JWH-018 (Spice) ADME Toxicology Studies & Discussion

[mouse99]

A series of pre-clinical ADME/Toxicity studies were conducted on JWH-018 including CYPs, Genotox, hERG, Cytotox, Rodent Tox (LD50, Acute Dose, Repeat Dose & Pharmakinetics). All tests passed within tolerable guidelines. JWH-018 tested negative for genotox (ie cancer) using standard GreenScreen HC both with and without S9 (fraction from liver hepatocytes which metabolizes compounds and looks for genotoxic metabolites).

Further detailed information is forthcoming.

See here for the study.

Reputation Comments on this post:

	good find
	"JWH-018 tested negative for genotox" nice to know. Good info!
	great find

[Lunar Loops]

This is VERY interesting and any more detail that can be provided would be greatly appreciated.

Originally Posted by mouse99

A series of pre-clinical ADME/Toxicity studies were conducted on JWH-018 including CYPs, Genotox, hERG, Cytotox, Rodent Tox (LD50, Acute Dose, Repeat Dose & Pharmakinetics). All tests passed within tolerable guidelines. JWH-018 tested negative for genotox (ie cancer) using standard GreenScreen HC both with and without S9 (fraction from liver hepatocytes which metabolizes compounds and looks for genotoxic metabolites).

Further detailed information is forthcoming.

[Alfa]

Yes, you can post links to show where the article comes from.
I found yours here: http://www.upi.com/Top_News/2008/12/...0461230693349/

I would very much like to see the tests Baetzing talks about, because as far as I know the above tests are the first and only tests toxicology ever done on Spice or JWH-018.

I doubt that Baetzing's claims are much more than assumptions based upon media sensationalism.

[enquirewithin]

Email from Prof. John W. Huffman

Mr. Markuse,
I can only supply limited answers to your questions. We have never investigated the long term effects of JWH-018 in animals and other than the anecdotal data from Der Spiegel and assorted blogs that my wife unearthed there are no data regarding its effects in humans. In mice it is considerably more potent than THC as we published almost ten years ago. I don’t have any idea regarding the safety or toxicity of this compound nor any information regarding its bioavailablity. THC is also a CB2 agonist, although with less affinity for the CB2 receptor than JWH-018. I have no idea if 018 is a CB2 agonist or inverse agonist/antagonist. I would note that we have made over 100 cannabimimetic indoles in the last 15 years and jWH-018 is just one of them.
I hope that I have answered your questions satisfactroily.
Regards,

John W. Huffman
Research Professor of Chemistry
Clemson University

http://www.pierre-markuse.de/2008/12...ohn-w-huffman/

[Alfa]

Note that the email from John W. Hoffman is dated from before Mouse99 released these studies.

[Jacquesy]

JWH-018 isn't the only thing in spice is it, or is the baybean, skullcap and so on total cover up? there's obviously a plant base before the JWH-018 is sprayed on. But if there are other plants and possible contaminates in it the crude plants matter would probably be more damaging to you're health than the JWH-018 as it acts in the same way as THC and "tested negative for genotox (i.e cancer)" Sorry if thats off topic.

[polidelaiko]

Originally Posted by Jacquesy

there's obviously a plant base before the JWH-018 is sprayed on.

I read somewhere, cant remember where, that the only plant found in Spice was Althaea officinalis, a.k.a marshmallow. I'll search the info.

[honourableone]

Originally Posted by polidelaiko

I read somewhere, cant remember where, that the only plant found in Spice was Althaea officinalis, a.k.a marshmallow. I'll search the info.

I was under the impression that all of the unactive plants listed as ingredients were actually used in the product, but I remember a report of a gcms test carried out on spice a while ago (that didn't pick up the JWH-018), that showed it had a great deal of Vitamin E in it, which confused the scientists untill they realised that it was from the marshmallow, so marshmallow is definitely there.

Here is a thread I just found that mentions plant bases, although a lot of the discussion is now irrelevant as we know about thw JWH-018:

http://www.drugs-forum.com/forum/showthread.php?t=37356

Although this probably is off topic, and not overly important IMO.

[rapax]

i think the only plant that spice ever contained in actual material (the "herb" who actually you smoked) was just marshmallow,rose, and red clover. honey was present as fermentation of those herbs, and vanilla was used as ethyl vanillin, an aroma used also in the food industry.

the high vitamin e content was from the red clover, wich could be unrelated, or purposely used as tocopherol is a good antioxidant and could had been used to help minimize the eventual loss of potency of jwh-018.

in any case, if any other herb listed in the packet was used, it was so in form of extracts, or not present altogheter, althou i cant confirm wich.

all this is marginally important considering that its effect at 99.8% were from jwh-018..

[Alfa]

Some interesting comments on JHW-018 is toxicity, by JW. Huffman and Christian Steup(THCPharm):

Christian Steup, a medical doctor and pharmacist in charge of quality control at THC Pharm who supervised the analysis, told Chemistry World that he was able to detect JWH-018 while bigger labs failed because he had synthesised the substance about two years ago and all information was still on the company computer.

JWH-018 is four to five times more potent than tetrahydrocannabinol, more commonly known as THC, which is the main psychoactive substance in cannabis, Steup says, adding that JWH-018 'is fascinating because the chemical structure does not look at all like THC, but it produces the same effects.'


The chemist who designed (and lent his initials to) JWH-18, John W Huffman, an organic chemist at Clemson University in South Carolina, told Chemistry World that his goal had been to make a simple compound to study structure-receptor relationships. The compound interacts with both cannabis receptors. The first batch was actually made by an undergraduate student working under a post-doc. 'It is really easy to make,' Huffman said.


JWH-018 has not been licensed anywhere in the world for medical applications and little is known about the effect on humans, as not even pre-clinical studies have been to determine potential toxicity. Steup says he is inclined to believe it is not toxic, and that he would be more concerned about any lingering impurities from the production process.


Huffman says, 'I don't have a clue.' But noting the similar highs produced by THC and JWH-018, he says: 'You cannot overdose on THC. You can forget your name or where you are, but too much THC will not kill you.'


Asked whether he sees any potential medical applications for JWH-018, he said: 'No. It's like LSD, the only thing it is good for is getting you high.'

Synthetic cannabis mimic found in herbal incense

[nibble]

I have trouble believing Huffman would make comments like that, what then was the point of his research into the aminoalkylindoles? Or the patent application for administration of it via transdermal patch that I believe was made? Strange comments..

[Synchronium]

Just because they have no use clinically doesn't mean they're not useful in research. Radioligand binding studies for example.

[honourableone]

As Nibble said, there are investigations into possible clinical uses (as well as the transdermal patch, quite a few other synthetic cannaboids are also being investigated, though there isn't evidence of their presence in any of the smoking blends and some work be inhibiting enzymes that prevent endocannaboid breakdown. You right about the research possibilities; CP 47,497 (a cannaboid that is present in spice) and many other research cannaboids are often used for research.

[enquirewithin]

Huffman comes from the school of thought that marijuana has no medical use-- at least is is sensible in talking about the 'dangers' of THC.

[Alfa]

From Synchronium's Blog:

JWH-018 Toxicology

Since my last post about the spice behind Spice, it has been brought to my attention that some initial toxicology testing has been done on the synthetic cannabinoid JWH-018. Before we get down to the details however, here’s some pretty weird background information - the sponsor and provider of these studies wishes to remain anonymous! Unfortunately, this makes the whole thing a lot less credible, but since this is the only information we have right now, let’s hope someone else can verify these things at a later date. So far, one professor (who also wishes to remain anonymous) thinks these are real, but as of yet, no one is willing to put their name down on any kind of formal statement. If you, or anyone you know, has the relevant expertise to look over these studies, please drop me a line!

Feel free to invent your own conspiracy theories, but for now, let’s take a look at the data. You can download the PDF documents in this Zip file [2.04 MB]

CYP450 Inhibition Assay

This first assay looks at the effect of a drug on specific enzymes in your liver. These Cytochrome P450 enzymes are responsible for metabolising the vast majority of drugs you might put in your body, so if you’ve got too much of one drug in your system (ie paracetamol/acetaminophen), then other drugs that are also metabolised by these enzymes (ie alcohol) may compete for these enzymes and so hang around in your system for longer. As you can imagine, it’s important to understand how one drug may affect the metabolism of another, in case of any disasterous drug-drug interactions.

Results: JWH-018 will probably interact with the metabolism of other drugs, so more in vivo work is necessary.

hERG Binding Assay

hERG stands for human Ether-à-go-go Related Gene. This gene codes for a particular type of potassium channel found on heart tissue. This channel pumps potassium ions out of the heart muscle cells and are critical in coordinating the heart’s electrical activity. Unfortunately, these channels are a prime target for drugs to bind to, disrupting their function. This can lead to “Long QT Syndrome”, associated with fainting and can lead to sudden death, so you can see why these kinds of tests are important. Here’s a typical ECG recording showing what’s called the “QT interval” shown in blue, which lasts for longer than it should do if these channels are disrupted.

Results: JWH-018 does not interfere with these channels. That’s a good thing.

Cytotoxicity Assay

This simple test essentially looks at how many cells die when you perfuse them with a drug. The more cells that die, the more toxic the drug.

Results: JWH-018 is not cytotoxic at low concentrations.

GreenScreen HC Genotoxicity Assay

This assay looks at how much a drug will interfere with our DNA. Typically, anything that damages DNA is bad news, being potentially carcinogenic, making the rationale behind this test glaringly obvious. This test was also performed in the presence of a fraction taken from liver cells, which will break down the drug. This not only checks if the drug will damage DNA, but also its breakdown products.

Results: JWH-018 does not damage DNA, so shouldn’t give you cancer.

Rat Repeat Toxicity Assay

Guess what happens in this experiment. A number of renagade lab rats looking for a bad time are rounded up and promised free drugs (kind of like Pleasure Island from Pinocchio; that shit was scary!). The rats are then dosed up and observed. Initially, they appear lethargic (read: totally baked) but a few of them died at higher doses. This appears to be down to problems breathing rather than organ toxicity, but only affected the male rats, who appeared more sensitive to the compound. The drug didn’t appear to accumulate in their systems either, but they did lose some weight, probably because they couldn’t be arsed to eat. JWH-018 showed a huge potency and was found to be tachyphalactic (my new favourite word - it means that more of a drug is required to reach the same state following an initial dosage).

Results: According to FDA guidelines, the human equivalent dose is 0.016 mg/kg but it should be tested in other species before this can be seen as reliable!

Rat Pharmacokinetics

Data is collected on a number of different “pharmacokinetic” aspects of the drug, such as how it is absorbed, distributed throughout the body, metabolised and excreted, which can help with the design of future clinical trials.

Results: JWH-018 is distributed well throughout the rat’s tissues. Metabolism and excretion are normal, with a plasma half-life of approximately 2 hours

Summary

Well, from the looks of these tests, JWH-018 seems to be pretty safe, but unless you want to piss off Ben Goldacre, it would be wise not to rely on this “test tube data” entirely. Also, like I said before, we don’t know where this data has come from, clouding the issue even further.

Reputation Comments on this post:

Brings attention to very interesting data, despite the reliability issues. Thanks.

[enquirewithin]

"...tachyphalactic"-- nice word-- and generally useful information.

BTW, tachyphylactic seems to be the correct spelling. Most DF users have probably experienced tachyphylaxis at one time or another:

a decreased response to a medicine given over a period of time so that larger doses are required to produce the same response.

[Sushi]

Interesting -and soothing- info indeed. And tachyphylactic is a nice word - Alf's impression is backed with science then: tolerance to JWH-018 is increasing rapidly.

Now, could someone educated briefly enlighten Alf, as this is still uncharted territory for him:
-P450 metabolizes JWH-018
-P450 2D6 (CYP2D6) metabolizes DXM

Are they same enzymes or not? Alf means, do JWH-018 and DXM "compete" for the same enzyme? And what is the enzyme that metabolizes cannabis?

[psyche]

I guess the more detailed version of P450 enzyme that metabolises JWH-018 isn't known. The one that is responsible for metabolism of THC is P450 2C9.

[Synchronium]

Thanks for pointing out that spelling mistake. I've updated my original post.


Edit:

Also the cytochrome p450 enzymes are a family of enzymes. That particular assay showed that this family metabolises the drug, not which one specifically. It takes quite a bit more than a preliminary study to tease that kind of information out.

[soul_firez]

So SWIM has looked on here and might have missed the thread but does any one know about the Psychological effects of JWH xxx specifically the 018 but any would be helpful. SWIM has noted a attitude change in this girl that was SWIMS girlfriend for 5 years now and it started when she started smoking the stuff all the time.

[Reaver]

As far as Swim has read there has not been any conclusive evidence showing JWH-018 having any long term psychological effects. There has been a reported case of a German man who was being treated for alleged "Spice addiction" and it was implied that the patient may have developed psychosis like symptoms. The evidence for this though is even flimsier than the evidence for cannabis psychosis.

Swim can only share their experience with quite long term use of JWH-018 and say that any psychological effects are short lived and only last for the duration of intoxication. The main effect that Swim noticed was extreme paranoia when accidently taking JWH-018 at higher doses than necessary and although the paranoia was quite intense it was also very short lived.

The opinions from fellow Swimmers also seems to point to the same short term, occasional psychological effects, however this is all anecdotal evidence since in the end Swiy and Swim are going to be the guinea pigs for the long term effects of synthetic cannabinoid usage...

(This may be off-topic though as this thread has mainly concerned itself with the chemical and physiological properties of JWH-018 rather than psychological effects)

Reputation Comments on this post:

Well written representation of information, with consideration given to rules

[osirisx]

What do you guys think of this from a post on Viceland?

"One published paper demonstrated that JWH-018 is metabolized into carcinogenic metabolites, which is very bad considering millions of people smoke JWH-018 each day. Well, I might say, “Why don’t you stick to marijuana, because it’s safer.” Smoking a compound with unknown biological properties in humans is a stupid thing to do.

It gave the mice malignant lung tumors. Seriously. Once ingested, the chemical is rapidly metabolized into a new carcinogenic chemical, which preferentially targets respiratory tissue. How this translates to humans is unknown."

from the comments of the post above, someone disputes the author's claims:


"The formation of epoxides with jwh-018 have not been proven, quantified, nor ever tested for with human liver michrosomes. rat livers are known to function at much higher metabolic rates and often provide very different metabololic results than humans. It is not clear as to whether such epoxides form with human liver metabolism, nor is it clear if such epoxides would cause cancer. There are many napthyl ring drugs with similar issues such as Duloxetine that have passed FDA approval.
It is true that the toxicological profile of jwh-018 is a great unknown territory and there may be unforeseen dangers. But it is completely false to say it causes malignant lung tumors in rats with no proof or evidence of such."

I tried posting the link but I guess I don't have enough points or something.

I myself am not a doctor or chemist and I cannot comment. I am just presenting this for posterity.

[Ratha]

That's the infamous Hamilton, who has been ripped for the poor and misleading quality of his article. (Which was published prior to the ADME toxicology study, although when it was released he seemed determined to find some way to prove it was fraudulent.) Hamilton's forum comments (last SWIM had seen) seem to indicate that if he still believes what he wrote, he doesn't practice that belief.

[Alfa]

Hamilton knew of the above studies before he published his article.
From his article:

Originally Posted by Hamilton

In late December 2008, scientists at a German lab isolated the active ingredient in Spice.

Mouse99 published the studies here on December 30th. I have seen mouse99 present the same studies to Hamilton and Murphy on another forum around the same date. Hamiltons article came quite a bit later.

Hamilton therefore must have been completely aware that the claims he published in his article where complete bollocks.
I don't know what his motivation was for knowingly publishing false information, but it seems pretty obvious that there is one.

[chrisjames13]

Has anyone seen this article, 'Inhibition of human tumour prostate PC-3 cell growth by cannabinoids R(+)-Methanandamide and JWH-015' and would this be relevant to JWH-018?

I copy and pasted the following from a website: pr.cannazine.co.uk/200909181198/green/eco-news/cannabinoid-cancer-fighters-the-pharma-industry-dont-want-you-to-know-about

JWH-018 Cures Cancer?
Published today, September 18th 2009, on a news website dedicated to Urology Professionals, (urotoday), was the headline; 'Inhibition of human tumour prostate PC-3 cell growth by cannabinoids R(+)-Methanandamide and JWH-015' which is a close relation to the newly banned JHW-018.

And this, after a German scientist claimed to have found a substance romantically named 'JWH-018' in a pouch of Spice artificial cannabis, which would ultimately see Spice being banned from most of the civilised world.

According to Christopher P Evans M.D, who is a Contributing Editor with UroToday.Com, "..investigators have found that JWH-015 inhibited human prostate cancer cell xenograft growth in mice. The study’s conclusion is that CB2 receptor agonists have potential therapeutic application in the treatment of human prostate cancer.

So it turns out the active ingredient in Spice artificial cannabis could have cancer curing properties as a result of its ability to 'tweak' our in built CB1 and CB2 receptors. A tweak which is necessary to shut down the processes cancer cells need to multiply and grow.
----------------------------------------------------------------------------------------------------------------------------------------------------------

I have seen this idea mentioned before online so could artificial cannabis or cannabinoids have cancer curing properties as a result of the ability to 'tweak' our in built CB1 and CB2 receptors?

chrisjames13 added 130 Minutes and 39 Seconds later...

I searched for information online regarding JWH-018 and other cannabinoids and found some articles that interested me.

ncbi.nlm.nih.gov/pmc/articles/PMC1859999/

Interestingly, cannabinoids exert opposite effects on the survival of transformed and non-transformed neuronal cells,
inducing apoptosis in tumour cells, but not in primary cells.

Results: ACPA (CB1 agonist), JWH (CB2 agonist), and metAEA (methanandamide, endogenous CB1/CB2 agonist) had no influence on the proliferation of these cells, even under low serum conditions. However, the CB1 receptor antagonist, AM251 (1–10 µM) alone had a profound antiproliferative effect on these cells. This implies that the activity of cannabinoid receptors is linked to the viability and survival of normal colonic epithelial cells. Further investigations revealed that cannabinoids impact on heme-oxygenase (HO)-1 expression, a protein thought to be important during restitution of inflammation.

Conclusion: These results support our suggestion that cannabinoids may have therapeutic potential during the healing phase of gastrointestinal inflammation.
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en.wikipedia.org/wiki/WIN_55,212-2
WIN 55,212-2, alongside HU-210 and JWH-133, are implicated in preventing the inflammation caused by Amyloid beta proteins involved in Alzheimers disease, in addition to preventing cognitive impairment and loss of neuronal markers. This anti-inflamatory action is induced through the agonization of cannabinoid receptors which prevents microglial activation that elicits the inflammation. Additionally, cannabinoids completely abolish neurotoxicity related to microglia activation in rat models.
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vincibiochem.it/NovitaCayman
The above site states this:
JWH 018 is a mildly selective agonist of the peripheral cannabinoid (CB2) receptor, derived from the aminoalkylindole WIN 55,212-2.

Is JWH-018 really derived from WIN 55,212-2 and if so then could it have positive effects like those described above in the wiki article about WIN 55,212-2, alongside HU-210 and JWH-133? I keep finding positive things about certain cannabinoids so why do some claim that JWH-018 is cancerous. Is it because people are smoking it? Could JWH-018 being that it is a cannabinoid not be as bad as some have speculated like in the Hammilton post?

Also, what exactly does this mean? Taken from above article in bold, 'Interestingly, cannabinoids exert opposite effects on the survival of transformed and non-transformed neuronal cells, inducing apoptosis in tumour cells, but not in primary cells.' If anyone can elaborate on any of this then please do.