

Before starting ketamine therapy, a patient meets with a ketamine provider or an interventional psychiatrist for a consultation. During this appointment, the provider discusses different treatment options and determines whether ketamine is the right choice.

For most patients, medical clearance is straightforward, as ketamine is generally a safe treatment with minimal side effects. However, individuals with complex cardiovascular conditions may need clearance from a cardiologist before proceeding.

Step 2: The first treatment session

Once approved, the patient arrives for their first session. The experience differs slightly depending on the method of administration:

• IV infusion: The patient sits in a comfortable reclining chair while an IV is placed. Ketamine is then infused into the bloodstream over a 40-minute period.
• Nasal spray: The patient self-administers the nasal spray under supervision. This method acts more quickly, but requires a longer observation period after use.

Throughout the session, the patient’s main task is simply to relax. Most people begin feeling the effects soon after the infusion starts. Within 20 to 30 minutes after the treatment ends, they typically return to feeling close to normal.

Step 3: The acute phase

Ketamine therapy begins with an intensive phase, where patients receive treatment twice a week for three to four weeks. This phase is important for determining the right dosage.

• The initial dose is typically low. If it’s not effective, the provider gradually increases it in subsequent sessions.
• One of ketamine’s greatest advantages is its rapid response time—once the correct dose is found, patients can often feel improvement within 24 hours, far faster than traditional depression treatments.

Step 4: Maintenance phase

Once the optimal dose is established, the provider gradually extends the time between sessions to maintain symptom relief while reducing the frequency of treatments. The schedule typically progresses from twice a week to once a week, then to every other week, and eventually to every four to six weeks. Patients using the nasal spray may require more frequent treatments.

Step 5: Long-term treatment plan

As treatment progresses, the provider and patient decide whether to continue ketamine therapy indefinitely or attempt to discontinue it. This decision is based on how well the patient maintains symptom relief between sessions. Some individuals require ongoing maintenance, while others can eventually stop treatment and sustain their progress through other therapeutic strategies.

Is ketamine therapy safe?

Short term data indicates ketamine therapy is extremely safe. “What’s really nice about ketamine is that because it’s a medication that has a relatively short half-life and clears your system quite quickly, most of the side effects are really just confined to when you’re getting the infusion,” says Dr. Ferber.

One potential risk is a temporary increase in blood pressure during treatment, he explains. However, the rise is usually mild—similar to what occurs during exercise—and subsides quickly. Serious complications, such as a hypertensive emergency, are extremely rare.

Concerns about addiction and withdrawal are also minimal. “Therapeutic ketamine does not increase your risk of becoming addicted to it,” Dr. Ferber confirms. However, individuals who use recreational substances, including marijuana, may not respond as well to ketamine therapy. For both safety and efficacy, Dr. Ferber advises patients to avoid recreational drugs.

While ketamine therapy is effective, certain individuals should avoid it. According to Dr. Ferber, those include but may not be limited to:

• Pregnant women, as its effects during pregnancy have not been studied.
• Individuals with a history of recreational ketamine use.
• People with severe cardiovascular conditions, such as an unstable aneurysm or a recent heart attack.
• Individuals experiencing depression with active psychotic symptoms, as research in this area is still evolving.

Ketamine for depression: Why can it work when other therapies don’t?

For many individuals struggling with depression, traditional antidepressants often fall short. “Generally speaking, after around four different treatments with antidepressants, only around one in three patients will have achieved remission,” shares Dr. Ferber.

That means a significant portion of individuals with depression may need alternative approaches beyond standard medication. These alternatives primarily include interventional treatments and neuromodulation therapies.

“Luckily, failure to respond to antidepressants is not a predictor of whether ketamine will or won’t work for you,” says Dr. Ferber. Many patients who seek ketamine therapy have already tried multiple antidepressants without success.

But why does ketamine work when other treatments fail? Researchers are still working to fully understand its effects. Dr. Ferber explains that part of the answer lies in ketamine’s novel mechanism. While one medication, Auvelity, has a somewhat similar action, most standard antidepressants do not target the NMDA receptor—the specific receptor that ketamine interacts with. “It may just be able to induce these positive neuroplastic changes from a different avenue than antidepressants would,” he says, offering one possible explanation.

Ketamine side effects

Like any medical treatment, ketamine therapy has potential side effects. However, due to its fast-acting nature, many of these are typically short-lived. Dr. Ferber highlights some of the most common ketamine side effects:

• Dissociation (feeling disconnected from reality): Since ketamine is a dissociative drug, patients may feel detached from their thoughts, body, or surroundings during treatment. This effect is to be expected and considered an essential part of its therapeutic mechanism.
• Nausea: Some patients experience nausea during or shortly after treatment, though this can often be managed with anti-nausea medication.
• Anxiety: A temporary increase in anxiety may occur, particularly during the infusion. However, because ketamine has a short duration of action, this typically subsides quickly after treatment.
• Blurred vision: Some patients report changes in vision, such as blurriness or light sensitivity, which generally resolve soon after the session.
• Elevated blood pressure: Ketamine can cause a temporary increase in blood pressure and heart rate, making careful monitoring important for patients with cardiovascular concerns.

What are ketamine wellness retreats?

Ketamine wellness retreats are usually held in spa-like or nature-focused environments, sometimes in group settings. These retreats focus on a holistic experience, combining ketamine sessions with meditation, breathwork, yoga, sound healing, and other wellness practices. While some retreats have medical professionals on-site, others may have minimal medical supervision. Dosing and administration methods vary, and safety protocols may not be as rigorous as in a clinical setting.

Additionally, some services allow individuals to obtain ketamine from a compounding pharmacy and use it at home while being monitored remotely. These at-home treatments may involve sublingual ketamine (taken under the tongue), lozenges, or a racemic nasal spray.

However, Dr. Ferber cautions that receiving treatment this way comes with serious risks, especially when patients aren’t under direct medical supervision. Although rare, a spike in blood pressure could lead to a life-threatening hypertensive emergency. “It’s important to be monitored in a medical setting because if that very rare but possible thing happens, we would be able to respond immediately.”

While at-home and retreat-based ketamine treatments make the therapy more accessible, Dr. Ferber emphasizes that medical supervision is key for safety.

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