New Mechanism Proposed For Why Some Psychedelics Act As Antidepressants (arstechnica.com) 53
An anonymous reader quotes a report from Ars Technica: New data suggests that psychedelics may activate serotonin signaling in a very different way than serotonin itself can, reaching the receptors in parts of the cell that serotonin can't get to. Serotonin signaling is complicated. There are seven classes of receptors in humans; some activate signaling pathways, while others inhibit them. One group of receptors allows ions into a cell in response to serotonin, triggering nerve impulses. The rest interact with proteins inside the cell, triggering longer-term responses to serotonin. Psychedelics such as LSD and mescaline bind to members of this latter group and activate it.
This action produces some rather dramatic changes in how people perceive their surroundings. But there's also some evidence that psychedelics promote changes to nerve cells that allow these cells to alter their connectivity. This occurs by causing the structures that receive input from other nerve cells, called dendrites, to grow and branch, potentially allowing additional or altered inputs. One hypothesis is that this altered connectivity allows cells to escape whatever network configuration has been associated with a medical disorder. The researchers confirmed these results using DMT, a psychedelic found in ayahuasca, and psilocin, the active form of the drug psilocybin, which is typically obtained from mushrooms. Twenty-four hours after mice received one of these drugs, nerve cells in their brains had an increased density of extensions from their dendrites. This growth was accompanied by an increased frequency of activity in individual nerve cells. Running the same tests in mice that lacked the gene for the specific serotonin receptor that these drugs target blocked both of these effects, confirming that serotonin signaling is central to the changes.
The researchers then started testing close chemical relatives of the drugs and saw a clear pattern: Making the drug less likely to interact with water boosted their effects on neurons. This suggested that the ability to cross membranes, which are very water-repellant, might be needed to promote changes in dendrites. To confirm this, the researchers poked holes in the membranes, which boosted the activity of water-friendly drug variants that wouldn't readily cross the membrane. This is all a bit confusing because the serotonin receptors sit inside the membrane and interact with the cell's exterior. They have to -- that's where the serotonin is. So why would anything that interacted with those receptors need to cross a membrane to the cell's interior? The receptors on the cell's surface are definitely key to the cell's response to serotonin. But the receptors don't just magically appear on the cell's surface -- they're made elsewhere in the cell and take a while to be processed and transported to the surface. The researchers found a population of serotonin receptors sitting inside a structure called the Golgi. It's not clear whether this population is simply on its way to the cell surface or whether it's retained there by some specific biological activity. Normally, these receptors wouldn't come into contact with serotonin, so they wouldn't signal from this location. But the researchers modified a protein to make it pump serotonin inside of cells and showed that it had the same effect the psychedelics had, suggesting the receptors could be activated and that this activation was key to altering neural connectivity. The study has been published in the journal Science.
This action produces some rather dramatic changes in how people perceive their surroundings. But there's also some evidence that psychedelics promote changes to nerve cells that allow these cells to alter their connectivity. This occurs by causing the structures that receive input from other nerve cells, called dendrites, to grow and branch, potentially allowing additional or altered inputs. One hypothesis is that this altered connectivity allows cells to escape whatever network configuration has been associated with a medical disorder. The researchers confirmed these results using DMT, a psychedelic found in ayahuasca, and psilocin, the active form of the drug psilocybin, which is typically obtained from mushrooms. Twenty-four hours after mice received one of these drugs, nerve cells in their brains had an increased density of extensions from their dendrites. This growth was accompanied by an increased frequency of activity in individual nerve cells. Running the same tests in mice that lacked the gene for the specific serotonin receptor that these drugs target blocked both of these effects, confirming that serotonin signaling is central to the changes.
The researchers then started testing close chemical relatives of the drugs and saw a clear pattern: Making the drug less likely to interact with water boosted their effects on neurons. This suggested that the ability to cross membranes, which are very water-repellant, might be needed to promote changes in dendrites. To confirm this, the researchers poked holes in the membranes, which boosted the activity of water-friendly drug variants that wouldn't readily cross the membrane. This is all a bit confusing because the serotonin receptors sit inside the membrane and interact with the cell's exterior. They have to -- that's where the serotonin is. So why would anything that interacted with those receptors need to cross a membrane to the cell's interior? The receptors on the cell's surface are definitely key to the cell's response to serotonin. But the receptors don't just magically appear on the cell's surface -- they're made elsewhere in the cell and take a while to be processed and transported to the surface. The researchers found a population of serotonin receptors sitting inside a structure called the Golgi. It's not clear whether this population is simply on its way to the cell surface or whether it's retained there by some specific biological activity. Normally, these receptors wouldn't come into contact with serotonin, so they wouldn't signal from this location. But the researchers modified a protein to make it pump serotonin inside of cells and showed that it had the same effect the psychedelics had, suggesting the receptors could be activated and that this activation was key to altering neural connectivity. The study has been published in the journal Science.
Serotonin (Score:1, Troll)
https://www.quantamagazine.org... [quantamagazine.org]
Quanta magazine published an article on a meta review that fealty calls serotonin into question. Some people self medicate because it a placebo that lets them escape. Other because it relives some other issue that contributes to their inability to function. Others just want to check out.
Re:Serotonin (Score:4, Interesting)
Like so many medical myths, serotonin Is likely based on mass hallucination.
SSRIs are like blowing in a Nintendo cartridge to get the game working. It's based on a limited understanding of the actual cause of the problem, but frequently achieves the desired result. Modern antidepressant drugs are still an indisputable improvement over when they used to treat depression with lobotomies and ECT, treatments which now seem downright barbaric.
Doctors have been using the "corrects a chemical imbalance" excuse because it's better bedside manner than telling a patient their brain isn't working properly, we really don't know precisely why, and that we're going to prescribe the car analogical equivalent of Fix-A-Flat to get your brain "back on the road". There's also probably a bit of a psychological component to getting over depression, and believing that your chemical imbalance has been "corrected" might have some therapeutic value in itself.
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The best theory I have seen is that SSRIs promote more neurogenesis and/or connections.
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Re: Serotonin (Score:2)
SSRI withdrawal is the worst. I'll take opiate withdrawal over SSRI withdrawal any day.
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Does this mean correlation is causation? In my experience with people on them, it can cause mood shifts and them to consider options that they would never even think of, if they were not popping them.
One of my best friends as a teen committed suicide while on Prozac. But is it the Prozac's fault, or did the Prozac just not work? You can't call it a success either way of course.
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Don't these drugs have black box warnings for teenagers and young adults?
Re: Serotonin (Score:2)
It would be nice if the doctors would at least tell people before prescribing them SSRIs how horrible the withdrawal can be.
Re:Serotonin (Score:4, Interesting)
> serotonin Is likely based on mass hallucination
But the theory has produced multiple highly regarded -- in the medical world -- placebo medications for depression like SSRIs.
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I personally know someone who suffered deep depression for many years, with constant suicidal thoughts. In desperation, she went to Peru and participated in several ayahuasca ceremonies to try and treat it. It's been pretty successful, in that she no longer has those deep depressions and self destructive thoughts. It's got risks using it, and not something you want to do without someone to guide you through the process. She still sometimes has bad mood swings, that may be partly linked to vitamin B12 uptake
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Years ago this young youtube athlete trainer guy (Yo Elliott I think was the name of his channel) read a question from a young man who said was depressed, didn't go to college, lives in his parents' basement and works at a low-paying dead-end job he hates, and has now started to drink more and more, what should he do?
The guy then said, this may be the worst advice I've ever given, but I'll say it anyway: do something dangerous. Like, sell all your stuff and go to a small town or wilderness in Mexico. When y
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Friends have described psychedelics as a "hard reset".
My suspicion is ECT operates in the same vein.
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IMO most people never really change except in exceptional circumstances. As long as whatever you're doing is [approximately] working, you'll keep doing it. It takes some kind of profound experience to shake up your model of the world.
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Re:Serotonin (Score:4, Interesting)
If you are at the end of the line and don't see any other way out except something terminal, it's possibly worth a shot.
Very true. And ought to try mushrooms, LSD, and DMT before giving up, too. Along the way, you might come up with some other ideas.
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Some people self medicate because it a placebo that lets them escape. Other because it relives some other issue that contributes to their inability to function. Others just want to check out.
All of those things are the same thing
For those that didn't bother reading (Score:4, Informative)
IN MICE
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the dendrite growth, yes. the antidepressant effect in humans is well known and not really disputed anymore.
it's an interesting finding. too soon to say that this is the main mechanism of that effect, imo that has more to do with a cognitive process and the transformational nature of the subjective experience, but an increase in neuron connectivity does indeed make a lot of sense.
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Absolutely. Evidence-based medicine is all about using what works—and it definitely works. The key to wider acceptance of it, though, would be to show exactly how it works. While this is a neat first step in that direction, science news really needs to lead with titles or at least first paragraphs that maintain this was a rodent study.
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Well they seem to work for me as well!
I think that some depression is situational (Score:2)
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Psychedelics activate the toddler-brain. (Score:2)
They remove hibition acquired through biografical and societal programming and trauma and thus eliminate mental and emotional blockades that prevent renewed or alternative inner narratives or perspectives.
When well placed and dosed they are basically a fast-track to the positive effects of mental, philosophical, spiritual and sometimes even physical training.
That's why microdosing them can be so effective and improve mental health.
"Microdosing" being the key term here.
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Except from study referenced by MAPS, hospice patients (I'm gonna assume they weren't in the best spirits) described taking mushrooms as one of the most profound experiences in their lives and eased the anxiety in facing down death.
Microdosing wasn't mentioned.
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That's why microdosing them can be so effective and improve mental health.
i have not seen any conclusive evidence that microdosing has any remarkable effect beyond placebo, from the few research papers i could find, and from my experience it is completely counterintuitive. if 0.5g dried shrooms is considered a microdose then i have done that too and at that dose you can indeed feel good and funny but there is nothing else going on.
a fast-track to the positive effects of mental, philosophical, spiritual and sometimes even physical training.
there is no fast-track to any of that :-) i recommend a single regular dose that radically shifts your perception, of course in a curated setting, then
no fun (Score:4, Insightful)
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Fuck big farma
What do John Deere and Cargill have to do with this?!
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And as more and more people use these chemicals to become undepressed the normal (i.e. untreated) mental state will seem depressed. We're already we'll into this situation. I sometimes wonder how many psychotherapists are on antidepressants and how that affects their relationship with the patients.
It is something I noticed some years ago. A lot of people have come to believe that they must be in a state of constant euphoria - sublime happiness.
So we end up with a mix. People who are badly in need of something, because they are suffering greatly, and what I think is a majority of so called depressives - just want that 24/7 euphoria.
So we end up with people on dangerous drugs like SSRI's that probably shouldn't be prescribed like candy.
And the fix for this is to invent more and more drugs, and
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You can see where these developments are taking us, right? They'll take all the fun stuff out
Whoever can achieve that will make tons of money. It is definitely a goal.
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You make a really good point. I read an article a while back agreeing with you: we're gonna dose people up and "grow their brains" so they can be happy with being exploited, change their minds to be more corporate. Have trauma? just work through it with Soma! Then get back to work. Don't drop out of the abusive system to have a good time, just get your brain worked on!
It may explain (Score:2)
It may explain why some subset of psychedelics seek to use the drug - not for the hallucinations, but for some secondary antidepressant function. The hallucinations would just be something users put up with in order to get the antidepressive effect.
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New Normal (Score:2)
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And as more and more people use these chemicals to become undepressed the normal (i.e. untreated) mental state will seem depressed. We're already we'll into this situation. I sometimes wonder how many psychotherapists are on antidepressants and how that affects their relationship with the patients.
I dunno - probably a lot.
I get it - I'm allergic to opiates, but the time I was shortly on it after a broken ankle - there was a brief moment of euphoria before the sweats and puking started. Would that euphoric state be good 24/7? Depends on the definition of good. Not mine, but a lot of people probably would love it.
Well (Score:1)
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Your anecdote is contradicted by decades of practicing experience and extensive clinical trials.
How much farther ahead could we be? (Score:4, Insightful)
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The DEA is directly responsible for thousands or perhaps millions of suicides over forty years.
MAPS has been fighting them nearly as long. Bitcoin tilted the balance. They may be about to win, finally. Donate.
Next we deal with the notional mass graves and crimes against humanity.