Does Dextromethorphan have Alpha Adrenergic activity?

[X11400]

I've always wondered what the exact cause of Dextromethorphan's autonomic CNS stimulatory effects were (especially at low doses) was. I have noticed that it consistently made my heart beat stronger like amphetamines do and I also remember the dangers of combining Dxm with stimulants. This also lead me to question if whether dxm Also has Beta Adrenergic binding because it dialates the blood vessels (along with other dissociatives). Does any one have any empirically aquired data on the full receptor affinity for Dxm in the human body?

 

[Kaleida]

Dextromethorphan is a well-known norepinephrine reuptake inhibitor, so at least indirectly yes it does.

 

[X11400]

Dextromethorphan is a well-known norepinephrine reuptake inhibitor, so at least indirectly yes it does.

I was specifically asking about possible Adrenergic activity, because I tend to not find to much pharmacological information about dxm other than its SNRI and NMDAr binding. Perhaps I should keep looking. Also here's what I found pertaining to the cause of vasodilation with regards to ketamine. https://www.ncbi.nlm.nih.gov/m/pubmed/19352184/

 

[X11400]

Also to add, the reason why I keep pushing this question is because IME, the cardiovascular effects are similar or directly identical to Psychedellics(which are well known Alpha Adrenergic agonists ) and amphetamines ( which are close chemical relatives to adrenaline or even include adrenaline)

 

[Cotcha Yankinov]

While DXM and metabolites are norepinephrine reuptake inhibitors, the NMDA antagonism of DXO tends to inhibit GABA interneurons which would normally exert an inhibitory tone over monoamine emitting neurons.

The NMDA receptors provide excitatory input onto the GABA interneurons (turning them on and causing them to release GABA) - the GABA then binds downstream to inhibit various neurons, including dopamine/norepinephrine/serotonin neurons.

When you block the NMDA receptors that are turning on the GABA cells, you turn off the GABA neurons, downstream GABA release decreases and aforementioned GABA exerts less of an inhibitory tone on monoamine emitting cells, which begin to emit more NE/DA/5-HT. This could partially explain the various effects on vasculature/autonomic function

 

[Kaleida]

I was specifically asking about possible Adrenergic activity

Being a norepinephrine reuptake inhibitor means that it does have adrenergic activity.

 

[X11400]

Being a norepinephrine reuptake inhibitor means that it does have adrenergic activity.

Okay yes I know that, however a drug can be a snri and still have alpha a2 binding. I also found out in my research that Pcp and Ketamine both have alpha Adrenergic activity. Regardless of if the norepinephrine releasing effects are the only cause of the cardiovascular stimulation, Yakinov's post (if he's right which is likely because I seen that information before) just lets us know that the pharmacology of Dissociatives is more complex than simply saying that the NRI effects are the only cause of the cardiovascular effects.

 

[X11400]

Being a norepinephrine reuptake inhibitor means that it does have adrenergic activity.

Hey Kaleida, I finally found it. The link I'm posting is some detailed information regarding the pharmacology and receptor binding of dxm. Just scroll down to #3.
http://www.sciencedirect.com/science/article/pii/S0163725816300560

 

[Cotcha Yankinov]

I'm not entirely convinced direct binding to a2 plays much of a role in DXM's effects, however the NRI effects and inhibition of inhibitory interneurons should be synergistic and create high synaptic NE levels, other monoamines aside

Mind us that the brain can still release its own stress hormones endogenously, such release could be encouraged via activity at a plethora of targets

 

[X11400]

I'm not entirely convinced direct binding to a2 plays much of a role in DXM's effects, however the NRI effects and inhibition of inhibitory interneurons should be synergistic and create high synaptic NE levels, other monoamines aside

Mind us that the brain can still release its own stress hormones endogenously, such release could be encouraged via activity at a plethora of targets

So you're saying that it's impossible for a chemical with a phenethylamine to have Adrenergic activity?

 

[Cotcha Yankinov]

I think the emphasis should always be on what effects of a drug are appreciable - many drugs are very promiscuous and bind to many targets. The important question is figuring out which targets actually produce the desirable effects of a drug.

As Kaleida has pointed out there is certainly appreciable NRI, and NMDA antagonism is known to induce release of monoamines which could act synergystically to produce stimulation.

Between the reuptake inhibition properties and NMDA antagonism properties, I think there is a sufficient explanation of the stimulating effects and we don't necessarily need to invoke agonist actions at adrenergic receptors to explain the stimulating effects.

Regarding table 1 of the paper you posted (http://www.sciencedirect.com/science/article/pii/S0163725816300560#t0005)

It looks like action at alpha adrenergic receptors by DXM/DXO isn't very appreciable, and the measurement of 60% inhibition at 1000nM could even be a little bit off (depending on whether an antagonist or agonist radioligand is used, measured affinities can vary, and lord knows there are plenty of issues with radioligand binding studies).

That is also just affinity - which has little to say on the matter of the intrinsic efficacy of a ligand, meaning that some ligands can bind with very high affinity to a receptor but they'll just block it and won't activate it (antagonists). So they would have to do some sort of functional assay to determine that DXM and friends are actually acting as agonists/antagonists at a2 receptors

Which brings us to another matter with a2 though - a2 receptors are actually mostly presynaptic autoreceptors that act to homeostatically inhibit the release of NE/5-HT when activated. There are some post-synaptic receptors, but for the most part when somebody takes something like clonidine (a2 agonist) they are going to be the exact opposite of stimulated.

DXM would need to be an antagonist at a2 in order for that to contribute to its stimulating properties, and by all accounts yohimbine et cetera is not very enjoyable.

 

[X11400]

I think the emphasis should always be on what effects of a drug are appreciable - many drugs are very promiscuous and bind to many targets. The important question is figuring out which targets actually produce the desirable effects of a drug.

As Kaleida has pointed out there is certainly appreciable NRI, and NMDA antagonism is known to induce release of monoamines which could act synergystically to produce stimulation.

Between the reuptake inhibition properties and NMDA antagonism properties, I think there is a sufficient explanation of the stimulating effects and we don't necessarily need to invoke agonist actions at adrenergic receptors to explain the stimulating effects.

Regarding table 1 of the paper you posted (http://www.sciencedirect.com/science/article/pii/S0163725816300560#t0005)

It looks like action at alpha adrenergic receptors by DXM/DXO isn't very appreciable, and the measurement of 60% inhibition at 1000nM could even be a little bit off (depending on whether an antagonist or agonist radioligand is used, measured affinities can vary, and lord knows there are plenty of issues with radioligand binding studies).

That is also just affinity - which has little to say on the matter of the intrinsic efficacy of a ligand, meaning that some ligands can bind with very high affinity to a receptor but they'll just block it and won't activate it (antagonists). So they would have to do some sort of functional assay to determine that DXM and friends are actually acting as agonists/antagonists at a2 receptors

Which brings us to another matter with a2 though - a2 receptors are actually mostly presynaptic autoreceptors that act to homeostatically inhibit the release of NE/5-HT when activated. There are some post-synaptic receptors, but for the most part when somebody takes something like clonidine (a2 agonist) they are going to be the exact opposite of stimulated.

DXM would need to be an antagonist at a2 in order for that to contribute to its stimulating properties, and by all accounts yohimbine et cetera is not very enjoyable.

I'm confused, why would I assume that the receptor binding is antagonism as opposed to agonism where the effects correspond with agonism? You're confusing me with your contradictory information, and it very well may be due to my ignorance, but the statement regarding Alpha a2 Adrenergic agonism is kind of fishy when you also consider that amphetamines bind to the same receptor that you claim causes "the exact opposite of stimulation" I'm also curious as to how you expect to disprove multiple sources coming to the same conclusion of dxm having Adrenergic effects.

 

[Cotcha Yankinov]

I'm confused, why would I assume that the receptor binding is antagonism as opposed to agonism where the effects correspond with agonism?

Its important to note that the a2 receptors are inhibitory pre-synaptic autoreceptors.

When an agonist binds to an autoreceptors expressed pre-synaptically (on the part of the neuron that releases transmitters) it acts to tone down the cells activity, through inhibiting cell firing or preventing vesicle fusion with the cell membrane.

When an agonist binds to a2 autoreceptors, it decreases the release of neurotransmitters emitted by that cell. See for example clonidine (a sedative a2 agonist) vs. yohimbine (the exact opposite, and by the reports I've heard, hardly enjoyable)

Thus a2 agonism typically results in decreased NE/5-HT release. As I've said there are some a2 receptors expressed post-synaptically where they can effect e.g. pyramidal cells in the PFC but the net effect of clonidine seems to always be sedation.

You're confusing me with your contradictory information, and it very well may be due to my ignorance, but the statement regarding Alpha a2 Adrenergic agonism is kind of fishy when you also consider that amphetamines bind to the same receptor that you claim causes "the exact opposite of stimulation" I'm also curious as to how you expect to disprove multiple sources coming to the same conclusion of dxm having Adrenergic effects.

Releasing agents like amphetamine can have various targets but I wouldn't tunnel vision on stuff that isn't related to their releasing agent/reuptake inhibition actions as those seem to be overwhelmingly more important. An exception here is stuff like MDA with its appreciable 5-HT2A agonism.

I'm not disagreeing with the fact that DXM has adrenergic effects - I'm saying that the adrenergic/stimulating effects can be explained with reuptake inhibition and NMDA antagonism, and that the radioligand studies seem to suggest that DXM's direct agonist/antagonist activity at NE receptors isn't too appreciable.