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Study about JWH-018 metabolites

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fedete

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Searching specific data about JWH-018, I found this study concerning to JWH -018 metabolites, it appears to bring some new data about this compound. Could someone with some knowledge comment about this? Does these studies confirm our most feared feelings about JWH-018?

Details:

In vitro phase I metabolism of the synthetic cannabimimetic JWH-018.

Wintermeyer A, Möller I, Thevis M, Jübner M, Beike J, Rothschild MA, Bender K.

Institute of Legal Medicine, Medical Faculty, University of Cologne, Melatengürtel 60-62, 50823 Cologne, Germany.

Abstract:

A potent synthetic cannabinoid receptor agonist, JHW-018, was recently detected as one of the most prominent active agents in abusively used incenses such as Spice and other herbal blends. The high pharmacological and addictive potency of JWH-018 highlights the importance of elucidating the metabolism of JWH-018, without which a meaningful insight into its pharmacokinetics and its toxicity would not be possible. In the present study, the cytochrome P450 phase I metabolites of JWH-018 were investigated, after in vitro incubation of the drug with human liver microsomes, followed by liquid chromatography-tandem mass spectrometry analysis. This revealed monohydroxylation of the naphthalene ring system, the indole moiety, and the alkyl side chain. In addition, observations were made of dihydroxylation of the naphthalene ring system, and the indole moiety, or as result of a combination of monohydroxylations of both the naphthalene ring system and the indole moiety or the alkyl side chain, or a combination of monohydroxylations of both the indole ring system and the alkyl side chain. There is also evidence of trihydroxylation at different locations of the hydroxyl groups in the molecule. Furthermore, dehydration of the alkyl side chain, in combination with both monohydroxylation and dihydroxylation as well as arene oxidation of the naphthalene ring system, combined with both monohydroxylation and dihydroxylation at different sites of oxidation were found. N-dealkylation also in combination with both monohydroxylation and dihydrodiol formation of the N-dealkylated metabolite was detected. Finally, a metabolite was found carboxylated at the alkyl side chain.

http://www.ncbi.nlm.nih.gov/pubmed/20838779
 
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See also this thread: Study on JWH-018 metabolites in urine analyisis [sic]! I recommend in particular to read the posts by wungchow and Vecktor!!! But as far as I can see did fedete post there and should know this thread.

The findings of the presented study were summarized in one scheme, have a look:
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The intermediate metabolites directly right of JHW-018 are what you should worry about. These are exactly the kind of reactive epoxides, which were predicted by some folks more than a year ago. Furthermore do the authors confirm that the observed metabolism shows great similarities to the one of JWH-015 in some aspects. This seems to confirm, too, that the publication dealing with the metabolism of JWH-015 in rats (!) was in fact well suited to draw some preliminary conclusions.

This note just goes out to all the people who constantly doubted the warnings issued by Vecktor, me, and some other Bluelighters. Of course is the presented study no proof that JWH-018 is carcinogenic (nobody ever claimed this actually) but the chances are quite good it still isn't really benign to humans, in particular not with respect to long-term use.


Another study dealing with this topic was launched here:

Ines Möller, Annette Wintermeyer, Katja Bender, Martin Jübner, Andreas Thomas, Oliver Krug, Wilhelm Schänzer, Mario Thevis
"Screening for the synthetic cannabinoid JWH-018 and its major metabolites in human doping controls"
DOI: 10.1002/dta.158
Drug Testing and Analysis 2010, no volume or pages yes (too new)
Abstract
Referred to as ‘spice’, several new drugs, advertised as herbal blends, have appeared on the market in the last few years, in which the synthetic cannabinoids JWH-018 and a C8 homologue of CP 47,497 were identified as major active ingredients. Due to their reported cannabis-like effects, many European countries have banned these substances. The World Anti-Doping Agency has also explicitly prohibited synthetic cannabinoids in elite sport in-competition. Since urine specimens have been the preferred doping control samples, the elucidation of the metabolic pathways of these substances is of particular importance to implement them in sports drug testing programmes. In a recent report, an in vitro phase-I metabolism study of JWH-018 was presented yielding mainly hydroxylated and N-dealkylated metabolites. Due to these findings, a urine sample of a healthy man declaring to have smoked a ‘spice’ product was screened for potential phase-I and -II metabolites by high-resolution/high-accuracy mass spectrometry in the present report. The majority of the phase-I metabolites observed in earlier in vitro studies of JWH-018 were detected in this urine specimen and furthermore most of their respective monoglucuronides. As no intact JWH-018 was detectable, the monohydroxylated metabolite being the most abundant one was chosen as a target analyte for sports drug testing purposes; a detection method was subsequently developed and validated in accordance to conventional screening protocols based on enzymatic hydrolysis, liquid-liquid extraction, and liquid chromatography/electrospray tandem mass spectrometry analysis. The method was applied to approximately 7500 urine doping control samples yielding two JWH-018 findings and demonstrated its capability for a sensitive and selective identification of JWH-018 and its metabolites in human urine.
Click to expand...


Peace! - Murphy
 
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"Does these studies confirm our most feared feelings about JWH-018?"

You have to understand that this forum has been walking right up to the line of telling people JWH-018 is evil for years, even before much was known about it. I have seen quite knowledgeable folk here who look at the data and say, "See? I told you this was dangerous. It may not give you cancer, but it's scary as hell." And I have seen quite knowledgeable folk here and elsewhere who look at the same data and say, "This doesn't really tell us much one way or the other. It produces metabolites that can be a concern, but we don't know to what degree we should be concerned if at all. It could be carcinogenic, but we don't know how much so, or if there is a realistic concern regardless of usage level. We don't know what a safe level of usage might be, or what a dangerous level might be. We don't know what long-term usage that could push someone into a higher risk group might be. A month? 6 months? 2 years? We just don't know."

If you start a thread asking if this confirms your nightmares, on this forum you're going to get confirmation. The production of carcinogenic metabolites has always been considered to be an unknown, but likely. That doesn't address the important questions, and these studies don't change my own thoughts on use. It was a risk going in, it's still a risk, this just makes one of the many obscuring shades of grey less opaque.

Edit: To be clear, I'm not bashing anyone, and I greatly appreciate the insights and knowledge passed on here. I'm simply pointing out that JWH-018 has been viewed with a heavily jaundiced eye here in particular from the beginning, and there is a strong bent against it.
 
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Basically it forms metabolites that have a very high chance of being carcinogenic. While this could turn out to be false, it is somewhat likely. And there is the matter of what percent of JWH-018 is converting into the epoxide metabolites, it could be high or very low, in which the risk is minimal.
 
mpomk said:
"See? I told you this was dangerous. It may not give you cancer, but it's scary as hell."

[...]

"This doesn't really tell us much one way or the other. It produces metabolites that can be a concern, but we don't know to what degree we should be concerned if at all. It could be carcinogenic, but we don't know how much so, or if there is a realistic concern regardless of usage level. We don't know what a safe level of usage might be, or what a dangerous level might be. We don't know what long-term usage that could push someone into a higher risk group might be. A month? 6 months? 2 years? We just don't know."
Click to expand...

If you read the posts by the "quite knowledgeable folk" carefully, you will see that in fact nobody said that this compound is "scary as hell". People expressed their justified (!) concerns and every data published so far on further confirms these concerns.

Nonetheless are these still only concerns. There is no definite proof whatsoever. That must be made absolutely clear! But looking at the huge variation, which is possible with the AAI-family, while retaining high potency in vivo, I don't see any viable reason to play down the potential risks. Do we really need to find out by a case study in maybe 5-10 years from now?
Seriously, it would make me sad to witness one day that somebody indeed developed lung or liver cancer from this stuff. That would allow me to reply "HA! I knew it...", but why should I want to do so? I prefer to warn drug users as soon as I have some well-thought reasoning for such a warning.

This is primarily a harm reduction forum and trivializing risks, which the "quite knowledgeable folk" considered to be at least in part justified doesn't help a thing.


- Murphy
 
Indeed!

I would rather see concerns overblown than underplayed. Yeah, JWH-018 may be very safe, but as it is, there is good reason to be concerned about the danger of these epoxide intermediaries. JWH-018 is hardly the best of these AAI's. Why is it the most commonly used? Because it's freaking cheap for vendors to produce. It's potent but very anxiogenic. It's decently long lasting.

There are better AAI's that are more expensive to produce. JWH-081, the phenylacetylindoles, etc. This is an enormous group that's extremely varied. No one has done much in the way of human testing. No one has taken a look at the whole bunch, looked for the least likely to produce carcinogens, then looked at which produce the best effects.
 
So is there anything that you take otc that wouod cause a test to come back positive even though your not using jwh
 
That's actually a different topic. :P
...
So we should ask whether the harmful intermediate metabolites are likely to be catabolized themselves prior to appearing in sufficient concentrations to cause harm. Also, since metabolites are the issue, would we expect mutagenesis localized to the liver?

I'd actually be even more worried about the constellation of products of partial combustion--who knows what's created under those types of variable conditions.

ebola
 
I know this is a question that is probably impossible to answer with the available data right now but I will throw it out there for comments or guesses or whatever. Ciggarettes are carcinogenic but smoking one ciggarette isnt gonna give you cancer its the prolonged exposure over time that kills you. Alot of people experimented with JWH-018 is the risk ciggarette like or plutonium lke?
 
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