Ketamine Therapy: Is Ketamine Depression Treatment Effective?

Low-dose ketamine is a controlled substance initially discovered as an anesthetic and pain reliever. Since its discovery, doctors have found its antidepressant effects may have clinical use as an effective alternative for treatment-resistant depression. If you’ve been considering the possibility of ketamine-assisted therapy in recent years, it can be helpful to look at the origins of ketamine depression treatment, how it differs from intranasal esketamine, and its effectiveness when administered by qualified clinicians. It’s crucial to speak to your doctor or another qualified medical professional when considering ketamine for depression.

History of ketamine in medicine

Ketamine was synthesized by a professor at Wayne State University in Detroit, Michigan, in the 1960s. After receiving FDA approval for clinical use in humans in 1970, ketamine was used as an analgesic and sedative during the Vietnam War. In large doses, ketamine can be an effective anesthetic and has been used for many years on humans and animals. Compared to other anesthetics, ketamine has fewer side effects related to breathing and blood pressure. In recent years, some clinicians have prescribed ketamine for certain medical conditions involving chronic pain.

Physical and mental health side effects of ketamine

Doctors discovered that ketamine has some psychoactive properties, potentially causing hallucinations or a "spaced-out" sensation. This discovery prompted ketamine's use as a recreational substance, which resulted in stricter rules regarding its distribution and use. Outside of medical settings, unregulated use of ketamine can cause serious side effects to a person’s physical and mental health. Recent findings suggest that ketamine may be able to treat depression. 

What is depression? 

There are several depressive disorders listed in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Major depressive disorder (MDD) is one of the most prevalent and severe of these conditions, and over 280 million people live with depression worldwide. When individuals refer to “depression,” they are often referring to MDD. 

Symptoms of depression can include, but are not limited to, the following: 

• Prolonged sadness and a low mood 
• Difficulty finding motivation 
• Appetite changes 
• Sleep changes
• A loss of interest and pleasure in previously enjoyed activities
• A sense of apathy or a lack of emotions 
• Difficulty caring for oneself 
• Suicidal thoughts 

Current depression treatments 

Current mainstream antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) were discovered around 60 years ago. These medications change the way serotonin is produced and used in the brain. However, only about 35% of patients on SSRIs may achieve complete remission, leaving as many as five million people in the US with what’s known as “treatment-resistant depression."

Rapid-relief antidepressants for treatment-resistant depression

For individuals who experience therapeutic benefits from SSRIs, the effects may take several weeks to occur, and there can be a high rate of symptom relapse. For some individuals, depression can come back. For this reason, there has been an unmet need for antidepressants providing more rapid relief, particularly for individuals with treatment-resistant depression or those with suicidal thoughts. 

Note that medications can work differently for everyone, and many people find benefit in antidepressants. If SSRIs or other medications have been prescribed to you by a doctor and work well for you, it may not be necessary to change your treatment. Consult your doctor or psychiatrist before stopping or changing your medication. 

The BetterHelp platform is not intended to provide any information regarding which drugs, medications, or medical treatments may be appropriate for you. This content provides generalized information that is not specific to any one individual. You should not take any action without consulting a qualified medical professional.

Ketamine and depression: Understanding ketamine depression treatment

Ketamine may display effectiveness in improving symptoms of depression. Research suggests that a sub-anesthetic dose of ketamine may be effective in lessening suicidal thoughts and in improving treatment-resistant depression. One 2014 study found that 60% to 70% of clients with treatment-resistant depression responded to ketamine almost immediately. Antidepressant effects were seen within hours of administration for many patients and were sustained for up to two weeks in some patients.

Ketamine depression treatment 

Healthcare providers can still prescribe and use ketamine off-label with clients if they have a license to prescribe medication and offer medical care. However, there may be a few safety concerns to keep in mind, which is why ketamine should only be used under a doctor’s supervision. These safety risks may include the following: 

• Sedation and sleepiness 
• Dissociation 
• Changes in heart rate and blood pressure 
• Racing thoughts 
• Potential for substance misuse or addiction
• Urinary incontinence 
• Respiratory depression 

Ketamine vs. intranasal esketamine

The primary difference between ketamine and intranasal esketamine is that ketamine is administered intravenously, while esketamine (a component of ketamine) is taken via nasal spray. Research suggests that IV ketamine may lead to quicker and stronger results, although both treatments have been shown to reduce depression severity in the short term. Clinical use must be supervised by a qualified primary care physician, mental health provider, or medical professional. In most cases, it’s not possible to use insurance coverage to pay for ketamine depression treatment, as it’s typically considered an off-label use of this medication.

How does ketamine depression treatment work for mood?

Evidence is unclear about how ketamine might support depressive symptoms. The anesthetic properties of ketamine are thought to occur by its blockade of N-methyl-D-aspartate (NMDA) glutamate receptors in the brain. 

Glutamate is one of the brain's major neurotransmitters and fast-acting excitatory molecules. This neurotransmitter contrasts with monoaminergic systems such as serotonin, which are more localized and slow-moving. Ketamine works through the fast-acting glutamate system, consistent with its rapid onset of action.

Studies suggest that ketamine's antidepressant effects may be due not only to a blockade of NMDA receptors but also to its simultaneous enhancement of another type of glutamate receptor: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The blockade of NMDA and the enhancement of AMPA receptors together may cause a rapid release of glutamate in the brain, which is thought to kick-start neuroplasticity (the ability of the brain to grow new neurons and new connections).

Contemporary theories of depression suggest that neuroplasticity is impaired in people with depression and that interventions that promote neuroplasticity may alleviate depression. Conventional antidepressants, as well as behavioral interventions (such as exercise), have also been shown to increase neuroplasticity and are considered safer by the FDA. However, because ketamine appears to work on the glutamate system, it may work more quickly. These results are not confirmed, and more studies are required to understand this treatment fully. 

The risks of ketamine treatment

Although the use of ketamine in treating depression may seem promising, individuals may have remaining questions and challenges. While some studies suggest ketamine is a safe treatment for depression in the short term, questions remain about the long-term risks and potential side effects of ketamine treatment, particularly when used off-label rather than for medical conditions for which ketamine is FDA-approved. For example, there may be a risk of nausea and vomiting, as well as blood pressure changes. For some, increased suicidal thoughts may occur, so crisis planning is recommended. Please note that the 988 Suicide & Crisis Lifeline is available 24/7 at 988.

Ketamine depression treatment is not FDA-approved

Because the FDA does not recommend ketamine treatment for depression, be cautious when discussing this treatment with doctors at a ketamine clinic who claim to offer it. Although licensed doctors can prescribe ketamine, it has been associated with some challenging symptoms and long-term impacts, such as addiction. 

In addition, ketamine's effects may be temporary, as some individuals may experience a relapse in depression symptoms over time. For this reason, regular infusions of ketamine may be required, which could lead to more significant side effects. Because the treatment is not FDA-approved, insurance companies may not cover it, meaning individuals may have to pay $400 to $800 per infusion. However, talk to your doctor before exploring these options in more detail, and note that there are FDA-approved and evidence-based treatments for treatment-resistant depression that do not include ketamine. 

Who may benefit from ketamine, may help and who should avoid it

If you’re interested in trying ketamine for treatment-resistant depression, it’s vital to speak to a qualified medical or mental health professional to determine whether you’re a good candidate for this type of treatment. Clinicians may consider depression scores, mental health history, and other factors. Ketamine may not be appropriate for individuals who:

• Have previously experienced psychosis 
• Have a diagnosis of schizophrenia
• Are pregnant
• Are living with uncontrolled hypertension
• Have acute cardiovascular disease or related medical conditions
• Have a history of substance misuse 

What ketamine treatment looks like in a clinic

Ketamine treatment at a clinic typically occurs in a comfortable space where you will receive the infusion from a clinician and then experience the effects of the treatment, which can last one to two hours. You’ll typically need someone to drive you home afterward, as ketamine can inhibit your ability to drive safely.

Protocols for a typical course of treatment may vary, depending on your clinician and your specific needs. Clinical use may involve two infusions per week for three weeks, for example. As this treatment is not FDA-approved, frequency may vary greatly.

During treatment, many patients experience a sense of dissociation or separation from themselves, allowing them to view their mental health challenges from a new perspective. It can also be common to experience a sense of weightlessness and an altered perception of time. Some enter a state of euphoria, and it’s also possible to have hallucinations. However, as ketamine usually suppresses the fight-or-flight response, hallucinations are not usually accompanied by fear. A clinician is typically present to provide support during the treatment experience, and it’s recommended to take the next day off work (if possible) to engage in self-care.

Clinicians may ask you to complete surveys to calculate depression scores before, during, and after the treatment process. This can help them understand the effectiveness of treatment for your specific situation.

Cost, insurance coverage, and how to find a legitimate provider

Cost can vary significantly by location and provider, and insurance coverage usually does not cover this type of treatment, as it is not FDA-approved. To find a legitimate provider, you might search for a qualified primary care physician or mental health provider, such as a psychiatrist, who has experience providing ketamine depression treatment. You might ask them about their qualifications and treatment protocols, and it may be helpful to tour the facility before starting treatment.

Therapy for better mental health 

For those who have exhausted contemporary antidepressants or treatment options and still struggle with severe depression or other mood disorders, it may be beneficial to consider evidence-based treatments, such as therapy. Many forms of depression therapy are effective in reducing depression symptoms and can be an option while you explore other treatments. 

Some people with depression may struggle to leave home, making it challenging to meet with a mental health provider in person. In these cases, online therapy through a platform like BetterHelp may be beneficial. With internet-based counseling, you can discuss your symptoms with a licensed therapist from the comfort of your home and choose between phone, video, and live chat sessions. You can also try other resources like virtual group sessions and journaling prompts. 

Online therapy in clinical trials

Researchers in the mental health field have been investigating the effects of online counseling for more than a decade, with studies suggesting that it can produce similar results to face-to-face therapy. For example, a randomized trial from 2022 stated that internet-based cognitive behavioral therapy was associated with greater depression response and remission compared to the control group. A mental health provider can help individuals make progress toward their mental health goals with a customized treatment plan.