Serotonin and LSD

[$linky]

Hmm If you're not able to understand MeDievIL's post, I'm doubtful that even if sources were provided, it would be difficult even more so tbh!

I really don't think MeDieViL said anything obscure, for the Advanced DD.

I understand everything he said, I had just never heard it before. I still am weary of saying concretely, that the reason for the unique effects of hallucinogens is because of the changes in signalling pathways. I wanted the sources, precisely because I can understand them, and am interested in reading the research. I'm a skeptic by nature, that is a good thing in this field remember.

 

[Hitoshi]

In the long run, SSRI antidepressants reduce the number/sensitivity of serotonin receptors, but SSRIs don't directly act on the receptors; they affect the transport system. Right?
Unlike taking a serotonergic substance like 5-HT or tryptophan, the SSRI seems to be engineered to achieve a certain effect on the transport of serotonin. SSRIs action/effect on the transport is the primary effect. Right? The SSRI itself isn't a dose of serotonin, right? the increase in available synapse serotonin is the result of effecting the transport, right?
The down-regulation of receptors is a secondary effect: it is due to the flooding of the receptors with excess serotonin. The initial action on the transport system that allows the flooding (prevents the reuptake) seems to be less well understood. Can anyone explain how the flooding occurs in the first place? which then has the secondary effect of down-regulating receptors. If anyone can straighten out this cause/effect it would be great. Which came first--the flooding of receptor sites with serotonin or the down regulation of reuptake receptors?
How much of the action of SSRIs is theoretical because can't be directly measured?
Is anyone here a neuroscientist?

 

[MeDieViL]

Blocking the transporter prevents the brain from throwing serotonin in the bin, thus it stays to activate your receptors, simple as that.

What do you mean what is theoretical? cutting open rodents makes it possible to measure everything, the happy rats didnt live long.

im not a neuroscientist i just like learning from scientific journals and putting them all togheter often coming to differened conclusions as whats generally accepted, may be wrong about some things for me and you to gues and the brain to know.

 

[Hitoshi]

QUOTE=There's alot of receptor regulation going on each benefitting diff types of depression (with a efficacy of 30% not very helpfull tough slightly better then placebo.)

What was the efficacy rate in rats?

 

[Ektor]

There is something i keep hearing from internet people that i cant really get/doesnt make much sense to me.

And thats the reason why ssri blunt lsd experience, people often say that the reason of such an effect is that ssri increase synaptic concentration of serotonin which in turn competes with LSD at 5HT2A receptor, making LSD bind less at such receptor and so decreasing its effects.

If serotonin competes with LSD at 5HT2A receptor, by common sense, it wouldnt decrease lsd effect because the 5HT2A would still be activated by serotonin!!!!

So,
the LSD blunting effect (of long/intermediate term use) of SSRI comes from receptor downregulation/desensitization caused by high conc of serotonine or,

LSD and serotonin have different activity/efficacy at 5HT2A, more precisely serotonin'd have to behave more like a partial agonist to that receptor in comparison with LSD which would have to be more full agonist-like at said receptor, however the fact is that i have often read that LSD is a PARTIAL AGONIST at 5HT2A and unless serotonin itself is a partial agonist at the 2A i cant see why LSD displacement by serotonin would result in decreased effects, I would really like to see values of Intrinsic Activity of serotonin and LSD at 5HT2A to understand better their relative efficacy.
Maybe 5HT2A receptor is so complex that doesnt follow the linear pattern of agonist/partial agonist/ antagonist, so maybe LSD and serotonin activate that receptor in radically different ways thus explaining competition.

Another possible explanation of SSRI blunting of LSD could be that serotonin activity at receptors that aren't target of LSD could simply counterbalance the overall psychedelic experience.

So, all my discourse about direct competition won't make sense if before we can't rule out the effect of receptor desensitization/downregulation on SSRI blunting of LSD,
a suggestion would be to investigate if even a non-chronic, single coadministration, of SSRI with LSD will decrease the psychedelic effects.
If it doesnt decrease, then the said effect is almost surely due to desensitization/downregulation, which occurs only (maybe) with cronic SSRI use,
but if psychedelic effect does indeed decrease it could be because of direct comperition OR more general unspecific effects.

Long story short, how to discriminate between these two last possibilities? anyone with LSD and serotonin Intrinsic Activity values on 5HT2A???

Meditate people, meditate!!!

 

[endotropic]

There is something i keep hearing from internet people that i cant really get/doesnt make much sense to me.

And thats the reason why ssri blunt lsd experience, people often say that the reason of such an effect is that ssri increase synaptic concentration of serotonin which in turn competes with LSD at 5HT2A receptor, making LSD bind less at such receptor and so decreasing its effects.

If serotonin competes with LSD at 5HT2A receptor, by common sense, it wouldnt decrease lsd effect because the 5HT2A would still be activated by serotonin!!!!

So,
the LSD blunting effect (of long/intermediate term use) of SSRI comes from receptor downregulation/desensitization caused by high conc of serotonine or,

LSD and serotonin have different activity/efficacy at 5HT2A, more precisely serotonin'd have to behave more like a partial agonist to that receptor in comparison with LSD which would have to be more full agonist-like at said receptor, however the fact is that i have often read that LSD is a PARTIAL AGONIST at 5HT2A and unless serotonin itself is a partial agonist at the 2A i cant see why LSD displacement by serotonin would result in decreased effects, I would really like to see values of Intrinsic Activity of serotonin and LSD at 5HT2A to understand better their relative efficacy.
Maybe 5HT2A receptor is so complex that doesnt follow the linear pattern of agonist/partial agonist/ antagonist, so maybe LSD and serotonin activate that receptor in radically different ways thus explaining competition.

Another possible explanation of SSRI blunting of LSD could be that serotonin activity at receptors that aren't target of LSD could simply counterbalance the overall psychedelic experience.

So, all my discourse about direct competition won't make sense if before we can't rule out the effect of receptor desensitization/downregulation on SSRI blunting of LSD,
a suggestion would be to investigate if even a non-chronic, single coadministration, of SSRI with LSD will decrease the psychedelic effects.
If it doesnt decrease, then the said effect is almost surely due to desensitization/downregulation, which occurs only (maybe) with cronic SSRI use,
but if psychedelic effect does indeed decrease it could be because of direct comperition OR more general unspecific effects.

Long story short, how to discriminate between these two last possibilities? anyone with LSD and serotonin Intrinsic Activity values on 5HT2A???

Meditate people, meditate!!!

Psychedelic effects of 5-HT2a agonists tends not to depend on efficacy per se (DOI = full agonist, LSD = partial agonist). Also last I checked serotonin is still considered a full agonist at every serotonin receptor (gets ready to eat those words), so you can't really use efficacy to explain its lack of psychedelic effects. I'm not even going to pretend I understand how some 5-HT2a agonists cause psychedelic effects but others (lisuride, serotonin) have none. We started discussing this here but didn't get very far: http://www.bluelight.ru/vb/threads/620862-5-HT2a-Highest-Efficacy-Agonists

There might be some better discussion archived out there somewhere, but this is the only one I can remember recently.

I don't think there is much evidence that chronic SSRI use downregulates 5-HT2a receptors in humans (let me know if you want links to some PET studies), but its still possible the receptors are being desensitized in other ways. Also I'm not sure if your idea for a single administration of an SSRI with LSD would prove anything definitively, remember that initially SSRI treatment only causes very modest increases in extracellular serotonin, so full blown psychedelic effects in the face of acute SSRI treatment could just be due to sub-maximal serotonin increases. I'm sure someone around here has tried it though, so let us know how it went!

 

[Hitoshi]

Ektor--I agree, the observed facts have not been explained.
1. why does use of SSRI diminish psychedelic effects of such drugs as LSD?
2. SSRI discontinuation causes LSD-like phosphenes -=-lots of reports of this. I took LSD years ago and that is the only time I ever got any effect like the flashing, swirling light visuals that I experience when in withdrawal from SSRI
3. SSRIs are not classic antagonists or agonists--they don't directly affect the receptors--they affect the SERT.
4. receptors are desensitized (down regulated) over time due to flooding of synapse with serotonin --this is a secondary effect.

 

[Hitoshi]

1. SSRIs impede psychedelic effects of LSD

2. Withdrawal from SSRI use can cause psychedelic effects

3. these are two sides of the same coin

4. what is the coin?

what do SSRIs and LSD have in common?
1. 5HT2a
2. ?
3.?

whatever the SSRI is doing that impedes LSD, the reversal of that effect occurs when discontinuing the SSRI: withdrawal produces effects of psychedelic visuals such as phosphenes

 

[skillet]

Serotonin has 100% efficacy by definition, the efficacy of a drug is given as a percentage of that of the endogenous ligand.

LSD and serotonin have different activity/efficacy at 5HT2A, more precisely serotonin'd have to behave more like a partial agonist to that receptor in comparison with LSD which would have to be more full agonist-like at said receptor, however the fact is that i have often read that LSD is a PARTIAL AGONIST at 5HT2A and unless serotonin itself is a partial agonist at the 2A i cant see why LSD displacement by serotonin would result in decreased effects, I would really like to see values of Intrinsic Activity of serotonin and LSD at 5HT2A to understand better their relative efficacy.

Efficacy has nothing to do with it, LSD and serotonin have similar affinities to the 2A receptor. If you have a receptor surrounded by 100 molecules of LSD and 100 molecules of serotonin it'll spend about as much time binding LSD as it will serotonin. If you increase the serotonin concentration so there are 1,000 molecules, it'll spend about 10x as much time binding serotonin as it will LSD, so the response to the LSD will be reduced.

So I think it's possible simple competition explains some of it, and yeah, downregulation/desensitisation might help as well.

Also I'm not sure if your idea for a single administration of an SSRI with LSD would prove anything definitively, remember that initially SSRI treatment only causes very modest increases in extracellular serotonin, so full blown psychedelic effects in the face of acute SSRI treatment could just be due to sub-maximal serotonin increases.

I don't know about that, 'citalopram challenge' is used in neuroimaging of the serotonin system because it causes a rapid rise in serotonin levels. But I can't find anything specific. You can certainly feel it pretty quickly.

2. Withdrawal from SSRI use can cause psychedelic effects

Uhh, I'm sceptical Visual weirdness by no means equals psychedelia.

 

[endotropic]

Efficacy has nothing to do with it, LSD and serotonin have similar affinities to the 2A receptor. If you have a receptor surrounded by 100 molecules of LSD and 100 molecules of serotonin it'll spend about as much time binding LSD as it will serotonin. If you increase the serotonin concentration so there are 1,000 molecules, it'll spend about 10x as much time binding serotonin as it will LSD, so the response to the LSD will be reduced.

What you're talking about here is affinity, LSD and serotonin may have ~= affinities, but they definitely have different efficacy at 2a. DOI and serotonin probably have equal efficacy at 2a for comparison.

I don't know about that, 'citalopram challenge' is used in neuroimaging of the serotonin system because it causes a rapid rise in serotonin levels. But I can't find anything specific. You can certainly feel it pretty quickly.

You're right, an SSRI will very rapidly raise serotonin levels, but the elevation will be submaximal for weeks. All I meant to say is that the elevation following an acute dose might not be high enough to counter LSD's effects, while the elevation following chronic dosing will be much higher, possibly enough so to counter psychedelic effects.

 

[skillet]

What you're talking about here is affinity, LSD and serotonin may have ~= affinities, but they definitely have different efficacy at 2a. DOI and serotonin probably have equal efficacy at 2a for comparison.

Efficacy doesn't matter, they can only cause an effect while they're bound and the extent of binding is determined by affinity and concentration.

You're right, an SSRI will very rapidly raise serotonin levels, but the elevation will be submaximal for weeks. All I meant to say is that the elevation following an acute dose might not be high enough to counter LSD's effects, while the elevation following chronic dosing will be much higher, possibly enough so to counter psychedelic effects.

I'd think the elevation is higher initially and then drops a bit/a lot as SERT is upregulated, but I'm not sure.

 

[specialspack]

Efficacy doesn't matter, they can only cause an effect while they're bound and the extent of binding is determined by affinity and concentration.

But the the relative efficacy of the different intracellular signalling pathways do appear to matter - AA accumulation vs IP accumulation, since psychedelic agonists tend to favour AA accumulation over IP, according to Parrish's thesis..?

 

[skillet]

It matters if you want a psychedelic, we were just talking about whether serotonin could compete for 5-HT2A with other agonists.

And I'm not convinced AA is the key, this paper suggests it's more to do with signalling via Gi.

 

[Hitoshi]

now that is an advanced discussion! Thanks all!!