Combinations - Harmlessly Potentiating Tramadol

[Gradient]

Harmlessly Potentiating Tramadol

Tramadol is a fully-synthetic opioid pro-drug with SSNRI activity. Upon ingestion, the digestive cytochrome enzymes - the cytochrome P450 family specifically - metabolize Tramadol into five distinct compounds. O-Desmethyltramadol, one of the five, has a markedly high affinity for the µ-opioid receptor, far more so than Tramadol itself. The same enzymes that convert Tramadol to its 5 metabolites, cytochrome P450, ionize these metabolites for water-soluble excretion. Therefore, the metabolism of Tramadol revolves entirely around the metabolic activity of cytochrome P450 in the liver.

Cimetidine (Tagamet) is a potent inhibitor of the cytochrome P450 enzyme, in addition to acting as a pH neutralizer. Therefore, if one were to ingest cimetidine prior to ingestion of Tramadol, one would likely experience a reduction of effects. However, if one were to wait until ingested Tramadol had time to be converted to its metabolites (30-180 mins), the ionization of the metabolites of Tramadol should be inhibited. This would be expected to enhance and prolong the effects of Tramadol at the µ-opioid receptor considerably. In sum, in order to potentiate the effects of Tramadol with cimetidine, timing and sequence is key.
In addition, subsequent to regular administration of recommended doses of cimetidine, the liver will up-regulate the expression of the enzymes responsible for converting Tramadol to its more potent metabolites. In other words, after ingesting cimetidine for a regular interval of time, one will become more sensitive to the effects of Tramadol. It should be noted, however, that this dynamic would render an individual less sensitive to other non-synthetic and semi-synthetic opiates over time.
A friendly chimp has revealed that this has been a highly effective and reliable method of potentiation. He doesn’t ingest Tramadol without cimetidine anymore. It should be noted that grapefruit juice has indeed been noted to be a cytochrome P450 inhibitor as well, though not quite as potently as cimetidine. This method should produce no anticipated ill-effects, as the magnitude of effects will never exceed the SSNRI activity inherent to the initial dose ingested. So long as one takes care not to initially ingest too-high a dose, this method of potentiation will not enhance SSNRI activity – rather, it should selectively enhance µ-opioid activity because it's the metabolites, not Tramadol, that are being enhanced.

Hope this helps to get the most bang-for-your-milligram in as safe a way as possible ! Since this method of potentiation is so distinct from typical methods for the majority of other opiates, I figured it warranted a thread of its own - I apologize if this was a mistake. I'd be quite interested to know if this works for any other chimps out there.

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Added subsequent to Richard_smoker's post: I've confirmed that the CYP2D6 is indeed responsible for both the metabolism of Tramadol to its five metabolites, as well as the ionization of o-desmethyltramadol for excretion. Therefore, the described relationship is likely to exist.

Here's a quickie abstract that suggests that cimetidine does indeed inhibit the cytochrome P450 family, and CYP2D6:
http://jcp.sagepub.com/cgi/content/abstract/40/2/193

Here's another to suggest that the O-demethylation of Tramadol is done by CYP2D6:
http://www.springerlink.com/content/910gnjjd610h24pu/

Here's a surprisingly nice wikipedia entry on the metabolism of O-Desmethyltramadol, which is indeed carried out by CYP2D6:
http://en.wikipedia.org/wiki/O-Desmethyltramadol

Please let me know if any are interested in reading the full article from either of those abstracts - I'll be happy to post them up.

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However, this doesn't necessarily mean that I'm correct! There is no study on this specific interaction (including the sequencing of ingestion of the compounds). Please suggest any potential issues with this theory that we might iron out, I'd greatly appreciate it!

Reputation Comments on this post:

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[Richard_smoker]

hmmm... you know there are several different specific subtypes of the CYP (cytochrome 450) enzyme. I can tell you a much more effective way of enhancing the drug than this approach.

Some information about which specific type of P450 enzyme breaks the tramadol down, and which one breaks down the O-Desmethyltramadol.

If there's any data out there for which enzyme breaks down the O-Desmethyl, then if that enzyme is DIFFERENT than the one which breaks down tramadol itself, then someone could presumably take a specific inhibitor of THAT p450 enzyme. this would allow the tramadol to convert into the 'better' drug which would accumulate in a hypothetical person's bloodstream because its break-down enzyme would be unavailable (cuz it's being inhibited).

[Gradient]

Originally Posted by Richard_smoker

hmmm... you know there are several different specific subtypes of the CYP (cytochrome 450) enzyme. I can tell you a much more effective way of enhancing the drug than this approach.

Some information about which specific type of P450 enzyme breaks the tramadol down, and which one breaks down the O-Desmethyltramadol.

If there's any data out there for which enzyme breaks down the O-Desmethyl, then if that enzyme is DIFFERENT than the one which breaks down tramadol itself, then someone could presumably take a specific inhibitor of THAT p450 enzyme. this would allow the tramadol to convert into the 'better' drug which would accumulate in a hypothetical person's bloodstream because its break-down enzyme would be unavailable (cuz it's being inhibited).

Richard_smoker,

Quite true. However, to the best of my knowledge, it is indeed the same enzyme: CYP2D6.

Here's a quickie abstract that suggests that cimetidine does indeed inhibit CYP2D6:
http://jcp.sagepub.com/cgi/content/abstract/40/2/193

Here's a surprisingly nice wikipedia entry on the metabolism of O-Desmethyltramadol, which is indeed carried out by CYP2D6:

http://en.wikipedia.org/wiki/O-Desmethyltramadol

Therefore, cimetidine would be expected act to inhibit the metabolism of Tramadol to its metabolites if ingested first - but would act to inhibit the metabolism of its metabolites if ingested subsequently.

Hope this clears things up a bit, and thanks for bringing this up!

[Gradient]

Thanks for bringing that up, the above post has been edited.

Hope that clears things up!

[Gradient]

I'm not sure that one would need the metabolite to be ionized by the same enzyme as the pro-drug. One might consider the enzyme-substrate interactions as more of a temporal spectrum of activity - therefore, most of the Tramadol will be metabolized before the o-desmethyltramadol is able to reach phase II metabolism. This is why is think that the sequencing is key.

It takes a given amount of time for all of the Tramadol to be metabolized, sure. However, given the fact that about an hour subsequent to ingestion, these enzymes have had plenty of time to perform phase I hepatic metabolism - the majority of psychoactivity derived from any given dose will be determined by the amount of Tramadol converted within that first hour of metabolism. Therefore, the rate at which o-desmethyltramadol will be ionized by CYP6D4 will hinder the effects more than the metabolism of any remaining (few molecules left) Tramadol might contribute.

I agree with your assertion that there will inevitably be some Tramadol left to be potentially converted after an hour has passed. However, the amount of o-desmethyltramadol in circulation after that first hour will likely outweigh the potential for additional o-desmethyltramadol to be generated from the remaining Tramadol after an hour has passed. In other words - I agree that there will be some remaining Tramadol that will fail to be converted to its 5 metabolites, but I believe that the enhancement of o-desmethyltramadol by inhibition of phase II hepatic CYP6D4 metabolism will serve to outweigh any potential additional metabolites from Tramadol.

I suppose one might consider it to be a question of 'do the benefits outweigh the positives?' - in this case I believe it will. Of course, if one wished to re-dose with more Tramadol, ingesting cimetidine would be quite counter-productive. However, this was a guide to potentiate Tramadol - not to get the best experience out of Tramadol (saving money, low on supply, etc...) I do, however, feel that the interaction you've brought up is indeed central to the fact that this method will not generate serotonin syndrome from a reasonable dose - there is indeed a limit as to how much o-desmethyltramadol can be generated from any given dose.

[Gradient]

My chimp has consistently observed that mild muscle-relaxants markedly enhance the general effects of Tramadol. When taken about 30 mins subsequent to ingestion of Tramadol, both carisoprodol and methocarbomol have noticeably generated a much higher level of analgesia and mood-lift than either of the substances alone. With only 100mg Tramadol and 800mg methocarbamol, the chimp observes effects he associates with 300mg+ Tramadol. The chimp hasn't tried NSAIDs in combination with Tramadol, but would be interested to see if there is a similar dynamic.

Has anyone else observed this relationship between mild muscle relaxants and Tramadol?

[killersnowman]

swim has taken over 800mg Tram in one sitting and felt nothing. perhaps swim will try this next time there is a chance.

[Spucky]

Originally Posted by killersnowman

swim has taken over 800mg Tram in one sitting and felt nothing. perhaps swim will try this next time there is a chance.

Tramadol is a special Drug,
many People reported that a low Dose, aka. 100-200mg.
have a higher Benefit than a Dose swiny consumed!
Also many People reported that the Tramal-High is a special High
and have to be learned (can swim say it so?)
it is not like other Opioids!

Everything above 400mg. in a 24 Hour Interval is a game with Fire
And People who are doing experience with cytochrome 450 have to remember
that the Calculation can be terrible wrong!!!

Edit:
Swims Knowledge of cytochrome 450 is very low,
but it is a Gene that introduce Cell-Death or is this only bond to Cancer-Cell`s?

[The baine]

Just to add a report my friend gave me:

He started dosage just before the peak of the response curve of the M1 metabolite with cimetidine. It canceled out all effects. even when he was feeling the mu action. his dosages were 300mg tramadol and 400 mg cimetidine. Since then he tried various dosages and timings based an scientific charts then by pure speculation. All in all it was a waste of tramadol and cimetidine for that matter.

[shivakiva2112]

^Including cimetidine in all cases reduced the effects of the tramadol? Did your friend give sufficient time between experiments to account for tolerance (mild though it may be)? Possibly he has a slower isoform of the CYPXXX enzyme (forgot which)? Just offering pure speculation here, this is a very interesting topic.

[BoyInTheCountry]

Great post with lots of information but SWIM has some further question around the chemical O-Desmethyltramadol found in Tramadol.

SWIM has recently found himself being able to get hold of O-Desmethyltramadol own its own and pure. SWIM had 5g of this chemical in his possesion his is has not used any yet as he is very unsure of the effects, dosage due to the lack of information on this chemical outside of its effect in tramadol. Do any SWIY who are more literate in science maybe give SWIM a rough idea on effects, potency, dosage and best route of administration (most efficient). SWIM is thinking of IV'ing but is also considering insufflating.

SWIM hopes his post isnt seen as going too off-topic as at the moment reading up on Tramadol is the closest he can get to finding information on said chemical.

SWIM made a thread on this chemical here : - http://www.drugs-forum.com/forum/sho...d.php?t=105916

Thank you.