Racemic Ketamine vs. R-Ketamine vs. S-Ketamine: What's the Difference? | ISHA Health

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Racemic Ketamine Vs R-Ketamine Vs S-Ketamine: What You Need to Know | Isha Health

Written by

Isha Team


August 17, 2022


October 27, 2023

If you've been following developments in the field of mental health, you may have heard about Ketamine. Ketamine is a dissociative anesthetic that has been used for many years in clinical settings for pain management and anesthesia. However, in recent years, Ketamine has been found to have a powerful effect on mental health disorders such as depression, bipolar disorders, anxiety disorders, and PTSD.

Ketamine is a chiral molecule, meaning it has two enantiomers - R-Ketamine and S-Ketamine. When both enantiomers are combined in equal parts, it is called Racemic Ketamine. Recent research suggests that both enantiomers have distinct effects on the brain, and it's important to understand the differences between them to get the most out of ketamine-assisted therapy.

In this blog post, we will explore the differences between Racemic Ketamine, R-Ketamine, and S-Ketamine, and their effects on mental health disorders. We will also examine the comparative effects of R/S Racemic Ketamine and S-Ketamine in clinical studies, as well as the neuroplasticity of both enantiomers.

Racemic Ketamine

Racemic Ketamine is a mixture of both R-Ketamine and S-Ketamine in equal parts. It is the most commonly used form of Ketamine in clinical settings. The use of Racemic Ketamine has been shown to be effective in the treatment of depression, anxiety disorders, bipolar disorders, and PTSD.

In 1962, Dr. Stevens from Wayne State University synthesized racemic ketamine as a short-acting anesthetic for phencyclidine (PCP). Then, in 1964, Dr. Domino and his team at the University of Michigan conducted the first clinical study of racemic ketamine in human volunteers. By 1970, racemic ketamine had gained approval as an anesthetic in the USA.

Moving forward to 2000, Dr. Berman and colleagues conducted a double-blind, placebo-controlled study using racemic ketamine in medication-free patients with Major Depressive Disorder (MDD). The results showed that a single intravenous infusion of racemic ketamine (0.5 mg/kg) induced rapid and sustained antidepressant effects in these patients. Similarly, in 2006, Dr. Zarate and his team reported that treatment-resistant patients with MDD experienced significant and lasting antidepressant effects after a single infusion of racemic ketamine (0.5 mg/kg).

These positive findings regarding the powerful antidepressant effects of racemic ketamine have been replicated by various research groups worldwide, particularly in individuals with treatment-resistant MDD or Bipolar Disorder (BD). Currently, racemic ketamine is commonly used off-label to treat psychiatric conditions like MDD, BD, and Post-Traumatic Stress Disorder (PTSD).Racemic Ketamine has been found to produce a rapid and robust antidepressant effect, with patients showing significant improvement within hours of treatment. This rapid effect is in contrast to traditional antidepressants, which can take several weeks to produce a therapeutic effect.

The exact mechanism of action of Racemic Ketamine is not fully understood, but a systematic review showed that the regulation of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) receptor and N-methyl-d-aspartate (NMDA) receptor subunits–Postsynaptic Protein 95 (PSD-95), Brain Derived Neurotrophic Factor (BDNF), and Tyrosine Receptor Kinase B (TrkB) are shared by all three types of ketamine, , reinforcing the central role of the glutamatergic system and neurogenesis on its therapeutic effects.  

While Racemic Ketamine has been shown to be effective in the treatment of depression, anxiety disorders, bipolar disorders, and PTSD, it does have some side effects. The most common side effects of Racemic Ketamine include dissociation, hallucinations, and confusion. These side effects are usually short-lived and resolve quickly once the medication wears off.


R-Ketamine is the pure, isolated form of the R-enantiomer of Ketamine. It has been found to have a longer-lasting antidepressant effect than Racemic Ketamine. In addition, R-Ketamine has been shown to produce fewer side effects than Racemic Ketamine, particularly in terms of dissociation and psychotomimetic effects.

In clinical studies, R-Ketamine has been found to produce a rapid and sustained antidepressant effect, with patients showing significant improvement within hours of treatment that lasts for several days. It is believed that the longer-lasting effect of R-Ketamine is due to its ability to bind more selectively to the NMDA receptor.

At the cell-level, r-ketamine induces a more potent beneficial effect on decreased dendritic spine density, BDNF–TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine.

Ok, it’s getting too technical. What’re prefrontal cortext, CA3 and dentate guru?

The prefrontal cortex is known not only to be involved in emotional responses, but also to have numerous connections with other parts of the brain that are responsible for controlling dopamine, norepinephrine, and serotonin, three neurotransmitters that are important in mood regulation. In healthy people, the left prefrontal cortex might also help to inhibit the negative emotions generated by limbic structures such as the amygdalae, which show abnormally high activity in depressed patients. In patients who respond positively to antidepressants, this overactivity is reduced, which was seen with r-ketamine. 

Hippocampal CA3 is a critical structure that plays an important role in stress response, which is closely related to depression The atrophy of hippocampus is known to contribute to the comorbidity between pain, depression and the cognitive deficits.

The dentate gyrus is part of the hippocampal trisynaptic circuit and is thought to contribute to the formation of new episodic memories, the spontaneous exploration of novel environments and other functions. The volume of the DG was significantly increased in severely depressed patients, leaving the other subfields of the hippocampus unaffected.


S-Ketamine, also known as esketamine, is the enantiomer of ketamine that is known to be responsible for most of the antidepressant effects of the racemic mixture. In fact, S-ketamine has been approved by the US Food and Drug Administration (FDA) as a treatment for treatment-resistant depression in adults in the form of a nasal spray called Spravato.

S-ketamine is four-fold more potent for the NMDA receptor than R-ketamine. S-ketamine was studied for depression based on the hypothesis that the blockage of NMDA recepter being responsible for ketamine’s antidepressant effect although the exact mechanism of ketamine is stil not fully understood. As a matter of fact, it has been reported that AMPAR antagonists block the antidepressant-like effects of (R,S)-ketamine and its enantiomers in rodents suggesting that AMPAR activation contributes to the antidepressant-like effects of ketamine and its enantiomers. In contrast, it is unlikely that AMPAR activation may play a role in the antidepress

Clinical studies have shown that S-ketamine has rapid antidepressant effects, with some patients reporting a reduction in symptoms within hours of administration. This is in contrast to traditional antidepressant medications that can take weeks or even months to take effect. Additionally, S-ketamine has been shown to have a longer duration of action than R-ketamine, which may make it a more practical option for maintenance therapy.

However, like racemic ketamine, S-ketamine can also cause side effects such as dissociation, dizziness, and nausea. It can also have an addictive potential, which is why it is only available through a restricted distribution system and can only be administered in a certified healthcare setting under the supervision of a healthcare professional.

Comparing the Effects of Racemic Ketamine and S-Ketamine

Numerous studies have compared the effects of racemic ketamine and S-ketamine in the treatment of depression and other mental health disorders. One study published in the Journal of Psychopharmacology found that S-ketamine was more effective than racemic ketamine in reducing symptoms of depression and anxiety in patients with treatment-resistant depression.

Another study published in the Journal of Affective Disorders compared the effects of racemic ketamine and S-ketamine in patients with bipolar disorder. The study found that both racemic ketamine and S-ketamine were effective in reducing symptoms of depression and mania, but S-ketamine was more effective in reducing suicidal ideation.

Comparing the Effects of Racemic Ketamine and R-Ketamine

One study published in JAMA Psychiatry examined the antidepressant effects of racemic ketamine and R-ketamine in patients with TRD. The findings suggested that both forms of ketamine demonstrated rapid and significant reductions in depressive symptoms. However, the study did not find any significant differences in efficacy between racemic ketamine and R-ketamine, suggesting that both may be effective for treating TRD.

Another study, published in the journal Translational Psychiatry, investigated the effects of racemic ketamine and R-ketamine on neural activity in individuals with major depressive disorder (MDD). The results indicated that both forms of ketamine produced similar effects on brain activity, promoting connectivity changes associated with improved mood and depressive symptom reduction.

Neuroplasticity of R-Ketamine and S-Ketamine

Recent research has shown that both R-ketamine and S-ketamine have distinct effects on neuroplasticity in the brain. Neuroplasticity refers to the brain's ability to change and adapt in response to experiences and is believed to play a role in the development of mental health disorders.

A study published in the journal Molecular Psychiatry found that S-ketamine was more effective than R-ketamine in increasing the production of brain-derived neurotrophic factor (BDNF), a protein that is involved in the growth and maintenance of neurons in the brain. This suggests that S-ketamine may have a greater impact on neuroplasticity and may be more effective in treating mental health disorders that are associated with decreased levels of BDNF, such as depression and PTSD.

Another study published in the journal Translational Psychiatry found that R-ketamine was more effective than S-ketamine in promoting the formation of new synapses in the brain. Synapses are the connections between neurons in the brain that allow for communication between brain cells. This suggests that R-ketamine may be more effective in treating mental health disorders that are associated with decreased synaptic connectivity, such as schizophrenia.

These findings highlight the importance of understanding the specific effects of each enantiomer of ketamine and tailoring treatment accordingly.

Starting Your Ketamine-Assisted Therapy Journey

If you're considering ketamine-assisted therapy for the treatment of mental health disorders, it's important to approach it with a clear mind and a realistic understanding of what it entails. Here are some things to keep in mind:

Choose a qualified provider: Not all ketamine providers are created equal. Look for a licensed and experienced medical professional who has specialized training in ketamine-assisted therapy.

Consider the cost: Ketamine-assisted therapy can be expensive, especially if it's not covered by insurance. It's important to weigh the potential benefits against the cost and determine if it's a feasible option for you.

Be prepared for the experience: Ketamine-assisted therapy is not a quick fix, and it's not for everyone. It's important to be mentally and emotionally prepared for the experience and to approach it with an open mind and a willingness to explore your innermost thoughts and feelings.

Follow up with aftercare: Ketamine-assisted therapy is just one part of a comprehensive treatment plan. It's important to follow up with aftercare, such as therapy and support groups, to maintain the benefits of the treatment.

At Isha Health, we offer personalized online ketamine-assisted therapy sessions with a licensed medical professional. Our sessions are tailored to meet your individual needs and goals, and we prioritize safety and effectiveness above all else.


Ketamine-assisted therapy has emerged as a promising treatment option for mental health disorders such as depression, anxiety, bipolar disorder, and PTSD. While there are different forms of ketamine, including racemic ketamine, R-ketamine, and S-ketamine, research suggests that S-ketamine may be more effective and have fewer side effects.

It's important to approach ketamine-assisted therapy with a clear mind and a realistic understanding of what it entails. Choosing a qualified provider, considering the cost, being prepared for the experience, and following up with aftercare are all important steps in ensuring a safe and effective treatment.

At Isha Health, we're committed to providing personalized, online ketamine-assisted therapy sessions that prioritize safety, effectiveness, and individualized care. Contact us today to learn more about how we can help you start your journey towards improved mental health.


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