Spravato® (esketamine) and its chemically related cousin, ketamine, share a common origin story, even though they differ significantly in how they are used, formulated, and regulated.
Both affect the brain’s glutamate system, which oversees learning, memory, mood, and cognition. Both improve synaptic plasticity, the brain’s ability to adapt and change. And each is used to treat depression, offering rapid results within hours or days.
Surprisingly, the discovery of ketamine and the history of Spravato as a mental health treatment happened quite by accident. Today, it is bringing hope to millions of people suffering from treatment-resistant depression (TRD,) major depressive disorder (MDD,) and suicidal ideation.
The history of Spravato
The ketamine molecule CI-581 was originally synthesized in 1962 by a team of researchers led by Calvin Lee Stevens, a professor of organic chemistry and chemical consultant to Parke Davis, a subsidiary of the pharmaceutical company Pfizer.
Stevens was looking for a safer anesthetic alternative to phencyclidine (PCP,) which was effective but also caused dangerous hallucinations and agitation.
By modifying PCP’s building blocks, Stevens was able to isolate its pain-relieving properties and reduce its adverse psychoactive side effects. The result was an anesthetic with fewer side effects and less intense dissociation, a mental state where a person feels disconnected from their body, thoughts, and surroundings.
By 1970, ketamine had been approved by the Food and Drug Administration for use as an anesthetic. It was immediately brought on to the battlefields of the Vietnam War and was praised for its ease of use and safety for wounded troops.
Ketamine’s potential as a mental health treatment
In the 1990s, ketamine was being used as an anesthetic in both inpatient and outpatient settings. It was also being used off-label as a treatment for chronic pain.
One curious side effect of ketamine was that patients who had suffered from depression reported feeling better emotionally just hours to a day after taking it. This was remarkable, considering that most antidepressants can take up to six to eight weeks to produce favorable results.
In 2000, a pivotal study conducted by Yale University scientists confirmed that patients given ketamine intravenously (IV) saw significant improvements in depressive symptoms within 72 hours.1 What’s more, those effects lasted up to a week after just one infusion.
Researchers knew ketamine affected the brain’s glutamate system by blocking overactive NMDA receptors, which help the brain transmit certain signals. But they didn’t know why it lifted depression so quickly.
Years of research would reveal that ketamine works by stimulating glutamate activity and brain plasticity, which aids in rebuilding and strengthening the neural connections that support mood and emotional regulation.
Soon, ketamine clinics were popping up across the nation and using the medicine to treat depression.
Esketamine answers the call for regulation
Despite its success as a treatment for depression, ketamine was not approved for psychiatric use by the Food and Drug Administration (FDA). Plus, the need to administer it through an IV made it invasive, expensive, and hard to scale.
Janssen Pharmaceuticals, a division of Johnson & Johnson, saw an opportunity to create a product that would meet FDA approval, be easy to use, and could be covered by insurance carriers.
Ketamine is a racemic mixture equally consisting of two mirror-image molecules: S-ketamine (esketamine) and R-ketamine (arketamine.) Researchers noticed that esketamine was more potent and predictable and had a lower risk of cognitive side effects compared to arketamine.
They decided to isolate and develop esketamine as a proprietary treatment and called it Spravato. Making it a nasal spray avoided the need for IV infusions and made it easier and safer to administer. As a result, Spravato was approved by the FDA in 2019 as an esketamine treatment for depression.
Ketamine, esketamine, and arketamine today
Today, racemic or generic ketamine, which contains a mix of esketamine and arketamine, continues to be used in hospital settings as an anesthetic. It is not FDA-approved to treat depression, but it is still preferred by some providers as being cheaper and more widely available.
Ketamine is typically administered through an IV infusion, in pill form, or as an injection. Because it can be taken frequently with little medical oversight, it does carry a risk for misuse and addiction. Known as “Special K” in club scenes, ketamine is often used recreationally in high doses, which increases the risk of overdose.
Spravato (esketamine) holds a lower risk for misuse and addiction because it is prescribed under strict FDA guidelines. Spravato is administered as a nasal spray in Pacific Mind Health’s clinical setting, where patients are carefully monitored for side effects.
Arketamine is the subject of continuing research. Preliminary studies suggest it holds promise as a treatment for treatment-resistant depression.
The future of Spravato (esketamine)
In 2025, Spravato was approved as a monotherapy, meaning it can now be prescribed without requiring patients to also take an antidepressant. This will make it far easier for patients suffering from TRD, MDD, and suicidal ideation to gain access to this life-changing treatment.
Ketamine-assisted therapy is being researched to see if it can be used to effectively treat post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), anxiety disorders, eating disorders, and substance use disorders.
Esketamine is being evaluated as a treatment for bipolar depression as well as chronic and postoperative pain. Additionally, research is underway to develop it into a once-daily extended-release oral pill.
What started as an accidental discovery has evolved into a promising treatment for depression. Spravato is approved and available in more than 77 countries and has been administered to more than 140,000 patients around the world. More people are getting the help they need.
Key Takeaways
- Ketamine was originally used as an anesthetic on the Vietnam War battlefields. It was later discovered by accident to have a rapid and positive effect on symptoms of depression.
- Spravato (esketamine) was created as a safer, regulated option to treat TRD and MDD.
- Spravato was recently approved as a stand-alone treatment, which will help expand access. Esketamine is also being studied for bipolar depression, pain conditions, and as a once-daily pill formulation.
Looking for Spravato treatment near you?
Pacific Mind Health offers Spravato (esketamine) therapy for treatment-resistant depression and major depressive disorder at our Long Beach and Irvine locations. Our experienced clinicians provide compassionate, evidence-based care.
Ready to take the next step? Schedule a consultation today to see if Spravato is right for you.
