Evening Glory - Where have you been all of my life? Seriously, you just answered 90% of the questions I've chewed on over the years with regard to SSRI's, MDMA, and their inner workings in the brain. I now also completely understand why SSRI's block the effects of MDMA! I'm now going on to read the rest of this thread, as I see you have supplied much more info. in the following posts!

Good stuff! Nice work! Peace!
-idt

Thanks for your wonderful words, brother! I am really just glad I can help. There is so much great knowledge from wonderful people in here, but we lack good information on pharmacology. As I have some knowledge on this subject, I hope I can help more with it in the future!

Please let me know if anyone reading this still have some questions. To the thread starter, I believe you have the answer to why SSRIs (even combined with 5-HTP) don't give you the empathogenic rush some would expect. No matter how you twist it, to block the serotonin transporter can not even be compared to reverse it's way of action.

I have some additional questions / comments on this thread. As a former prescribed SSRI user (now off of them thankfully) I will add some personal experience:

1.) When I was taking daily SSRI's (always at the low to medium efficacy levels for adults), I would not get ANY effects at all from MDMA (ecstacy), regardless of the dose. This to me would indicate that serotonin MUST be the primary neurotransmitter creating effects from MDMA and it's relatives, and that norepinephrien, and dopamine transmission have little to do with the effects. Is this a flawed theory?

An additional note is that SSRI's never had any effects on the efficacy of triptamines of any sort for me, only the MDMA family.

Additionally, (and this was reckless of me, but...) I WOULD occasionally get that warm serotonin bliss when taking SSRI's in combination with other over the counter serotonin "boosters" such as 5-HTP and St. John's Wort. This effect was remarkably increased with the addition of alcohol. At one time I was taking something called Anxietol-7, which is a compound of a whole host of homeopathic herb's and molecular precursors. Combining the SRRI, Anxietol, and alcohol was an almost overwhelming sense of well being and bliss. Much, much more than any one of the substances on their own. The effect was comparable to a mild to moderate dose of ecstacy w/o the slightly psychedelic indications in sight and sound. FYI... this was discovered out of ignorance on my part, and not necessarily intentional for the purpose of "getting high".

2.) With regard to MAOI's and RIMA's. How do they act on the neurotransmitters? I realize that they bind to MAO's and render them ineffective, and thus the body produces more serotonin. What is confusing to me is how they can cause serotonin syndrome when they are combined with SSRI's. If SSRI's act as closed gates on the receptors, it seems like one would have the same reaction with MAOI's / RIMA's (i.e. no effects), as they do with ecstacy.
If I were to take a stab at answering this question, I would say it's that MAOI's / RIMA's actually INCREASE the levels of serotonin in the body, where as ecstacy merely changes how the existing serotonin is managed by the brain. This would make sense to me, because it would mean that the body is producing excess serotonin, but because of the SSRI, it is unable to process it, hence serotonin poisoning or overdose / serotonin syndrome. Is my thinking correct here?

I love learning about this stuff. In hind site, I should have spent my higher education money on neuro-chemistry instead of business and engineering!

Peace!
-idt

1) The reason for the lack of effects from MDMA would obviously be that the serotonin transporter is blocked, so it's way of action can't be reversed. It is certainly true that serotonin plays the most prominent role, it is the reason behind the empathogenic effects.

The complete effects of MDMA is, however, from a combination of excessive serotonin and dopamine (and to a lesser extent norepinephrine) levels. A user on SSRI should therefore feel some dopamine and norepinephrine stimulation. If not, the SSRI could act on these systems as well, not every SSRI is as selective as the name implies.

Take a look at this picture from the Dancesafe slideshow:


Here you see the inner workings of serotonin. Serotonin (the red 'dots' is transported from the synapse into the axon (the blue area to the left) through the reuptake transporter (the arrowed ring). Some of it makes it's way back into the vesicle, where it is released into the synapse again by vesicle trafficking. Now, with MDMA, this gets really interesting.

MDMA will find it's way into the synapse, side-by-side with serotonin. As MDMA has a higher affinity for the serotonin reuptake transporter than serotonin does (a flawed creation, I must say, God!), it binds to the transporter instead of serotonin. Then the transporter change it's direction, and release MDMA into the axon.

By reasons beyond my knowledge, the transporter's configuration is now changed by MDMA to accept cytoplasmic serotonin from the axon. Serotonin therefore binds to the transporter, the transporter turns, and serotonin that earlier was in the axon is released into the synapse. Then MDMA binds again, and the cycle repeats. The transporter's way of action is now effectively reversed for the duration MDMA is to be found inside the synapse.

SSRIs have a higher affinity for the transporter than serotonin, just as MDMA does. While MDMA change the direction of the transporter, SSRIs does nothing but sit in the transporter, and therefore rendering it useless in transporting any serotonin out of the synapse. If you were to take MDMA now, there would be no (or at least very few) transporters it could act on, as SSRIs have a higher affinity for the transporters than MDMA.

Serotonin is made inside the axon through the conversion of 5-HTP. When more 5-HTP is added, more serotonin will indeed be made. This does, however, have some limitations - you can't simply eat a lot of 5-HTP and then get a lot of serotonin. The body will get rid of whatever 5-HTP it does not deem necessary.

The serotonin now made from 5-HTP is readily available for vesicle trafficking into the synapse. SSRIs do, however, also reduce this trafficking by binding to 5HT-1B and 5HT-1D receptors. Even though this trafficking is reduced, it is by no means completely stopped. If it were, synaptic serotonin levels would stay exactly the same on SSRIs as without, but SSRIs cause a slight increase.

2) MAO works in the axon. If you now were to take MAOIs, the serotonin in the axon would not be broken down, thus dramatically increasing serotonin levels. This would cause a lot of serotonin to get into the vesicle. A lot of serotonin would therefore be trafficked from the vesicle into the synapse.

While vesicle trafficking is partly inhibited by SSRIs, it is not completely inhibited. Potentially too much serotonin would therefore be trafficked into the synapse. This serotonin can't get out, because the serotonin transporter is blocked. That can lead to serotonin syndrome.

You have the exact same problem with MDMA. Therefore, never ever combine MAOIs with neither SSRIs nor MDMA.


Higher education, you say? That is not needed - all the knowledge is out there, just grab whatever you want!

I hope this helps!

Peace

Thanks a lot for your post Evening Glory. I read it carefully, and have one question:
you wrote:
>>While vesicle trafficking is partly inhibited by SSRIs, it is not completely inhibited. Potentially too much serotonin would therefore be trafficked into the synapse.<<
How would completely inhibiting the trafficking cause more serotonin to be trafficked into the synapse? Wouldn't inhibiting trafficking cause LESS serotonin to be trafficked into the synapse?

An Important note... Until my most recent experience I was using enteric coated 5htp. I chewed them up in this experience and I believe it changed the effects dramatically (much faster onset, though may have caused nausea).

I took 10mg escitalopram, and 4-5 hours later I consumed I believe 400mg of 5htp (chewed up enteric coating). For several hours, this experience closely resembled the 20mg escitalopram experience I had. (note I do NOT take escitalopram regularely).
I felt like I wanted to puke (likely the chewed up 5htp). There was a feeling of being stimulated, but it wasn't emotional (I didn't get into music as much, or feel very good). It wasn't mental, as I found that my thoughts seemed 'less frequent', and it wasn't an 'adrenaline' type of feeling. Almost like my brain was being overstimulated, but not in any way that was pleasant or even very interesting. It was very hard to put my finger on, but quite noticeable.
I find this hard to understand. There was a definite effect, but it was almost entirely neutral to unpleasant.
SURELY if more serotonin in the synapse = more happiness/empathy/good body feeling, and my effects must have been due to more serotonin in my synapses, then why did I receive not so much as a 'really good mood'?

Cheers,
Crisp

I would like to briefly interject and say this is an excellent discussion, fellas! Thanks!