Tramadol is a Serotonin Releasing Agent, Not Reuptake Inhibitor

[rocknroll714]

Tramadol has been found to act as a serotonin (5-HT) releasing agent (SRA) ex vivo in cultured rat brain slices, an action that has been repeatedly demonstrated in three separate studies (Driessen & Reimann 1992; Bamigbade et al. 1997; Reimann et al. 1998). It induces the release of tritium-labeled serotonin ([3H]5-HT) from nerve terminals and is blocked by the serotonin reuptake inhibitor (SRI) 6-nitroquipazine (all releasing agents are blocked by reuptake inhibitors, hence why MDMA ("Ecstasy") doesn't work while on SSRIs). Conversely, however, in a single later study (Gobbi et al. 1999), tramadol has been demonstrated to act merely as an SRI with weak but negligible SRA action in vitro in cultured rat synaptosomes, and can even block the 5-HT efflux evoked by administration of the SRA d-fenfluramine. In one final study, the same author as the last found that meta-chlorophenylpiperazine (mCPP) and 4-methylthioamphetamine (4-MTA) were similarly able to induce 5-HT release in brain slices but not synaptosomes (Gobbi et al. 2002), and a potential explanation applicable to all three compounds was proposed:

In synaptosomes, mCPP and 4-MTA do not induce 5-HT release although they interact with SERTs in such a way as to antagonize the releasing effect of pCA. This in vitro finding is also at variance with the in vivo situation, where (1) mCPP does not antagonize the pCA-induced depletion of brain 5-HT (Fuller et al.1981) and (2) 4-MTA, while inducing the serotonin syndrome, does not antagonize pCA-induced neurotoxicity (present data).

The discrepancy is even more striking in the light of the data obtained in superfused brain slices preloaded with [3H]5-HT, a model that does not appear very different from ours. 4-MTA and mCPP, however, are not the only compounds that unmask differences between the two models. Tramadol, a centrally acting opioid analgesic also acting on central 5-HTergic transmission, inhibited synaptosomal [3H]5-HT reuptake (Giusti et al. 1997) and induced tritium release from [3H]5-HT-preloaded slices (Reimann and Schneider 1998).

However, in superfused rat brain cortex synaptosomes preloaded with [3H]5-HT tramadol had no releasing effect but significantly inhibited d-fenfluramine-induced [3H]5-HT release (Gobbi and Mennini 1999). Tramadol is not neurotoxic to 5-HT nerve endings, as chronic treatment did not affect [3H]5-HT uptake parameters (Giusti et al. 1997).

The discrepancy between our data and those obtained in vivo or in brain slices 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 4-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).

The lack of a cytoplasmic pool of 5-HT seems to be an intrinsic characteristic of our synaptosomal preparation more than the result of our experimental protocol. Thus, we did not find higher 5-HT-releasing effects of MTA, mCPP and tramadol when measured after a very short superfusion period, or by measuring the endogenous neurotransmitter or, most importantly, in the presence of pargyline [this paper and Gobbi and Mennini (1999)].

In translation, they suggest that in brain slices, cytoplasmic concentrations of 5-HT are retained, whereas in synaptosomes, even despite preloading them with 5-HT, they are not (probably due to being rapidly taken up into vesicles by VMAT2 and/or oxidized by MAO). Therefore, tramadol, mCPP, and 4-MTA are only able to act as SRAs in brain slices, as in synaptosomes there is nothing there to release and they act merely as weak SRIs (note that all known SRAs also act as SRIs to a much lesser extent). Conversely, SRAs like d-fenfluramine, para-chloroamphetamine (pCA), and MDMA can induce 5-HT efflux from synaptosomes because unlike tramadol, mCPP, and 4-MTA, they can force the intracellular vesicles to dump their contents, thereby providing 5-HT for release.

-----

In summary, despite a little confusion, it appears that tramadol acts as a potent and predominant serotonin releasing agent, not reuptake inhibitor. This likely plays a major role in its unique analgesic and antidepressant effects, as well as in its rapid onset of mood-related benefits. Coupled with its other pharmacological effects like mu-opioid receptor agonism, norepinephrine reuptake inhibition (yes tramadol's a pure norepinephrine reuptake inhibitor, with no releasing efficacy at all; another study investigated its effects on norepinephrine after the discovery of its serotonin releasing action and didn't come up with anything), 5-HT2C receptor antagonism, and NMDA receptor antagonism, tramadol is looking to me like a potentially incredible therapeutic agent for treating depression and anxiety.

Comments, questions, or opinions? Knock yourselves out.

P.S.: Just a note, to anyone that's tried tramadol and didn't notice anything special regarding mood-related benefits, as mentioned above, if you were on an SSRI at the time, that would have cancelled out its serotonin-releasing effects, and it would've provided far less of a boost (if any) than normally. So if you tried it already and gave up on it while on an SSRI, I highly recommend giving it another shot!

References:

• Interaction of the Central Analgesic, Tramadol, With the Uptake and Release of 5-HT in the Rat Brain In Vitro (1992)
• Actions of Tramadol, its Enantiomers, and Principal Metabolite, O-Desmethyltramadol, on Serotonin (5-HT) Efflux and Reuptake in the Rat Dorsal Raphe Nucleus (1997)
• Induction of 5-HT Release by Tramadol, Fenfluramine, and Reserpine (1998)
• Release Studies With Rat Brain Cortical Synaptosomes Indicate That Tramadol is a 5-HT Reuptake Blocker and Not a 5-HT Releaser (1999)
• 4-Methylthioamphetamine (4-MTA) and mCPP, 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 (2002)

[crayzyMed]

Very interesting post.

[nork123]

sounds interesting, do you need to have a prescription to get this stuff?

[crayzyMed]

Originally Posted by nork123

sounds interesting, do you need to have a prescription to get this stuff?

In europe you do.

[Vini Vidi Vici]

Originally Posted by rocknroll714

Tramadol has been found to act as a serotonin (5-HT) releasing agent (SRA) ex vivo in cultured rat brain slices, an action that has been repeatedly demonstrated in three separate studies (Driessen & Reimann 1992; Bamigbade et al. 1997; Reimann et al. 199. It induces the release of tritium-labeled serotonin ([3H]5-HT) from nerve terminals and is blocked by the serotonin reuptake inhibitor (SRI) 6-nitroquipazine (all releasing agents are blocked by reuptake inhibitors, hence why MDMA ("Ecstasy") doesn't work while on SSRIs). Conversely, however, in a single later study (Gobbi et al. 1999), tramadol has been demonstrated to act merely as an SRI with weak but negligible SRA action in vitro in cultured rat synaptosomes, and can even block the 5-HT efflux evoked by administration of the SRA d-fenfluramine. In one final study, the same author as the last found that meta-chlorophenylpiperazine (mCPP) and 4-methylthioamphetamine (4-MTA) were similarly able to induce 5-HT release in brain slices but not synaptosomes (Gobbi et al. 2002), and a potential explanation applicable to all three compounds was proposed:



In translation, they suggest that in brain slices, cytoplasmic concentrations of 5-HT are retained, whereas in synaptosomes, even despite preloading them with 5-HT, they are not (probably due to being rapidly taken up into vesicles by VMAT2 and/or oxidized by MAO). Therefore, tramadol, mCPP, and 4-MTA are only able to act as SRAs in brain slices, as in synaptosomes there is nothing there to release and they act merely as weak SRIs (note that all known SRAs also act as SRIs to a much lesser extent). Conversely, SRAs like d-fenfluramine, para-chloroamphetamine (pCA), and MDMA can induce 5-HT efflux from synaptosomes because unlike tramadol, mCPP, and 4-MTA, they can force the intracellular vesicles to dump their contents, thereby providing 5-HT for release.

-----

In summary, despite a little confusion, it appears that tramadol acts as a potent and predominant serotonin releasing agent, not reuptake inhibitor. This likely plays a major role in its unique analgesic and antidepressant effects, as well as in its rapid onset of mood-related benefits. Coupled with its other pharmacological effects like mu-opioid receptor agonism, norepinephrine reuptake inhibition (yes tramadol's a pure norepinephrine reuptake inhibitor, with no releasing efficacy at all; another study investigated its effects on norepinephrine after the discovery of its serotonin releasing action and didn't come up with anything) 5-HT2C receptor antagonism, and NMDA receptor antagonism, tramadol is looking to me like a potentially incredible therapeutic agent for treating depression and anxiety.

Comments, questions, or opinions? Knock yourselves out.

P.S.: Just a note, to anyone that's tried tramadol and didn't notice anything special regarding mood-related benefits, as mentioned above, if you were on an SSRI at the time, that would have cancelled out its serotonin-releasing effects, and it would've provided far less of a boost (if any) than normally. So if you tried it already and gave up on it while on an SSRI, I highly recommend giving it another shot!

References:

• Interaction of the Central Analgesic, Tramadol, With the Uptake and Release of 5-HT in the Rat Brain In Vitro (1992)
• Actions of Tramadol, its Enantiomers, and Principal Metabolite, O-Desmethyltramadol, on Serotonin (5-HT) Efflux and Reuptake in the Rat Dorsal Raphe Nucleus (1997)
• Induction of 5-HT Release by Tramadol, Fenfluramine, and Reserpine (199
• Release Studies With Rat Brain Cortical Synaptosomes Indicate That Tramadol is a 5-HT Reuptake Blocker and Not a 5-HT Releaser (1999)
• 4-Methylthioamphetamine (4-MTA) and mCPP, 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 (2002)

awesome....awesome. so this means i can almost safely take Tramadol with an SSRI!!! not really, but at least it won't kill me. ive read reports where people get extreme nausea from Tramadol when they are on SSRIs and SNRIs at the same time, but maybe its from a different mechanism.

Tramadol is sweet...but it seriously sucks to get addicted to it, and its really easy to up the dosage without even noticing that you are doing it. i suggest anyone trying it to first google tramadol addiction and withdrawl, just so they can be prepared and make an informed decision. Nevertheless, i must give props to tramadol. It helped me endure, and brought me through 4 months of extreme depression and OCD, so i could function. I can honestly say it is a more effective med than most antidepressants out there. It would be wise, to stock up, and buy at least 30,000 tablets, in case it gets scheduled. I still find it hard to believe, that such an opiate is unscheduled, and that doctors are not sufficiently aware of its properties. ....This could be a good thing, though, especially for all the pain patients who are denied relief except through SNRIs and Lyrica....and a good thing obviously for depressed people, well, good for about 2-3 weeks before they get tolerant and it stops working.

[crayzyMed]

Originally Posted by Vini Vidi Vici

awesome....awesome. so this means i can almost safely take Tramadol with an SSRI!!! not really, but at least it won't kill me. ive read reports where people get extreme nausea from Tramadol when they are on SSRIs and SNRIs at the same time, but maybe its from a different mechanism.

Tramadol is sweet...but it seriously sucks to get addicted to it, and its really easy to up the dosage without even noticing that you are doing it. i suggest anyone trying it to first google tramadol addiction and withdrawl, just so they can be prepared and make an informed decision. Nevertheless, i must give props to tramadol. It helped me endure, and brought me through 4 months of extreme depression and OCD, so i could function. I can honestly say it is a more effective med than most antidepressants out there. It would be wise, to stock up, and buy at least 30,000 tablets, in case it gets scheduled. I still find it hard to believe, that such an opiate is unscheduled, and that doctors are not sufficiently aware of its properties. ....This could be a good thing, though, especially for all the pain patients who are denied relief except through SNRIs and Lyrica....and a good thing obviously for depressed people, well, good for about 2-3 weeks before they get tolerant and it stops working.

I wouldnt be too sure that it wont kill you.

[Freesix88]

Time to order some tramadol. Can I take it with klonopin?

[crayzyMed]

Originally Posted by Freesix88

Time to order some tramadol. Can I take it with klonopin?

Yes, in theory it should even slow tolerance to klonopin down (due to its NMDA antagonism) if its strong enough as a nmda antagonist atleast.

[jim_morrison]

Originally Posted by Freesix88

Time to order some tramadol. Can I take it with klonopin?

Be careful, combining benzos with opioids isn't the greatest idea in general, albeit tramadol seems to be a fairly weak opioid so idk.

[RockiNToM]

As said before, if you want to know about my experience with tramadol and its anti-depressant effects read here:

http://www.socialanxietysupport.com/...ression-74753/

Also warning to others, the information I have given is my own experience, and is not something to be taken as medical advice.

[Vini Vidi Vici]

Originally Posted by crayzyMed

Yes, in theory it should even slow tolerance to klonopin down (due to its NMDA antagonism) if its strong enough as a nmda antagonist atleast.

i believe it must have slowed my tolerance somewhat....because Xanax continued to help me, even for about 3 months, in general i should have been completely tolerant by then, taking 4 mg every day. Well i guess some people report absolutely no tolerance to Benzos anyway....butstill.