SSRI vs MDMA/LSD

[hawaii]

Good afternoon everyone, I have this question in my mind for a few weeks and here's the place I might get some more infos.
Pardon me for the newbe type of question but, as SSRI and MDMA/LSD and other psychedelics affect serotonin, which are the similarities between anti-depressant and serotonigenic drugs?
Or are they their complete opposites?
How do they work?

 

[phuckingnutz]

Quick answer: SSRI keeps 5-HT in the synapse longer and a serotonergic psychedelic such as LSD USES the 5-HT receptor to affect a change in your brain...

 

[.:Holy::Toast:.]

None at all, serotonergic psychedelics work by essentially mimicking serotonin and acting as a substrate for specific serotonin receptors, more specifically 5-HT2A and 5-HT2B iirc.
MDMA works by causing a large release of serotonin and oxytocin and dopamine to achieve it's effects, whereas SSRI's block the reuptake of serotonin ensuring more serotonin is kept in the synaptic cleft so more receptor stimulation occurs.
The effects are not similar at all, although MDMA can cause some psychedelia due to slight 5-HT agonism

 

[hawaii]

So they are complete opposites?
Where SSRIs tend to keep the serotonin "closed", psychedelics increase its release?

 

[hawaii]

Again, sorry if I might sound confusing but I have no clear ideas of how the brain works

 

[phuckingnutz]

http://en.wikipedia.org/wiki/Serotonergic_psychedelic

this'll tell you more than I can...

 

[Black]

None at all, serotonergic psychedelics work by essentially mimicking serotonin and acting as a substrate for specific serotonin receptors, more specifically 5-HT2A and 5-HT2B iirc.
MDMA works by causing a large release of serotonin and oxytocin and dopamine to achieve it's effects, whereas SSRI's block the reuptake of serotonin ensuring more serotonin is kept in the synaptic cleft so more receptor stimulation occurs.
The effects are not similar at all, although MDMA can cause some psychedelia due to slight 5-HT agonism

for psychedelics it's 5-HT2A and 5-HT2C, although most popular (and imho subjectively nicer) psychedelics have an appreciable affinity for 5-HT2B too (iirc LSD has the highest affinity for 5-HT2B as opposed to other serotonin receptors).

MDMA actually binds to 5-HT2B and mediates serotonin release that way (5-HT2B activation sends serotonin back outside via SERT) and blocking 5-HT2B abolishes most effects from mdma in rats. of course that's not the only mechanism of action for mdma, but right now it looks to be the most important imho.

 

[shoo-bop]

Hello Hawaii, the thing you need to understand is that each neurotransmitter (e.g. serotonin, dopmaine, glutamate, GABA, etc.) has multiple different kinds of receptors that do different things when they're activated. So for example, transmitter "X" might influence mood when it activates receptor "type 1", but influence appetite at receptor "type 2". Some transmitters might even do the opposite at one type of receptor compared to what they do at another one of their receptors! Plus, each neurotransmitter also has a transporter which controls its levels in the synapse (synapses are the spaces between the end of one neuron and the beginning of another, where there are usually a range of types of receptors).

A drug that influences receptors might act at one specific type of receptor or transporter, or multiple ones. At each receptor, it might block it from being activated (antagonist), activate it fully (full agonist) or partially (partial agonist), or in the case of some kinds of receptors, make it do the opposite of what it usually does (inverse agonist, which again, can be partial or full). If it acts at a transporter, it might increase its activity (reuptake enhancer), block its activity (reuptake inhibitor), or reverse it (release the neurotransmitter back out through the transporter). So even if two drugs are both "serotonergic" (or any other "-ergic"), their effects can be vastly different.

In the case of LSD, it's a partial agonist at very specific serotonin receptors (5-HT-2A, most importantly), so it activates those serotonin receptors, but not others (and I think it also has some activity at dopamine receptors?). In the case of MDMA, it causes massive release of serotonin (and some other monoamines) into synapses, causing generalised activation of a large number of receptor types, and ALSO activates some receptors itself. In the case of SSRIs, all they do is block the transporter to increase synaptic serotonin levels, but not as dramatically as MDMA, and usually in a more stable, long-term fashion, and they also don't usually affect other monoamine transporters (e.g. dopamine, noradrenaline) as much as MDMA (hence the "SS" standing for "selective serotonin")

 

[Xorkoth]

LSD actually is quite promiscuous and interacts with a wife variety of receptors, though, as you said, primarily 5-HT2a.

 

[.:Holy::Toast:.]

So they are complete opposites?
Where SSRIs tend to keep the serotonin "closed", psychedelics increase its release?

Ok so very simply, MDMA causes a large release of serotonin (in this case the red things) and floods your brain and receptors with serotonin, causing lots of receptor stimulation (the little curved things on the right side of the synapse in the picture.
This picture is not perfect because it does not show reuptake, but after the serotonin stimulates the receptor it can be taken up by the pre synaptic neuron (on the left) via transporters to be reused again, and SSRI's block this from occurring so more serotonin is kept in the synaptic cleft to repeatedly stimulate receptors.
Now psychedelics are different from both entirely.
They do not affect neurotransmitter release (at least not to an appreciable degree, their mechanism of action is not derived from that mechanism) and instead mimic the shape of serotonin, allowing them to fit into some receptor sites.
The lock and key analogy is best, with the receptor sites being the different locks, and psychedelics being the key which fits in to this.
This way, they are able to stimulate receptors without affecting neurotransmitter levels in your brain.

 

[Black]

LSD actually is quite promiscuous and interacts with a wife variety of receptors, though, as you said, primarily 5-HT2a.

i've found that nice graph for lsd's affinities again (lower bars mean higher affinity).

apparently i mixed up the thing with lsd's affinity for 5-ht2b with 1a or 5b or something.

 

[.:Holy::Toast:.]

Those are some seriously non selective binding affinities haha

 

[hawaii]

Ok so very simply, MDMA causes a large release of serotonin (in this case the red things) and floods your brain and receptors with serotonin, causing lots of receptor stimulation (the little curved things on the right side of the synapse in the picture.
This picture is not perfect because it does not show reuptake, but after the serotonin stimulates the receptor it can be taken up by the pre synaptic neuron (on the left) via transporters to be reused again, and SSRI's block this from occurring so more serotonin is kept in the synaptic cleft to repeatedly stimulate receptors.
Now psychedelics are different from both entirely.
They do not affect neurotransmitter release (at least not to an appreciable degree, their mechanism of action is not derived from that mechanism) and instead mimic the shape of serotonin, allowing them to fit into some receptor sites.
The lock and key analogy is best, with the receptor sites being the different locks, and psychedelics being the key which fits in to this.
This way, they are able to stimulate receptors without affecting neurotransmitter levels in your brain.

So could we think that psychedelics are a "gentler" to the brain compared to MDMA, perhaps?
Instead of affecting serotonin levels they just "imitate" it for a while?

Again, sorry for the newbe questions but I'm curious and want to understand how this things work

 

[Black]

So could we think that psychedelics are a "gentler" to the brain compared to MDMA, perhaps?
Instead of affecting serotonin levels they just "imitate" it for a while?

Again, sorry for the newbe questions but I'm curious and want to understand how this things work

not necessarily. the massive release of serotonin by mdma is also mediated by it "imitating" serotonin at one receptor. but yes, mdma leaves your brain a bit lower on serotonin afterwards, while psychedelics typically do not. all in all, the brain is a hugely complex machine and we still do not understand how exactly those parts all play together

 

[777xog]

So they are complete opposites?
Where SSRIs tend to keep the serotonin "closed", psychedelics increase its release?

Not exactly.
Psychedelics are serotonin receptor agonists. I think the "opposite" of that would be a serotonin receptor *antagonist*. Those would be the class of drugs known as Antipsychotics. (http://en.wikipedia.org/wiki/Atypical_antipsychotic)