Contra Dynomight contra me, but also kinda contra me and in support of Dynomight, on Diet Coke
It's probably the phenethylamine
In case you’ve been living under a rock, there’s an ongoing intellectual skirmish over whether Diet Coke is a (cognitive) performance enhancing drug. I’m pretty sure I threw the first punch with this series of Tweets:
To be clear, I was never making the claim that there is a simple causal chain leading from “drinking Diet Coke” to “high cognitive performance,” but rather that this dopaminergic phenomenon had some important role to play in the explanation of, well, things like this:
But my glory was short-lived. A few days ago, fellow and much more prolific Substacker Dynomight (whom you should definitely subscribe to), wrote a great red team of my cute little theory. I’ll quote his conclusion in full:
When I started looking into this, I thought this was a fun theory that would collapse after a light breeze of investigation. I don’t think that’s happened. Certainly, most evidence is against the theory. But it could be true if:
allometric scaling is a better model than linear scaling for aspartame, and
people are drinking like 12 cans of Diet Coke a day, and
the limited tests that were done for cognitive benefits on humans missed a real effect, and
at least one of
the tiny increase in dopamine in rats is real, plus humans respond even more strongly, or
the effect is coming from reduced tryptophan levels, or
the effect is coming from something else completely.
Is this likely? Nah. I’d bet against it at 10:1 odds, maybe higher. But I’m surprised it wasn’t possible to totally rule it out.
(Diet Cokes consumed while writing this: 5)
Much of this skepticism from the fact that a bunch of studies find little to no effect of phenylalanine or similar amino acids on dopamine or cognitive performance. From that post:
What about real experiments? Here’s a summary of all the papers I could find:
Fernstrom et al. (1983) fed massive amounts of aspartame (200 mg/kg) to rats and dissected their brains. They found this increased phenylalanine and tyrosine, decreased tryptophan, and maybe caused a tiny increase in dopamine.
How much is 200 mg/kg? Well, in a 70 kg human, that would be 76 cans of Diet Coke. But you might believe in allometric scaling—the extremely controversial idea that you should scale doses according to body surface area. In that case, 200 mg/kg would only correspond to 12 Diet Cokes.
Reihmerr et al. (1986) did a non-blinded trial, giving tons of tyrosine to 12 adults with attention deficit disorder for 8 weeks. They saw some improvement in a few of them after a few weeks, but none at the end of the trial. They conclude that tyrosine “is not useful in attention deficit disorder, residual type”
Miler et al. (1986) took slices from rat brains, exposed them to phenylalanine and/or tyrosine, and checked if this changed the amount of dopamine neurons release. I find this paper sort of incomprehensible, but the conclusion seems to be that phenylalanine sometimes slightly increased dopamine release and sometimes slightly decreased it but nothing was really significant. Also, the careful reader will note subtle differences between “slices of rat brain with controlled amino acid levels in buffer” and “human billionaire drinking diet soda”.
During et al. (1988) took anesthetized rats and injected their brains with amounts of phenylalanine ranging from huge (200 mg/kg) to planetary (1000 mg/kg). They found that the merely huge dose majorly increased levels of dopamine, while the larger doses either did nothing or actually decreased dopamine.
Now, 200 mg/kg of phenylalanine in rats corresponds to 135.5 Diet Cokes in a 70 kg human, or 22 Diet Cokes if you believe in allometric scaling. But this isn’t a fair comparison at all since you don’t (please) inject Diet Coke into your brain. When consumed orally much of the phenylalanine is converted to tyrosine or doesn’t go to the brain at all.
Bergwerff et al. (2016) examined the blood and urine of 83 children with ADHD, looking for abnormalities in phenylalanine, tyrosine, and tryptophan. They found none.
Miura et al. (2021) gave 30 adult Japanese men doses of phenylalanine ranging from 3 g/day (29 Diet Cokes) to 12 g/day (116 Diet Cokes) for 4 weeks. They tested blood levels for a million things (liver enzymes, protein, cholesterol, triglycerides, minerals, blood cells, glucose, amino acids). Nothing was statistically significant except a small increase in chloride and tyrosine. They also looked at sleep quality and mental fatigue, and again saw no significant effect.
I was wrong :/ (sorta)
Cool, I think all this is decent enough evidence that the “phenylalanine increases dopamine” theory is at least missing something important.
Before I go any further, let me acknowledge that modifying a theory post-hoc—which I am about to shamelessly do—is generally considered a bad epistemic look. But I don’t think doing this is damning or wholly inexcusable, especially if Theory 2.0 seems legitimately more compelling than version 1.
So, without further ado, I present Diet Coke as PED 2.0:
It’s the phenethylamine, not the dopamine
In short, I now think it’s more likely (though still very far from certain) that the isolated phenylalanine present in Diet Coke leads to improved mood, focus, mental energy, and concentration by causally increasing phenethylamine (abbreviated “PEA,” sometimes spelled “phenylethylamine,” and not to be confused with “phenylalanine”) synthesis.
Long story short, this makes more sense for two reasons:
There’s an enzyme that limits how quickly phenylalanine can turn into dopamine, but (as far as I can tell) no such “rate limiting” enzyme exists as a bottleneck to PEA production.
As with dopamine, there’s good evidence that PEA is important for cognition. Unlike with dopamine, however, there’s also good evidence that:
PEA levels are robustly correlated with measures of executive function.
The drugs taken by ADHD patients (namely, amphetamine/Adderall and methylphenidate/Ritalin) causally increase PEA levels.
I’ll elaborate just a bit on each:
1) No enzymatic speed limit (it seems)
As any semi-literate r/nootropics browser with half a brain cell can tell you, the pathway from phenylalanine (or tyrosine) to dopamine in the brain looks like this:
All those polysyllabic terms in red are the enzymes which “do” the conversion, and these exist in limited quantities. After some threshold of (tyrosine+phenylalanine) is reached, additional supplementation won’t lead to dopamine synthesis without increased levels of tyrosine hydroxylase. This is probably at least part of the reason why weird shit doesn’t happen if you ingest even very large amounts of tyrosine.
The synthesis of the major trace amines is shown in Fig. 1. 2-Phenylethylamine (PE), p- and m-tyramine (p-TA, m-TA) are formed by the enzymatic decarboxylation of the precursor amino acids l-phenylalanine and l-tyrosine, respectively. This decarboxylation occurs by the enzyme aromatic l-amino acid decarboxylase
Or as I translate into English:
An enzyme called “decarboxylase” turns phenylalanine into phenylethylamine (PEA).
Ok, so there’s still an enzyme needed to make PEA, but is this bottleneck, so to speak, on the whole operation? While I’m (once again) far from sure, I don’t think it is not
Why? Because decarboxylase doesn’t seem to limit the creation of dopamine from l-dopa, which is why Parkinson’s patients are often given l-dopa (called “levodopa” when taken as a medication) to directly increase dopamine synthesis.1 It would be pretty weird if this enzyme was “rate-limiting” when applied to one amino acid (phenylalanine, for conversion to PEA) but not to another (l-dopa, for conversion to dopamine).
Long story short, it seems pretty plausible that ingesting isolated phenylalanine via aspartame via Diet Coke causes increased PEA synthesis.
PEA might be the (or a) reason ADHD medications work
At least to my limited understanding, PEA is kinda like the brain’s homemade Adderall (amphetamine). The two molecules are structurally very similar, and they both (to oversimplify) tell neurons to release other neurotransmitters like dopamine, norepinephrine, and glutamate.
And, unlike basically every other cognitive/mood disorder, ADHD reliably responds well to a certain class of drugs. As one review article puts it,
Stimulants [amphetamine and methylphenidate] remain the US FDA-approved medical treatment of choice for patients with ADHD and are associated with an exceptional response rate.
The same can’t be said for, say, depression or anxiety!
The point is that we have really good reason to believe that stimulant medications can increase cognitive aptitudes like executive function, even in the long term, at least for people with ADHD.
As I gestured to above, there is robust evidence that people with ADHD have lower levels of phenethylamine (as proxied by urinary PEA), and that urinary PEA normalizes after treatment with stimulants. And, as far as I can tell, urinary PEA doesn’t increase in response to taking random shit like blueberry extract or curcumin either. This isn’t proof that PEA is responsible for the effects of Adderall and Ritalin, but it’s a few points in PEA’s favor.
Oh, and while most urinary neurotransmitter testing is probably useless, you can buy an OTC kit like this one that tests for PEA for around $150. Not a doctor, etc., etc…
The study I’d like to see
To test my hypothesis, I think I’d run something like the following:
40 subjects fast for, say, 12 hours, and all drink the same amount of water during this time.
At t=0, measure everyone’s urinary PEA concentration.
10 subjects are each assigned to the following test arms, corresponding to what they ingest after the t=0 test:
Placebo + 1 cup water
200mg phenylalanine (~2 Diet Coke’s worth) + 1 cup water
1g phenylalanine (normal supplement dose) + 1 cup water
37g whey protein (which contains ~1g phenylalanine) + 1 cup water
At some reasonable time after ingestion (maybe t=2 hours?), all 40 subjects test urinary PEA again.
Primary endpoint would be mean change in urinary PEA concentration.
That’s right, I’m preregistering a study that doesn’t even exist. Take that, p-hackers.
If this new theory is correct, I’d expect to see the 200mg phenylalanine group show a greater increase in PEA than the placebo and whey groups, and the 1g group to display the greatest increase of all.
Of course, urinary PEA doesn’t matter in and of itself. However, it’s cheap, easy, and objective to test for, and seems pretty good at predicting ADHD medication outcomes, so I’ll take it as a proxy for something like “improved executive function.”
I started off with a 50% credence that the “phenylalanine→dopamine” theory was right, and I think doing a post-hoc modification should knock a few percentage points off, all else equal. And, in hindsight, that 50% seems too high even ex ante.
On the object level, though, this theory has a fair amount going for it, and certainly more than the old dopamine version.
So, all in all…
I think a better ex ante credence in the dopamine version was 35%.
I’ll knock off 10 percentage points for making the post-hoc adjustment, which puts it at 25%
I have no idea if this is a good Bayesian thing to do, just going off of vibes here.
But this theory seems to fit the evidence (i.e., what we know about the world) much better. Intuitively, it seems like it should be do 1.5-2 times better than the 25% figure. And (once again going off of vibes), I’ll put my new credence at 40%.
Diet Cokes consumed while writing this blog post: 0.5.2
Note: yes, you *can* buy and ingest l-dopa, but this is probably pretty dangerous and a really bad idea for reasons I’m not going to explore here. Don’t do it.
Don’t worry, I’m a slow writer.