I wonder, why do we have 5ht2a receptors inside our neurons if our natural neurotransmitters like serotonin would never reach them due to their polarity? And why would triggering them cause psychedelic effects / dendritic growth? And are the subjective effects and dendritic growth unrelated effects of the stimulus, or do the subjective effects cause the dendritic growth (or vice versa)?
I'm assuming that when we're young and our brains are developing we experience a lot of dendritic growth- what causes that? Is it activation of the same receptors, and if so what is activating them?
This is the key question. Does it mean endogenous lipophilic molecules (such as DMT) are activating internal 5HT2A receptors rather than serotonin? A few gaps in our understanding remain no doubt.
Right, all receptors are in a cycle from the Golgi and other internal membranes to the surface membrane and back again as they're recycled. What most people aren't aware of is the active signalling from these receptors when still in internal compartments. Clearly, it's important for neuroplasticity wrt to the 5HT2AR as shown in this paper.
I think this is really nice science. I’m going to share it with my undergrad general biology class tomorrow since we just finished covering the Endomembrane system. thanks for breaking it down! 👏
Such a great distillation and explanation of that paper, Andrew. I had been meaning to get round to it but other things got in the way. Inspiring read for my Friday morning (distracting me from work) haha :) I have to admit, I wasn't aware of intracellular 5HT-2A receptors before this so it was something of a personal paradigm shift.
Maybe this answers my previous comment - anecdotally it seems that LSD has a "long LSD" effect of years or even a lifetime. However anecdotes need real experiments to be believed.
What future experiments would you like to see? Are there techniques that or models that the authors could have used? Or what would you like to see next from this line of thinking?
Andrew are you familiar with this old 1979 paper claiming that DMT was identified in the urine of patients demonstrating symptoms of psychosis? The authors are clearly looking for a source of psychosis but a more interesting hypothesis is that DMT is potentially acting as a mood stabilizer, as it is noted to dissipate in urine as clinical symptoms disappear. It would be very interesting, cheap, and easy to attempt to replicate this work.
my peak experiences feel completely different than a normal breakthrough. the feel more like a hijacking of my consciousness than me inhabiting a space. I also completely forget the appearance of the entities, which as become an ongoing joke for them.
5ht2a is postulated as the mechanism of psychedelic experience because, when blocked, the experience doesn't occur. What this means is that it is a necessary condition for the experience, but 5ht2a activation alone does not explain the experience, it is not a sufficient condition. Neuroplasticity is also not sufficient as much of the phenomenological brunt of the experience and subsequent meaningfullness occurs in the blink of an eye. If anything, this can only be explained in the context of gestalt psychology whereby psychedelics catalyse the psychological gestalt shift or seeing as. synaptic reductionist explanation cannot account for the profundity and immediacy of the psychological phenomenon I think.
Actually, we have quite a good understanding of why activating 5HT2A receptors elicits a psychedelic effect, from the level of intracellular signalling networks, to neuronal function, to the cortical networks affected.
but what effect? there are many discrete experiences we can point to specific to drugs and doses, from ecxtatic to epistemic to noetic, to whatever tf is going on in the DMT realm. some overlap, some don't. is the 'psychedelic experience' a myth? by this I ask, is it scientifically useful to refer to one phenomenon such that it is the goal of this work to discover its biochemical origin, when the phenomenon has no adequate definition. perhaps this is a better way to put the point. Shulgin I'm sure would spin on his grave if he knew that rodent head twitching was the scientific definition of psychedelic experience.
Head twitching is not the definition of psychedelic experience. There's still a lot we don't understand about psychedelic mechanisms and effects, but to claim that our understanding doesn't go beyond "blocking 5HT2A receptors prevents psychedelic effects" is incorrect. We understand how 5HT2A affects neuronal function and, to some extent, how this maps to the changes in neural activity at the global level as measured by functional imaging. But of course there remain gaps in our current understanding. You really should read my latest book, Reality Switch Technologies, if you want to understand more fully how it all works.
oh I've got it baby! (and loved it), my point is that the phenomenology of these experiences needs to be used in combination with the basic science to guide the work and avoid prematurely reductive explanations. example: what does harmala pace the DMT experience? why does a simple tryptophan supplement radically enhance the visual experience of oral DMT and psilocybin? why is there amnesia correlative to peak DMT? the unique subset of phenomena within psychedelic experience demonstrate (to me anyway ) that if subtle additions to the psychedelic formula can facilitate dramatic and profound phenomenological change, then perhaps the same process should be used to clarify what experience is supposedly being explained by what exactly neurological process. and more importantly, what reasoning substantiates the analogies at work. I do think you are the boss, btw! this substack has been gold.
Yes you're correct -- it certainly cannot start and end with animal studies. The phenomenology should be central. Once that mouse head starts twitching, it's time to go to humans...
I’ve often felt whilst breaking through on DMT that something is happening to my consciousness that’s beyond our current understanding of the brain and the effects of these substances within it. I get the distinct feeling and impression that my consciousness is being transported on a quantum level.
Amazing breakdown, thank you!
I wonder, why do we have 5ht2a receptors inside our neurons if our natural neurotransmitters like serotonin would never reach them due to their polarity? And why would triggering them cause psychedelic effects / dendritic growth? And are the subjective effects and dendritic growth unrelated effects of the stimulus, or do the subjective effects cause the dendritic growth (or vice versa)?
I'm assuming that when we're young and our brains are developing we experience a lot of dendritic growth- what causes that? Is it activation of the same receptors, and if so what is activating them?
This is the key question. Does it mean endogenous lipophilic molecules (such as DMT) are activating internal 5HT2A receptors rather than serotonin? A few gaps in our understanding remain no doubt.
Excellent breakdown
Right, all receptors are in a cycle from the Golgi and other internal membranes to the surface membrane and back again as they're recycled. What most people aren't aware of is the active signalling from these receptors when still in internal compartments. Clearly, it's important for neuroplasticity wrt to the 5HT2AR as shown in this paper.
I think this is really nice science. I’m going to share it with my undergrad general biology class tomorrow since we just finished covering the Endomembrane system. thanks for breaking it down! 👏
Make sure you tell them to subscribe! ;)
Done!
Thank you for doing this!
Such a great distillation and explanation of that paper, Andrew. I had been meaning to get round to it but other things got in the way. Inspiring read for my Friday morning (distracting me from work) haha :) I have to admit, I wasn't aware of intracellular 5HT-2A receptors before this so it was something of a personal paradigm shift.
Haha, I suppose this would seem like a "new mechanism" to a lot of people! Thanks for the article;)
Maybe this answers my previous comment - anecdotally it seems that LSD has a "long LSD" effect of years or even a lifetime. However anecdotes need real experiments to be believed.
I just found your substack via the Twitter algorithm. Absolutely fantastic breakdown. Thanks!
Thank you for the great breakdown of the article!
What future experiments would you like to see? Are there techniques that or models that the authors could have used? Or what would you like to see next from this line of thinking?
https://pubmed.ncbi.nlm.nih.gov/286576/
Andrew are you familiar with this old 1979 paper claiming that DMT was identified in the urine of patients demonstrating symptoms of psychosis? The authors are clearly looking for a source of psychosis but a more interesting hypothesis is that DMT is potentially acting as a mood stabilizer, as it is noted to dissipate in urine as clinical symptoms disappear. It would be very interesting, cheap, and easy to attempt to replicate this work.
Andrew, would combining Niacin with psychedelics still result in neuroplasticity but without the psy effects?
https://bibliography.maps.org/citation/261
my peak experiences feel completely different than a normal breakthrough. the feel more like a hijacking of my consciousness than me inhabiting a space. I also completely forget the appearance of the entities, which as become an ongoing joke for them.
5ht2a is postulated as the mechanism of psychedelic experience because, when blocked, the experience doesn't occur. What this means is that it is a necessary condition for the experience, but 5ht2a activation alone does not explain the experience, it is not a sufficient condition. Neuroplasticity is also not sufficient as much of the phenomenological brunt of the experience and subsequent meaningfullness occurs in the blink of an eye. If anything, this can only be explained in the context of gestalt psychology whereby psychedelics catalyse the psychological gestalt shift or seeing as. synaptic reductionist explanation cannot account for the profundity and immediacy of the psychological phenomenon I think.
Actually, we have quite a good understanding of why activating 5HT2A receptors elicits a psychedelic effect, from the level of intracellular signalling networks, to neuronal function, to the cortical networks affected.
but what effect? there are many discrete experiences we can point to specific to drugs and doses, from ecxtatic to epistemic to noetic, to whatever tf is going on in the DMT realm. some overlap, some don't. is the 'psychedelic experience' a myth? by this I ask, is it scientifically useful to refer to one phenomenon such that it is the goal of this work to discover its biochemical origin, when the phenomenon has no adequate definition. perhaps this is a better way to put the point. Shulgin I'm sure would spin on his grave if he knew that rodent head twitching was the scientific definition of psychedelic experience.
Head twitching is not the definition of psychedelic experience. There's still a lot we don't understand about psychedelic mechanisms and effects, but to claim that our understanding doesn't go beyond "blocking 5HT2A receptors prevents psychedelic effects" is incorrect. We understand how 5HT2A affects neuronal function and, to some extent, how this maps to the changes in neural activity at the global level as measured by functional imaging. But of course there remain gaps in our current understanding. You really should read my latest book, Reality Switch Technologies, if you want to understand more fully how it all works.
oh I've got it baby! (and loved it), my point is that the phenomenology of these experiences needs to be used in combination with the basic science to guide the work and avoid prematurely reductive explanations. example: what does harmala pace the DMT experience? why does a simple tryptophan supplement radically enhance the visual experience of oral DMT and psilocybin? why is there amnesia correlative to peak DMT? the unique subset of phenomena within psychedelic experience demonstrate (to me anyway ) that if subtle additions to the psychedelic formula can facilitate dramatic and profound phenomenological change, then perhaps the same process should be used to clarify what experience is supposedly being explained by what exactly neurological process. and more importantly, what reasoning substantiates the analogies at work. I do think you are the boss, btw! this substack has been gold.
Yes you're correct -- it certainly cannot start and end with animal studies. The phenomenology should be central. Once that mouse head starts twitching, it's time to go to humans...
I’ve often felt whilst breaking through on DMT that something is happening to my consciousness that’s beyond our current understanding of the brain and the effects of these substances within it. I get the distinct feeling and impression that my consciousness is being transported on a quantum level.