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Serotonin and LSD

Hitoshi

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Nov 1, 2012
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During withdrawal from an SSRI antidepressant (Zoloft) some people experience visual distortions like the phosphenes caused by LSD. Can anyone help with a possible neurochem explanation of this?

Premise: Both SSRIs and LSD have primary effect on serotonin. My hypothesis is that during withdrawal of the SSRI, serotonin levels are randomly fluctuating as the native system tries to adjust to absence of the SSRI, in order to once again take over serotonin transport on its own (the SSRI having overridden the system for a number of years)--it takes time for the receptors to regain equilibrium so the system is in flux during the withdrawal period. (For some this w/d from SSRIs results in brain zaps and all manner of bizarre brainery, but my only concern here is with the LSD-like visuals).

In what way might the SSRI w/d situation be similar to taking LSD -- from a chemistry/pharmacology perspective?

Since both drugs primarily effect serotonin, there's an obvious general connection. What I'm trying to find out is more specific -- if anyone with a lot more neurochemistry background than i have can suggest any biochemical explanation for why SSRI withdrawal can mimic LSD visuals, i would really appreciate your suggestions.
Note: in this case study there is no possibility that SSRI withdrawal effects are caused by LSD or LSD-flashbacks.
 
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People have a lot of misconceptions about visual distortions. It may be the result of taking too much acid, or it could be simply from any shock the body undergoes. I experience visual distortions when my mood is poor.

However I do know that SSRIs inhibit the subjective "high" of psychedelics in most users; I also suspect SSRIs have somewhat of an anti-psychotic effect but this is merely a hypothesis of mine untested (and I can't find substantial evidence). This would nevertheless more explain the backlash of which you speak.
 
Right--lots of studies and anecdotal evidence confirms that SSRIs block the effects of LSD.
LSD binds to serotonin receptors while SSRIs affect the SERT-the serotonin transporter system? I think the comparison/contrast between LSD and SSRIs lies in their respective actions on serotonin as agonist/antagonist//autoreceptor down regulators . . . but I don't know enough about it. Can anyone help?
 
LSD mainly affects 5HT-2a, but also shows affinity to bind to multiple other serotonin receptors which many SSRI/anti-depressants bind to as well. some AD's and SSRI's even straight up antagonize 5HT-2a completely negating the psychological effects of LSD.
 
Is there a general consensus about how LSD's affect on 5HT-2a and other serotonin receptors causes LSD's visuals/hallucinations?
 
Is there a general consensus about how LSD's affect on 5HT-2a and other serotonin receptors causes LSD's visuals/hallucinations?

Don't think so, I haven't heard anything more specific than a decreased energy in the prefrontal cortex as a mechanism of LSD's visual effects (and psychedelics in general).

As far as I knew, the mechanism of action of SSRI's was mainly due to the down regulation of the 5-HT1a autoreceptors, with antagonism at most receptor sub-types.

While LSD's main effect was due to agonism at 5-HT2a with full agonism, partial agonism and antagonism along with some general bad-assery at the other 5-HT receptors depending on their subtype. I struggle to imagine an increased sensitivity of a receptor that reduces serotonin transmission could have the same effect as something as complex as that.

As for SSRI's as antipsychotics, a friend swears by mirtazapine for killing trips, but that might be due to its effect on NA
 
Don't think so, I haven't heard anything more specific than a decreased energy in the prefrontal cortex as a mechanism of LSD's visual effects (and psychedelics in general).

As far as I knew, the mechanism of action of SSRI's was mainly due to the down regulation of the 5-HT1a autoreceptors, with antagonism at most receptor sub-types.

While LSD's main effect was due to agonism at 5-HT2a with full agonism, partial agonism and antagonism along with some general bad-assery at the other 5-HT receptors depending on their subtype. I struggle to imagine an increased sensitivity of a receptor that reduces serotonin transmission could have the same effect as something as complex as that.

As for SSRI's as antipsychotics, a friend swears by mirtazapine for killing trips, but that might be due to its effect on NA

I'm sorry but either a lot of what you posted is wrong or I'm misunderstanding what you said. The hypothesized mechanism of action of SSRI's is an increase in synaptic serotonin in serotonergic projection areas (hippocampus, hypothalamus, frontal cortex, etc.), but the increase is submaximal at the start of treatment because of activation of 5-HT1a autoreceptors in the DRN. Once the autoreceptors are desensitized (but not downregulated) synaptic serotonin in target areas can reach therapeutic levels.

LSD is a partial agonist at the 5-HT2a receptor. A single drug can't be a full/partial agonist and an antagonist at the same receptor. LSD does have a bias for some downstream pathways over others though. I remember a few threads that talk about the bias in some depth but this is the best I can drag up right now: http://www.bluelight.ru/vb/threads/490491-functional-selectivity?highlight=lsd+biased+agonist

SSRI's can end trips if the increased synaptic serotonin is enough to outcompete the psychedelic bound to the 5-HT2a receptor. Obviously this is going to be a less effective strategy the more potent your psychedelic is. This is also partially why people on SSRI's find LSD and other psychedelics less effective (more serotonin in the synapse for LSD to compete with), although receptor downregulation/desensitization could also play a role.
 
^^ Woops, I have a tendency interchange down regulation and desensitisation :(. What I meant was that while the blockade of serotonin uptake is more widespread, the increase of serotonin is only in the somatodendritic area of the neuron (so not so useful therapeutically) until the autoreceptors have been desensitised. So wouldn't it be correct to say most of its therapeutic benefit is from the desensitisation?

As for LSD, not at the same receptor, at the different sub-types. So its a partial agonist at 5-HT2a and a full agonist at 5-HT1a and an antagonist at 5-HT1b etc etc (just an example I can't remember exactly which was which). I Could be wrong but I remember it precisely because I was surprised when I read it, as I had never heard of that before. (In "The pharmacology of LSD: A critical review" only flicked through it briefly unfortunately, I will see if I can hunt down a copy).
 
thanks for the info. Is it correct that due to legal status, there's not a lot of definitive research on LSD? ALso, is it true that absolute levels of brain serotonin can't be measured? (That these levels are inferred by observing associated responses, as in-- "LSD reduced the turnover rate of 5-HT in rats’ rate of discharge of raphe nuclei neurons located in the area of reticular formation containing most of the serotonergic cell bodies. LSD antagonizes the potentiating action of reserpine (the chemical involved with releasing large amounts of serotonin) thus lowering the levels of serotonin in the brain.)
Is all the neurochem research study of LSD done on rats --not humans?
 
^^ Woops, I have a tendency interchange down regulation and desensitisation :(. What I meant was that while the blockade of serotonin uptake is more widespread, the increase of serotonin is only in the somatodendritic area of the neuron (so not so useful therapeutically) until the autoreceptors have been desensitised. So wouldn't it be correct to say most of its therapeutic benefit is from the desensitisation?

As for LSD, not at the same receptor, at the different sub-types. So its a partial agonist at 5-HT2a and a full agonist at 5-HT1a and an antagonist at 5-HT1b etc etc (just an example I can't remember exactly which was which). I Could be wrong but I remember it precisely because I was surprised when I read it, as I had never heard of that before. (In "The pharmacology of LSD: A critical review" only flicked through it briefly unfortunately, I will see if I can hunt down a copy).

I thought that might be what you meant for LSD, that makes a lot more sense.

I would still say that the therapeutic benefit is from the increased serotonin in the target areas (hippocampus, hypothalamus, FC), but you're right this can only happen once the autoreceptors are desensitized, so I guess it just depends on how you think about it.


thanks for the info. Is it correct that due to legal status, there's not a lot of definitive research on LSD? ALso, is it true that absolute levels of brain serotonin can't be measured? (That these levels are inferred by observing associated responses, as in-- "LSD reduced the turnover rate of 5-HT in rats’ rate of discharge of raphe nuclei neurons located in the area of reticular formation containing most of the serotonergic cell bodies. LSD antagonizes the potentiating action of reserpine (the chemical involved with releasing large amounts of serotonin) thus lowering the levels of serotonin in the brain.)
Is all the neurochem research study of LSD done on rats --not humans?

Look up MAPS if you haven't already heard of them, they have a few studies on LSD in humans and quite a few other psychedelics as well. As far as measuring synaptic serotonin directly there's a method called in vivo microdialysis that can allow you to measure extracellular neurotransmitters directly (albeit on a fairly imprecise time scale). It's a fairly invasive procedure though (insert a probe into the brain) so it's the kind of measurement you can only get from a research animal.
 
Extremely good information here, thanks guys, learnt a bit! :)


....but the increase is submaximal at the start of treatment because of activation of 5-HT1a autoreceptors in the DRN. Once the autoreceptors are desensitized (but not downregulated) synaptic serotonin in target areas can reach therapeutic levels....

Interesting! Does/would continual use actually cause down regulation (of said receptors)?


...SSRI's can end trips if the increased synaptic serotonin is enough to outcompete the psychedelic bound to the 5-HT2a receptor. Obviously this is going to be a less effective strategy the more potent your psychedelic is. This is also partially why people on SSRI's find LSD and other psychedelics less effective (more serotonin in the synapse for LSD to compete with), although receptor downregulation/desensitization could also play a role.

Randomly (not including receptor down regulation/desensitisation) - what possibility is there of the use of (an) SSRI specifically indicated for treatment regarding LSD? (I don't mean as in use at the moment or anything similar, more so the effectiveness and such?) :)

Cheers
 
Psychedelics induce secondary intracellulalur pathways when activating 5HT2A, serotonin and lisuride dont do this and lack psychedelic activity.
 
As far as I knew, the mechanism of action of SSRI's was mainly due to the down regulation of the 5-HT1a autoreceptors, with antagonism at most receptor sub-types.
Depends on type of de5HTpression, 5HYT2A and c agonism will help atypical while downregulation of those and increased 5HT1A (prob 5HT4 agonism) help melancholic.
 
Depends on type of de5HTpression, 5HYT2A and c agonism will help atypical while downregulation of those and increased 5HT1A (prob 5HT4 agonism) help melancholic.

Psychedelics induce secondary intracellulalur pathways when activating 5HT2A, serotonin and lisuride dont do this and lack psychedelic activity.

Sources? You're spewing out a bunch of scientific words, and you're not making any sense. The second comment especially.
 
Ill post links tomorrow.

Search intracellular pathways on the fora or google and psychedelics, its been explained before, it does make sense.
 
Sources? You're spewing out a bunch of scientific words, and you're not making any sense. The second comment especially.

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.
 
This has indeed allready been discussed numerous times so wont bother posting sources.

Interesting! Does/would continual use actually cause down regulation (of said receptors)?
Yes,
SSRI's slowly downregulate the autoreceptors so sero levels slowly rise over the course of a few weeks. There's alot of receptor regulation going on each benefitting diff types of depression (with a effiacy of 30% not very helpfull tough slightly better then placebo.)

5HT releasers like MDAI bypass the autoreceptors and also shift balance to phasic instead of tonic serotogenic activity (and may for example help apathy instead of cause it) shulgin studied those as fast acting antidepressants.
I used MDAI in low daily doses of 30mg (few times a day) for that purpose.
 
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Interesting! Does/would continual use actually cause down regulation (of said receptors)?

When I talk about down regulation I'm using that term very specifically to mean a reduction of 5-HT1a receptors on the plasma membrane available for drug binding, as opposed to any reduced effectiveness of the drug at that receptor (which I would call desensitization). And looking at PET binding data, no, down regulation does not occur with chronic SSRI use. This has already been discussed in the history of humanity so I don't need to post sources either.
 
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