Esketamine and Arketamine: Chemistry Matters — But So Does Delivery
Not all ketamine is the same. Chemically, ketamine comes in two mirror-image forms — S-ketamine and R-ketamine — that behave differently in the brain. And not all delivery methods are created equal. Some offer fast, precise absorption; others involve more variability.
To make informed choices about treatment, it’s helpful to understand both:
- The stereochemistry (shape & structure) of ketamine
- The routes of administration that affect how well the medication works in your body
This article explains what makes S-ketamine more active, why bioavailability matters, and how these two factors converge in treatment design.
**will put a picture of both isomers next to each other
S-Ketamine as the Active Component
Ketamine, as commonly used in clinics, is a racemic mixture — a 50/50 blend of two mirror-image molecules: S-ketamine and R-ketamine.
Among these, S-ketamine is considered the more active component in the treatment of depression. It has:
- Greater affinity for the NMDA receptor
- More potent glutamate modulation
“S-ketamine is what’s doing the heavy lifting when it comes to blocking the NMDA receptor and initiating downstream changes.” — Dr. Ben Yudkoff
This is the form isolated and used in Spravato, the FDA-approved intranasal therapy for treatment-resistant depression.
R-Ketamine: Less Active (and Less Absorbable)
While R-ketamine still binds to NMDA receptors, it does so with less potency and requires higher concentrations to achieve therapeutic effects. According to Dr. Yudkoff and broader clinical consensus:
- R-ketamine has lower clinical activity
- It may play a supportive role in racemic mixtures
- But it’s not clear if R-ketamine is necessary for the antidepressant effect to occur
That said, some early research suggests R-ketamine may have unique anti-inflammatory or longer-lasting benefits. These areas remain under investigation, but for now, the clinical guidance is clear: S-ketamine drives the core therapeutic effect.
“We think of R as more inert, at least for now. That could change with new data, but in practice, it’s S-ketamine we’re relying on.” — Dr. Ben Yudkoff
Practical Implications: Ketamine Route and Formulation Matter
While chemical differences matter, how the medication gets into the body plays a crucial role in whether it works effectively. This is where the conversation shifts to bioavailability — the percentage of a drug that reaches systemic circulation in an active form.
Direct Bloodstream Routes: IV and IM Ketamine
Intravenous (IV) and intramuscular (IM) routes offer the highest bioavailability, close to 100%, because the medication enters the bloodstream directly. These methods:
- Deliver consistent, predictable dosing
- Allow flexible titration for rapid symptom changes
- Are commonly used in off-label ketamine clinics
“IV and IM are where we see the most dosing precision. When timing and intensity matter, those routes are often preferred.” — Dr. Ben Yudkoff
Intranasal and Transbucchal (aka: held in the mouth and absorbed through the gums) Racemic Ketamine: More Variability
Intranasal and transbucchal forms of racemic ketamine (used off-label) have lower and less predictable bioavailability:
- A portion of transbucchal ketamine is often swallowed which is then broken down and rendered inactive, reducing the overall amount that gets into the blood stream
- Intranasal delivery (which requires higher volumes) can sometimes result in small leakages and swallowed ketamine with the same issues as transbucchal ketamine
These factors can lead to inconsistent results in some cases — especially when patients are not monitored or formulations are not optimized.
S-Ketamine Nasal Spray (aka esketamine or “Spravato”): Engineered for Fidelity
Spravato, by contrast, uses S-ketamine in a low-volume, high-concentration nasal spray specifically designed to minimize leakage and maximize mucosal absorption.
“It’s not just about esketamine being the right molecule. It’s that Spravato delivers it in a way that’s repeatable — and that matters for insurance, monitoring, and safety.” — Dr. Ben Yudkoff
This route may not be superior in effect, but delivers more of the medicine, reliably. It is often more accessible and covered by insurance when prescribed through a REMS-certified clinic.
When it comes to ketamine therapy, structure and delivery matter. At Lumin Health, we help patients and families make sense of these differences — not to complicate, but to clarify. Because when you understand what’s happening biologically and logistically, it’s easier to make a treatment plan that fits your goals, your access, and your life.
