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DMT salt binding efficiency in the brain

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rawmo

rawmo

Rising Star
Hey there,

does anyone know anything re binding efficiency to 5HT-2A receptors for different salts of DMT and DMT allies?

e.g. from memory -
DMT phosphate(?) [i.e. DMT with phosphoric acid] is stronger binding than other DMT salts.
or does it all become DMT past the blood/brain barrier?

basically so e.g. a table could be made up of different strengths of DMT types.
and e.g. bufotenine (Bufo citrate is lower binding apparently)

even anecdotal reports may be handy?
 
Hi rawmo,

dmt crosses the blood brain barrier (BBB) as a freebase, so if you inject/eat dmt in salt form it will be freebased in the blood before it becomes available to the brain. Note that the pH of the blood is 7.2-7.4. With dmt having a pKa of 8.68, 3.2% to 5% of the dmt in the blood will exist as a freebase. This portion will cross the BBB, then some more of the salty dmt in the blood will get freebased, cross the BBB and so on. Mechanisms that actively facilitate the absorption of dmt may also exist which will increase the rate of its absorption.

Now, in the brain dmt will form salts with whatever anions is around, phosphates, chloride, carbonate, etc etc. We have no control of the latter. In any case however, dmt is not going to interact with a receptor as a salt, but as its freebase form. One reason smoking has such a fast onset is because freebased dmt is carried freebased from the pipe to the lungs to the blood to the brain and straight onto the the receptors.

(Injection of dmt fumarate also has a fast onset, fastest than expected from the normal cycle of freebasing in the blood and BBB crossing, that's why Strassman from his studies speculated that dmt is actively transported through the BBB)
 
In some cases it is the free protonated amine that inter-acts with the receptor (no anion but the amine is protonated and thus charged). I know this is the case with phenethylamines and 5-HT2a but not sure about tryptamines. Not matter what salt a drug is taken in, this will change once in the body. If a drug has to be absorbed (it is the freebase that is absorbed. ALWAYS UNIONIZED) this occurs in the small intestine.

Once absorbed some may be reprotonated in the blood. As the freebase distributes more of the protonated form from the blood is converted to freebase, until equilibrium is reached with distribution it is until it is metabolized. The freebase is the most efficient form for distribution (pharmacokinetics) (transporters aside). Some molecules may form salts with different anions in the body, it is unlikely to stay with its original anion (pKa's and concentrations considered). Also a charged molecule dissociates from its anion in solution. Thus the net charge of the solution maybe neutral but that doesn't mean that protonated DMT has an anion bound to it in solution. Thus what salt was taken does not make a difference. It is the free protonated form that would interact with the receptor.

Additionally within a protein there can be specific pH ranges, that can alter the charge on a molecule. For example an amine may become protonated within the receptor itself. The anion technically being some amino acid residue but the protonated form exists independently of an anion.
 
I am not convinced that DMT requires a transporter especially a specific one. Freebasing or injecting a drug (or smoking a low bp drug) in most cases leads to rapid effects. We would thus have to assume that drugs like cocaine, THC, JWH-018, opiates, amphetamines, ... all have transport mechanisms. While they may they are probably then non-specific or it is just that the drugs are all lipid soluble even when protonated for enough to cross the BBB is significant quantities to induce rapid pharmacological effects. Maybe a combination of both?
 
bufoman said:
I am not convinced that DMT requires a transporter especially a specific one. Freebasing or injecting a drug (or smoking a low bp drug) in most cases leads to rapid effects. We would thus have to assume that drugs like cocaine, THC, JWH-018, opiates, amphetamines, ... all have transport mechanisms. While they may they are probably then non-specific or it is just that the drugs are all lipid soluble even when protonated for enough to cross the BBB is significant quantities to induce rapid pharmacological effects. Maybe a combination of both?
Click to expand...
That's true, thanks for pointing that out! Strassman just make a speculation about the active transportation of dmt, maybe trying to further glorify its effects in the brain I think.

Very true is also the note that protonated forms can bind to receptors, what does not happen is actually a dmt-anion complex binding to the receptor. Receptor binding sites do not usually have enough space (or favourable environment) to accommodate whole salt complexes. And in practise a ligand binding to receptor is stabilised by all sorts of interactions that may (or may not) involve local protonation of the prospective ligand.

Long story short, it's just the dmt molecule (protonated or not) that binds on the receptor(s) and exerts its effects.
 
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