S-Ketamine vs. R-Ketamine: Key Facts You Ought to Know

S-Ketamine Vs. R-Ketamine

The World Health Organization (WHO) classifies depression as one of the leading causes of disability in the world, with about 5% suffering from this condition.

In the United States alone, it is estimated that 7% of Americans suffer from major depression. A substantial number of patients find success with therapy and antidepressants.

However, some patients have been diagnosed with treatment-resistant depression or TRD.

Powdered Ketamine
Powdered Ketamine

What Is Treatment-Resistant Depression?

Treatment-resistant major depression, also known as clinical depression, is a condition where a patient has a persistent feeling of sadness coupled with disinterest even after sustained antidepressant treatment.

Patients suffering from this condition find it difficult to perform normal activities that the average person does as a part of their daily routines.

Major depression differs from mood fluctuations because patients can’t just snap out of their conditions.

Patients may sometimes find it difficult to find progress with therapy and antidepressants. As such, experts continue to explore alternatives to treat depression. One such treatment that has shown promise in treating depression is ketamine.

Currently, there are two types of ketamine treatments used in treating depressed patients: IV ketamine and Spravato (S-ketamine).

What Is Ketamine?

Initially, ketamine was used in Belgium as an anesthetic for veterinary medicine. During the Vietnam War, the drug was used for treating injured soldiers.

Later on, medical personnel discovered that ketamine effectively calmed down soldiers battling depression and suicidal thoughts.

These healthcare providers stumbled upon a then-unknown effect of ketamine: it can be used for treating depression and psychiatric disorders.

These anecdotes from the battlefield captured the attention and imagination of medical professionals who have been looking for solutions to treat depression and mood disorders.

How Is Ketamine Used for Treating Depression?

Ketamine can come in different forms. However, the Food and Drug Administration or FDA has only approved Spravato, a nasal spray, for treatment-resistant major depression.

Esketamine can only be prescribed to adults who have clinical depression, are suicidal, or have tried antidepressant medication before.

Spravato is administered in a healthcare facility under the supervision of qualified professionals. Dosage varies depending on the condition being treated.

Typically, a patient with clinical depression needs to get two nasal sprays a week for anywhere between one to four weeks.

After that, the dosage goes down to one spray per week for the succeeding weeks until the patient’s dosage goes down to once every one or two weeks.

Aside from Spravato, there are other treatments that involve ketamine. These include IV drips, lozenges, and injections. Take note that the FDA has not approved these treatments.

What Are the Effects of Ketamine?

Ketamine produces a trip or what medical professionals call dissociative experience. Patients treated with this drug have reported feelings of euphoria, sensory distortion, unusual thoughts, and a disconnection from their bodies and surroundings.

A typical trip can last for roughly two hours.

According to some studies, people with clinical depression have neurons or nerve cells that are either weakened or deactivated and cannot communicate with the neurotransmitter known as glutamate.

Glutamate is a chemical associated with moods. If you have depression or other mood disorders, the glutamate in your body can’t make a proper connection with your neurons.

When ketamine is used as a treatment, it revives the connection between your neurons and glutamate.

Essentially, ketamine reshapes the brain by reactivating the connection between neurons and glutamate.

Common side effects

When prescribed by qualified professionals, you can expect side effects like

  • Dizziness
  • Nausea or vomiting
  • Confusion
  • Drowsiness
  • Double vision

Once ketamine wears off, you may experience

  • Anxiety
  • Clumsiness
  • Disorientation
  • Impaired judgment
  • Pain

Risks and adverse side effects

Generally, ketamine is safe for a diverse range of patients. However, a few risks are involved in using the drug to treat depression.

These include

  • Heart instability
  • Liver injury
  • Respiratory depression
  • Agitation
  • Cognitive impairment

Ketamine isn’t recommended for patients with hypertension as the drug may cause heart and blood pressure issues as well as aneurysms.

Pregnant women and patients with schizophrenia are disqualified from this treatment.

Ketamine Types: Racemic Ketamine vs. Esketamine

Interest in using ketamine for the treatment of depression has been around for decades. But with the release of Spravato into the market along with FDA approval, many experts can’t help but feel a combination of optimism and exasperation.

On the one hand, initial studies and anecdotal evidence were confirmed. And on the other hand, many felt that the approval of Spravato was another case of pharmaceutical companies patenting isomers.

The approval of Spravato was filled with a few roadblocks. For starters, ketamine is one of the generic drugs currently available to patients, having been around for decades.

That is a critical fact that people ought to know because being a generic drug means that big companies cannot take advantage of and profit from ketamine. Second, Spravato needed the approval of the FDA.

So how did Janssen Pharmaceuticals overcome these hurdles?

First, the pharmaceutical company invested a hefty sum of money in manipulating ketamine’s molecule to create and market a new drug.

It certainly helped that Janssen Pharmaceuticals was able to take advantage of its Fast Track and Breakthrough Therapy Designation for S-ketamine.

The question now swirling in the minds of professionals and their patients is whether S-ketamine is better than racemic ketamine.

Understanding Ketamine Chirality

To help you decide whether S-ketamine or racemic ketamine is better for treating your depression, it is a good idea to start with the concept of chirality.

In chemistry, chirality refers to the asymmetry of molecules. Ketamine is composed of enantiomers which are oriented into two different versions.

These two different versions are just like your hands – similar but not identical. You can’t superimpose one over the other.

In the case of ketamine, chirality is important because it means that its enantiomers have different effects once consumed.

Ketamine’s two enantiomers are called S-ketamine (or esketamine) and R-ketamine. You can think of S-ketamine as your left hand, while R-ketamine is your right hand.

Generic ketamine has a racemic mixture meaning it contains both S-ketamine and R-ketamine.

Spravato, on the other hand, only contains S-ketamine. Janssen Pharmaceutical was able to do this by isolating S-ketamine.

Racemic Ketamine vs. S-Ketamine in Lab Tests

Why does chirality or handedness matter when it comes to comparing S-ketamine and racemic ketamine?

Multiple studies were conducted on rats to determine the differences between the two enantiomers as a remedy for treatment-resistant depression. Researchers discovered that racemic ketamine is the superior of the two when it comes to managing symptoms associated with clinical depression.

In one of these studies, the subjects were given racemic ketamine and S-ketamine. After two days, the ketamine was removed from the test subjects. To the surprise of the researchers, they discovered that racemic ketamine provided a sustained antidepressant effect even after it was eliminated from the blood of the subjects.

In the case of the subjects treated with esketamine, their symptoms returned to their baseline levels.

In a separate study, researchers discovered that both types of ketamine helped neurons to establish new connections. The key difference between R-ketamine and S-ketamine is that the neural connections were stronger with the former.

This discovery is crucial because many experts have suggested that depressed patients experience many of the symptoms of their conditions due to the disruption in the connection between their brain cells.

How S-Ketamine Treatment Works

The FDA formally approved Spravato for treatment-resistant depression in 2019. This approval marks the first time that ketamine was approved for treating depression.

To date, scientists do not completely understand how S-ketamine works to treat depressed patients. But according to current information, ketamine’s S molecule seems to bind with N-methyl-D-aspartate or NMDA receptors in the human brain.

Spravato increases glutamate levels in the brain. This increase in glutamate levels in the brain triggers the brain cells to boost cognitive functions like memory and learning.

How does S-ketamine compare to other treatments?

Unlike other treatments available to patients, S-ketamine does not boost other chemicals inside the brain. These chemicals include dopamine, serotonin, and norepinephrine.

Instead, Spravato increases glutamate levels inside the brain.

Who can benefit from S-Ketamine

S-ketamine can be prescribed to people with the following conditions:

1. Patients seeking rapid antidepressant effects

Conventional treatments for depression work slowly. In some cases, antidepressant effects may take several weeks before a patient can experience noticeable effects.

With Spravato, depressed patients can expect an antidepressant response in as little as a few hours.

2. Patients with suicidal thoughts

Unlike other antidepressants, S-ketamine and lithium do not increase suicidal thoughts, especially at the start of the treatment. Children and young adults, in particular, are prone to experience this adverse side effect.

Because of this, the use of Spravato as a treatment for bipolar disorder is now being strongly considered.

3. People with treatment-resistant depression

It’s estimated that 33% of depressed patients do not respond to most of the available treatments.

Based on clinical trials, S-ketamine works on people with TRD, reducing most symptoms.

Who’s qualified for S-ketamine treatment?

To be considered a good candidate for S-ketamine treatment, your mental healthcare provider needs to look at two things.

First, you should have tried at least two other antidepressant treatments, and second, you should have undergone treatment for at least six weeks for each of these.

You’re disqualified if you have found some improvement in your mood by at least 50%.

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How Does a Racemic Mixture Treatment Work?

Racemic ketamine is typically administered intravenously. However, it may also be administered orally, via injection, or through a spray.

When administered intravenously, R-ketamine is 100% bioavailable. This simply means that the whole dose is absorbed fully by the body.

Although racemic ketamine was first used as an anesthetic, the dosage for the depressed patient is lower. A higher dose can induce dissociation.

Like S-ketamine, a racemic mixture works by increasing the glutamate levels in the brain of depressed patients.

Aside from helping improve the communication between neurons, R-ketamine has also been observed to reduce inflammation. According to some studies, inflammation may play a key role in mood disorders.

Take note that racemic ketamine is classified as an off-label treatment. This is because it hasn’t received FDA approval.

R-Ketamine Molecular Structure
R-Ketamine Molecular Structure

How Many Doses of Racemic Mixture Do You Need?

Like Spravato, a racemic mixture is administered in a healthcare facility.

Typically, depressed patients start with six infusions. You’ll need to visit your healthcare provider two to three times a week for two to three weeks.

Dosage often starts at 0.5 mg/kg of body weight.

In some patients, the antidepressant response is rapid, while in others, it may take a few infusions before they see noticeable results.

What are the side effects of racemic ketamine?

The side effects of a racemic mixture treatment are the same as those of Spravato. These include vomiting, nausea, and confusion.

Which Treatment is Right for You: Racemic Ketamine or S-Ketamine?

If you have been battling treatment-resistant depression with hardly any improvement, both racemic ketamine and S-ketamine may provide you with the solution you are after.

One isn’t necessarily better than the other. However, there are a few factors that you may want to look into to help you make a better decision for treating depression.

First, consider the mode of administration. Although racemic ketamine may be administered in various ways, IV transfusion is the most common. If you are afraid of needles, S-ketamine may be better for you.

Second, there’s a slight difference in treatment times. R-ketamine treatment often lasts three weeks, while treatment with Spravato usually lasts eight weeks.


Most insurance companies cover Spravato for treatment-resistant depression and other similar conditions.

If you are unsure whether or not your insurance company covers S-ketamine, you can call them directly to inquire.

In one clinical trial, researchers discovered that Spravato could provide a 50% symptom reduction in 70% of patients.

In the same trial, half of the participants went into full remission.

However, the medications used in conjunction with S-ketamine will vary among patients. Treatment time may also take longer in some patients.

Although some patients report the rapid onset of effects for both S-ketamine and R-ketamine, one dose is not enough to achieve long-term benefits.

You will need to follow your healthcare provider’s recommendation to get the full effects of each type of treatment.