Is Tramadol a serotonin reuptake inhibitor, or a releaser?

[rnd.id.]

*delurks*
Hello bluelight, and happy new year

I would like to start a discussion on the question:
Does Tramadol merely inhibit the serotonin transporter, or does it displace serotonin from the vesicles and release it through the transporter (like MDMA)?

I think this is not hair-splitting but rather an important question, because as everyone knows, there is a huge difference between the effects of MDMA and SSRIs. In particular, two implications of Tramadol being a serotonin releaser would be:
- Tramadol would have quite a different risk profile than normal opioids
- It would give me insight that I'm not actually in love with opioids but with the serotonergic effect, which would be somewhat more palatable to me

I'm not studying in a field related to this, so this is more or less wild speculation. My own experience with this is also might be very biased because I'm seeing things through the lens of my hypothesis. (To complete the disclaimer: English is not my primary language; I'm on Tramadol at the moment; it's getting late here ).

These two abstracts say that Tramadol is a releaser:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9671098&query_hl=1&itool=pubmed_docsum
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1596676&query_hl=1&itool=pubmed_docsum

While this one says that this is not the case:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10323276&query_hl=1&itool=pubmed_docsum

The swiss "Kompendium" (enter Tramadol there, sorry, it's in german) also says (translation by me):

"Other mechanisms which contribute to the analgesic effect are the inhibition of the
neuronal reuptake of noradrenaline and the amplification/enhancement of serotonin release"

("Andere Mechanismen, die zu einer analgetischen Wirkung beitragen, sind die Hemmung der neuronalen Wiederaufnahme von Noradrenalin sowie die Verstärkung der Serotonin-Freisetzung.")

So, the scientific evidence on this appears to be inconclusive (I might have missed some papers, of course!).

Subjective experience: Tramadol clearly has empathogenic effects for me, such as:
- Improved ability to sense intuitively whether what I want to say/do is going to hurt other people's feelings
- Then, having the "energy" to act in a nice way (I *want* to be equally nice when I'm sober but for some reason, I just *can't* )
- A feeling like I'm belonging in a group (this is *very* beautiful if you don't get it when sober...)
- A general feeling of "love" towards other humans; the world appearing to be "ok"
- Apologizing more, sometimes even excessively
- Rapid talking, huge urge to communicate (well, this is not really empathetic, but it is probably related to serotonin (but also noradrenaline; don't forget it acts on that one too))
- Feeling of weightlessness and effortless movements similar to MDMA; dancing is fun

[OMG, this sounds like an advertisement. Please don't start taking tramadol because of this; it can be enormously addictive for some people.]

Unfortunately, the memories of my experiences with other opioids are fading so it is hard
for me to distinguish which of these effects are caused by all opioids (and thus not
by direct action on serotonin).

Further evidence for "releaser":
- Some other people say that it reminds them of MDMA too
- These effects appear to fade much quicker than the opioid effects - on a time course somewhat comparable to MDMA. But this is also explainable by Tramadol being metabolised to O-Desmethyl-Tramadol, which is a much stronger opioid and weaker on the monoamines. Can anyone else confirm this two-phase effect?


But then, on the other hand, the effects are still much weaker than MDMA (IIRC). Shouldn't one be able to achieve the same effects as with MDMA if Tramadol was a releaser? Well, maybe it is just a very weak releaser. Or maybe the difference is that MDMA is a dopamine releaser in addition. But then, Tramadol can increase dopamine through the mu opioid receptors too

Another thing which is strongly against Tramadol being a releaser: The comedown and after-effects are nowhere near MDMA.

The above-mentioned effects would *not* be explained by pure serotonin reuptake inhibition. SSRIs don't do this at all IMO. But I have made the following wild hypothesis (which would be against Tramadol being a releaser):
Maybe the reason why serotonin reuptake inhibition alone doesn't cause positive effects (I'm not talking about the long-term antidepressant effect) is that the serotonergic neurons just don't fire often enough, so the reuptake inhibition just can't do much. But the opioid receptor activation might indirectly cause an increase in the firing of serotonin neurons, which might be synergistic with the reuptake inhibition and resemble an actual serotonin releaser.

Well, I realise that at this point I'm probably babbling nonsense...
So I would love to hear what you people more knowledgable in this field think about this


Edit: Being high made me totally exaggerate the positive effects, sorry Looking back sober, they seem not that great and not really worth the risk of addiction!

 

[BilZ0r]

Yeah, the evidence is mixed. Most people are going to say its an uptake inhibitor, but there is some evidence that is a releaser like this. But the best evidence is this which you can see the full text of, and being synatosomes is far more convincing, and it pretty conclusively shows that it is an uptake inhibitor.

 

[hugo24]

Interesting topic,for sure.Adding to BilZOr's post:

-Tramadol is being described as atypical antidepressant on www.biopsychiatry.com (great link anyway!),as is Aniracetam.Something doctors should seriously take into consideration (I checked it with good results)-just wanted to say it.

-Serotonin release is not something pleasurable (at least in my view),MDMA feels so euphoric because of simultan Dopamin release.MBDB (Eden) is more selective and more calm,some say even a bit dysphoric.MDAI,which is very selective, appears to have this dysphoric properties rather pronounced,the few times I tasted it.But I'm not the typical Exstacy organism (needing 200-300mg and fried/avoiding the MD cluster)

-tactile enhancement from Tramadol is IMHO nil (but maybe the analgesic effect kills it?),a typical sign of serotonin releasers.Even though SSRI's have slight enhancement effects as well.

 

[lifeisforliving]

^^^ I think biopsychiatry is a little out of date on a number of issues. Read with caution - backup that discussion with searches on pubmed.com to find the actual studies.

-Serotonin release is not something pleasurable (at least in my view),MDMA feels so euphoric because of simultan Dopamin release.MBDB (Eden) is more selective and more calm,some say even a bit dysphoric.MDAI,which is very selective, appears to have this dysphoric properties rather pronounced,the few times I tasted it.But I'm not the typical Exstacy organism (needing 200-300mg and fried/avoiding the MD cluster)

From a subjective point of view from a person who has had wayyyyy too much fun abusing his dopamine system, MDMA's effecf are from the release of serotonin. The two highs feel very, very different.

Do you have any sources for the idea of MDMA releasing massive amounts of dopamine? (more so than cocaine for example).

 

[hugo24]

-point taken re: biopsychiatry

-re: massive dopamin release,no sources,only copying the theories going around.Admittetly MDMA is different to a dopamin high-maybe serotonin is like oil,masking the dopamin somehow?But if SER release alone is so different/dysphoric,there must be something else on MDMA's path,no? Maybe it doesen't need that much dopamin(+noradrenaline?) release to "kick start" euphorie?

-I'd like to point to a theory I made elsewhere ,that MDMA has some opiate effects.I found this pronounced on very high doses,even though I don't know opiates besides tramadol.But somehow found it here exactly again,years later after my E adventures.Theres a paper doing an overlap of Morphine and MDMA.

-I'm wondering about methylone,that one feels more like a dopamin suck,agree?

 

[Chuff]

Anything that gets you high or gives you a rush through either the dopamine or serotonin reward pathways will also trigger associated simultaneous circuits elsewhere in the brain, The old view of dopermine working alone through the Ventral Tegmental area to the Nucleus acumbus (septum, amygdala and prefrontal cortex) are now know to be a partial picture as the brain is very good at building additional pathways that can be more reinforcing to use than the actual drug (Carey R.J. DePalma G & Damianopolos -acute and cronic cocaine effect in novel v's familiar enviroments 2005) (martim M et al 2000 place preference sensitization cocaine but not morphine) It makes sense that if opiate activating neurotransmitters also fire off dopamine by association that the reverse is true?

I generally think in terms of systems striving towards balance when it come to brain chemistry rather than looking for action response processes though its fairly new to me

 

[BilZ0r]

MDMA definately releases dopamine, though how much of it is through an amphetamine action, and how much is subsequent to serotonin mediated-5-HT2A receptor activation is unclear.

But the percentage increases in released monoamines from MDMA in rodents go something like "MDMA produced significant increases in DA (700% at 10 mg/kg and 950% at 20 mg/kg)... MDMA also increased 5-HT (350% at 10, and 575% at 20 mg/kg)"[1]. While the increases caused by cocaine are generally more subtle. (the high dopamine vs serotonin ration probably partially reflects that the percentages were measured in the caudate, MDMA causes a bigger serotonin release in the cortex)

 

[Cagliostro]

Subjective experience: Tramadol clearly has empathogenic effects for me, such as:
- Improved ability to sense intuitively whether what I want to say/do is going to hurt other people's feelings
- Then, having the "energy" to act in a nice way (I *want* to be equally nice when I'm sober but for some reason, I just *can't* )
- A feeling like I'm belonging in a group (this is *very* beautiful if you don't get it when sober...)
- A general feeling of "love" towards other humans; the world appearing to be "ok"
- Apologizing more, sometimes even excessively
- Rapid talking, huge urge to communicate (well, this is not really empathetic, but it is probably related to serotonin (but also noradrenaline; don't forget it acts on that one too))
- Feeling of weightlessness and effortless movements similar to MDMA; dancing is fun

These effects are more likely due to the mild µ opioid effects of tramadol than it's SSRI properties.

There are two ways the body can metabolize tramadol: by O- and by N-demethylation. If you're one of those minority people who metabolize it mainly by O-demethylation, you're gonna enjoy the drug, because your body converts it into a reasonably potent opioid. If you belong to the majority who predominantly N-demethylates it, tramadol is little fun for you, because it never hits your µ opioid receptors in a meaningful way. Its SSRI properties are not particularly recreational.

 

[rnd.id.]

Thanks for your answers! Sorry to bump this old thread, but I have found another interesting paper about this. As far as I understand (please correct me if I'm wrong), they postulate that:

Neurotoxic 5-HT releasers (e.g. MDMA) both

1. displace 5-HT from the vesicles into the cytoplasm, and
2. cause release of 5-HT from the cytoplasm into the synaptic cleft through the transporters

whereas non-neurotoxic 5-HT releasers (among which they mention Tramadol) only do the latter.

p-Methylthioamphetamine and 1-(m-chlorophenyl)piperazine,
two non-neurotoxic 5-HT releasers in vivo, differ
from neurotoxic amphetamine derivatives in their mode
of action at 5-HT nerve endings in vitro

[...] can be explained by postulating that
nerve endings from intact brain tissue, but not our synaptosomal
preparation (Gobbi et al.1998, 1999), retain a
cytoplasmic pool of 5-HT and that compounds such as MTA,
mCPP and tramadol induce SERT-dependent 5-HT release
only (or preferentially) from this cytoplasmic pool (Mennini
et al.1981).Compounds such as pCA and MDMA are
capable of inducing 5-HT release from synaptosomes too
because of additional properties such as: (1) stimulation of
vesicular [3H]5-HT efflux with the consequent redistribution
of [3H]5-HT from the vesicles to the cytoplasm (Rudnick and
Wall 1992a; Rudnick and Wall 1992b; Schuldiner et al.
1993) and/or (2) direct induction of a Ca2+-dependent,
exocytotic-like release (Crespi et al.1997).

This could also explain why although tramadol feels somewhat serotonergic, it is far from MDMA.

-Serotonin release is not something pleasurable (at least in my view),MDMA feels so euphoric because of simultan Dopamin release.

Yes, but tramadol also releases dopamine indirectly via µ-opioid-agonism. Also, serotonin+dopamine release appears to be more pleasurable than dopamine alone; thus serotonin could add to the euphoric effects of tramadol.

These effects are more likely due to the mild µ opioid effects of tramadol than it's SSRI properties.

Interesting, I had thought that pure opioids make most people care less rather than more about social interaction. Is my reaction somewhat typical for opioids?