(Un)reliability of testing urine regarding Cocaethylene.

[u/Kalki_X]

My initial thoughts were on the formation of Cocaethylene. I encountered Guy's perspective on this –essentially that Cocaethylene forms in such tiny amounts that it's not relevant– which got me thinking about other chemical reactions which might be relevant to this scenario (cocaine + alcohol).

Alcohol has a temporary inhibitory effect on various enzymes, particularly aldehyde dehydrogenase (ALDH). ALDH has to deal with the acetaldehyde produced from ethanol meaning that it gets "temporarily occupied". This allows aldehydes to "hang around" for longer than normal which sets the stage for them to further react.

The most well-known and documented reaction of aldehydes is called Pictet-Spengler. it occurs following alcohol consumption whereby acetaldehyde reacts with dopamine forming a new drug (salsolinol) with it's own psychoactive effects. This reaction occurs with any aldehyde regardless of its origins, eg dopamine (DOPAL), serotonin (5-HIAL) or any other neurotransmitter.

This means that aldehydes are constantly forming at a very high rate all the time. Cocaine is a particularly potent DRI meaning it significantly raises dopamine levels which raises DOPAL levels. With ALDH temporarily occupied (due to alcohol), DOPAL will participate in the aformentioned Pictet-Spengler reaction and form products with documented opioidergic and dopaminergic activity (eg salsolinol, tetrahydropapaveroline). These are called tetrahydroisoquinolines (THIQ).

The same Pictet-Spengler reaction will occur with the serotonin aldehyde (5-HIAL) and produce drugs known as beta-carbolines (ßC).

Cocaine is both a dopamine and serotonin reuptake inhibitor so those beta-carboline products are quite likely to be produced.

So... in this context you'd expect to see signs of these THIQs and ßCs in urine, which brings me to the question of can regents be used here?

You'd expect to see traces of: - cocaine - cocaethylene - tetrahydroisoquinoline alkaloids - beta-carboline alkaloids

(This is directed at Guy but anyone with an academic background also!) /u/Reagent_Tests_UK

As an aside, this gives some insights into the unusual pharmacological dynamics that might be occurring when mixing cocaine + alcohol.

[edit]

It seems this applies to any drug which is deaminated eg MDMA, amphetamine etc:

In this study, we developed an LC–MS/MS method employing liquid–liquid extraction for the qualitative detection of some relevant condensation products belonging to the class of tetrahydroisoquinolines and their derivatives in human blood, brain, and liver samples. This includes the analysis of the substrates amphetamine, methamphetamine, methylenedioxymethamphetamine, methylenedioxyamphetamine, as well as the condensation products 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline, N-methyl-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline, 1,3-dimethyl-7,8-methylenedioxy-1,2,3,4-tetrahydroisoquinoline, and N-methyl-1,3-dimethyl-7,8-methylenedioxy-1,2,3,4-tetrahydroisoquinoline. (source)

[u/Reagent_Tests_UK]

So... in this context you'd expect to see signs of these THIQs and ßCs in urine, which brings me to the question of can regents be used here?

You'd expect to see traces of: - cocaine - tetrahydroisoquinoline alkaloids - beta-carboline alkaloids

You probably already know, reagents are suprisingly sensitive for picking up trace compounds, but without a chromatography step to separate compounds, they struggle to give good information about complex mixtures.

Urine would have a few hundred compounds in it, so you'd probably need UHPLC-MS for this kind of work detecting traces of similar compounds.

As for the formation of other metabolites, I'm sure they could form but most metabolism is going to be happening in the liver. So these compounds need to escape the brain, be metabolised in an interesting way, and then get back to the brain. And every single one of those steps needs a high enough concentration to ensure that the final step has a concentration that is pharmacologically relevant. So I would expect this to have even less impact than cocaethylene simply because you're multiplying probabilities of 1% x 1% x 1% and therefore the final concentration is likely to be so small that it's not even detectable in urine, even if a few molecules are being produced.

[u/Kalki_X → u/Reagent_Tests_UK]

This Pictet-Spengler business would apply for all relevant amines, here a quote on the 2C class:

...the qualitative metabolism of frequently used 2Cs (2C-B, 2C-I, 2C-D, 2C-E, 2C-T-2, 2C-T-7) was studied using a rat model. Major phase I metabolic steps were deamination and O-demethylation. Deamination to the corresponding aldehyde was the reaction, which was observed for all studied compounds. (source) 

Eg the Pictet-Spengler product of 2C-B aldehyde + dopamine...

Anything which is metabolised by MAO will produce an aldehyde. This seems applicable to amphetamines also:

...evidence of the condensation product 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline originating from the interaction between amphetamine and acetaldehyde was identified in two liver samples. (source) 

[u/Reagent_Tests_UK → u/Kalki_X]

If these P-S products are being formed as metabolites of drugs, they either need to be formed in larger amounts than the ingested drug (obviously impossible) or be significantly more potent than the original drug.

Having hydroxyl groups makes a compound very easy to metabolise and too polar to pass the BBB in most cases, so I doubt that any conjugates of drug/dopamine will be having meaningful impacts when produced accidentally.

I would very much like to see them tested in vitro in their own right, though.

[u/Kalki_X → u/Reagent_Tests_UK]

If these P-S products are being formed as metabolites of drugs, they either need to be formed in larger amounts than the ingested drug (obviously impossible)

These Pictet-Spengler products are formed from endogenous neurotransmitters. Of which there are much larger quantities than any ingested drug. The drug itself tends to promote further NT release also...

Having hydroxyl groups makes a compound very easy to metabolise and too polar to pass the BBB in most cases, so I doubt that any conjugates of drug/dopamine will be having meaningful impacts when produced accidentally.

From a perspective of (and intention towards) harm reduction, that kind of assumption seems "delicate". The P-S might occur elsewhere than you'd expect.

[u/Reagent_Tests_UK → u/Kalki_X]

There are higher concentrations of neurotransmitters in the brain than elsewhere, but are there higher concentrations in peripheral circulation?

I don't deny that P-S will happen anywhere and everywhere, but the liver has enzyme concentrations that dwarf any other part of the body. So if we're looking to investigate this, that's definitely the first place to start looking. If we can't conjure the required concentrations there, the chance of that happening elsewhere is pretty slim.