Ketamine to Treat Treatment-Resistant Depression

nasal spray bottle

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Depression is the second most common mental health disorder in the United States. 17.3 million (7.1%) U.S. adults have experienced at least one episode of major depression within a calendar year.

Depression can affect your professional life and personal life and destroy your self-worth and ultimately wreak havoc on your life. Depression can affect anyone and everyone without a clear-cut reason. 

Treating depression is often a combination of medications, specifically antidepressants and psychotherapy approaches such as cognitive behavioral therapy (CBT). Antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs), take approximately four to six weeks to work.

But what happens if you have tried numerous medications, therapy approaches, and different combinations of each without any improvement? Not every individual will benefit from traditional therapy and antidepressants. This kind of depression is known as treatment-resistant depression.

Ketamine, a hallucinogen and dissociative anesthetic, has been approved to treat treatment-resistant depression. This article explores how ketamine treats depression, its efficacy, and its potential side effects.

What Is Ketamine?

Ketamine was introduced in the 1960s as an anesthesia medicine for soldiers on the battlefields during the Vietnam War. Today, ketamine is only legal and administered via a prescription and is used in veterinary medicine during surgery. 

It is a Schedule III drug according to the Drug Enforcement Administration (DEA), which means that it has medically accepted uses but also has potential for abuse, including physical and psychological dependence.

Ketamine is a dissociative anesthetic, meaning that it changes the individual's perception of sight and sound and creates feelings of detachment from the environment (dissociative) while simultaneously relieving pain (anesthetic).

Ketamine is also classified as a hallucinogen. However, ketamine is very loosely defined as a hallucinogen because the class of hallucinogens also includes drugs like lysergic acid diethylamide (LSD), salvia, peyote, phencyclidine (PCP), and psilocybin (mushrooms).

Ketamine, when administered as a prescription, has the potential to treat post traumatic stress disorders (PTSD), treatment-resistant depression, anxiety, and both chronic and severe pain. 

Ketamine as an Illegal Drug

Ketamine serves a purpose in medicine when prescribed correctly, but it is also a commonly abused drug. Commonly referred to as "Special K" and "Cat Valium," Ketamine is sold illegally as a mind-altering drug that enhances or alters mood and perception.

The anesthetic properties can also cause the individual to feel numb, which may lead to accidents and severe injuries while under the influence of ketamine.

Usually, the “high” lasts for less than an hour and can cause a state of utter bliss, also known as euphoria. In addition to the typical “out of body experience,” higher doses that are typically injected can lead to an effect known as the “K-hole.”

“K-hole” refers to a near-death, out-of-body experience, where the user is incapable of interacting with others. 

Treatment-Resistant Depression

Approximately 30% of individuals with major depressive disorder experience symptoms that do not improve with treatment. An individual, who does not improve with two different depression medications of adequate doses taken for at least six weeks in duration, is said to have treatment-resistant depression.

It is difficult to determine who will have treatment-resistant depression, but research has shown that female gender and older age are risk factors for treatment-resistant depression.

Individuals who have chronic medical illnesses such as chronic pain and thyroid disorders are also at an increased risk for treatment-resistant depression and individuals who have a history of eating disorders, substance abuse disorders, and sleep disorders.

There are effective treatment options that do work to treat this type of depression, as well as new research in the pipeline. 

Ketamine For Depression

The Food and Drug Administration (FDA) approved Ketamine, under the name esketamine (called “Spravato” by the manufacturer) for treatment-resistant depression in the spring of 2019.

Ketamine has been used as an off-label drug to treat this type of depression for years before the FDA approved it. Ketamine does not target the same brain activities as antidepressants like fluoxetine (Prozac), venlafaxine (Effexor), and sertraline (Zoloft). Rather, it blocks a receptor called N-methyl-D-aspartate, or NMDA.

Researchers are still not certain why some people with depression respond to ketamine and others do not. Still, without FDA approval, this drug has been used for “off label” uses in individuals with treatment-resistant depression, pain management, and palliative care.

Before ketamine was FDA-approved for treatment-resistant depression, ketamine was administered intravenously. Following its approval by the FDA, individuals can administer it themselves as a nasal spray under medical supervision. 

How Ketamine Is Administered

Now that ketamine, under the brand name, Spravato is FDA approved, there are strict guidelines for its use as a depression treatment. Spravato is administered as a nasal spray and is only available at specific certified ketamine clinics and pharmacies.

The individual with treatment-resistant depression administers ketamine to themself in the doctor’s office, waits in the office for two hours of monitoring, and then is transported home. This way, the individual is always under supervision when under the influence of ketamine, specifically because of its dissociative properties.

To be approved for ketamine, the individual must currently be taking another antidepressant and ketamine can only be administered to those who meet the criteria for treatment-resistant depression. 

IV ketamine, also known as ketamine infusions, is not approved by the FDA but is still used as an off-label medication in Ketamine clinics for treatment-resistant depression, chronic pain, anxiety, and trauma.

IV ketamine is administered at a slow, controlled rate throughout a 40-minute duration. The infusion dose is calculated according to the individual’s weight and adjusted according to its tolerability. A course of treatment includes 6 to 8 infusions over a 3 to 4 week period.

Ketamine For Treatment-Resistant Depression Has Shown Positive Results

Ketamine is a promising treatment for treatment-resistant depression and has shown positive results on depression and suicidal ideations. As a result, this medication brings hope to those who have been battling depression and giving them a window of significant improvement.

This window can allow other interventions, including psychotherapy, to be implemented. Psychotherapy is an integral part of treatment for depression. Still, when individuals are extremely depressed, they usually cannot engage in psychotherapy in a meaningful manner, which can be too much of a psychological burden for them.

Ketamine is a medication that can potentially help alleviate depression rapidly, which can allow meaningful psychotherapy engagement for the long-term healing process. 

Ketamine Clinics

If you type in “ketamine clinics” or “ketamine infusions” into your online search engine, you will be inundated with endless ketamine treatment clinics within your geographical area.

Over the past few years, ketamine clinics have rapidly grown in the United States. From 2015 to 2018, the number of clinics increased from 60 to 300; that number is much higher today, especially since ketamine is now FDA-approved for treatment-resistant depression.

Ketamine clinics are the new “methadone clinics” and are advertised to treat individuals with depression, anxiety, PTSD and pain disorders. These high-profit clinics are popping up all over the country to treat mental health conditions while simultaneously turning a high cash profit. Yes, they are controversial, but not all ketamine clinics are created equal.

Some of these clinics play by the rules and follow the American Psychiatric Association’s (APA) treatment guidelines, whereas other clinics may not align with the therapeutic research. In other words, you must educate yourself and become familiar with how these clinics function, especially if you are looking to treat your depression. 

For instance, some clinics don’t thoroughly screen patients for treatment-resistant depression or suicidal ideations and will potentially offer the medication for anyone who is willing to pay.

Clinics can charge anywhere from $350 to $1,000 per infusion, and many individuals get at least six rounds of the treatment. Some clinics do not have an in-house psychiatrist or other mental health professionals on staff, and not all clinics collaborate with the patient’s primary mental health provider. 

What to Know Before Undergoing Ketamine Treatment

Although not an official guideline, the APA issued a statement that was published in JAMA Psychiatry in 2017. The APA recommended that before treatment, a doctor should:

  • Perform a comprehensive assessment of the individual’s depressive symptoms and check for a history of substance abuse or other psychiatric disorders, including suicidal thoughts.
  • Confirm that standard treatments for depression were not effective for the individual.
  • Evaluate the individual’s overall health and the possible risks of ketamine treatment for that person.

Because some clinics do not operate under proper protocols, if you are looking for a ketamine clinic to help with your treatment-resistant depression, you'll want to keep the following guidelines, listed below, in mind:

  • Evaluation
  • Experience
  • Administration and monitoring
  • Cost


  • Who is actually evaluating you and determines if this treatment is appropriate for you? 
  • What does this person base their evaluation on? 
  • How much time do they spend on their evaluation? 
  • Do they communicate with your primary care physician or mental health therapist?
  • How do they address substance abuse?
  • Is the physician who does the evaluation the same physician who provides treatment?


  • Is the physician who provides ketamine treatment specialized to be able to treat your condition itself? In other words, is this doctor a psychiatrist who specializes in treating severe mood and anxiety disorders?
  • What is the extent of the provider’s ketamine infusion experience?
  • Ask about numbers, outcomes, whether they keep a registry of their own patient data and results, how they follow outcomes both during a treatment course and afterward, and how they coordinate your care with everyone else who’s treating you.

 Administration and Monitoring

  • Is the route for administration of ketamine specifically IV?
  • Is ketamine given with a computerized infusion pump?
  • Is the dose adjusted during infusions or throughout the treatment course?
  • How often are doses administered?
  • Is the adjustment standardized or does it vary?
  • Is there continuous monitoring of your vital signs? 
  • How are you monitored psychologically during and after your treatment? 


  • How much does this treatment cost, and does your insurance provide coverage?
  • How many rounds of ketamine are recommended? 

What Interferes With Ketamine Treatment

Below is a list of conditions and behaviors that can interfere with ketamine treatment:

  • Active substance abuse (alcohol, cannabis, non-prescribed medications, prescription pain medications, etc.)
  • History of psychosis
  • History of increased intracranial pressure
  • Current pregnancy 
  • Uncontrolled high blood pressure
  • Acute or unstable heart disease
  • A previous negative response to ketamine

Ketamine Side Effects

Like all medications, over-the-counter or prescribed, ketamine does have potential side effects, and each individual should be counseled about these side effects before starting ketamine therapy:

  • Rapid heartbeat
  • High blood pressure
  • Spontaneous vocal sounds (vocal tics)
  • Confusion
  • Hallucination
  • Muscle tremors
  • Increased muscle tone
  • Drowsiness
  • Memory loss

Addiction Potential

Like opioids, also known as prescription painkillers, ketamine has addictive properties and can result in substance use disorders in certain individuals or when it's misused.

It is essential to understand this when weighing the risks and benefits of ketamine for treatment-resistant depression. Suppose you have a history of substance abuse, including alcohol or drugs. In that case, it is extremely important for you and your treatment provider to consider whether ketamine is a good option for you.

Trading treatment-resistant depression for an addiction can be a slippery and dangerous slope. Although a diagnosis can’t be based solely on physical symptoms, these can be a warning sign that you or a loved one are struggling with a ketamine addiction:

Red flags of a problem with ketamine can include:

  • Chronic cough if the drug is smoked
  • Stuffy nose or nosebleeds if it is snorted
  • Skin wounds and track marks if it is injected
  • Changes in eating, hygiene, and sleep patterns
  • Decreased response to painful stimuli
  • Dilated pupils
  • Increased saliva and tear production
  • Extreme sleepiness
  • Slurred speech
  • Stiffened muscles
  • Uncontrollable and rapid motion of the eyes

A “Whole Person Approach” to Treatment

Depression is a common mental health disorder that is best treated using a multitude of treatment options. 

Depression is best treated when we understand the individual, his or her underlying triggers, and by offering this individual a multidisciplinary approach to treating them.

An interdisciplinary approach to managing individuals for mental health or substance abuse disorders includes medications and psychotherapy and adjunctive strategies such as yoga and lifestyle modifications.

Treating depression (or any mental health or substance abuse disorder) is not a “one-stop-shop,” meaning that it often takes a village and a combination of different modalities and approaches to find the best treatment plan for each individual. 

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7 Sources
Verywell Mind uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
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