Esketamine for Substance Use Disorders and Treatment-Resistant Depression

Understanding esketamine

In 2019, the FDA approved esketamine under the brand name Spravato, which is a closely related formulation of the drug ketamine, as an approved medication for treatment-resistant depression (TRD). Ketamine was originally developed as an anesthetic in the 1960s and has been widely used in human medicine for decades. It is also used in veterinary medicine and has a history of recreational abuse for its dissociative and psychedelic effects. The FDA approval of esketamine for depression represented a significant expansion of its therapeutic role beyond anesthesia. ^[1][2]

The FDA approval came after several studies showed that esketamine has powerful and fast-acting antidepressant effects. The effects of esketamine are especially helpful in severe cases of depression that have not responded to frontline treatments like SSRI antidepressants and behavioral therapy. ^[1]

Since the approval, researchers have begun exploring other therapeutic uses of esketamine, including as a treatment for disorders like OCD, eating, and substance use disorders. Research into these areas is still investigational, with some early promising results. ^[2][3]

Differences between ketamine and esketamine

Ketamine is an older drug that was developed as an anaesthetic in the 1960s and was widely used in veterinary medicine. Ketamine is a 50/50 mixture of R-ketamine and S-ketamine, and esketamine is a formulation that only contains S-ketamine. Esketamine is a newer version of ketamine that is FDA-approved as a treatment for depression and is available as a nasal spray under the brand name Spravato. ^[4]

Formulations of racemic ketamine that combine R-ketamine and S-ketamine are still available, but are only offered as infusions where the medication is administered on-site. When people report they are receiving ketamine-assisted psychotherapy or ketamine treatment, they may be referring to either formulation of ketamine. Direct head-to-head comparisons are limited, and the evidence is not yet strong enough to draw definitive conclusions about the relative effectiveness of each formulation. The choice between esketamine nasal spray and IV racemic ketamine often depends on factors like insurance coverage, clinical setting, and individual patient response. ^[4]

How esketamine works

Esketamine is made from the drug ketamine and has very similar effects in the body and brain. Esketamine primarily works on glutamate and NMDA receptors in the brain, helping to repair synaptic connections and promote neuroplasticity. This is believed to lead to improvements in mood, motivation, learning, thinking, and behavioral patterns. ^[1][2]

Glutamate and NMDA play a key role in promoting new neural connections, supporting the brain’s ability to learn new information, form memories, and adapt to new circumstances. By working on these receptors, researchers believe that esketamine can help support the brain’s ability to reset and rewire itself. ^[1][2]

This is a different mechanism of action than traditional antidepressants that work on mood-related chemical messengers like dopamine and serotonin. Because of this novel mechanism of action, esketamine works much faster to relieve symptoms than traditional antidepressants. ^[1]

When esketamine was first approved in 2019, it was required to be used alongside an oral antidepressant. However, in January 2025, the FDA approved esketamine as the first standalone treatment for treatment-resistant depression, meaning it can now be used without a concurrent oral antidepressant for this indication. Many clinics also offer ketamine-assisted psychotherapy (KAP), which involves guided psychotherapy sessions after being given esketamine.

Esketamine for treatment-resistant depression

Esketamine was FDA-approved for treatment-resistant depression (TRD) in 2019, after multiple trials showed it was highly effective at reducing depressive symptoms when other treatments had failed. TRD describes major depressive disorder that has not responded to at least two frontline treatments like SSRI antidepressants and psychotherapy. ^[2]

Often, TRD involves more severe and debilitating symptoms of depression, including suicidal ideation. Esketamine is FDA-approved for treating depressive symptoms in adults with MDD who have acute suicidal ideation or behavior, and clinical trials have shown it can reduce depressive symptoms within 24 hours in this population. However, it is important to note that the FDA has stated the effectiveness of esketamine in preventing suicide or directly reducing suicidal thoughts or behavior has not been demonstrated. ^[1]

Because esketamine works much faster than traditional treatments for depression, it can provide rapid relief of symptoms, sometimes as quickly as within 24 hours. Studies have reported improved mood, motivation, and interest in activities following esketamine, but these effects may not be lasting for everyone. Many individuals describe that a week or two after treatment, their depressive symptoms begin to return. ^[1][2]

Esketamine for substance use disorders

Because esketamine is believed to improve the brain’s ability to reset and rewire itself, researchers are exploring whether it can help people struggling with drug and alcohol addictions. Specifically, formulations of ketamine are being explored as treatments for cocaine, opioid, and alcohol use disorders. ^[2][3]

Preliminary research has shown promising results, including lower rates of withdrawals and cravings, and improved rates of abstinence. For example, one study found that 70% of those receiving ketamine-assisted therapy for alcohol use disorder remained sober after a year of treatment, compared to 24% who received therapy alone. ^[3]

Overall, there is less robust research to support claims that esketamine can be as effective for substance use disorders as it is for depression. The studies that have been done have small sample sizes, and more research is needed to validate whether or not esketamine can be effective in the treatment of addiction. ^[1][2][3]

Potential benefits of esketamine in dual diagnosis treatment

There are many shared risk factors between depression and substance use disorders, and these conditions often co-occur. Individuals who struggle with both depression and addiction often benefit from treatments that can address both issues simultaneously. For these reasons, esketamine and ketamine-assisted psychotherapy are being explored as a potential dual diagnosis treatment for comorbid depression and substance use disorders.

While more research is needed, initial research suggests that esketamine can be helpful to people struggling with co-occurring disorders. Specifically, the effects of esketamine on glutamate and NMDA receptors can promote synaptic repair and rewiring in neural pathways involved in both conditions. ^[2][3]

Potential risks of esketamine in dual diagnosis treatment

There are some potential risks and adverse effects associated with the use of esketamine in dual diagnosis treatment. One of the primary concerns is that ketamine has a history of being abused for recreational purposes and may be addictive for some people. Addiction is much less likely because of the controlled settings and dosing of esketamine, but it may be more of a risk factor for individuals with a history of substance use disorders. ^[2][3]

Esketamine can also cause unwanted side effects. The most commonly reported side effects are dissociative symptoms, dizziness, and sedation, which are typically transient in nature and wear off once the drug is metabolized. Some people also report that esketamine leads to slight cognitive impairments, like slower processing and memory recall. Esketamine can also lead to increased blood pressure, which is usually a temporary effect. ^[1][2]

Determining if esketamine is right for you

Esketamine is a novel treatment that has been recently FDA-approved for treatment-resistant depression and is being explored as a treatment for other conditions, including substance use disorders. Most of the time, esketamine will only be recommended to people who have tried other treatments for depression and have not found them successful at reducing their symptoms. ^[1][2]

While esketamine has shown promising results for people struggling with depression and substance use disorders, it may not be the best treatment for everyone. Like all medications, esketamine can cause unwanted side effects and risks, which may be heightened for people with certain conditions or circumstances. The best way to determine if esketamine is right for you is to schedule an appointment with a licensed medical provider who is knowledgeable about this treatment.