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Serotonin Reuptake

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iksaxophone

Bluelighter
Joined
Jul 6, 2015
Messages
201
Maybe this is obvious and I'm just not seeing it but...why do SNRIs and SSRIs block the effects of classical psychedelics, and at the same time increase risk of serotonin syndrome? What chemistry is at play here?
 
I don't think they have both actions at once -premedication with SSRI tends to block the effects of drugs that need serotonin release via the SERT protein (e.g. MDMA) as well as the direct receptor agonism (due to higher absolute concentrations of serotonin) but drugs that cause serotonin release through other mechanisms (autoreceptors, MAO) can still cause SS.

You tend to only have one or the other effect, and actually SS is rarer than you would think. It's more common for SSRIs / SNRIs to block the drugs entirely.
 
sekio said:
I don't think they have both actions at once -premedication with SSRI tends to block the effects of drugs that need serotonin release via the SERT protein (e.g. MDMA) as well as the direct receptor agonism (due to higher absolute concentrations of serotonin) but drugs that cause serotonin release through other mechanisms (autoreceptors, MAO) can still cause SS.

You tend to only have one or the other effect, and actually SS is rarer than you would think. It's more common for SSRIs / SNRIs to block the drugs entirely.
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I'm not sure I agree with this mechanism. First of all, most common psychedelics have extremely high binding affinity to relevant 5HT receptors and can easily displace serotonin. Secondly, if serotonin was really out competing all the psychedelics at occupying receptors, then surely you'd just trip anyway. Unless, of course, psychedelics are biased in their signalling and activate a different pathway to that activated by serotonin. Although I have heard serotonin activates all the signalling pathways.
 
That's reassuring that SS is uncommon. I take it the psychedelics are in the group that needs SERT protein?

Aced126, I'be heard that increased concentrations of serotonin in the brain doesn't cause trips....if excess serotonin outcompetes a psychedelic at the receptors you just get the symptoms of SS.
 
Oh, maybe I wasn't clear, I meant that the higher absolute concentrations of serotonin induced by regular SSRI usage causes downregulation of serotonin receptors nonspecifically.
 
iksaxophone said:
That's reassuring that SS is uncommon. I take it the psychedelics are in the group that needs SERT protein?

Aced126, I'be heard that increased concentrations of serotonin in the brain doesn't cause trips....if excess serotonin outcompetes a psychedelic at the receptors you just get the symptoms of SS.
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Psychedelics directly bind to relevant 5HT receptors and thus do not require SERT to exert their effect.
 
it's the opposite... lower Ki means higher affinity since it's a dissociation constant that represent the inhibitor's concentration that would occupy 50% of his target if there was no agonist or substrate competing with it
 
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