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Comment by logiclogic | Hacker News Reader

And why not just regular old ketamine instead of a dangerous, untested new derivative? The whole system is broken beyond repair.

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It amazes me how the problems with our drug and medical regulation system never come up even when it's staring us in the face. This article is typical, framing it as a problem with pharm companies rather than with the regulatory system. Between stuff like this, the opioid crisis, and cannabis deregulation, it should be obvious how broken and monopolistic the system is (referring to the FDA, DEA, and medical licensure system).

It is being tested and it's not a "dangerous, untested new derivative", it's a enantiomer of ketamine, it's literally 50% of the molecules in ketamine. And why don't we just use normal ketamine, why test any new drug, to see if it works better than what we had before.

> it's a enantiomer of ketamine, it's literally 50% of the molecules in ketamine

I’m not a biologist or a chemist. Why does this imply the chemical is as safe? What is the benefit? It seems like a blatant patent grab to bypass the low profit margins of ketamine. Is there evidence otherwise?

The short answer is it can be both (ie safe, beneficial and effectively a patent grab). It is also unlikely that an enantiopure chemical is less safe then it’s racemic counterpart and not unlikely that it is beneficial (this is not without precedent... this is also chemistry 101 and I don’t feel this is the forum for it)...

The doubt is not so much the safety but is the benefit of the enantiopure version worth the cost.

Per my comment above, thalidomide is a clear exception. This stands even if the chirality changes within the body.

That was an example on the other direction. A pure chirality was safe, but a racemic mixture was dangerous. Here we know the racemic mixture is safe, which strongly suggests that either chirality in isolation is also safe.

And to make in the previous worse it would apparently "autobalance" and flip to chirality which meant that even if they 100% isolated it at great expense is why we never saw "rebranded Thalimoide but isolated to be all morning sickness drug no birth defects". I don't know enough details to tell how long it took and if it could even be used safely under ludicrously impractical assumptions like "if you it freshly isolated in bulk and take it within five seconds it would be safe but expire in an hour".

I think it flipped when in the body, so however long the shelf life was, it still wouldn't matter.

Incidentally, and AIUI, the body has a tagging system for unwanted proteins. Once tagged, the proteins are removed. Thalidomide tagged the proteins the were specific to embryonic limb formation, and the body duly cleared them, leading to the infamous result. Again AIUI.

Not a biologist or chemist either, but I'll try to give my layperson understanding: basically, many molecules exist in two different versions which are mirror images of each other (enantiomers). Most drugs are actually an equal mixture of both enantiomers (called a racemic mixture), but often only one of the enantiomers has the desired drug effect, and the other doesn't actually do anything. It is possible to create a drug which has only the effective enantiomer; usually, a pure dose of the effective enantiomer will be effective at half the dose as the racemic mixture. Medically, there are some advantages – both forms need to be metabolised by the liver, so being able to use half the dose to get the same effect gives the liver less work to do, which can reduce the risk of drug-induced liver injury. If the racemic mixture is already being widely used, then the risk of the pure effective enantiomer is likely to be low, since it is basically just a more effective form of the already used drug, and the side effect profile should be similar to the existing drug. Chemically, the manufacturing process is more complex, which adds to manufacturing costs; however, the main driver of additional costs is that you can get a new patent for the active enantiomer even after the patent on the racemic mixture is expired. For example, the common SSRI anti-depressant citalopram is the racemic mixture, whereas escitalopram is the S-enantiomer. Similarly, esketamine would be the S-enantiomer of ketamine.

A lot of chemicals are "50%" of each other but completely different. That's not how chemistry works.

Water is H₂0. Hydrogen peroxide is H₂0₂. I wouldn't substitute one for the other.

Do you know of any examples where a racemic mixture has an effect dramatically different from what you'd expect from a combination of the enantiomers' effects?

Thalidomide. One enantiomer is a great morning sickness drug, the other causes catastrophic birth defects.

Thalidomide interconverts in the body. There is no difference between the enantiomers in the human body (there is in a petri dish).

I'm not sure I understand the question[0] fully but thalidomide? https://en.wikipedia.org/wiki/Thalidomide

"Thalidomide is provided as a racemic mixture of two enantiomers; while there are reports that only one of the enantiomers may cause birth defects, the body converts each enantiomer into the other through mechanisms that are not well understood."

[0] because a racemic mixture (https://en.wikipedia.org/wiki/Racemates) is a 50/50 mix of enantiomers: "In chemistry, a racemic mixture, or racemate [...] has equal amounts of left- and right-handed enantiomers of a chiral molecule" so if you took a racemic mixture surely you'd be getting a combination of the enantiomers' effects?

Amphetamine, for one. Levoamphetamine or dextroamphetamine provide two different physiological experiences (think coffee vs meth). The effects profile of racemic amphetamine is markedly different and much easier to handle physiologically than just dextroamphetamine by itself (the most common isomer found in amphetamine prescription products).

From a perspective of safety, I don't have any reason to suspect esketamine to be any worse. However from a psychological perspective, we could be talking pretty big differences in some individuals where subtle changes in behavior or thought can have cascading effects on mood.

But... that's why we're testing its efficacy, right? It's stupid not to try, and these test subjects are willing. One of the two isomers will be better in some categories. Could be that both together are the way to go. Having only encountered racemic ketamine I can definitely understand its uses in treating depression.

Commenters so far haven't actually answered your question. They just gave examples where the 2 enantiomers have different effects. There are countless examples of these since our bodies' molecules naturally have "handedness".

What you were essentially asking was would 100% of the "bad" enantiomer be significantly worse than a 50/50 mixture. This is the real question here. For there to be a significant difference in this case one of the ketamine enantiomers would need to counteract the other's ill effects.

Disclaimer: although I am a medical doctor, and my first University degree was in organic chemistry and biochemistry, some of this academic stuff is but a hazy memory for me.

> What you were essentially asking was would 100% of the "bad" enantiomer be significantly worse than a 50/50 mixture.

I literally said:

> The effects profile of racemic amphetamine is markedly different and much easier to handle physiologically than just dextroamphetamine by itself

I did answer the question... exactly as OP asked.

> For there to be a significant difference in this case one of the ketamine enantiomers would need to counteract the other's ill effects.

This is precisely the case with amphetamine, where levoamphetamine is more relaxing and subtle and dextroamphetamine is much more physiologically demanding. A racemic mixture provides the perfect combination of effects whereas just dextroamphetamine by itself can be pretty rough on you.

The difference in effect can be quite profound and drastically change your mood and behavior. I would know because I was force fed large amounts of amphetamines for my entire childhood. Name it and I've been prescribed to it.

So a double strength dose of the racemic mixture has a much milder effect than a single strength dose of the strong enantiomer?

> So a double strength dose of the racemic mixture has a much milder effect than a single strength dose of the strong enantiomer?

Is that the angle here? I thought we were comparing the total mass of each substance. OP asked about noticeable differences, not paradoxical effects. 25mg of dextro is obviously going to have a weaker overall effect than 50mg of racemic amp.

But that's not what OP asked and it's not the context. The context is whether esketamine and racemic ketamine could provide a noticeably different experience. And the answer is yes. Just like amphetamine, the ketamine isomers have similar pharmacokinetic properties but not necessarily similarly pharmacodynamic properties.

You do realise we can prescribe whatever dose we like, right? Some drugs I prescribe in grams, some in milligrams and some in micrograms. The strength of a drug is somewhat irrelevant. I'm not going to prescribe a new and expensive drug just because the dose is 150mg when it's well-established, cheap cousin is available that happens to need a dose of 300mg.

It certainly is the context, and I believe it's what OP asked. If it wasn't, it should be, because it's the only question that really matters to me as the prescriber.

If what you're saying about the different pharmacodynamics is true (and this is actually what I'm talking about. I only mentioned milder effect because that seemed to be the difference in pharmacodynamics you were getting at), then this is an important difference. It would still have to somehow be quite different to the effect of the racemic version at any arbitrary dose to be preferentially prescribed.

> You do realise we can prescribe whatever dose we like, right? Some drugs I prescribe in grams, some in milligrams and some in micrograms. The strength of a drug is somewhat irrelevant. I'm not going to prescribe a new and expensive drug just because the dose is 150mg when it's well-established, cheap cousin is available that happens to need a dose of 300mg.

I've no wish to argue here, but I am confused about how this has anything to do with it. No one brought up the idea that the doses would be different. We're talking equivalent doses of either an enantiopure or racemic substance.

> It would still have to somehow be quite different to the effect of the racemic version at any arbitrary dose to be preferentially prescribed.

Like I said, we don't know this about ketamine, thus the trials. But we do know this about amphetamine. You would simply have to experience each enantiomer and the racemic mixture in order to understand what I am saying here. The effects are markedly different. My analogy was coffee vs meth.

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