Thebaine

[Sturnam]

Buprenorphine would do the same thing... that does not mean that it has no place in w/d.

This is really interesting, and I cannot wait to get to the bottom of it.

Well, wouldn't that fact that it precipitates w/d and fails to suppress w/d symptoms mean that it is useless for treatment?

And as far as the CD50, it seems like its the same across the board for several different animals. Any ideas why?

Convulsions were observed in almost all species of animals including the skate, frog, sparrow, pigeon, mouse, guinea pig, rabbit, cat and dog. In the rhesus monkey, transient tremors, restlessness, hyper-irritability and convulsions were observed. The convulsive doses were around 20 mg/kg s.c. in mice, rabbits, cats, dogs and rhesus monkeys.

Also, does anyone have an idea what mediates the convulsant effects of thebaine? this article says that it's not anything you can develop tolerance to, which seems like it would not be associated with the opioid receptors.

In an attempt to produce tolerance to the convulsant effect of thebaine in rhesus monkeys, Yanagita and Miyasato repeatedly administered 2 mg/kg of thebaine 6 to 24 times daily for 6 weeks or longer to 4 monkeys by programmed injection through intravenous in-swelling catheters. Every two weeks the monkeys were challenged with 4 mg/kg of thebaine which is the convulsant dose. No evidence for the development of tolerance to the convulsant effect of thebaine was obtained.

 

[nabollocks]

The convulsive doses were around 20 mg/kg s.c. in mice, rabbits, cats, dogs and rhesus monkeys.

At 20mg/kg a 100kg man could ingest 2g of Thebaine before convulsions would be observed. Now I know that this is probably nonsense but most opiates given at 2 grams would kill a man.

Every two weeks the monkeys were challenged with 4 mg/kg of thebaine which is the convulsant dose.

At 4mg/kg a 100kg man could ingest 400mg of thebaine before convulsions would be observed. This sounds a little more in line with other typical opiates.

Does thebaine display any effects on serotonin? Are we seeing SS with high doses of thebaine?

 

[Sturnam]

Well, you're taking the 400mg dose of thebaine as a convulsant dose out of context. Where i got it from, they're talking about IV administration.

Now that you put it that way, i think you're right about the CD50 being 400mg, although i'm guessing it could easily be below 100mg. What i'm interested in is the allosteric inhibition that Limpet_Chicken mentioned very briefly at the beginning. Could you tell us any more about this? If it does act in the same way as strychnine, then I'm guessing the CD50 will be closer to 50-100mg, more along the lines of strychnine's LD50 for humans.

 

[nabollocks]

I'm guessing the CD50 will be closer to 50-100mg, more along the lines of strychnine's LD50 for humans.

This is what I am getting at. I would love to know what is causing the convulsions.

I found some literature on the metabolic pathway of Thebaine. Could someone with more experience please explain if anything here would cause convulsions?

Seems the main metabolites from thebaine are: free codeine, norcodeine, normorphine, morphine and 14-hydroxycodeinone as some of the minor metabolites, and oripavine and glucuronide conjugates of normorphine and norcodeine as major metabolites.

Relationship of pharmacokinetic and metabolic parameters to the absence of physical dependence liability with thebaine-3H Journal Cellular and Molecular Life Sciences (CMLS)
Publisher Birkhäuser Basel
Issue Volume 29, Number 9 / September, 1973

 

[Limpet_Chicken]

http://www.pnas.org/content/86/2/716.full.pdf?ck=nck

The reference to strychnine like properties is near the end of that paper.

Strychnine acts as an allosteric antagonist at strychnine-sensitive (well well what a surprise) GLyRs in spinal neurones.

An interesting test, should anybody be in the position to perform a patch-clamp recording, would be to see if gelsemine (obtainable from Gelsemium Sempervirens, yellow false jasmine) which acts as an allosteric agonist at ssGLyRs reverses depolarisation induced by thebaine in those neurones.

(Preferable to inducing convulsions in an animal and trying to reverse the effect with gelsemine, kinder, and more prescise) If its useful, gelsemine is UV-fluorescent, which could help should anyone wish to try this, just a tip for isolation.

 

[Hammilton]

Seems obvious it's the ssGLyR agonism causing the convulsions, that is what it's known for

 

[nabollocks]

Hmm... thanks for the paper.

However, thebaine can stimulate the central nervous system and cause convulsions (21-25). Morphine and codeine also produce convulsion but only at high doses (21, 23, 26), whereas at low doses, morphine can exert an anticonvulsant action (26). Thebaine can reverse some of the effects of morphine (27, 28). Electrophysiological studies indicate that the spasmodic effect of thebaine was different from that of morphine and codeine but was similar to that of strychnine (29). Thebaine has been shown to inhibit binding to the glycine receptor and the -y-aminobutyric acid receptor (30). Both receptors seem to be involved in the convulsive properties of the opiates (31, 32).

I am not convinced with your assumption Ham.

I think I need more evidence.

Anybody got these references?

29. Longo, V. G. (1962) in Rabbit Brain Research (Elsevier,
Amsterdam), Vol. 2.

30. Goldfinger, A., Muller, W. E. & Wollert, U. (1981) Gen.
Pharmacol 12, 477-479.

31. Dingledine, R., Iversen, L. L. & Breuker, E. (1978) Eur. J.
Pharmacol 47, 17-27.

32. Werz, M. A. & Macdonald, R. L. (1982) Brain Res. 236, 107-
119.

For some reason, thebaine reminds me of tramadol.

There is definately a lot of negatives about thebaine, but maybe the reason it has been written off in the past is because of the relative lack of naloxone to reverse its effects. But with the introduction of buprenorphine, why not look at this chemical again.

Ham, have you ever heard of anyone having convulsions from PPT?

 

[Jabberwocky]

The point is that most PPT drinkers are taking it unknowingly, and I want to know what the dangers of doing so are... call it HR if you will.

some drugs are only toxic in conjunction with other present chemicals, so basing your knowledge about the toxicity of thebaine off of studies that administer only thebaine is going to create a possibility for error.

 

[nabollocks]

^This is why we study things... because we do not understand them.

GP: Let me know if you do not want me to post about this anymore.

 

[Jabberwocky]

whoa slow down buddy

take it easy

 

[cire113]

Wait a second isnt oxycodone synthesized from Thebaine? it cant be that crappy

 

[MurphyClox]

Wait a second isnt oxycodone synthesized from Thebaine? it cant be that crappy

Oh believe me (and the rest here): It actually IS crappy! That's why chemists changed it into oxycodone. The differences is both structures lead to quite different receptor affinities resp. activities.

One can NOT draw a conclusion this easily by comparing a compound with it's synthetical presursor. That lacks a rational basis.

Peace! Murphy

 

[nabollocks]

There are specific high thebaine varieties grown in places like tasmania.

Seems you are right on the money there vecktor. I was searching around for more info on thebaine tonight and turned up this little abstract.

Analgesia: morphine-pathway block in top1 poppies by
Millgate AG, Pogson BJ, Wilson IW, Kutchan TM, Zenk MH, Gerlach WL, Fist AJ, Larkin PJ. CSIRO Plant Industry, Black Mountain, Canberra, ACT 2601, Australia. Nature. 2004 Sep 23;431(7007):413-4
ABSTRACT
The opium poppy is a source of the pharmaceuticals codeine, morphine and their derived analgesics. Here we describe the initial characterization of the poppy mutant known as top1 (for 'thebaine oripavine poppy 1'), which accumulates the morphine and codeine precursors thebaine and oripavine and does not complete their biosynthesis into morphine and codeine. The original discovery of top1 stimulated a re-engineering of the opioid industry in the island state of Tasmania, which grows over 40% of the world's licit opiates, in order to produce thebaine and oripavine efficiently from morphine-free poppy crops to provide precursors for highly effective analgesics and for treatment of opioid addiction.

top1 sounds like a nasty poppy. I would suggest you do not ingest top1...

Yeh, SY (December 1981). "Analgesic activity and toxicity of oripavine and phi-dihydrothebaine in the mouse and rat". Archives Internationales de Pharmacodynamie et de Therapie 254 (2): p223–40. PMID 6121539
Oripavine possesses an analgesic potency comparable to morphine; however, it is not clinically useful due to severe toxicity and low therapeutic index. In both mice and rats, toxic doses caused tonic-clonic seizures followed by death, similar to thebaine.

Click here for a document on oripavine dependance.

This might explain why Tasmania has all those poppy fields and no-one touches them...

Edit: I also noticed there is a poppy that contains high levels of thebaine in its roots. This poppy is not banned as far as I know... hmm, I will look into this further.

 

[Hammilton]

thebaine is a controlled substance, so it matters little legally.

 

[nabollocks]

^True, but here in Australia you are allowed to grow certain varieties of poppies. Not sure what that means, but anyway. I am not trying to get around the law, I was just stating something interesting I read today.

Just a note: It was interesting to see that the dose they used for oripavine was in the ug's.

It is just so interesting that when all these alkaloids are put together into one plant it seems to work, but you take them individually and they devastate. (Not really ADD but I though I would add my thoughts)

 

[Hammilton]

What were they looking at though? Oripavine is about as potent as Morphine; no clue about it's strychnine sensitive GlyR's though.