Determining the golden ratio of ketamine stereoisomers

What if you created ketamine with ‘Adderall’ 3:1 proportion of stereoisomers?

Ketamine is the drug that, in smaller doses, slows down time, makes the world around you more viscous, and makes you kind of "drunk" in a way that's not entirely dissimilar to alcohol. And in larger doses it pretty much completely disconnects you from reality, gets you to float in a nowhere-land without any sense of the body while your mind is rearranging emotional memories. If you are lucky perhaps you also dissolve in a universal consciousness and meet god. When you come down your mood typically improves for the next few days at least. 

The post-trip mood enhancing effect is so strong that ketamine is officially used as an instant antidepressant for a treatment-resistant depression. Ketamine has been used for anesthesia for ages, but not long ago, in 2019, big Pharma ended up patented ketamine under the name esketamine. But why is it called esketamine? 

It turns out that answering this question can help us answer another question: could ketamine be better? Is ketamine all it could be? What would it take to make a better, shinier, and more effective type of ketamine? 

Esketamine stands for S-ketamine.

Ketamine, like many other drugs, has stereoisomers: different "versions" of it, with different orientations in physical space. Two to be exact: S-ketamine and R-ketamine. If you only care about which atoms are connected with which then they have the same structure. However, they are mirror images, like the left and right hands. 

For drugs the shape of their molecules matters because they are like little 3D gears you throw into the complex micro machinery of the human brain. Imagine a lock with an asymmetric key. If you mirrored the key, it might no longer produce the desired result of opening the lock. And much like that, stereoisomers can have drastically different effects.

As well, if you take the stereoisomers in combination, they can complement each other.

Amphetamines and Adderall

One of the most prominent examples of a drug with drastically different stereoisomers is methamphetamine. Dextromethamphetamine (aka S-methamphetamine) is a fun stimulant that gets people high, thus it’s heavily controlled (and not entirely banned: sometimes used to treat ADHD). Whereas levomethamphetamine (aka R-methamphetamine) is unfun to such a degree that it’s sold as an over-the-counter nasal decongestant. This is why Mr Walter White goes on an angry rant: “and if our reduction isn’t stereospecific how can our product be enantiomerically pure”. My sorry ADHD ass needs Walter's product to watch the series, otherwise my attention is too scattered to watch one-hour long episodes. But from watching this clip, it seems like, being a conscientious drug manufacturer, he only wants isolated dextromethamphetamine without any levo- in it.

A similar but a bit less pronounced relationship exists between stereoisomers of amphetamine. Dextroamphetamine is the more fun, powerful and useful stimulant. Levoamphetamine is the more physically stimulating one with more unpleasant side effects like jitters and anxiety. 

Normally, if you take a bunch of molecules and do some magic chemistry with them, you end up with equal amounts of D- (shortened dextro-) and L- (levo-) versions (if they are chiral, i.e. have D- and L- versions at all). This version is called a racemic mixture or racemate. So we can have D-amphetamine, L-amphetamine, and racemic amphetamine (1:1 mix of the two).

Ok great, the fun drug, the unfun side effects drug, and the fun drug with added side effects. Ez. But Big Pharma wouldn’t be Big Pharma if they didn’t overcomplicate things by producing a 3:1 mixture of D- and L- amphetamines called Adderall. The story of how they got there is a bit complicated, and involves approximately zero science: Know Your Amphetamines.

Racemic ketamine

The black market typically has two versions of ketamine available: S-ketamine and Racemic ketamine, which is a 1:1 mixture of S-ketamine and R-ketamine. (Despite somewhat similar names Racemic and R-ketamine are two different things, “Racemic” here just means an equal mix of two compounds, R-ketamine being one of them and S-Ketamine being the other).

You don’t usually find R-ketamine on its own because it’s less potent as a dissociative, so it is less recreationally useful. As with amphetamines, we have a fun isomer, and a less fun one. 

However, R-ketamine, while less fun, is a helpful additive when treating depression. That makes racemic ketamine (the 1:1 mix) more useful than straight S-ketamine. And it was already available, cheap and easily prescribable as infusion, because it’s used for anaesthesia. 

But for that very reason, Big Pharma couldn’t easily patent a new nasal formulation of racemic ketamine, so, in spite of it being arguably less helpful, in 2019, they went for S-ketamine.

But what if neither of these are the best option?

What if the default 1:1 ratio of racemic ketamine isn’t the most effective one? What if a 2:1 ratio is better? Or a 1:10? We don’t do the 1:1 ratio because it’s optimal, we just have it because it’s convenient to produce.

Time to experiment.

But before we do this, let’s talk about the difference between racemic ketamine and s-ketamine, the two existing options.

Trip difference between the racemate and S-ketamine

I have tried both, and I prefer S-ketamine out of the two. S-ketamine is certainly a more potent dissociative. It is more “psychedelic”, it more readily pulls up emotional memories from your system and makes you look at them.

S-ketamine fragments your mind and decouples the fragments from each other. Different parts of your personality and cognition feel clearly separate and compete with each other: it becomes very clear that the illusion of a single coherent mind is an illusion. Whereas racemic ketamine is much more noisy: it perturbs the mind rather than “cleanly” decoupling it. 

However, while S-ketamine can be more fun, it’s always a cold, distant and floaty kind of fun. Racemic ketamine is a much more emotionally vibrant experience due to, I think, to the same noise-producing quality. It doesn’t make you happy or okay about your circumstances, it just adds a noisy firework-y sparkly emotional glitter on top of the dissociation that gives the whole experience an emotive quality. 

S-ketamine is like letting lots of your personal stories loosely float around in a hyperspace, whereas  racemic ketamine is like finding an old VHS record of your childhood, getting surprised that it still plays, and marveling at the fancy tape-reading artifacts. 

Perhaps the worst aspect of the racemate is that trips are harder to remember. S-ketamine trips are already tricky to make sense in retrospect, and adding R-ketamine on top of this further disrupts memory formation. The racemate would probably be twice as good of a drug if not for this aspect.

Pure R-ketamine

My intuition is that one can get a sense of R-ketamine unique effects by mentally subtracting S-ketamine effects from racemate. How accurate would this be? Perhaps I’ll never know from the firsthand experience, but these replies from @cube_flipper on twitter seem to suggest that it’d be a fairly accurate.

3:1, “Adderall” ratio

The fact that the most common R-ketamine-containing formulation contains exactly 50% of it has nothing to do with psychopharmacology and has everything to do with basic chemistry: that's what you get by default if you don't separate the two stereoisomers. 

For my first experiment with a different ratio, I went with a  3:1 proportion, just like Adderall, for memetic reasons. We are doing Science™. It's easy to make it: just mix racemate and S-ketamine in equal proportions. 

Here is how the arithmetic works out: 10 mg of racemate is 5 mg of S-ketamine and 5 mg of R-ketamine, and 10 mg of S-ketamine is, well, 10 mg of S-ketamine. Hence the mixture would contain 15 mg of S- and 5 mg of R-.

To start with I measured 225 mg of S-ketamine and 225 of racemic ketamine. Note: this is a high dose, I don't recommend starting with it. I have tolerance and I am pretty used to ketamine’s effects. If you are just starting, I recommend starting with a “common” dosage range from psychonautwiki.  

I measured my dose and snorted it. And you know what? I liked it and it was about what you’d expect: the greater psychedelic depth of S-ketamine, with some of the emotional aspect of R-ketamine, but with less noise. Nice synergy between the two, but I don’t want to overstate the effect, it was still: ketamine.

The trip itself was relatively typical compared to my other ketamine trip: forgetting you have a body and floating in a soup of thoughts and memories. But the comedown, after most of the consciousness booted back, was very interesting. 

I had a much more coherent and singular sense of self than usual with S-ketamine: I typically have competing fragments of my mind overlap with each other. So I spent half of an hour contemplating how believing in yourself is a good idea and how having stronger self-beliefs is more functional. I think this contemplation had a lasting impact on my week: I seemed to make decisions more quickly, be it what task to do next or simply what sandwich to have for lunch.

Other ratios

A few days later I tried a 6:1 S:R ratio, and the results were good and as expected: enough R-ketamine warmth, more S-ketamine depth.

More experimentation would be good here. But so far it seems to me like the effect profile follows a fairly predictable dependency from the variable ratio. Perhaps it's useful to think of S-ketamine as the main drug, whose effects you can nicely tweak by adding 10-20% of R-ketamine. If you experiment with different ratios, please drop me a message on twitter or leave a comment here!

And Big Pharma CEOs, if after reading this you’re now mixing and snorting ketamine stereoisomers on your desks to find out the most lucrative one, don’t forget to pay me royalties!