Brain serotonin is very bad – alcohol to the rescue?

Young man drinking alcohol, in bad mood

What they aren’t telling you about drinking and serotonin…

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Brain serotonin is very bad – alcohol to the rescue?

Serotonin and ethanol – that is a controversial topic.

There have been many trees killed, much ink used, and endless academic squabbles over just how ethanol affects serotonin.

Recently, this topic has gained a wider audience thanks to Jordan Peterson…

While not exactly a biochemist, he is a clinical psychologist and public figure.

“Studies of the effects of acute ethanol administration on serotonin activity in healthy, non-alcohol-abusing, non-alcoholic volunteers have produced results too contradictory to summarize here.” –Peterson

This topic is extremely controversial…

So controversial that researchers can hardly agree whether or not alcohol actually increases or decreases total brain serotonin levels.

But this “paradoxical effect” of ethanol on serotonin metabolism/kinetics is a misconception.

Exactly how ethanol intake affects serotonin metabolism is actually quite clear.

The confusion stems mostly from just a few early researchers who used primitive analytical techniques, drew improper conclusions…

And they perpetuated their results with the help of others who’d only read the abstracts – re-reporting the wrong conclusions.

When scientists not only anticipate but actually expect paradoxical effects, they don’t make much effort to realistically explain anything.

It’s so much easier to just toss in the towel and say “Well… It’s so like serotonin to do that” than it is to make the effort to discover the reason for inconsistent results.

We can think of brain serotonin as the quantum mechanics of biochemistry.

“Serotonin levels in rabbit brain were reported to be decreased by single doses of ethanol in vivo… Subsequently, several groups were unable to confirm this finding in rabbit brain…or in rat brain… Other groups reported an increase in rat brain serotonin levels under the influence of ethanol and other anesthetic.” –Feldstein (1967)

So what actually occurs?

Does whole-brain serotonin actually increase or decrease?

Or is it really just like flipping a coin?

Fortunately, cause and effect still hold in our universe.

We still live in a deterministic reality, and something as simple as ethanol’s effects on serotonin can actually be reliably predicted.

Ethanol reliably decreases brain serotonin.

But in doing so, it reliably increases the sleep-promoting compound tryptophol.

The Relevant Tryptophan Metabolites

It does this by shifting the NADH∶NAD⁺ ratio (Feldstein, 1973).

(NADH and NAD⁺ are two forms of nicotinamide adenine dinucleotide – a coenzyme found in every single living cell.)

The early studies that showed this increase used the more reliable procedures of their day, performed by chemists.

The other early studies that showed the opposite were done by medical doctors using shortcut extraction techniques.

The studies purporting an increase of serotonin had been measuring serotonin and tryptophol together, which would show the apparent increase (as reported by DJ Palaić in 1971).

Effects of ethanol

For instance, the largest increase of brain serotonin (56%) was reported by Bonnycastle, a medical doctor from Yale.

Bonnycastle used the quick extraction procedure developed by Mead & Finger.

This procedure was a modification of one intended to extract both serotonin and catecholamines together in one step…

This saved time and required less specialized equipment.

“A combined extraction method (MEAD and FINGER, 1961) permits the assay of both amines in one sample, but suffers a loss in sensitivity.” –Maikel

But this method also extracts 5-hydroxytryptophan and tryptophol, among others, with no attempt made to resolve them afterwards.

And these all show up together when detected using UV light.

All Indoles Have Similar Ultraviolet Emission Spectra

Mead & Finger themselves admit that 5-hydroxytryptophan is also extracted by their procedure.

But, since this exists at very low concentrations, it can be neglected.

But tryptophol cannot be neglected.

And, at the time, scientists didn’t yet know that this occurs in the brain…

And they certainly didn’t know that ethanol predictably increases its concentration.

“It was reasonable then to assume that ethanol in man decreased 5-HIAA due to acceleration of the alternate pathway leading to 5-hydroxytryptophol and its conjugates.” –Feldstein

The better biochemists of the day all demonstrated a decrease in brain serotonin.

These people used a proper basic pH to extract the serotonin.

They followed that by a re-acidification to get it back into the water phase (separating out the tryptophol).

With the 1970s came the far more advanced high-pressure liquid chromatography technique.

This process actually physically separates each indole using a fine porous column.

Chromatographic Separation of a solution of indole derivatives on a Purospher RP-18e column

This leaves no ambiguity…

And studies using this method all show a decrease in total brain serotonin after ethanol ingestion.

If high-pressure liquid chromatography is the Cadillac of separation techniques, the Mead & Finger extraction method would be the Honda Accord.

This is consistent.

And should a person speak of “paradoxical effects” of ethanol and serotonin, you can probably take that as evidence of ignorance.

But there are a few more details to consider.

For example, free serotonin always increases.

This most likely occurs because ethanol displaces it from binding sites (Palaić, 1971).

The results are expressed as percent of 5-HT in total brain homogenate. Mean of 6-8 determinations.

But the total amount always decreases because cerebrospinal fluid flushes away the released serotonin.

More importantly, the sleep-promoting tryptophol – which is more bioactive than serotonin in many respects – increases.

This is because the same enzymes that metabolize ethanol also metabolize tryptophol…

After all, they are both alcohols.

Structures which possess the B-substituted ethoxy chain

Tryptophol is like an indole with an ethanol attached. Sometimes it is even written as indole-3-ethanol (Seed, 1978).

While the initial serotonin release can explain the feeling delivered by the first few drinks, it takes tryptophol to convincingly explain the drunken and comatose states.

This is because it’s the only tryptophan metabolite that can produce sleep when given directly.

No other indole besides tryptophol and its derivatives can do this (Seed, 1978).

Only tryptophol and 5-methoxytryptophol induces sleep; serotonin does not

Tryptophol also explains how tryptophan will lead to drowsiness even though serotonin will not.

The molecule tryptophol is the missing link… It explains ethanol’s effects and makes assumed “paradoxical results” seem perfectly straight forward.

But most scientists still fixate myopically on serotonin – just serotonin and even more serotonin.

It is tryptophol, not serotonin, that causes the reduced glucose metabolism in the brain (Cornford, 1981):

Ethanol decreases brain metabolic rate but tryptophol does so more

Both serotonin and tryptophol levels return to baseline a few hours after drinking…

So you don’t have to worry about a chronically imbalanced mind state from occasional drinking.

Here’s what alcohol causes:

(1) An increase in tryptophol

(2) A serotonin shift from the bound to the free state

(3) A slight reduction in total serotonin levels afterwards

“Ethanol in vivo in rats markedly decreased the conversion of serotonin-C¹⁴ to 5-hydroxyindoleacetic acid-C¹⁴ from 84% to 47% in liver homogenates with a concomitant increase in the formation of 5-hydroxytryptophol from 13% to 51%.” –Feldstein

But many foods will actually increase total brain serotonin concentrations by increasing the blood tryptophan ratio.

Tryptophan in the bloodstream is where all brain serotonin comes from.

The ratio of tryptophan vs its competing amino acids matters more to the process of brain uptake than total amount.

Among proteins, whey powder, soy protein isolate, and egg white do this the most powerfully.

And, perhaps surprisingly, even protein-free glucose or starch will do as much to modify brain serotonin as ethanol…

These foods all release insulin. And this hormone draws every amino acid out of the blood and into the cells.

Effects of insulin on Concentrations of Tryptophan, Other Amino Acids, and Glucose in Rat Plasma

Well, every amino acid besides albumin-bound tryptophan, which remains in the blood.

The tryptophan-enriched blood has more available tryptophan for brain uptake and serotonin synthesis.

Some proteins will increase brain serotonin, but drinking soda will do so even more.

So you have to worry just as much about what you mix with your ethanol as about the ethanol itself.

A dry martini will produce tryptophol and transiently release free serotonin.

A Rum & Coke, for example, will do the same but will also increase the tryptophan available to the brain.

It’s easier to maintain composure while drinking dry alcohol.

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Matt Cook is editor-in-chief of Daily Medical Discoveries. Matt has been a full time health researcher for 26 years. ABC News interviewed Matt on sexual health issues not long ago. Matt is widely quoted on over 1,000,000 websites. He has over 300,000 daily newsletter readers. Daily Medical Discoveries finds hidden, buried or ignored medical studies through the lens of 100 years of proven science. Matt heads up the editorial team of scientists and health researchers. Each discovery is based upon primary studies from peer reviewed science sources following the Daily Medical Discoveries 7 Step Process to ensure accuracy.
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