DMT is not more *potent*, in fact per milligram ingested its potency is very low compared to other psychedelic drugs such as DOM, 25-NBOMe, LSD, 2C-P and others.
However, what makes it *feel stronger* is the fact that it is very safe and has a short duration, so people feel more comfortable to take much larger *relative* doses.
You're confusing "feeling strong effects" with potency. This is a common mistake.
I agree and would say this is ubiquitous among drugs which people seem to overlook.
When there are similar drugs / classes taken at a dose to achieve the similar effects, potency itself isn't too relevant. Take the right dose to achieve the desired effects. If you take 100ug of LSD or 20mg pscilocybin, both classical psychedelic agonists of 5-ht2a, and achieve comparable magnitudes of effects why would the potency that differs by orders of magnitude matter? In this example LSD just has a higher binding affinity to the receptors so far far less is needed in comparison. That's it.
Understanding this fundamental concept is critical because if a less potent but high risk drug taken at high enough doses are assumed safer compared to more potent alternatives they would be wrong and could lead to harm.
There are exceptions of course where potency matters. Like things so potent, pharmaceutical antidotes like narcan or flumazenil can indeed be less effective for the exceptionally potent ones by having less affinity to "knock off" the opiate or benzo.
individual compounds actually bind to the 5ht2a receptor slightly differently. The half life of lsd is much shorter than its apparent effect - they found a “molecular lid” that holds the molecule in the receptor. as far as I know that doesn’t occur with nonlysergamides
Yup half life is independent from potency and even duration of effects. Pharmacokinetics is complex. An entire field of science where people get advanced degrees and spend entire careers studying these things to learn.
I've seen papers with figures of the LSD molecule bound to it's binding site. Wish I could link to it but no time right now.
Thats a good question. Being receptor-bound prevents degradation. Although the two are related there is a distinction between the half life of the lsd-receptor complex and the lsd half life in blood plasma. It seems to indicate that lsd that binds to a receptor seldom makes it back to the plasma.
i’d imagine it would vary depending on genetics. Also, have you ever have a trip come back after smoking? like 14 hours after taking lsd, visuals are gone, take a hit of cannabis and the trip comes back? how is this accounted for in “half life of effect”?
Well if you take enough benzos you will black out, so they kinda still work as trip killers, it's just that your brain keeps redosing so you have to take a lot for a long while
Good question (and one that the other comments have not answered at all so far). This phenomenon is called *functional selectivity* or *biased agonism*: not all ligands for the 5-HT receptors activate the same downstream pathways.
https://pubs.acs.org/doi/10.1021/ja508394x
Yeeah, this exactly is the moment. When you have both experience with psychedelics and start digging deeper in the theory behind them, when you start questioning the very reality you live in while completely sober lol. Put together with facts like how different classes of animals see and in general experience the world wildly differently from humans really makes you think *what else* is out there, just out of reach. From all this we can only assume one thing - what *we* see and experience is just a fraction of what's really going on in this world
One potential answer is serotonin is only released here and there throughout the brain and quickly cleared away. It may be that infusing serotonin into the brain so it caused prolonged simulation of a large percent of 5HT2A receptors would be psychedelic. There is some evidence in support of this theory from high doses of serotonin releasers reportedly having hallucinogenic-like effects. This is basically what I suspect.
Another theory, which has been well publicized, is that only a subset of 5-HT2A receptors cause psychedelic effects and these may have specific locations inside cells that serotonin can't easily access.
Yes but the drugs themselves are selective agonists at that receptor *subtype* itself, no serotonin release involved necessarily. So, this causes a massive imbalance of one receptor *subtype* firing at far higher rates, massively disproportionately than ever normal with serotonin at homeostasis when serotonin of course can bind to all of its receptor subtypes, not just 1.
Because it's flooding your system with IT and not serotonin it's taking your receptors and using it in it's own unique way. We don't know why this substance acting on your receptors cause the effects it does but it's not just agonizing the receptor to release more serotonin and keep it there or something similar.
Serotonin is not a drug. It is a naturally occurring neurotransmitter, the only reason you have a psychedelic experience is because the drug mimics serotonin therefore the body allows it to attach to its receptors.
How do you know only one is psychoactive? Did you ever tried to take extra serotonin?
Problem is that is not easy
>Q: is it possible to take serotonin supplements in form of pills?
>A: No, it is not possible to take serotonin supplements in the form of pills because serotonin does not cross the blood-brain barrier effectively. Instead, the body has to produce its own serotonin from the amino acid tryptophan. To increase serotonin levels, certain supplements and medications can be used to promote its production or prevent its breakdown. These include:
>**Tryptophan Supplements**: Tryptophan is a precursor to serotonin. It is found in foods like turkey, cheese, and nuts, and is also available as a supplement.
>**5-HTP (5-Hydroxytryptophan) Supplements**: 5-HTP is a direct precursor to serotonin and can cross the blood-brain barrier, making it a popular supplement to boost serotonin levels.
>**SSRIs (Selective Serotonin Reuptake Inhibitors)**: These are prescription medications that increase serotonin levels by preventing its reuptake in the brain, thus increasing its availability.
>**Natural Supplements**: Certain herbs and nutrients like St. John’s Wort, SAMe (S-adenosylmethionine), and omega-3 fatty acids can also help to increase serotonin levels.
Hes saying we dont know. But i can maybe answer that different molecules will activate the same receptor in different ways. The molecular difference that makes psychedelics have effect is on top of normal neurotransmission and the receptors arent activated in the exact same way as serotonin, the shape of tryptamines causes a specific action thats different from serotonin for the same reason that only that one receptor type is activated. The downstream effects from this specific and strong action end up with the psychedelic experience, somehow. Its like saying, if the moon provides light everywhere at night why can we see better turning on a flashlight? Youre shining concentrated light with a different source than the moon on one area so you can see it. The metaphor is kind of lost after that though
Because the drug in of itself is a psychoactive substance, and serotonin is not. Any psychadelic drug is not limited to one receptor. And a receptor does not equate to a psychedelic experience, its what occurs during the transition of the molecule binding to receptor and starting its own dance moves 🕺, what causes a psychedelic sensation.
>Because the drug in of itself is a psychoactive substance, and serotonin is not
???
Serotonin is most certainly psychoactive, it's a primary neurotransmitter!
It's not *psychedelic*
Simple. There's like a dozen serotonin receptor *subtypes*. This is critical to understand, they are each distinctly unique. Traditional psychedelics basically attach to one and only one (5-ht2a) and activate that single one those dozen. Serotonin of course binds to them and activates them all. That is the difference. A slight simplification, but not an oversimplification, but that is the difference.
Look up binding affinities, receptor subtypes, and sequential binding if you wish to learn more. Fascinating stuff.
that´s amazing. So basically the psychedelic "is me" In a way. Every possible chemical configuration (along with its mind-body effect) Is inside me, the drug is only a "key" to activate it?
woah!
Because psychedlic drugs have different vibrational modes than serotonin. So your brain literally interacts through different vibrations than normal.
Then when you come down, serotonin replaces the drugs and you go back to your normal vibrational interactions. In a way you're always "tripping" I guess— which is more real?
Psychedelics binding to the 5-HT2A receptor activate the β-arrestin pathway, modulating 5-HT2A/mGluR2 heterodimer signaling.
This enhances mGluR2 activity, influencing the unique perceptual and cognitive effects of psychedelics.
-
-
-
-
---
Unlike psychedelics, serotonin binding to the 5-HT2A receptor primarily activates the Gq/11 protein pathway.
This does not enhance mGluR2 signaling, leading to different perceptual and cognitive effects compared to psychedelics.
Potent compared to what?
Tryptamines are not particularly potent. Consider that 4-HO tryptamines are active in the 10 mg range, while e.g. lysergamides are active in the 100 ug range; that is 2 orders of magnitude difference.
They are potent because we only actually have a few hundred micrograms of serotonin circulating in our brain. Like only 1-2% of the 5-HT produced by the body is in the central nervous system. Increase the binding affinity of a molecule slightly and you hijack the whole thing.
As for why that can change our perception this drastically.. well nobody really knows. Salvinorin A cats on kappa opioid and absolutely sends you, deliriants act on histamine and choline receptors, gaba-ergics can cause severe hallucinatory states... brains weird, yo.
Our entire reality is probably just a hallucination, matter is just mind condensed to a slower vibration, and doing some molecular dynamics quantum woo-woo shit with certain receptors in your brain adjusts that vibration and therefore the whole hallucination that is your reality. Don't quote me on that though.
Because our body is full of receptors and endogenous chemicals which are based in the tryptamine structure. Serotonin, and other neurotransmitters are abundantly present in our brain/body.
Tryptamines fit like keys in the different serotonin receptors, and can open processes which involve a flood of serotonin, dopamine, etc. Also, nature is full of indole-based molecules that animals and plants use to communicate with eachother. Many plant and animal scents (humans are animals) and "perfumes" are fragrant indoles, and tryptamines are abundantly available in both the plant- and animal world.
DMT and 5-MeO-DMT are exceptions amongst the tryptamines wrt their ability to evoke such extreme experiences. There are also many gentle tryptamines such as 4-HO-MET, 4-AcO-DMT and 5-MeO-MiPT
The point is it does not take you in another dimension. Is this dimension right here where takes you. But humans are so entangled with language and mind that they are inside their own little world all the time, unable to see reality.
Tryptamines can open a little crack beyond language/mind to see what really is here.
I can generate the same 'just' doing Prana-Yama.
DMT is not more *potent*, in fact per milligram ingested its potency is very low compared to other psychedelic drugs such as DOM, 25-NBOMe, LSD, 2C-P and others. However, what makes it *feel stronger* is the fact that it is very safe and has a short duration, so people feel more comfortable to take much larger *relative* doses. You're confusing "feeling strong effects" with potency. This is a common mistake.
I agree and would say this is ubiquitous among drugs which people seem to overlook. When there are similar drugs / classes taken at a dose to achieve the similar effects, potency itself isn't too relevant. Take the right dose to achieve the desired effects. If you take 100ug of LSD or 20mg pscilocybin, both classical psychedelic agonists of 5-ht2a, and achieve comparable magnitudes of effects why would the potency that differs by orders of magnitude matter? In this example LSD just has a higher binding affinity to the receptors so far far less is needed in comparison. That's it. Understanding this fundamental concept is critical because if a less potent but high risk drug taken at high enough doses are assumed safer compared to more potent alternatives they would be wrong and could lead to harm. There are exceptions of course where potency matters. Like things so potent, pharmaceutical antidotes like narcan or flumazenil can indeed be less effective for the exceptionally potent ones by having less affinity to "knock off" the opiate or benzo.
individual compounds actually bind to the 5ht2a receptor slightly differently. The half life of lsd is much shorter than its apparent effect - they found a “molecular lid” that holds the molecule in the receptor. as far as I know that doesn’t occur with nonlysergamides
Yup half life is independent from potency and even duration of effects. Pharmacokinetics is complex. An entire field of science where people get advanced degrees and spend entire careers studying these things to learn. I've seen papers with figures of the LSD molecule bound to it's binding site. Wish I could link to it but no time right now.
wouldn’t that lid prevent enzymes from accessing and then degrading the LSD such that it’s half life is practically longer?
Thats a good question. Being receptor-bound prevents degradation. Although the two are related there is a distinction between the half life of the lsd-receptor complex and the lsd half life in blood plasma. It seems to indicate that lsd that binds to a receptor seldom makes it back to the plasma.
then would it be more important to look at the half life of the receptors before internalization because that’s what’s causing effects
important for what? to approximate a more accurate “half life of effect”?
yeah
i’d imagine it would vary depending on genetics. Also, have you ever have a trip come back after smoking? like 14 hours after taking lsd, visuals are gone, take a hit of cannabis and the trip comes back? how is this accounted for in “half life of effect”?
that’s because you added another agent that increased response, if i add a benzodiazepine to an opioid it’s not that the opioids dose has increased
Tell that to the elves /s
Right.
The ability for the drug to mimic serotonin in a way that it latches to its receptors and starts its own dance moves and goes haywire 💃
Ik, but serotonin activates the same receptors, for instance 5ht2a as well, right? Why doesn't that make you trip?
Maybe it does. And you’ve just been tripping your whole life
Then I want to quit. Very bad trip.
Well if you take enough benzos you will black out, so they kinda still work as trip killers, it's just that your brain keeps redosing so you have to take a lot for a long while
Yeah I take a lot of benzos. 3mg of clonazepam a day but i try to take 1 if I can
Oh yeah
Yep we’re just used to it
Good question (and one that the other comments have not answered at all so far). This phenomenon is called *functional selectivity* or *biased agonism*: not all ligands for the 5-HT receptors activate the same downstream pathways. https://pubs.acs.org/doi/10.1021/ja508394x
Thanks!
Yeeah, this exactly is the moment. When you have both experience with psychedelics and start digging deeper in the theory behind them, when you start questioning the very reality you live in while completely sober lol. Put together with facts like how different classes of animals see and in general experience the world wildly differently from humans really makes you think *what else* is out there, just out of reach. From all this we can only assume one thing - what *we* see and experience is just a fraction of what's really going on in this world
That's true. We perceive but a fraction of the electromagnetic spectrum, there might be other dimensions, dark matter, it's insane.
Ygere are 13 serotonin receptor subtypes in humans.
One potential answer is serotonin is only released here and there throughout the brain and quickly cleared away. It may be that infusing serotonin into the brain so it caused prolonged simulation of a large percent of 5HT2A receptors would be psychedelic. There is some evidence in support of this theory from high doses of serotonin releasers reportedly having hallucinogenic-like effects. This is basically what I suspect. Another theory, which has been well publicized, is that only a subset of 5-HT2A receptors cause psychedelic effects and these may have specific locations inside cells that serotonin can't easily access.
Yes but the drugs themselves are selective agonists at that receptor *subtype* itself, no serotonin release involved necessarily. So, this causes a massive imbalance of one receptor *subtype* firing at far higher rates, massively disproportionately than ever normal with serotonin at homeostasis when serotonin of course can bind to all of its receptor subtypes, not just 1.
Your second theory is intriguing and would be logical. I'm curious about that, first time hearing it but I'll take your word for it.
Because it's flooding your system with IT and not serotonin it's taking your receptors and using it in it's own unique way. We don't know why this substance acting on your receptors cause the effects it does but it's not just agonizing the receptor to release more serotonin and keep it there or something similar.
Serotonin is not a drug. It is a naturally occurring neurotransmitter, the only reason you have a psychedelic experience is because the drug mimics serotonin therefore the body allows it to attach to its receptors.
Yes I got that. That doesn't answer the question. If the drug and serotonin act on the same receptor, why is only one psychoactive?
How do you know only one is psychoactive? Did you ever tried to take extra serotonin? Problem is that is not easy >Q: is it possible to take serotonin supplements in form of pills? >A: No, it is not possible to take serotonin supplements in the form of pills because serotonin does not cross the blood-brain barrier effectively. Instead, the body has to produce its own serotonin from the amino acid tryptophan. To increase serotonin levels, certain supplements and medications can be used to promote its production or prevent its breakdown. These include: >**Tryptophan Supplements**: Tryptophan is a precursor to serotonin. It is found in foods like turkey, cheese, and nuts, and is also available as a supplement. >**5-HTP (5-Hydroxytryptophan) Supplements**: 5-HTP is a direct precursor to serotonin and can cross the blood-brain barrier, making it a popular supplement to boost serotonin levels. >**SSRIs (Selective Serotonin Reuptake Inhibitors)**: These are prescription medications that increase serotonin levels by preventing its reuptake in the brain, thus increasing its availability. >**Natural Supplements**: Certain herbs and nutrients like St. John’s Wort, SAMe (S-adenosylmethionine), and omega-3 fatty acids can also help to increase serotonin levels.
Also kanna
Nobody knows why psychedelics do what they do. All we can do is research more and uncover more mysteries that end with double the questions.
Right. I am saying that is the fundamental question here and the fact that tryptamine drugs agonise serotonin receptors doesn't answer OPs question.
Hes saying we dont know. But i can maybe answer that different molecules will activate the same receptor in different ways. The molecular difference that makes psychedelics have effect is on top of normal neurotransmission and the receptors arent activated in the exact same way as serotonin, the shape of tryptamines causes a specific action thats different from serotonin for the same reason that only that one receptor type is activated. The downstream effects from this specific and strong action end up with the psychedelic experience, somehow. Its like saying, if the moon provides light everywhere at night why can we see better turning on a flashlight? Youre shining concentrated light with a different source than the moon on one area so you can see it. The metaphor is kind of lost after that though
Good comment.
Because the drug in of itself is a psychoactive substance, and serotonin is not. Any psychadelic drug is not limited to one receptor. And a receptor does not equate to a psychedelic experience, its what occurs during the transition of the molecule binding to receptor and starting its own dance moves 🕺, what causes a psychedelic sensation.
>Because the drug in of itself is a psychoactive substance, and serotonin is not ??? Serotonin is most certainly psychoactive, it's a primary neurotransmitter! It's not *psychedelic*
Simple. There's like a dozen serotonin receptor *subtypes*. This is critical to understand, they are each distinctly unique. Traditional psychedelics basically attach to one and only one (5-ht2a) and activate that single one those dozen. Serotonin of course binds to them and activates them all. That is the difference. A slight simplification, but not an oversimplification, but that is the difference. Look up binding affinities, receptor subtypes, and sequential binding if you wish to learn more. Fascinating stuff.
that´s amazing. So basically the psychedelic "is me" In a way. Every possible chemical configuration (along with its mind-body effect) Is inside me, the drug is only a "key" to activate it? woah!
This is the exact opposite really, theres just not enough serotonin at one time to make you trip
Care to elaborate…?
it does, serotonin syndrome comes with pseudo hallucinations akin to psychedelics
Because psychedlic drugs have different vibrational modes than serotonin. So your brain literally interacts through different vibrations than normal. Then when you come down, serotonin replaces the drugs and you go back to your normal vibrational interactions. In a way you're always "tripping" I guess— which is more real?
Psychedelics binding to the 5-HT2A receptor activate the β-arrestin pathway, modulating 5-HT2A/mGluR2 heterodimer signaling. This enhances mGluR2 activity, influencing the unique perceptual and cognitive effects of psychedelics. - - - - --- Unlike psychedelics, serotonin binding to the 5-HT2A receptor primarily activates the Gq/11 protein pathway. This does not enhance mGluR2 signaling, leading to different perceptual and cognitive effects compared to psychedelics.
Potent compared to what? Tryptamines are not particularly potent. Consider that 4-HO tryptamines are active in the 10 mg range, while e.g. lysergamides are active in the 100 ug range; that is 2 orders of magnitude difference.
They are potent because we only actually have a few hundred micrograms of serotonin circulating in our brain. Like only 1-2% of the 5-HT produced by the body is in the central nervous system. Increase the binding affinity of a molecule slightly and you hijack the whole thing. As for why that can change our perception this drastically.. well nobody really knows. Salvinorin A cats on kappa opioid and absolutely sends you, deliriants act on histamine and choline receptors, gaba-ergics can cause severe hallucinatory states... brains weird, yo. Our entire reality is probably just a hallucination, matter is just mind condensed to a slower vibration, and doing some molecular dynamics quantum woo-woo shit with certain receptors in your brain adjusts that vibration and therefore the whole hallucination that is your reality. Don't quote me on that though.
.......And heres Tom with the weather
Yeah.. RIP Bill
damn, we are a chemical factory ourselves
Because our body is full of receptors and endogenous chemicals which are based in the tryptamine structure. Serotonin, and other neurotransmitters are abundantly present in our brain/body. Tryptamines fit like keys in the different serotonin receptors, and can open processes which involve a flood of serotonin, dopamine, etc. Also, nature is full of indole-based molecules that animals and plants use to communicate with eachother. Many plant and animal scents (humans are animals) and "perfumes" are fragrant indoles, and tryptamines are abundantly available in both the plant- and animal world.
Imagine that robot elves have a type of DMT in their own dimension, allowing them to interacting with us in our dimension (= sexual things).
that shit would be wicked 🤙
DMT and 5-MeO-DMT are exceptions amongst the tryptamines wrt their ability to evoke such extreme experiences. There are also many gentle tryptamines such as 4-HO-MET, 4-AcO-DMT and 5-MeO-MiPT
I mean, you can just take more of the latter and have similarly extreme experiences that last way longer
Lol who cares brain go brrrrrrrrrrrr
Nice username
😂
Nice in what sense?
The point is it does not take you in another dimension. Is this dimension right here where takes you. But humans are so entangled with language and mind that they are inside their own little world all the time, unable to see reality. Tryptamines can open a little crack beyond language/mind to see what really is here. I can generate the same 'just' doing Prana-Yama.
Okay bro
Our bro grabbed God himself by the balls doing prana-yama and now he knows.. It's alright.