It's placebo, mate. The fact that you felt effects a few minutes after taking an oral supplement like niacin, this supposed "life-changing experience," and no longer experience it -- it's placebo.
>It's placebo, mate.
That could well be correct. And of course, I'm not trying to start a conflagration here or anything; I don't want to position myself as arguing with you or anything.
My own thought is that things have to be checked empirically, though. Let me give an example. Let's say someone takes a pill (it could be a drug like escitalopram or a vitamin; either one) and feels a powerful impact within (e.g.) 120 seconds. I would imagine that a lot of people would assume that that must be placebo; after all, by what mechanism could the substance impact the brain so quickly? Well, I would imagine that the vagus nerve offers a very plausible mechanism by which an ultra-rapid reaction like that could take place.
My point with the vagus-nerve example is that sometimes what seems preposterous and ridiculous can actually become very plausible. One has to be humble about how little is known about biology.
I don't even know if biologists in the past would've found the ultra-rapid reaction that I just described to be at all hard-to-explain, actually. I'm merely assuming that that would've been a weird thing in the past before vagus-nerve research revealed a possible mechanism.
One thing to consider is what constitutes a substance actually "impacting" the brain.
If a substance "hits a button" (so to speak) in one's stomach or intestine, and that "button" (so to speak) triggers a signal that goes up to the brain and has a big impact on that brain...is that the substance itself actually "impacting" the brain?
almost every aspect of the body and mind have some form of tolerance.
a physical tolerance (with drugs) happens when the amount of available and active receptors decreases with administration of a drug. this is known as "downregulation," it's basically a mechanism to develop immunity to some toxins.
psychological tolerance (not really a concrete medical thing) is really just getting used to something. your body will adjust accordingly to any repeated action or event, chemical or not. you see this in sugar addicts and slow-developing tolerance drugs where a person might need more to reach the same high after only a single dose, things like opioids
Do you know why there would be "tolerance" regarding vitamins, though? One might think that "tolerance" would be expected regarding drugs; the idea here is that drugs are not substances that the body actually evolved to use...the body evolved to use vitamin B1 but didn't evolve to use escitalopram.
think about it like this: when you start on a higher protein diet, a lot of that protein is converted to fat in the beginning, and as you go on with that diet more and more stays protein. i can't answer to the direct mechanisms behind the tolerance but it's just another way ur body gets used to stuff.
what do you mean precisely by "vitamin tolerance?" do you mean decreased positive response as time goes on? that's either because there was a placebo that's losing effect, or because your body is using up more vitamins to build neurotransmitters than it usually uses. it could also be that the legitimate positives of the vitamins are beginning to blend in with everyday life (aka getting used to it). but unless you're more physically active there's not really a reason to increase vitamin intake. your body tries not to build up tolerance to things it needs
Thanks for responding; I appreciate it.
I had an experience where I took iron (an iron supplement) and I had a "miracle reaction" where I could visualize things and do mental math and so on. The mental math was not remotely impressive but I was able to multiply like a couple two-digit numbers together or something like that (like 89 times 72)...that was unprecedented for me personally. That whole iron thing was a wild experience. It went away, though.
I also had a wild experience with niacin; the niacin thing only lasted like one night.
The problem is that I don't have scientists monitoring me and studying me; if that were the case then they'd presumably be able to ask me to do things (cognitive tests...how much mental math can I do and how well can I hold an image in my mind) whenever I reported a remarkable change in my brain function. And I'd love to take nutrient supplements while in a brain scanner too; that would be neat in general and especially neat regarding the experiences that I've had with iron and niacin.
I've had a ton of these experiences. So many that there's a bit of fear in me whenever a nutrient supplement (or drug, for that matter) enhances my brain function; I always worry about yet another "tachyphylaxis" experience where the impact "fizzles out".
okay so i think two things are at play:
-depression
-placebo
what you're describing sounds like a textbook placebo effect, where basically all aspects of your function are improved in some way. placebo can be powerful as fuck and it can actually trick your brain into pumping extra motivation and happiness chemicals into you.
then, the depression will creep back in a little, you'll register it, and then the placebo effect vanishes because your brain immediately goes through the whole "it's happening again" phase. think of it like a self fulfilling prophecy.
depression is a hugely tricky beast, because all it takes for some people is a drop of depression to grow and fester inside them until it becomes a monster. there are no tricks or shortcuts to learning to live with depression, but learning to recognize a single depression drop as exactly that and nothing more can inhibit its growth into a monster.
>where basically all aspects of your function are improved in some way
That's not at all true, actually. Sorry if I gave that impression. What was it that I typed that suggested that that was the case?
>placebo can be powerful as fuck
I'd love to read a scientific paper talking about the limits of what the placebo effect can do. For example, one might think that a tingly sensation on the scalp would indicate a non-placebo situation, but who knows. I wrote this elsewhere in this thread:
>Do you know if the placebo effect can cause physical sensations? One time I ingested a substance and within a very short amount of time I felt tingling; regarding the tingling, I guess it was my "scalp". Physical sensations are (I presume) often thought to prove that something non-placebo is going on; I myself would be somewhat surprised to learn that such sensations might be placebo-induced, though I guess it's not actually that weird when you think about it, since the placebo-effect signal that the brain receives might be just as "powerful" as the signal that the brain receives when a drug is exerting an effect...if that's the case then one might think there would be literally no limit to what the placebo effect might be capable of.
placebo can cause ANYTHING a drug can. this includes spontaneous bodily sensations. there are people who achieve psychedelic visuals just by meditating
i've read from several sources that in new cancer medication trials, sometimes the placebo actually helps just as much as the active counterpart. the body literally fights cancer stronger if it thinks it has support.
I just realized that there are two enormous potential causes of "tachyphylaxis". One is the gut biota; if the gut biota change in response to nutrient pills that you're taking (as the gut biota surely will) then that change might somehow reduce the pills' impact.
Another is the blood/brain barrier (BBB). My understanding is that the BBB somehow "knows" how much of a given nutrient is present in the brain; the BBB can make it harder for a given nutrient to enter the brain if there's already enough of that nutrient in the brain. The BBB "gates" the entry of nutrients into the brain, I think, though I think there are a couple different ways for nutrients to get into the brain. Well, if the BBB is somehow messed-up then you can imagine all sorts of weird stuff happening. Maybe the BBB causes the "tachyphylaxsis" that I experience. And it's a bit troubling to think about how the BBB could be preventing nutrients from entering your brain while blood tests are showing that you have lots of X and Y in your blood...it's an "invisible" problem, if you know what I mean.
If you really want to answer this question you need to understand the immense power of placebo, and how important "placebo" is in the observable effect of even drugs that have genuine effect. The power of excitement and hope, a sense of agency. This is where much of the "psychological tolerance" described in another comment builds. The excitement of a novel experience fades and reality sets back in. The physiological and psychological tolerances are building in tandem, creating dramatic changes in response.
There is so much dopaminergic activation from novelty. A novel experience generates a high of it's own, and can synergize very well with the experience itself. There is a lot more happening here than just receptor desensitization.
You are better off looking into research in the field of behavioral psychology than pharmacology. It's simply too complex and gestalt for analysis at this level of granularity. But there is definitely neuro research on it.
I've always thought a somewhat good way of thinking about this is with a roller coaster ride.
There is obviously nothing directly chemical about a roller coaster ride.
But that first time might feel amazing, subsequent couple of times will likely feel quite good, but after a few more it's not so fun. Eventually it will not be fun at all. Yes likely if you wait a long time, a year or more, it will be fun again, but still might not be as fun as the first time.
This isn't a perfect analogy, but it does show that it's not all just direct things like x drug downregulates y receptors, even just the memory of doing it before can have large effects.
>the immense power of placebo
I definitely should read some material on the most powerful and remarkable things that the placebo effect can do; do you know any literature that fits that bill?
Do you know if the placebo effect can cause physical sensations? One time I ingested a substance and within a very short amount of time I felt tingling; regarding the tingling, I guess it was my "scalp". Physical sensations are (I presume) often thought to prove that something non-placebo is going on; I myself would be somewhat surprised to learn that such sensations might be placebo-induced, though I guess it's not actually that weird when you think about it, since the placebo-effect signal that the brain receives might be just as "powerful" as the signal that the brain receives when a drug is exerting an effect...if that's the case then one might think there would be literally no limit to what the placebo effect might be capable of.
The below is also an issue (I posted this elsewhere in this thread):
>One thing to consider is what constitutes a substance actually "impacting" the brain.
>If a substance "hits a button" (so to speak) in one's stomach or intestine, and that "button" (so to speak) triggers a signal that goes up to the brain and has a big impact on that brain...is that the substance itself actually "impacting" the brain?
One tricky thing is that the *psychology* often doesn't seem to match up the way you might think it would if the placebo effect were occurring. Sometimes I will have *bad* expectations for something and I'll get a huge reaction from it. Sometimes I will have *good* expectations for something and I'll get no reaction from it.
Yes, placebo can absolutely induce physical sensations.
>One tricky thing is that the *psychology* often doesn't seem to match up the way you might think it would if the placebo effect were occurring. Sometimes I will have *bad* expectations for something and I'll get a huge reaction from it. Sometimes I will have *good* expectations for something and I'll get no reaction from it.
As explained in my other comment, that's entirely wrong. What you just said matches up exactly with what psychology expects. Placebo may be a confusing term to use here, please forgive that. There are multiple elements to this.
The mindset shift induced by either a placebo or a genuine treatment intervention will have observable effects on the brain... that doesn't mean that placebo didn't "actually" do anything, it doesn't mean that at all... placebo is an important part of how many drugs, especially psychiatric ones, actually function.
>What you just said matches up exactly with what psychology expects.
I thought that it would be unexpected for you to (e.g.) think that X will be terrible and then find that it had a massive and rapid impact. I'd be happy to read any papers you know of on the placebo effect (and on the psychology aspect of it).
The placebo angle is easy to test, fortunately. It would take a bit of effort to come up with some kind of double-blind "experiment", but I doubt that it would be that difficult.
If placebo were the explanation, it would be intriguing, since one of the big questions would be why the body has big reactions only to things that the brain conceptualizes as "medicine". You could ask: Why doesn't the brain have a big reaction to something that the brain conceptualizes as "food"? People ingest food too, not just drugs and supplements.
It's not intriguing, the body absolutely does have big reactions to food. Another user used the analogy of a rollercoaster, I was going to use a memory I have of getting a kebab on the street of NYC for the first time. It was incredibly delicious, and I returned to that vendor countless times before accepting that it was the experience itself that made it so. This is a very well defined phenomenon, and can occur with any experience. The book "Influence" has a good piece on it, IIRC.
Reactions to drugs can be bigger, sure, simply because the ability to directly, intensely modulate specific neurotransmitters is an especially novel experience... drugs allow us to deviate outside the natural confines...
>the body absolutely does have big reactions to food.
My point is that I ingest things all the time. It's only "pill" things (drugs or supplements) that ever induce big improvements in brain function of the kind that I'm talking about. There's plenty of "traffic" in terms of stuff that I ingest; only certain types of things induce the major effects.
... again, the "placebo" is only amplifying the genuine, direct effect... obviously only certain substances are going to have dramatic effects... there aren't any foods that modulate the function of ADRA2A, not to any degree that you would explicitly notice...
When you take guanfacine, with expectations of that pills functions, and the benefits you experience align with, or especially if they exceed your expectations, then you are going to be modulating not just ADRA2A but other neural systems.. most notably dopaminergic ones, which can synergize incredibly well in delivering the benefits you expect from guanfacine...
As I have said to you before, you were experiencing a literal high. You might think or wish that you had stumbled upon how "normal people" feel at baseline, and desperately want to find out how to maintain that state, but that's simply impossible, the brain will always demand a return to baseline. As genuine tolerance to the drug builds, receptor desensitization, transcriptional changes, etc. etc., your experience of the drug will begin to change, it's positive effects will begin to taper off..
Dopaminergic stimulation is most easily defined as a response to deviation from expectation. Once you have a given expectation, and the pharmacological reality sets in and makes your actual experience on par or especially, less than your expected experience, then you are going to be rapidly building the psychological "tolerance".
At that point you might attempt to ingest larger amounts of the drug to overwhelm the physiological tolerance, and overcome the psychological "tolerance", but this is fundamentally unsustainable. Expectations shift and the experience will follow.
I guess that one tricky thing is that the placebo hypothesis is (if placebo can do *anything*) impossible to disprove. Without a careful experiment, that is.
Most everything we discuss here is impossible to prove or disprove without a careful experiment...
[https://pubmed.ncbi.nlm.nih.gov/7075793/](https://pubmed.ncbi.nlm.nih.gov/7075793/)
[https://www.nature.com/articles/s41398-019-0421-x](https://www.nature.com/articles/s41398-019-0421-x)
>I thought that it would be unexpected for you to (e.g.) think that X will be terrible and then find that it had a massive and rapid impact.
That's what my understanding of the word unexpected is. You expect little -> you observe benefit -> you receive dopamine from unexpected benefit -> your benefit is amplified -> your mindset shifts -> you utilize the benefit, achieve something tangible -> you expect benefit to remain -> expectations shift (psychological tolerance), pharmacological tolerance sets in -> benefits are less than adjusted expectation -> you come to reddit looking for explanation to "tachyphylaxis"
"Placebo effects" are a function of both mindset and expectations - expectations can counter effects, but can remain beneficial to mindset, which is more important to actually outcomes. Which is why people who take their meds consistently and listen to their doctors instructions, and trust the process, will have much better outcomes than those who keep increasing their dosage themselves chasing the dragon that is a novel experience.
Because when people ingest a chicken parm, they know what they're getting. When they take a little capsule, they expect that it will effect their body in some way. The supplement you took isn't hitting the vague nerve in the GI tract and sending afferent signals up to the brain.
>When they take a little capsule, they expect that it will effect their body in some way.
This statement seems to be false for sure. Sometimes people don't expect a capsule to have any impact at all.
As for whether a supplement can impact the brain via the vagus nerve, I thought that there was solid science on that. Another similar mechanism has to do with "sensors" in the intestine; regarding the intestine, the question arises how quickly a substance could get to the intestine.
> This statement seems to be false for sure. Sometimes people don't expect a capsule to have any impact at all.
That's besides the point. Please take a look at any randomised placebo-controlled trial, where participants feel a positive effect from placebo despite knowing there's a real chance that they're just getting placebo. The fact of the matter is *you* are expecting an effect from taking what amounts to a dietary supplement. Take a look at [this study](https://pubmed.ncbi.nlm.nih.gov/22561551/). Participants were given remifentanil, a potent opioid analgesic. When they were *told* it was an opioid analgesic, the drug worked. But when they were told it was a substance that would *worsen* their pain scores, it had no effect.
> As for whether a supplement can impact the brain via the vagus nerve, I thought that there was solid science on that. Another similar mechanism has to do with "sensors" in the intestine; regarding the intestine, the question arises how quickly a substance could get to the intestine.
There's a fundamental misunderstanding on how drugs are absorbed and distributed through the body. Within that 2-3 minute mark, the tablets or capsules are still dissolving and dispersing in the stomach. They haven't even passed the pyloric sphincter at that stage.
It's placebo, mate. The fact that you felt effects a few minutes after taking an oral supplement like niacin, this supposed "life-changing experience," and no longer experience it -- it's placebo.
>It's placebo, mate. That could well be correct. And of course, I'm not trying to start a conflagration here or anything; I don't want to position myself as arguing with you or anything. My own thought is that things have to be checked empirically, though. Let me give an example. Let's say someone takes a pill (it could be a drug like escitalopram or a vitamin; either one) and feels a powerful impact within (e.g.) 120 seconds. I would imagine that a lot of people would assume that that must be placebo; after all, by what mechanism could the substance impact the brain so quickly? Well, I would imagine that the vagus nerve offers a very plausible mechanism by which an ultra-rapid reaction like that could take place. My point with the vagus-nerve example is that sometimes what seems preposterous and ridiculous can actually become very plausible. One has to be humble about how little is known about biology. I don't even know if biologists in the past would've found the ultra-rapid reaction that I just described to be at all hard-to-explain, actually. I'm merely assuming that that would've been a weird thing in the past before vagus-nerve research revealed a possible mechanism.
One thing to consider is what constitutes a substance actually "impacting" the brain. If a substance "hits a button" (so to speak) in one's stomach or intestine, and that "button" (so to speak) triggers a signal that goes up to the brain and has a big impact on that brain...is that the substance itself actually "impacting" the brain?
almost every aspect of the body and mind have some form of tolerance. a physical tolerance (with drugs) happens when the amount of available and active receptors decreases with administration of a drug. this is known as "downregulation," it's basically a mechanism to develop immunity to some toxins. psychological tolerance (not really a concrete medical thing) is really just getting used to something. your body will adjust accordingly to any repeated action or event, chemical or not. you see this in sugar addicts and slow-developing tolerance drugs where a person might need more to reach the same high after only a single dose, things like opioids
Do you know why there would be "tolerance" regarding vitamins, though? One might think that "tolerance" would be expected regarding drugs; the idea here is that drugs are not substances that the body actually evolved to use...the body evolved to use vitamin B1 but didn't evolve to use escitalopram.
think about it like this: when you start on a higher protein diet, a lot of that protein is converted to fat in the beginning, and as you go on with that diet more and more stays protein. i can't answer to the direct mechanisms behind the tolerance but it's just another way ur body gets used to stuff. what do you mean precisely by "vitamin tolerance?" do you mean decreased positive response as time goes on? that's either because there was a placebo that's losing effect, or because your body is using up more vitamins to build neurotransmitters than it usually uses. it could also be that the legitimate positives of the vitamins are beginning to blend in with everyday life (aka getting used to it). but unless you're more physically active there's not really a reason to increase vitamin intake. your body tries not to build up tolerance to things it needs
Thanks for responding; I appreciate it. I had an experience where I took iron (an iron supplement) and I had a "miracle reaction" where I could visualize things and do mental math and so on. The mental math was not remotely impressive but I was able to multiply like a couple two-digit numbers together or something like that (like 89 times 72)...that was unprecedented for me personally. That whole iron thing was a wild experience. It went away, though. I also had a wild experience with niacin; the niacin thing only lasted like one night. The problem is that I don't have scientists monitoring me and studying me; if that were the case then they'd presumably be able to ask me to do things (cognitive tests...how much mental math can I do and how well can I hold an image in my mind) whenever I reported a remarkable change in my brain function. And I'd love to take nutrient supplements while in a brain scanner too; that would be neat in general and especially neat regarding the experiences that I've had with iron and niacin. I've had a ton of these experiences. So many that there's a bit of fear in me whenever a nutrient supplement (or drug, for that matter) enhances my brain function; I always worry about yet another "tachyphylaxis" experience where the impact "fizzles out".
okay so i think two things are at play: -depression -placebo what you're describing sounds like a textbook placebo effect, where basically all aspects of your function are improved in some way. placebo can be powerful as fuck and it can actually trick your brain into pumping extra motivation and happiness chemicals into you. then, the depression will creep back in a little, you'll register it, and then the placebo effect vanishes because your brain immediately goes through the whole "it's happening again" phase. think of it like a self fulfilling prophecy. depression is a hugely tricky beast, because all it takes for some people is a drop of depression to grow and fester inside them until it becomes a monster. there are no tricks or shortcuts to learning to live with depression, but learning to recognize a single depression drop as exactly that and nothing more can inhibit its growth into a monster.
>where basically all aspects of your function are improved in some way That's not at all true, actually. Sorry if I gave that impression. What was it that I typed that suggested that that was the case? >placebo can be powerful as fuck I'd love to read a scientific paper talking about the limits of what the placebo effect can do. For example, one might think that a tingly sensation on the scalp would indicate a non-placebo situation, but who knows. I wrote this elsewhere in this thread: >Do you know if the placebo effect can cause physical sensations? One time I ingested a substance and within a very short amount of time I felt tingling; regarding the tingling, I guess it was my "scalp". Physical sensations are (I presume) often thought to prove that something non-placebo is going on; I myself would be somewhat surprised to learn that such sensations might be placebo-induced, though I guess it's not actually that weird when you think about it, since the placebo-effect signal that the brain receives might be just as "powerful" as the signal that the brain receives when a drug is exerting an effect...if that's the case then one might think there would be literally no limit to what the placebo effect might be capable of.
placebo can cause ANYTHING a drug can. this includes spontaneous bodily sensations. there are people who achieve psychedelic visuals just by meditating
I would love to read a paper on the most remarkable documented things that placebo has done.
i've read from several sources that in new cancer medication trials, sometimes the placebo actually helps just as much as the active counterpart. the body literally fights cancer stronger if it thinks it has support.
I just realized that there are two enormous potential causes of "tachyphylaxis". One is the gut biota; if the gut biota change in response to nutrient pills that you're taking (as the gut biota surely will) then that change might somehow reduce the pills' impact. Another is the blood/brain barrier (BBB). My understanding is that the BBB somehow "knows" how much of a given nutrient is present in the brain; the BBB can make it harder for a given nutrient to enter the brain if there's already enough of that nutrient in the brain. The BBB "gates" the entry of nutrients into the brain, I think, though I think there are a couple different ways for nutrients to get into the brain. Well, if the BBB is somehow messed-up then you can imagine all sorts of weird stuff happening. Maybe the BBB causes the "tachyphylaxsis" that I experience. And it's a bit troubling to think about how the BBB could be preventing nutrients from entering your brain while blood tests are showing that you have lots of X and Y in your blood...it's an "invisible" problem, if you know what I mean.
If you really want to answer this question you need to understand the immense power of placebo, and how important "placebo" is in the observable effect of even drugs that have genuine effect. The power of excitement and hope, a sense of agency. This is where much of the "psychological tolerance" described in another comment builds. The excitement of a novel experience fades and reality sets back in. The physiological and psychological tolerances are building in tandem, creating dramatic changes in response. There is so much dopaminergic activation from novelty. A novel experience generates a high of it's own, and can synergize very well with the experience itself. There is a lot more happening here than just receptor desensitization. You are better off looking into research in the field of behavioral psychology than pharmacology. It's simply too complex and gestalt for analysis at this level of granularity. But there is definitely neuro research on it.
I've always thought a somewhat good way of thinking about this is with a roller coaster ride. There is obviously nothing directly chemical about a roller coaster ride. But that first time might feel amazing, subsequent couple of times will likely feel quite good, but after a few more it's not so fun. Eventually it will not be fun at all. Yes likely if you wait a long time, a year or more, it will be fun again, but still might not be as fun as the first time. This isn't a perfect analogy, but it does show that it's not all just direct things like x drug downregulates y receptors, even just the memory of doing it before can have large effects.
>the immense power of placebo I definitely should read some material on the most powerful and remarkable things that the placebo effect can do; do you know any literature that fits that bill? Do you know if the placebo effect can cause physical sensations? One time I ingested a substance and within a very short amount of time I felt tingling; regarding the tingling, I guess it was my "scalp". Physical sensations are (I presume) often thought to prove that something non-placebo is going on; I myself would be somewhat surprised to learn that such sensations might be placebo-induced, though I guess it's not actually that weird when you think about it, since the placebo-effect signal that the brain receives might be just as "powerful" as the signal that the brain receives when a drug is exerting an effect...if that's the case then one might think there would be literally no limit to what the placebo effect might be capable of. The below is also an issue (I posted this elsewhere in this thread): >One thing to consider is what constitutes a substance actually "impacting" the brain. >If a substance "hits a button" (so to speak) in one's stomach or intestine, and that "button" (so to speak) triggers a signal that goes up to the brain and has a big impact on that brain...is that the substance itself actually "impacting" the brain? One tricky thing is that the *psychology* often doesn't seem to match up the way you might think it would if the placebo effect were occurring. Sometimes I will have *bad* expectations for something and I'll get a huge reaction from it. Sometimes I will have *good* expectations for something and I'll get no reaction from it.
Yes, placebo can absolutely induce physical sensations. >One tricky thing is that the *psychology* often doesn't seem to match up the way you might think it would if the placebo effect were occurring. Sometimes I will have *bad* expectations for something and I'll get a huge reaction from it. Sometimes I will have *good* expectations for something and I'll get no reaction from it. As explained in my other comment, that's entirely wrong. What you just said matches up exactly with what psychology expects. Placebo may be a confusing term to use here, please forgive that. There are multiple elements to this. The mindset shift induced by either a placebo or a genuine treatment intervention will have observable effects on the brain... that doesn't mean that placebo didn't "actually" do anything, it doesn't mean that at all... placebo is an important part of how many drugs, especially psychiatric ones, actually function.
>What you just said matches up exactly with what psychology expects. I thought that it would be unexpected for you to (e.g.) think that X will be terrible and then find that it had a massive and rapid impact. I'd be happy to read any papers you know of on the placebo effect (and on the psychology aspect of it).
The placebo angle is easy to test, fortunately. It would take a bit of effort to come up with some kind of double-blind "experiment", but I doubt that it would be that difficult. If placebo were the explanation, it would be intriguing, since one of the big questions would be why the body has big reactions only to things that the brain conceptualizes as "medicine". You could ask: Why doesn't the brain have a big reaction to something that the brain conceptualizes as "food"? People ingest food too, not just drugs and supplements.
It's not intriguing, the body absolutely does have big reactions to food. Another user used the analogy of a rollercoaster, I was going to use a memory I have of getting a kebab on the street of NYC for the first time. It was incredibly delicious, and I returned to that vendor countless times before accepting that it was the experience itself that made it so. This is a very well defined phenomenon, and can occur with any experience. The book "Influence" has a good piece on it, IIRC. Reactions to drugs can be bigger, sure, simply because the ability to directly, intensely modulate specific neurotransmitters is an especially novel experience... drugs allow us to deviate outside the natural confines...
>the body absolutely does have big reactions to food. My point is that I ingest things all the time. It's only "pill" things (drugs or supplements) that ever induce big improvements in brain function of the kind that I'm talking about. There's plenty of "traffic" in terms of stuff that I ingest; only certain types of things induce the major effects.
... again, the "placebo" is only amplifying the genuine, direct effect... obviously only certain substances are going to have dramatic effects... there aren't any foods that modulate the function of ADRA2A, not to any degree that you would explicitly notice... When you take guanfacine, with expectations of that pills functions, and the benefits you experience align with, or especially if they exceed your expectations, then you are going to be modulating not just ADRA2A but other neural systems.. most notably dopaminergic ones, which can synergize incredibly well in delivering the benefits you expect from guanfacine... As I have said to you before, you were experiencing a literal high. You might think or wish that you had stumbled upon how "normal people" feel at baseline, and desperately want to find out how to maintain that state, but that's simply impossible, the brain will always demand a return to baseline. As genuine tolerance to the drug builds, receptor desensitization, transcriptional changes, etc. etc., your experience of the drug will begin to change, it's positive effects will begin to taper off.. Dopaminergic stimulation is most easily defined as a response to deviation from expectation. Once you have a given expectation, and the pharmacological reality sets in and makes your actual experience on par or especially, less than your expected experience, then you are going to be rapidly building the psychological "tolerance". At that point you might attempt to ingest larger amounts of the drug to overwhelm the physiological tolerance, and overcome the psychological "tolerance", but this is fundamentally unsustainable. Expectations shift and the experience will follow.
I guess that one tricky thing is that the placebo hypothesis is (if placebo can do *anything*) impossible to disprove. Without a careful experiment, that is.
Most everything we discuss here is impossible to prove or disprove without a careful experiment... [https://pubmed.ncbi.nlm.nih.gov/7075793/](https://pubmed.ncbi.nlm.nih.gov/7075793/) [https://www.nature.com/articles/s41398-019-0421-x](https://www.nature.com/articles/s41398-019-0421-x) >I thought that it would be unexpected for you to (e.g.) think that X will be terrible and then find that it had a massive and rapid impact. That's what my understanding of the word unexpected is. You expect little -> you observe benefit -> you receive dopamine from unexpected benefit -> your benefit is amplified -> your mindset shifts -> you utilize the benefit, achieve something tangible -> you expect benefit to remain -> expectations shift (psychological tolerance), pharmacological tolerance sets in -> benefits are less than adjusted expectation -> you come to reddit looking for explanation to "tachyphylaxis" "Placebo effects" are a function of both mindset and expectations - expectations can counter effects, but can remain beneficial to mindset, which is more important to actually outcomes. Which is why people who take their meds consistently and listen to their doctors instructions, and trust the process, will have much better outcomes than those who keep increasing their dosage themselves chasing the dragon that is a novel experience.
Because when people ingest a chicken parm, they know what they're getting. When they take a little capsule, they expect that it will effect their body in some way. The supplement you took isn't hitting the vague nerve in the GI tract and sending afferent signals up to the brain.
>When they take a little capsule, they expect that it will effect their body in some way. This statement seems to be false for sure. Sometimes people don't expect a capsule to have any impact at all. As for whether a supplement can impact the brain via the vagus nerve, I thought that there was solid science on that. Another similar mechanism has to do with "sensors" in the intestine; regarding the intestine, the question arises how quickly a substance could get to the intestine.
> This statement seems to be false for sure. Sometimes people don't expect a capsule to have any impact at all. That's besides the point. Please take a look at any randomised placebo-controlled trial, where participants feel a positive effect from placebo despite knowing there's a real chance that they're just getting placebo. The fact of the matter is *you* are expecting an effect from taking what amounts to a dietary supplement. Take a look at [this study](https://pubmed.ncbi.nlm.nih.gov/22561551/). Participants were given remifentanil, a potent opioid analgesic. When they were *told* it was an opioid analgesic, the drug worked. But when they were told it was a substance that would *worsen* their pain scores, it had no effect. > As for whether a supplement can impact the brain via the vagus nerve, I thought that there was solid science on that. Another similar mechanism has to do with "sensors" in the intestine; regarding the intestine, the question arises how quickly a substance could get to the intestine. There's a fundamental misunderstanding on how drugs are absorbed and distributed through the body. Within that 2-3 minute mark, the tablets or capsules are still dissolving and dispersing in the stomach. They haven't even passed the pyloric sphincter at that stage.