Hi and welcome to Lumin Health. It’s great to see you here learning more about ketamine and sketamine. My name is Ben Yudkoff and I’m the chief medical officer and co-founder of Lumin Health. Let’s dive in and try to understand the differences between ketamine and esketamine.
The story begins with ketamine. Ketamine is a medicine composed of molecules, and much like your hands have three-dimensional structure, the molecules have three-dimensional structure. Just as your hands exist as mirror images of each other, the molecules that comprise ketamine also have mirror images. We have one molecule of ketamine that’s oriented to the right, and one molecule of ketamine that’s oriented to the left. We call that chirality.
The right-sided oriented molecule we call dextrorotatory ketamine. The left-sided oriented molecule we call levorotatory ketamine or esketamine. Ketamine as a medicine is an equal part mixture of both the dextrorotatory (right-sided oriented) and levorotatory (left-sided oriented) molecules. They are combined for a reason: both have activity in parts of the brain where they’re supposed to deliver action, with the left-sided oriented molecule — the esketamine or S-ketamine — having stronger activity.
Another important point is that the medicine is poorly absorbed transmucosally. The mucosa is the pink lining in our nose, eyes, and mouth. Ketamine as a whole has a hard time being reliably absorbed across the mucosa because the right-sided molecule has a much harder time crossing it than the left-sided molecule. That’s why ketamine is usually delivered either by intravenous infusion or intramuscular injection.
There are some places that deliver ketamine (also called racemic ketamine, a term used to differentiate it from the distillate of just the S-ketamine) intranasally or orally. In those cases, the left-sided molecule — the S-ketamine — is the one most readily absorbed. Hold that in mind.
S-ketamine is simply the levorotatory molecule, the left-sided oriented form of ketamine. It has some key properties. First, it very readily crosses the mucous membrane. Second, it acts more strongly at NMDA receptors than its companion, the right-sided molecule. Because it crosses mucous membranes more readily and is the more active version of the medication, pharmaceutical companies saw an opportunity to bring it to market specifically for depression.
S-ketamine — also called Spravato or levorotatory ketamine — is therefore used in practice alongside ketamine. At Lumin Health, we provide ketamine as an intramuscular injection, given as a shot in the arm much like a flu vaccine. This allows both the right- and left-sided molecules to enter the bloodstream and exert their impact. Some places deliver it as a take-home intranasal or oral treatment, which improves accessibility, though bioavailability differs because higher volumes are needed to deliver an effective dose.
Ketamine is used off-label, meaning the FDA hasn’t granted approval for its use in depression. In medicine, FDA approval specifies what condition a drug is approved to treat. When a drug is used for something other than its original indication, that’s called off-label use. Off-label doesn’t mean unsafe or ineffective — it simply refers to the regulatory status. In psychiatry, off-label use is very common. Many medications approved for depression are used to treat anxiety, OCD, or PTSD. Similarly, seizure medications are often used off-label for psychiatric conditions.
In the case of ketamine, we use it off-label to treat major depressive disorder, bipolar depression, anxiety disorders, OCD, and PTSD — conditions where it has been studied the most. Because it is off-label and has some safety concerns, insurance companies typically don’t cover it, making intramuscular treatment an out-of-pocket expense.
In contrast, S-ketamine (Spravato) was brought to market by Janssen Pharmaceuticals and received FDA approval for treatment-refractory major depressive disorder and major depressive disorder with suicidal thoughts. These are on-label uses, which is why most insurers cover Spravato. This creates a significant difference for patients deciding between ketamine and S-ketamine: one is covered, the other is not.
Which is more effective? The answer is unclear. In theory, they should be equivalent, since S-ketamine is the most active component of ketamine. In practice, differences arise due to dosing. With ketamine, dosing can be adjusted based on patient response. With S-ketamine, the FDA restricts doses between 0 mg and 84 mg, which may not be enough for some patients. Some studies suggest IV ketamine outperforms standard doses of esketamine; others show similar effectiveness, with esketamine simply taking longer to work.
At Lumin Health, we evaluate each patient before treatment, discussing medication options, personal values, and financial considerations to find the best choice. And importantly, if the initial choice doesn’t work, we adjust and pivot until we find what helps. The goal is not just pharmacology but ensuring patients have enough information to make the best decision — and the support of a team who will walk with them through it.
Spravato, being insurance-covered, is delivered in a regimented schedule: twice weekly for four weeks, then once weekly for four weeks, and then weekly or biweekly thereafter, depending on response. Over time, some patients can space treatments even further. At Lumin, treatment schedules are tailored based on patient needs, symptoms, and convenience.
With ketamine, because it’s an out-of-pocket expense, we work to respect financial constraints. We aim to provide relief while minimizing frequency early in treatment so it stays accessible and sustainable.
In closing, I hope this helps. There are many blogs on our webpage that summarize the information we’ve just covered. Thank you for taking the time to learn more about these medicines, and I hope this helps you take the best possible care of yourself.
**this is a written transcript from the video on https://www.lumin.health/ketamine-and-esketamine
