Written and medically reviewed by Dr. Ladan Eshkevari, CRNA, PhD, FAAN
Ketamine exists in two mirror-image forms, S-ketamine and R-ketamine, and each may affect depression differently. As of 2026, S-ketamine is the faster-acting form and is FDA-approved as Spravato (esketamine) for treatment-resistant depression, while R-ketamine (arketamine) remains in early research and is not yet available for treatment.[1][13] The two forms can also feel different during treatment, with S-ketamine more likely to produce a noticeable dissociative experience. Understanding the difference helps you make sense of what depression treatments are available today.
Key takeaways
- S-ketamine and R-ketamine are enantiomers, not different drugs: they share one chemical formula and mirror-image shapes, and clinical ketamine is usually a 50/50 racemic mix of both.[1]
- S-ketamine (esketamine) is the only FDA-approved single-enantiomer option: approved as Spravato in 2019 for treatment-resistant depression, backed by large Phase 3 trials.[4][13]
- R-ketamine (arketamine) is still investigational: preclinical data suggest it may act longer with less dissociation, but larger human trials have not yet confirmed an antidepressant advantage.[3][11]
- The “high” differs: S-ketamine binds NMDA receptors far more tightly and is more dissociative; R-ketamine binds weakly and feels more grounded in early research.[1]
Understanding Ketamine & Its Mirror-Image Forms (S & R)
Ketamine contains mirror-image molecules (enantiomers) called S-ketamine (esketamine) and R-ketamine (arketamine).[1] When you receive ketamine in a hospital for anesthesia or in a clinic for depression, you are typically receiving a 50/50 mixture of both, known as a racemic blend.
Ketamine R and S share the same chemical formula. However, their unique shapes determine how each one fits into and interacts with receptors in your brain. Neither form is a “ketamine analog,” a separate compound built to imitate ketamine; they are the two halves of the ketamine molecule itself.
Once in the brain, both S- and R-ketamine influence systems involved in mood, perception, and neural communication. Together, they drive the antidepressant and sensory effects that ketamine is known for. At the same time, each form appears to contribute something slightly different to the overall experience and response, which is why researchers continue to study them separately.
How S-Ketamine and R-Ketamine May Affect the Depressed Brain Differently
S-ketamine and R-ketamine differ primarily in how “tightly” they bind to NMDA brain receptors and potentially how long their antidepressant effects last. Both molecules trigger the release of glutamate, a chemical messenger that helps the brain regrow neural connections. However, they take different biological pathways to do so.[1]
Esketamine acts as a high-potency “blocker” of NMDA receptors, leading to a rapid shift in glutamate across brain regions. Conversely, R-ketamine is a weaker NMDA binder but could be a more potent stimulator of the long-term growth factors that keep the brain resilient against depression.[3]
S-Ketamine Mechanisms
S-ketamine binds to NMDA receptors nearly four times more strongly than the R-form.[1] This high affinity allows it to trigger an immediate antidepressant signal and dissociative “out-of-body” sensations.
Esketamine can be highly effective. However, some researchers theorize that S-ketamine’s effects may not last as long as R-ketamine’s because it creates a temporary shift in brain signaling rather than supporting longer-term changes in how brain cells connect and function.
R-Ketamine Mechanisms
Arketamine has a much weaker grip on NMDA receptors, leading to almost no dissociative effect and a more grounded patient experience.
Pre-clinical research suggests R-ketamine could also be superior at activating BDNF (brain-derived neurotrophic factor), a protein that acts like “fertilizer” for neurons. This suggests that R-ketamine may be better at promoting the long-term structural brain changes needed to keep depression in remission.[3] This work is largely in animal models and has not yet been confirmed in large human trials.
S-Ketamine vs R-Ketamine Effects
The “high” from S-ketamine vs R-ketamine effects differs in intensity, clarity, and how detached or grounded patients feel during treatment.
Esketamine Effects
- creates a noticeable sense of dissociation, such as feeling separated from the body or surroundings
- can shift perception of time, space, and sensory input in a more noticeable way
- symptoms typically appear within minutes of the first dose and resolve naturally within about 90 to 120 minutes[4]
- most common adverse events include dissociation, nausea, vertigo, dysgeusia, and dizziness[4]
Arketamine Effects
- appears to produce a milder, more relaxed mental state in early research
- may involve subtle shifts in mood and perspective without strong detachment
- tends to feel less disruptive to awareness while still supporting antidepressant effects in early studies
- reported side effects are so far limited to mild blurred vision or dizziness without intense mental disruption[9]
What Does the Research Say About S-Ketamine for Depression?
Esketamine became a prescription medication (Spravato) for depression in 2019 after large-scale clinical trials supported its safety and efficacy.[13]
Clinical Trials Supporting Depression Relief
Phase 3 efficacy and safety trials, such as the TRANSFORM program, showed that patients who added esketamine nasal spray to a new oral antidepressant saw a significantly greater reduction in symptoms than those using a placebo.[4] Those who continued treatment saw further improvement.
The relapse-prevention Phase 3 study (SUSTAIN-1) showed that esketamine patients who achieved stable remission were about 51% less likely to relapse than those who switched to a placebo.[5]
Long-term data from Phase 3 maintenance studies (SUSTAIN-2 and SUSTAIN-3) found that S-ketamine’s antidepressant effects can persist for at least one year of treatment, with no new safety signals and no evidence of lasting cognitive impairment.[6]
A small 2025 real-world study extended these observations to an average of 2.5 years of esketamine treatment. In that single-clinic retrospective of 20 patients, 85% showed improvement in depression severity and 65% improved in anxiety severity.[12] Because the sample was small and had no control group, the findings are encouraging but preliminary.
Research Limitations & Questions (S-Ketamine)
Not every esketamine trial showed the same level of benefit across all patient groups, and questions remain about how it compares to other forms of ketamine.
For instance, in the TRANSFORM-3 trial in adults aged 65 and older with treatment-resistant depression, esketamine plus a new oral antidepressant did not separate significantly from placebo at four weeks (p = 0.059).[7] Some patients still improved, but the results suggest that age and overall health can influence how well treatment works.
Additionally, a 2025 study from Mass General Brigham found that IV ketamine led to a 49.2% reduction in depression scores, compared with a 39.6% reduction for esketamine. Patients in that study also reported faster relief with IV ketamine, sometimes after a single session.[8]
R-Ketamine Depression Research
Arketamine research has grown as scientists look for ways to treat depression with fewer side effects.
Preclinical and Early Clinical Findings
In animal models of depression, arketamine has shown stronger and longer-lasting antidepressant-like effects than S-ketamine, with fewer dissociative and behavioral side effects.[3]
Early human data is more limited but still informative. A small pilot study in patients with treatment-resistant depression found that a single intravenous dose of arketamine led to swift improvement in symptoms after one day, with minimal dissociation.[9]
Additional case reports have followed TRD patients after arketamine treatment and observed sustained improvements in mood and in social and vocational functioning.[10]
Research Limitations & Questions (R-Ketamine)
Despite strong early signals, larger R-ketamine trials have not yet confirmed an antidepressant advantage.
In a Phase 2a trial (PCN-101) involving more than 100 patients with treatment-resistant depression, arketamine did not show a clear improvement over placebo at the 24-hour timepoint.[11] Most human studies on arketamine remain small, early-stage, or exploratory, with limited data on optimal dosing, treatment frequency, and long-term outcomes.
Differences Between S and R Ketamine at a Glance
| Feature | S-Ketamine (Esketamine) | R-Ketamine (Arketamine) |
|---|---|---|
| Current status | FDA-approved as Spravato nasal spray.[13] | Investigational; currently in clinical trials.[11] |
| NMDA receptor grip | High potency: binds nearly 4x more strongly.[1] | Low potency: much weaker grip.[1] |
| Primary brain effect | Rapid NMDA “blockade” to quickly lift mood. | Focuses on long-term repair by stimulating growth factors such as BDNF.[3] |
| The “high” experience | Moderate to high: dissociation and sensory shifts; resolves in about 2 hours.[4] | Grounded: milder, with fewer dissociative side effects in early research. |
| Speed of relief | Often within hours of the first dose.[8] | Early trials showed no clear advantage at 24 hours.[11] |
| Duration of relief | Effects can persist with continued dosing (SUSTAIN maintenance data).[6] | Animal studies suggest longer duration; not yet confirmed in humans.[3] |
| Clinical evidence | Large Phase 3 trials (TRANSFORM and SUSTAIN).[4][5] | Preclinical data plus small human pilot studies.[9] |
| Known limitations | Did not separate from placebo in adults 65+; nausea and vertigo common.[7] | Larger trials (PCN-101) have not confirmed an advantage over placebo at 24 hours.[11] |
Why Pharmaceutical Companies Focused on Esketamine First
Pharmaceutical companies focused on esketamine before racemic ketamine and R-ketamine because it offered a more practical path to drug approval. As a single enantiomer, S-ketamine could be packaged into a patented nasal spray with standardized dosing and tested in large, regulated trials.[14]
- S-ketamine could be developed as a proprietary single-molecule product rather than a generic racemic drug
- it fit a standardized nasal-spray model that worked well for large clinical trials
- it already showed enough antidepressant activity to justify major investment
- arketamine remained mostly a preclinical candidate while esketamine advanced through Phase 3 and Phase 4 studies
What This Means for Patients Considering Ketamine Therapy
If you are considering ketamine therapy for depression, the key difference between S-ketamine vs R-ketamine effects comes down to what is available now. Today, treatment involves FDA-approved esketamine (Spravato) or racemic IV infusions. Arketamine is not yet available outside of research settings.
- S-ketamine (esketamine) offers the most established, regulated option, with insurance coverage for qualifying conditions.
- Racemic ketamine is commonly used in mental health clinics and includes both ketamine R and S working together.
- R-ketamine is not yet available, but ongoing research is exploring its potential.
If you are considering esketamine nasal spray or IV ketamine therapy, connect with our care team to talk through your options and choose the right path forward.
Frequently Asked Questions
What is the difference between esketamine and arketamine? Esketamine (S-ketamine) and arketamine (R-ketamine) are the two mirror-image halves of the same ketamine molecule, and they affect the brain in different ways. Esketamine is FDA-approved and has strong clinical evidence for depression, while arketamine is still being studied and may offer longer-lasting effects with fewer side effects.
Is esketamine stronger than arketamine? It depends on what you are measuring. Esketamine binds the brain’s NMDA receptors roughly three to four times more tightly, so it is more potent chemically and more dissociative. Arketamine binds weakly, but early research suggests it could be better at promoting long-term brain healing (neuroplasticity) with fewer side effects. Large studies are still needed to confirm this.[1][3]
Why is esketamine FDA-approved when arketamine is not? Esketamine completed the large, regulated Phase 3 trials that the FDA requires and was approved as Spravato in 2019.[13] Arketamine is still in early-stage research and is only available in clinical trials, so it has not yet been approved for depression.
Is R-ketamine available as a treatment now? No. R-ketamine (arketamine) is investigational and is only accessible through clinical trials. Available options today are FDA-approved esketamine (Spravato) and racemic IV ketamine.
References
- Jelen LA, Stone JM, Young AH, et al. “The ketamine enantiomers: pharmacology, mechanisms, and antidepressant effects of S-ketamine and R-ketamine.” Review, PMC11505277. Establishes S- and R-ketamine as enantiomers (racemic = 50/50) and that S-ketamine binds NMDA receptors roughly 3-4x more strongly than R-ketamine. Accessed July 2026.
- Hashimoto K. “Molecular mechanisms of the rapid-acting and sustained antidepressant actions of (R)-ketamine.” Biochemical Pharmacology, 2020. R-ketamine and BDNF/neuroplasticity. Accessed July 2026.
- Hashimoto K, et al. “(R)-ketamine as a rapid-acting antidepressant: preclinical evidence for longer, less dissociative effects.” Biochemical Pharmacology, 2022. Preclinical superiority signal for arketamine. Accessed July 2026.
- Popova V, Daly EJ, Trivedi M, et al. “Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression (TRANSFORM-2).” American Journal of Psychiatry, 2019;176(6):428-438. Phase 3 efficacy; common adverse events (dissociation, nausea, vertigo, dysgeusia, dizziness). Accessed July 2026.
- Daly EJ, Trivedi MH, Janik A, et al. “Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression (SUSTAIN-1): A Randomized Clinical Trial.” JAMA Psychiatry, 2019;76(9):893-903. ~51% lower relapse risk in stable remitters. Accessed July 2026.
- Wajs E, Aluisio L, Holder R, et al. “Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2).” Journal of Clinical Psychiatry, 2020;81(3):19m12891. Long-term maintenance safety/efficacy. Accessed July 2026.
- Ochs-Ross R, Daly EJ, Zhang Y, et al. “Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression (TRANSFORM-3).” American Journal of Geriatric Psychiatry, 2020;28(2):121-141. Did not separate from placebo at 4 weeks (p=0.059) in adults 65+. Accessed July 2026.
- Mass General Brigham / McLean Hospital. “Two Forms of Ketamine Therapy Can Reduce Symptom Severity in Patients With Treatment-Resistant Depression.” September 2025 (n=153; IV ketamine 49.2% vs IN esketamine 39.6% symptom reduction; published in the Journal of Clinical Psychiatry). Accessed July 2026.
- Leal GC, Bandeira ID, Correia-Melo FS, et al. “Intravenous arketamine for treatment-resistant depression: open-label pilot study.” European Archives of Psychiatry and Clinical Neuroscience, 2021;271:577-582. Single-dose arketamine, rapid improvement, minimal dissociation. Accessed July 2026.
- Bandeira ID, et al. “Sustained antidepressant and functional response after arketamine in treatment-resistant depression: a case series.” 2024. Sustained mood and vocational functioning improvements. Accessed July 2026.
- atai Life Sciences. “atai Life Sciences Announces Results From Phase 2a Trial of PCN-101 (R-ketamine) in Treatment-Resistant Depression.” Company press release. Arketamine did not separate from placebo at the 24-hour primary timepoint. [Press release; replace with the peer-reviewed publication once available.] Accessed July 2026.
- Al-Harbi K, et al. “Long-term effectiveness and side-effects of intranasal esketamine in treatment-resistant depression: a real-world, single-arm study of over 100 sessions.” BJPsych Open, 2025, PMC12835693. Single-clinic retrospective, 20 patients, mean 2.5 years: 85% improved in depression severity, 65% improved in anxiety severity. Accessed July 2026.
- U.S. Food & Drug Administration. “FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic.” March 5, 2019. Spravato (esketamine) approval. Accessed July 2026.
- Jamed A, et al. “The development of esketamine versus racemic ketamine and arketamine: regulatory and pharmaceutical considerations.” Review, 2024, PMID 39428602. Why a single-enantiomer, patentable product advanced first. Accessed July 2026.
