Is Peat Wrong About LSD? Or Just Too Vague? Antagonism Vs Agonism

[energyandstruct]

This is something that's been bugging me about Ray's work for a little while. He claims that LSD is "approximately" a serotonin receptor antagonist.
To start with, the claim seems very broad, given how many different subtypes of serotonin receptors there are.
And its a claim that he doesn't cite, but seems central to a portion of his argument. Although the stuff about excess serotonin causing learned helplessness would stand, he is claiming (and I would agree, based on experience) that LSD and related substances cause creativity, vibrant health, and play, and then he is connecting that to serotonin antagonism.
If LSD is not generally an agonist, I don't understand why serotonin antagonists like trazodone and seroquel are generally the strongest ways to block its effects (more so than general sedatives).
[devils advocate: this could possibly be explained simply by their antihistaminic effect being sedating and possibly having weaker efficacy so that they don't have similar effects to psychedelics but block them by binding at same receptors]
I guess this could be explained by competitive binding, but then one would expect the trazodone or seroquel to have similar effects to LSD, unless they had lower efficacy. I guess some of this all goes back to ray's critique of transmitter receptor models, which I don't quite understand. i'm trying to read too much at once while sick and kinda frying my brain, but discovering these theories that say "everything you know is wrong" is a little destabilizing and I feel like I need to continue to inquire deeper...
I can't find good info that elaborates at which subtypes of receptors LSD is an agonist and/or antagonist. I would guess this would vary from tryptamines to phenethylamines, but LSD has characteristics of both, and ray chose it as an example.
One thing that seems to suggest ray is right is that LSD seems to differ strongly from more toxic serotonin releasers like mdma...

 

[energyandstruct]

Is there any Clear Evidence on whether LSD is an agonist or antagonist at Serotonin Receptors? • r/AskDrugNerds

well this thread blew up on reddit

 

[energyandstruct]

@haidut I would be interested in your thoughts on this

 

[energyandstruct]

Oh i forgot to put the source of peat's claim: Serotonin, depression, and aggression - The problem of brain energy.

that article, just command F "LSD"

 

[energyandstruct]

http://onlinelibrary.wiley.com/stor...al&s=801022a86f9f57ee4749c32ed71595970b7f3e51

relevant

 

[energyandstruct]

Functional Selectivity of Hallucinogenic Phenethylamine and Phenylisopropylamine Derivatives at Human 5-Hydroxytryptamine (5-HT)2A and 5-HT2C Receptors

also relevant

 

[Tarmander]

One thing you could perhaps look at is the action of substances derived from LSD, like Lisuride, which really strongly agonizes dopamine. I think there are other substances as well derived from LSD, but I do not know them very well.

 

[energyandstruct]

One thing you could perhaps look at is the action of substances derived from LSD, like Lisuride, which really strongly agonizes dopamine. I think there are other substances as well derived from LSD, but I do not know them very well.

LSD is dopaminergic, and i think its even recognized by mainstream science that it is. this is a way it differs from tryptamines if i recall. doesn't mean it cant be serotonergic tho

 

[Such_Saturation]

Something that blocks LSD could just be a weaker antagonist than LSD

 

[energyandstruct]

Something that blocks LSD could just be a weaker antagonist than LSD

did i not say this? I feel like i said this as a devils advocate position, maybe only on the reddit post. it could have stronger binding affinity but weaker efficacy. also antagonism vs agonism CAN be dose-dependent


nevertheless i believe there are studies that show agonism from lsd at some serotonin receptor subtypes

 

[Tarmander]

LSD is dopaminergic, and i think its even recognized by mainstream science that it is. this is a way it differs from tryptamines if i recall. doesn't mean it cant be serotonergic tho

HAve you looked at Lisuride and those other compounds serotonin receptor activity?

 

[Such_Saturation]

did i not say this? I feel like i said this as a devils advocate position, maybe only on the reddit post. it could have stronger binding affinity but weaker efficacy. also antagonism vs agonism CAN be dose-dependent


nevertheless i believe there are studies that show agonism from lsd at some serotonin receptor subtypes

but you forgot to add the meme image

 

[energyandstruct]

but you forgot to add the meme image

yr right... its a good one

 

[energyandstruct]

HAve you looked at Lisuride and those other compounds serotonin receptor activity?

not yet, i kind of exhausted myself articulating all this so far... it takes a lot of energy to even write... i may need to try some pregnenolone or adrenal glandulars today

 

[energyandstruct]

not yet, i kind of exhausted myself articulating all this so far... it takes a lot of energy to even write... i may need to try some pregnenolone or adrenal glandulars today

i feel like i don't have the energy to manage all aspects of my treatment and need to trust a doctor, but nothing's helped so far, and my naturopath tried to get me to take licorice and iron, which ray advises against

 

[Kartoffel]

If LSD is not generally an agonist, I don't understand why serotonin antagonists like trazodone and seroquel are generally the strongest ways to block its effects (more so than general sedatives).

I think that the lock-and-key-thinking is preventing you from coming to any meaningful conclusions. Administration of some 5-HT2 antagonists do not decrease the effects of LSD, as you would expect if LSD was a serotonin agonist. Activation of 5-HT2 receptors seems to cause serotonin to have an excitatory effect on some neurons, and injection of serotonin into the brain causes a drastic decrease in ATP. LSD prevents this action, thus having an antagonistic effect on the 5-HT2 serotonin system. The proteins that are called serotonin or dopamine receptors can be many other things and interact with all kinds of substances. Things like LSD, serotonin, and dopamine all have affinities for several protein "receptors" and thereby "compete" in several ways.
I think the simple observations that supplementation with LSD and serotonin have effects that are exactely opposite should be enough evidence to answer the question whether LSD is an antagonist of serotonin.

 

[energyandstruct]

I think that the lock-and-key-thinking is preventing you from coming to any meaningful conclusions. Administration of some 5-HT2 antagonists do not decrease the effects of LSD, as you would expect if LSD was a serotonin agonist. Activation of 5-HT2 receptors seems to cause serotonin to have an excitatory effect on some neurons, and injection of serotonin into the brain causes a drastic decrease in ATP. LSD prevents this action, thus having an antagonistic effect on the 5-HT2 serotonin system. The proteins that are called serotonin or dopamine receptors can be many other things and interact with all kinds of substances. Things like LSD, serotonin, and dopamine all have affinities for several protein "receptors" and thereby "compete" in several ways.
I think the simple observations that supplementation with LSD and serotonin have effects that are exactely opposite should be enough evidence to answer the question whether LSD is an antagonist of serotonin.

which 5ht2 antagonists don't decrease the effect?

you are probably right.. I am just too tired to comprehend in full rn... when I increase my energy state somehow I will return to this thread, I feel it is an interesting problem and is a microcosm of my misunderstandings of ray's work

 

[energyandstruct]

I think that the lock-and-key-thinking is preventing you from coming to any meaningful conclusions. Administration of some 5-HT2 antagonists do not decrease the effects of LSD, as you would expect if LSD was a serotonin agonist. Activation of 5-HT2 receptors seems to cause serotonin to have an excitatory effect on some neurons, and injection of serotonin into the brain causes a drastic decrease in ATP. LSD prevents this action, thus having an antagonistic effect on the 5-HT2 serotonin system. The proteins that are called serotonin or dopamine receptors can be many other things and interact with all kinds of substances. Things like LSD, serotonin, and dopamine all have affinities for several protein "receptors" and thereby "compete" in several ways.
I think the simple observations that supplementation with LSD and serotonin have effects that are exactely opposite should be enough evidence to answer the question whether LSD is an antagonist of serotonin.

well i really feel that serotonin antagonists like trazodone or mirtazapine feel not that great and don't feel subjectively like lsd... although that might be partially because of the antihistamine effect... ARe there pure serotonin antagonists that aren't antihistamines??

 

[Kartoffel]

Also, I think the theory (as I understand it) about how serotonin agonists and antagonists work is really confusing. Both theories describe an agonist and an antagonist as a substance that binds to serotonin receptors. The only difference is that an agonist is said to "activate" the receptor and therby increase the action of serotonin, while an antagonist is said to "block" the receptor and therby decrease the action serotonin. I think this vague and mechanistic concepts contributes to the confusion about whether something is an agonist or antagonist of serotonin.

 

[energyandstruct]

Also, I think the theory (as I understand it) about how serotonin agonists and antagonists works is really confusing. Both theories describe an agonist and an antagonist as a substance that binds to serotonin receptors. The only difference is that an agonist is said to "activate" the receptor and therby increase the action of serotonin, while an antagonist is said to "block" the receptor and therby decrease the action serotonin. I think this vague and mechanistic concepts contributes to the confusion about whether something is an agonist or antagonist of serotonin.

right but peat was vague too and there are many subtypes of serotonin receptors that do diff. things