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View Full Version : (opioids) Is it an oddity that Milk Thistle RADICALLY potentiates Oxycodone?



OxyChem
20-04-2011, 21:25
Firstly, it will take at least 100mg of Oxycodone considering current tolerance to start a decent nod. Many potentiators have been tried, and the best results were experienced with the use of Promethazine or Butalbital until recently when Milk Thistle was used.

According to a wide variety of sources, oral Milk Thistle inhibits Cytochrome P-450 3A4 and others by up to nearly 100% depending on amount ingested. I assume this is why potentiation of Oxycodone has been experienced.

Anyways, due to the consumption of various medications, periodic supplementation with Milk Thistle was decided upon to help liver health. Taking 400mg Milk Thistle Standardized 80% Extract 45 minutes before oral consumption of 50mg Oxycodone resulted in effects similar to what would be expected if 100mg Oxcodone was taken. None of the many potentiators previously tried comes remotely close to this level of potentiation.

Has anyone else experienced or heard of this? The reports about Milk Thistle in regards to opiate potentiation are few and far between. It seems that if such extreme/quality results as mentioned above are normal, more reports about Milk Thistle would be around bluelight and the greater internet. Is it truly unusually odd for such radical potentiation effects as described above to be experienced?

Thoughts/Comments/Whatever anyone?


WARNING: If anyone attempts potentiation with Milk Thistle, I recommend using Milk Thistle ONLY to potentiate opioid medications that are NOT combined with other substances (i.e APAP).

EDIT: Please note, I take an enhanced version of Milk Thistle extract which contains soy phospholipids which increase bioavailability of Silymarin. Regular Milk Thistle products and most extracts do not have this.

psychopath
20-04-2011, 21:36
My first question is, how are you ingesting the 50 or 100 mg? It would take the combination of a few different pills to get those doses. Oh and by oral consumption, do you just take it, chew/suck on it or parachute it?

I have never heard of this. I am impressed it potentiated more than promethazine (one of if not my favorite opiate potentiator).

I am interested to see the responses.

OxyChem
20-04-2011, 21:58
My first question is, how are you ingesting the 50 or 100 mg? It would take the combination of a few different pills to get those doses.

I have never heard of this. I am impressed it potentiated more than promethazine (one of if not my favorite opiate potentiator).

I am interested to see the responses.

The Oxycodone is taken orally (parachuted as powder) on an empty stomach. Tums or the store brand equivalent are also used about 30 minutes before the Oxycodone is taken.

I think I may be very sensitive or something to Silymarin (Milk Thistle extract) and that it might inhibit my liver enzymes more than normal. I've read several peer-reviewed articles including some from medical journals and results indicate that major inhibition of cytochrome p-450 enzymes typically only occurs in fairly large doses of Milk Thistle.

BrokedownPalace
20-04-2011, 21:58
My first question is, how are you ingesting the 50 or 100 mg? It would take the combination of a few different pills to get those doses. Oh and by oral consumption, do you just take it, chew/suck on it or parachute it?



What is so strange about 50 or 100mg dosages of oxycodone? He could have 10mg oxycodones, or just combining other various IR Oxycodone formulations.

This is interesting though. I am kinda outta commission today in regards to research and stuff so hopefully this can generate a good discussion.

If it does in fact work as well as you say it does, this could definitely help some people I know.

psychopath
20-04-2011, 22:06
Different preparations and method of consumption could have an effect on the potentiation.

drzoidbergphd
20-04-2011, 22:17
has milk thistle shown to work effictively to potentiate opiates besides oxycodone?

skoat
20-04-2011, 22:21
keep talking, you've got my attention.

OxyChem
20-04-2011, 22:34
Well, the procedure I go through is pretty simple. I do the following on a completely or at least mostly empty stomach.

I take between 400mg and 1000mg of Milk Thistle extract (Silybum marianum) (seed) (standardized to contain 80% Silymarin). Approximately 30 minutes later I take a few antacid tablets and about 20-30 minutes after that I parachute 50mg of crushed/powder Oxycodone placed inside a Gelatin capsule. It feels much stronger than 50mg of Oxycodone normally would. I also, have done this with and without Naproxen in my system, and the results are the same either way.

psychopath
20-04-2011, 22:36
Well, the procedure I go through is pretty simple. I do the following on a completely or at least mostly empty stomach.

I take between 400mg and 1000mg of Milk Thistle extract (Silybum marianum) (seed) (standardized to contain 80% Silymarin). Approximately 30 minutes later I take a few antacid tablets and about 20-30 minutes after that I parachute 50mg of crushed/powder Oxycodone placed inside a Gelatin capsule. It feels much stronger than 50mg of Oxycodone normally would. I also, have done this with and without Naproxen in my system, and the results are the same either way.

I assume you partake precisely the same without the Milk Thistle?

OxyChem
20-04-2011, 22:38
I assume you partake precisely the same without the Milk Thistle?

Yes.

OxyChem
20-04-2011, 22:46
And you have used the same gelatin capsules and antacids throughout as well?

Yea, everything is the same in terms of the gelatin capsules, antacids, Oxycodone and RoA.

The only difference would be that I don't eat the exact same foods at the exact same times everyday, but I would imagine my food intake wouldn't have any extreme affect in regards to the Milk Thistle potentiation of Oxycodone. But just as an fyi in case it actually does matter, I eat a mostly vegetarian diet and typically consume the same basic foods on a daily basis unless I eat out. I eat out 3 or 4 times a week.

BrokedownPalace
20-04-2011, 22:46
You say between 400mg and 1000mg, that's quite a large window. Do you find the potentiation increases by increasing the dose that high? Have you found an optimal dose?

BanginMyLifeAway
20-04-2011, 22:55
interesting i might pass this on being that i dont use any more

OxyChem
20-04-2011, 22:58
You say between 400mg and 1000mg, that's quite a large window. Do you find the potentiation increases by increasing the dose that high? Have you found an optimal dose?

I've been experimenting a bit with the amount of Milk Thistle, and it does seem to have better effects when used in closer to the 1000mg range.

The thing that bothers me, is that according to what I've read, significant inhibition of liver enzymes shouldn't start until at least 4500mg (oral) or more is taken. I guess I could be really sensitive or something, I have no idea. I don't have full access to peer-reviewed articles at my current location (just abstracts), but I can post some sources and quotes later on tonight or tomorrow when I have full access to my academic databases. Googling around will return some generic results about linver enzyme inhibition though (i.e http://www.mskcc.org/mskcc/html/69303.cfm). No idea if that's a quality source or not, it's simply the first result from my google search haha.

avcpl
21-04-2011, 00:16
I've been experimenting a bit with the amount of Milk Thistle, and it does seem to have better effects when used in closer to the 1000mg range.



Are you using one of the enhanced formulations?

from wiki here's what it says about the BA:
"Poor water solubility and bioavailability of silymarin led to the development of enhanced formulations. Silipide (trade name Siliphos), a complex of silymarin and phosphatidylcholine (lecithin), is about ten times more bioavailable than silymarin."

A google of Siliphos finds several brands. I'll have to get some since I've always noticed that my Milk Thistle powder never mixes very well...

CaPoNe.
21-04-2011, 01:53
Hmm interesting have you tried this with any other opiates bexides Oxycodone?

OxyChem
21-04-2011, 07:47
Are you using one of the enhanced formulations?

from wiki here's what it says about the BA:
"Poor water solubility and bioavailability of silymarin led to the development of enhanced formulations. Silipide (trade name Siliphos), a complex of silymarin and phosphatidylcholine (lecithin), is about ten times more bioavailable than silymarin."

A google of Siliphos finds several brands. I'll have to get some since I've always noticed that my Milk Thistle powder never mixes very well...

Yea, the kind I use has some sort of soy based phospholipid in it which makes it have greater bioavailability compared with regular Milk Thistle.

The first time I bought Milk Thistle, I got some from the grocery store and it didn't have the increased bioavailability properties. I tried to make tea with it and it wasn't very soluble.

OxyChem
21-04-2011, 07:47
Hmm interesting have you tried this with any other opiates bexides Oxycodone?

Unfortunately no. I have only had the opportunity to use Oxycodone with the Milk Thistle.

avcpl
21-04-2011, 18:45
WARNING: If anyone attempts potentiation with Milk Thistle, I recommend using Milk Thistle ONLY to potentiate opioid medications that are NOT combined with other substances (i.e APAP).



This is interesting since APAP is damaging to the liver but Milk Thistle is primarily marketed for improving liver health!

If I ever had too much APAP and alcohol, I would take Milk Thistle thinking I was doing good, but I was probably doing more harm...


I would imagine that a Cold Water Extraction of hydrocodone would be fine? (even though it doesn't remove all the APAP? or would even a little be too much?)



.

OxyChem
21-04-2011, 19:41
This is interesting since APAP is damaging to the liver but Milk Thistle is primarily marketed for improving liver health!

If I ever had too much APAP and alcohol, I would take Milk Thistle thinking I was doing good, but I was probably doing more harm...


I would imagine that a Cold Water Extraction of hydrocodone would be fine? (even though it doesn't remove all the APAP? or would even a little be too much?)



.


APAP is metabolized by the same enzymes that Milk Thistle inhibits in larger doses. So, APAP will accumulate to higher levels in your system temporarily if you take Milk Thislte a bit before ingesting APAP. Milk Thistle is amazing for treatment of APAP toxicity although, and is all around amazing for liver health. If you take APAP and wait until it's mostly metabolized, taking some Milk Thistle is great thing to do. I'd have to double check on this following point, but I would imagine that after APAP has gone through phase I metabolism, Milk Thistle is probably excellent to take :)

The amount of APAP in a CWE solution is typically negligible. You should be fine to take Milk Thistle.

avcpl
21-04-2011, 22:35
granted the study did not use quite the dosage you are using, but it is interesting:

"Two studies, one vitro and one in vivo studies have shown that its effects on CYP3A4 in vivo are not significant when compared to its effects in vitro."

"Silibinin, the main component of silymarin (a milk thistle extract used for treatment of liver injury), has been shown to inhibit CYP3A4 in human liver microsomes. The present study was conducted to examine whether inhibition of CYP3A4 by silymarin is also present IN VIVO."

"...administration of silymarin (280 mg administered 10 hours and 1.5 hours prior to the administration of nifedipine)"

"In conclusion, our data suggest that co- administration of silymarin does not considerably change the extent of absorption or metabolism of nifedipine but may decrease the absorption rate. Silymarin thus is not a potent CYP3A4 inhibitor IN VIVO."

http://personalizedmedicineblog.com/2008/02/21/assessment-of-drug-drug-interaction-for-silymarin/

OxyChem
21-04-2011, 23:09
granted the study did not use quite the dosage you are using, but it is interesting:

"Two studies, one vitro and one in vivo studies have shown that its effects on CYP3A4 in vivo are not significant when compared to its effects in vitro."

"Silibinin, the main component of silymarin (a milk thistle extract used for treatment of liver injury), has been shown to inhibit CYP3A4 in human liver microsomes. The present study was conducted to examine whether inhibition of CYP3A4 by silymarin is also present IN VIVO."

"...administration of silymarin (280 mg administered 10 hours and 1.5 hours prior to the administration of nifedipine)"

"In conclusion, our data suggest that co- administration of silymarin does not considerably change the extent of absorption or metabolism of nifedipine but may decrease the absorption rate. Silymarin thus is not a potent CYP3A4 inhibitor IN VIVO."

http://personalizedmedicineblog.com/2008/02/21/assessment-of-drug-drug-interaction-for-silymarin/

I've seen numerous peer-reviewed studies that have demonstrated in laboratory animal models, significant inhibition of CYP3A4 in vivo does in fact occur. There have been a few in vivo human studies as well.

I'm working atm (not a lot of spare time) and I'm also not exactly a liver expert or biochemist but as an example:

"With the lowest concentration of 1.5 μg/ml dry extract from S. marianum no or minor inhibition of less than 25% of positive control for any of the 9 CYP isoenzymes was observed (Fig. 3). However, there was significant inhibition of the isoenzymes 2C8, 2C9, 2C19, 2D6, and 3A4, at the higher concentrations, ranging from 40% to 80% inhibition rate." -Assessment of a dry extract from milk thistle (Silybum marianum) for interference with human liver cytochrome-P450 activities

This experiment used freshly plated hepatocytes for tests in vitro, and milk thistle was also administered in vivo and hepatocytes were extracted afterwards and plated to see if enzyme inhibition occurred. Inhibition was seen in both cases at moderate to higher doses.

avcpl
21-04-2011, 23:40
and as you said, there could be individual variances too. It's definitely worth a shot since it's not that expensive. White grapefruit juice didn't seem to do much for me (even at 700ml) and that's quite a bit of calories to consume.

Also, that study I sited may not have used the high absorbsion delivery. (btw, I ordered some this morning :)

OxyChem
21-04-2011, 23:45
and as you said, there could be individual variances too. It's definitely worth a shot since it's not that expensive. White grapefruit juice didn't seem to do much for me (even at 700ml) and that's quite a bit of calories to consume.

Also, that study I sited may not have used the high absorbsion delivery. (btw, I ordered some this morning :)

You know, for some reason grapefruit juice has never worked well for me either, but I know there are A LOT of people who swear by it. Individual variance is a crazy thing.

Good luck with your milk thistle! :)

laCster
22-04-2011, 00:32
which is the better inhibitor of the CYP3A4 enzyme, tagamet or milk thistle?

smackcraft
22-04-2011, 03:58
My dad buys the expensive milk thistle liquid form and ive used it many times when ive been feeling ill

Im on methadone but not sure i felt any difference tbh , should of i felt anything different with that combo ?

OxyChem
22-04-2011, 04:23
My dad buys the expensive milk thistle liquid form and ive used it many times when ive been feeling ill

Im on methadone but not sure i felt any difference tbh , should of i felt anything different with that combo ?

Well, I've only used Milk Thistle to potentiate Oxycodone, thus I really can't say for sure what would happen with Milk Thistle + Methadone. I don't know much about Methadone and am not sure what enzymes are responsible for its metabolism :(

smackcraft
22-04-2011, 04:25
I have heard people say that if u drink a glass of greapfruit juice an hour before taking methadone it does something but ive never tried that, maybe its the same idea

I just like to have a nice cup of Earl Grey tea after my methadone xD

k20
22-04-2011, 13:59
will give it a try tomorrow and report back

k20
22-04-2011, 15:50
ok so i'm on 90mg of temazepan, took 25mg diphenhydramine and 600mg of milk thistle about 15mins ago.

I was planning to do this tomorrow sober but my benzo mindset got me taking the latter two.

I initally took 60mg of temmies to sleep but my insomnia is really being a bitch so I decided to do this experiment out of boredom.

In about another 15, I'm gonna rail 15mg of oxycodone. I know this experiment has wayyyy too many variables but I'll report back regardless.

I've been taking 60-180mg of oxy a day for about two weeks. This last week I've been taking 60-90mg orally through out the day.

I'm really running low on oxys so hopefully this theory will work when I have to go to work tomorrow (I've been going on oxys as it makes work much easier and enjoyable).

Going on tangents...stupid benzos not doing its job. Should be sleeping right now...

anyway will report back after 15mg of oxy intake

peaaaaaaaaace

OxyChem
22-04-2011, 16:01
ok so i'm on 90mg of temazepan, took 25mg diphenhydramine and 600mg of milk thistle about 15mins ago.

I was planning to do this tomorrow sober but my benzo mindset got me taking the latter two.

I initally took 60mg of temmies to sleep but my insomnia is really being a bitch so I decided to do this experiment out of boredom.

In about another 15, I'm gonna rail 15mg of oxycodone. I know this experiment has wayyyy too many variables but I'll report back regardless.

I've been taking 60-180mg of oxy a day for about two weeks. This last week I've been taking 60-90mg orally through out the day.

I'm really running low on oxys so hopefully this theory will work when I have to go to work tomorrow (I've been going on oxys as it makes work much easier and enjoyable).

Going on tangents...stupid benzos not doing its job. Should be sleeping right now...

anyway will report back after 15mg of oxy intake

peaaaaaaaaace

Are you using a standardized milk thistle silymarin extract or just regular powder seed or plant matter or what? Also, just for the note I typically wait a good 45 minutes to an hour after taking milk thistle before I take any Oxycodone. Good luck to you sir, I hope it works well!!!

OxyChem
22-04-2011, 16:10
I just came across a post from "amapola" a bluelight moderator (http://www.bluelight.ru/vb/showthread.php?t=562857&highlight=milk+thistle).

Amapola posted the following:



If you want to get higher off of hydrocodone you want a broken liver not a healthy functioning one ;)

Milk thistle has been shown to inhibit the enzyme's which break down hydrocodone.



Indeed, in recent experiments using milk thistle and human liver cells, the researchers found that
relatively small concentrations of milk thistle did significantly slow down the activity of the liver enzyme
CYP3A4 by 50% to 100%.

source: http://www.hcvadvocate.org/news/News...s/mthistle.pdf


The flavonolignans silybin A and silybin B from milk thistle (Silybum marianum) inhibit CYP2C9-mediated warfarin metabolism at clinically achievable concentrations

source: http://jpet.aspetjournals.org/content/332/3/1081.full


So that 10mg dose didn't get broken down nearly as efficiently as usual and you got much higher than you normally would have.

I'm glad to know I'm not the only one who has experienced decent potentiation with Milk Thistle!!! I'm reallllllyyyyy hoping that this stuff is going to work well for a lot of other people as well. I get the feeling although, that it may not be ordinary to get good potentiation like I've expereinced... NEED to figure out why it works so well for me! There has to be some sort of reason that can be identified hehe.

k20
22-04-2011, 16:29
Are you using a standardized milk thistle silymarin extract or just regular powder seed or plant matter or what? Also, just for the note I typically wait a good 45 minutes to an hour after taking milk thistle before I take any Oxycodone. Good luck to you sir, I hope it works well!!!

I'm using the standardized extract.

I know my experience proves nothing because I'm on so much other shit.

15mg of nasal oxy without anything prior gives me a slight sense of well being, and slight stimulation.

Right now I feel as if my oxy stimulation is getting rid of the benzo-ed out feeling. My head feels more clear and I feel wide awake, almost as if I haven't taken any benzos.

I feel less of the "well being" but I'm almost positive it's the benzos dulling it out.

Also, my tolerance probably is a lot higher than the last time I railed oxy.

Again, I can't really tell if the milk thistle did anything and will probably regret taking the oxy tomorrow (seems like a waste).

Will try 30mg of oxy orally with 600mg milk thistle extract 45 mins prior tomorrow.

Really hope it works because now I have only 65mg to last me until saturday...

I'm just gonna take another 15mg for the fuck of it. (probably the benzo-ed thinking). I'll regret it tomorrow but oh well...


edit: just re-read the original post as I didn't thoroughly read it due to the temmies. (everything is the benzo's fault)

my milk thistle is the GNC brand and 80% silymarin and does not contain the special soy milk

edit2: soy milk??? lol soy phospholipids

k20
22-04-2011, 16:44
Ok, I'm starting to feel a lot more sedated and comfortable (something that the 90mg of temazepam couldn't do)

But it's probably due to the DPH and the temmie/oxy combo...

there's probably no useful info on my posts...sorry about that lol

but again, will contribute tomorrow

OxyChem
22-04-2011, 16:54
Ok, I'm starting to feel a lot more sedated and comfortable (something that the 90mg of temazepam couldn't do)

But it's probably due to the DPH and the temmie/oxy combo...

there's probably no useful info on my posts...sorry about that lol

but again, will contribute tomorrow

All info is appreciated regardless of whether it might be the milk thistle/oxy or the temazepan/oxy combo!

Out of curiosity, do you feel like there is any additional euphoria or things like opiate itches as opposed to just sedation that the temazepan probably wouldn't be responsible for?

k20
23-04-2011, 15:54
All info is appreciated regardless of whether it might be the milk thistle/oxy or the temazepan/oxy combo!

Out of curiosity, do you feel like there is any additional euphoria or things like opiate itches as opposed to just sedation that the temazepan probably wouldn't be responsible for?

Couldn't only take milk thistle and oxycodone again because I was on diazepam earlier and thought would effect my buzz. This time I was on 30mg temazepam, 5mg diazepam, 600mg milk thistle extract on top of 50mg benadryl with my 60mg of oxycodone. I ran out now so I can't due the experiment unless I hook more :(

I also think my tolerance grew so fast during the past two weeks that I need slightly more than 60mg oxycodone (alone) to cause a good nod.

Sorry, being the junkie that I am, I didn't perform the experiment.

The only interaction I found between the milk thistle and oxycodone was increased stimulation and that was it.

Maybe you're just lucky or it's actually the soy phospholipids that indirectly causes the potentiation, but I will give it ANOTHER go when I have a good amount of oxys

bpayne
23-04-2011, 18:38
Daaaaayuuuuuum!!! Interesting!!! I've had an unopened bottle of this stuff in my Cabinet the whole time, Left over from the times I use to drink a 12 pack a day for months straight.... thought it might come in handy ya dig. but I never knew it could come in handy in handy like "That"... I must do more Research!

mrflowers00
24-04-2011, 00:59
if anyone else has tried milk thistle and it helped significantly IM me and tell me what dose and how soon before you do opioid drugs you take the milk thistle cause i'm going to buy 1000mg caps and try them out

oxycontiin
23-12-2011, 13:25
Normally oxy will always grind up his 80's with a hose clamp and snort them because he finds the effects much stronger than any other method. However, after repeated use, tolerance has lead to in many cases absolutely no high from doing as much as 50 - 60mg. He's looked at potentiators, but there's always a counter argument for every argument for things such as grapefruit juice and others like it. This milk thistle seems very promising so oxy thinks he'll try it tomorrow. Since it peaked his interest, he discovered this article http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2010.03653.x/abstract, which interestingly tested exactly what we're all interested in, whether or not inhibiting the enzymes CYP 2D6 (milk thistle) and 3A4 would increase the potency of oxycodone. Skipping to the conclusion, he found the results to state that inhibiting just CYP 2D6 made minor changes, but the metabolization of oxycodone mostly just shifted to the other enzyme CYP 3A4. But, if the test subjects inhibited both CYP 2D6 and 3A4 there were significant increases in potency. Significant increases sounds good to oxy :) So he promptly went and found a product called biaxin purchasable without a prescription with the active ingredient clarithromycin, which is known to be a strong inhibitor of CYP 3A4.

So, today oxy will hunt down some milk thistle and biaxin and see what improvements this will have. Although he doesnt have much to go on because he has only once or twice ground up some ox to place under his tongue and has never ingested it, besides drips. He doesn't have a very good reference then, but the plan is to pop some milk thistle (750mg) with biaxin (750mg) and half an hour later, buck a 60 of ox and then drop another 40 or so.

Its hard for oxy to eat it because it feels like such a waste, but nowadays so is putting it up his nose so he'll give it a try for the sake of science. Oxy will return to the forum with results later.

Thank you Oxychem for sharing this fantastic information!

Poodles!
08-08-2012, 06:17
APAP is metabolized by the same enzymes that Milk Thistle inhibits in larger doses. So, APAP will accumulate to higher levels in your system temporarily if you take Milk Thislte a bit before ingesting APAP. Milk Thistle is amazing for treatment of APAP toxicity although, and is all around amazing for liver health. If you take APAP and wait until it's mostly metabolized, taking some Milk Thistle is great thing to do. I'd have to double check on this following point, but I would imagine that after APAP has gone through phase I metabolism, Milk Thistle is probably excellent to take :)

The amount of APAP in a CWE solution is typically negligible. You should be fine to take Milk Thistle.

Hmm, personally I'd recommend Milk Thistle to be taken alongside paracetamol (APAP, Acetaminophan).

APAP is primarily metabolised via glucuronidation and sulfation, whilst N-acetyl-p-benzoquinone imine (NAPQI, the BAD stuff) is formed mostly from CYP2E1 as well as 1A2, 3A4 and to a lesser extent 2D6. Wiki has a nice little graphic showing this:
http://upload.wikimedia.org/wikipedia/commons/1/12/Paracetamol_metabolism.svg
It's worth reading these abstracts too:

Kinetics of acetaminophen glucuronidation by UDP-glucuronosyltransferases 1A1, 1A6, 1A9 and 2B15. Potential implications in acetaminophen-induced hepatotoxicity.
[There seems to be a lack of info out there on UGT enzyme inhibitors, but check out the "Sweet UGT enzyme chart" and "metablism beyond the CYP's" threads.
http://www.ncbi.nlm.nih.gov/pubmed/16696573

Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice.
http://www.ncbi.nlm.nih.gov/pubmed/9772215

AM404 (the GOOD stuff) is responsible for much, if not the majority of APAP's actions through a combination of TRVP1 agonism, elevated anandamide (endocannabinoid, CB1 agonist) levels and COX-1/2 inhibition. This metabolite is formed by conjugation with arachidonic acid via fatty acid amide hydrolase (FAAH). It should also be noted that AM404 is an inhibitor of this enzyme, which would suggest that it faces the same problem that codeine > morphine metabolism faces (codeine is a CYP2D6 inhibitor), although in this case morphine is only responsible for some of codeine's effects (most from C6G via UGT2B7). I've not actually checked but I would think APAP is not a strong FAAH inhibitor since redosing works well...

Although by far the best supplement to take alongside APAP is N-acetyl-L-cysteine (NAC (http://en.wikipedia.org/wiki/Acetylcysteine)). NAC is an important precursor to Glutathione (GSH (http://en.wikipedia.org/wiki/Glutathione)) which is biosynthed from L-cysteine + glutamic acid + Glycine (I often add some Glycine and L-Glutamine to my NAC capsules). Alpha Lipoic Acid (ALA (http://en.wikipedia.org/wiki/Alpha_lipoic_acid)) and of particular relevance, Silymarin have been shown to elevate GSH levels too. Just noticed this on these interesting bits on the GSH wiki:
"Calcitriol, the active metabolite of vitamin D synthesized in the kidney, increases glutathione levels in the brain and appears to be a catalyst for glutathione production.[27]"
"Melatonin has been shown to stimulate a related enzyme, glutathione peroxidase,[40]".

The actual mechanisms of APAP's therapeutic effects aren't well understood though. Here's some sauce:

Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system.

... "acetaminophen, following deacetylation to its primary amine, is conjugated with arachidonic acid in the brain and the spinal cord to form the potent TRPV1 agonist N-arachidonoylphenolamine (AM404)" ... "These findings identify fatty acid conjugation as a novel pathway for drug metabolism and provide a molecular mechanism for the occurrence of the analgesic N-acylphenolamine AM404 in the nervous system following treatment with acetaminophen."
http://www.ncbi.nlm.nih.gov/pubmed/15987694

Paracetamol-induced hypothermia is independent of cannabinoids and transient receptor potential vanilloid-1 and is not mediated by AM404.
http://www.ncbi.nlm.nih.gov/pubmed/21628499

TRPV1 in Brain Is Involved in Acetaminophen-Induced Antinociception
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012748

Regarding Milk Thistle/Silymarin and APAP:

Acetaminophen-induced Hepato- and Nephrotoxicity and Amelioration by Silymarin and Terminalia chebula in Rats.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997457/?tool=pubmed

Stimulatory effects of silibinin and silicristin from the milk thistle Silybum marianum on kidney cells
..."n vitro experiments with kidney cells damaged by paracetamol, cisplatin, and vincristin demonstrated that administration of silibinin before or after the chemical-induced injury can lessen or avoid the nephrotoxic effects. The results warrant in vivo evaluations of the flavonolignan derivatives."
http://www.ncbi.nlm.nih.gov/pubmed/10454517 [Full text is also available]

Protective effects of Phyllanthus acidus (L.) Skeels leaf extracts on acetaminophen and thioacetamide induced hepatic injuries in Wistar rats.
..."In two different sets of experiments, the P. acidus extracts (200 and 400 mg/kg, body weight) and silymarin (100 mg/kg, body weight) were given orally for 7 days and a single dose of APAP (2 g/kg, per oral) or TAA (100 mg/kg, subcutaneous) were given to rats. The level of serum aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin and total protein were monitored to assess hepatotoxicity and hepatoprotection."...
..."The P. acidus extracts and silymarin prevented the toxic effects of APAP or TAA on the above serum parameters indicating the hepatoprotective action."...
http://www.ncbi.nlm.nih.gov/pubmed/21771701

Evaluation of prophylactic and therapeutic effects of silymarin and N-acetylcysteine in acetaminophen-induced hepatotoxicity in cats.
http://www.ncbi.nlm.nih.gov/pubmed/20444031

Poodles!
08-08-2012, 06:48
This is a good thread. I've posted some useful stuff in this thread about enzyme inhibition and opioids (near the bottom).
• Opiate/Opioid Potentiators [INDERALL?] (http://www.bluelight.ru/vb/threads/631287-Opiate-Opioid-Potentiators-INDERALL)

Also recommended:
•Project - Codeine-6-Glucuronide (C6G) (http://www.bluelight.ru/vb/threads/499846-Project-Codeine-6-Glucuronide-(C6G))
• Messing with drug metabolism beyond the CYPs (http://www.bluelight.ru/vb/threads/581384-Messing-with-drug-metabolism-beyond-the-CYPs)
• Sweet UGT enzyme chart (inhibitors/inducers) (http://www.bluelight.ru/vb/threads/586307-Sweet-UGT-enzyme-chart-(inhibitors-inducers))
• Awesome CYP-450 Chart! (http://www.bluelight.ru/vb/threads/191439-Awesome-CYP-450-Chart!)
• potentiation of drugs from milk thistle? (http://www.bluelight.ru/vb/threads/619092-potentiation-of-drugs-from-milk-thistle)
• Potentiate benzos with milk thistle? (http://www.bluelight.ru/vb/threads/608295-Potentiate-benzos-with-milk-thistle)
• Milk Thistle Liver Detox = Lowered Opiate Tolerance? (http://www.bluelight.ru/vb/threads/562857-Milk-Thistle-Liver-Detox-Lowered-Opiate-Tolerance)

Various useful stuff I've picked out:

Indeed, in recent experiments using milk thistle and human liver cells, the researchers found that
relatively small concentrations of milk thistle did significantly slow down the activity of the liver enzyme
CYP3A4 by 50% to 100%.

source: http://www.hcvadvocate.org/news/News...s/mthistle.pdf

The flavonolignans silybin A and silybin B from milk thistle (Silybum marianum) inhibit CYP2C9-mediated warfarin metabolism at clinically achievable concentrations

source: http://jpet.aspetjournals.org/content/332/3/1081.full


Interactions between Natural Health Products and Antiretroviral Drugs: Pharmacokinetic and Pharmacodynamic Effects

There is a lot of good stuff in this review (pub.2006), the whole text is available so I recommend having a skim through at least, and also checking out relevant references... but here's some particularly thread-relevant bits:
…"Silybins, the active components of milk thistle, were found to inhibit CYP3A4 in vitro [25] and, thus, could increase ARV drug concentrations."…
…"Silymarin, a component of milk thistle, inhibits P-gp activity and enhances doxorubicin toxicity in vitro [36]. Other NHPs that inhibit P-gp in vitro include garlic, green tea, turmeric, ginseng, rosemary, flavonoids from many plants [37], African potato, and S. frutescens [28]. However, data are lacking on the clinical significance of these effects on P-gp."…
…"Two uncontrolled clinical studies [41, 42] revealed trends toward reduction in concentrations of indinavir after coadministration of milk thistle. A 3-period, randomized, controlled trial revealed a similar trend; however, there was an even greater reduction in area under the curve (AUC; 21.5%), trough concentrations (Cmin; 53.1%), and peak concentrations (Cmax; 9.4%) in subjects in the control group, which persisted after a washout period [43]. Compared with the control group, the milk thistle group demonstrated a significant but small increase in Cmin and trends toward increases in AUC and Cmax (table 1). Other clinical studies involving milk thistle and CYP3A4 [44] or P-gp [45] probe drugs revealed no pharmacokinetic interactions, indicating that clinically important interactions between milk thistle and PIs or NNRTIs are unlikely."…
http://cid.oxfordjournals.org/content/43/8/1052.full

Clinical Evidence of Herbal Drugs As Perpetrators of Pharmacokinetic Drug Interactions.

..."The clinical evidence was found to be most robust and informative for Gingko biloba (GB; 21 studies) and milk thistle/silymarin (MT; 13), and appears still limited for ginseng (9), goldenseal/berberine (GS; 8), garlic (8), and Echinacea (7). Collectively, the available evidence indicates that, at commonly recommended doses, none of these herbs act as potent or moderate inhibitors or inducers of cytochrome P450 (CYP) enzymes or P-glycoprotein (ABCB1). Weak effects in terms of either induction or inhibition were found for GB (presystemic/hepatic CYP3A4 induction/inhibition, CYP2C19 induction at high doses), milk thistle/silymarin ([weak]CYP2C9 inhibition), GS/berberine (CYP3A4 and CYP2D6 inhibition), Echinacea (presystemic/hepatic CYP3A4 inhibition/induction, CYP1A2 and CYP2C9 inhibition at high doses). Information was found not always complete for the major drug metabolizing CYP enzymes in the less well-studied herbs and is largely limited to P-glycoprotein (ABCB1) when effects on drug transporters have been investigated."
http://www.ncbi.nlm.nih.gov/pubmed/22855269

A review of the bioavailability and clinical efficacy of milk thistle phytosome: a silybin-phosphatidylcholine complex (Siliphos).

..."The standardized extract known as silymarin contains three flavonoids of the flavonol subclass. Silybin predominates, followed by silydianin and silychristin. Although silybin is the most potent of the flavonoids in milk thistle, similar to other flavonoids it is not well-absorbed. Silybinphosphatidylcholine complexed as a phytosome provides significant liver protection and enhanced bioavailability over conventional silymarin."...
http://www.altmedrev.com/publications/10/3/193.pdf [Full text .PDF]

Bioavailability and Activity of Phytosome Complexes from Botanical Polyphenols: The Silymarin, Curcumin, Green Tea, and Grape Seed Extracts

..."Silybin is a proven liver protectant; in animal experiments it blocked the oxidative toxicities of acetaminophen, alcohol, carbon tetrachloride, and the mushroom toxins phalloidin and alpha-amanitin"...
..."Although in animal experiments and some human studies, milk thistle constituents have conserved liver glutathione, inhibited liver fibrogenesis, and supported liver regeneration,4,8 clinical trials have been inconsistent. In trials of viral hepatitis,18 alcoholic liver damage,19 or other liver diseases, silymarin and silybin improved enzyme damage indicators and (at times) improved antioxidant status,4,18,19 but did not consistently improve symptoms."...
…"The utilization of non-phytosome silybin intravenously in mushroom-toxic patients (at 20-50 mg/kg/day) or of high-dose silymarin at 600 mg/day in diabetic patients has resulted in meaningful symptom improvement,19 presumably because the preparations were given either intravenously or at a high oral dose. Overall, the efficacy patterns are consistent with poor intestinal absorption of these important flavonolignans, making the phytosome form a more appropriate oral delivery vehicle for this class of polyphenols."...
http://s16.postimage.org/ywisqndib/Silybin_phytosomes_and_silymarin_absorbtion.png
NSFW as it's a pretty large image/graph
http://www.altmedrev.com/publications/14/3/226.pdf [Full text .PDF]

Occurrence of aflatoxins in milk thistle herbal supplements.

..."A total of 83 MT samples from the US market were analysed. AFs were detected in 19% of the samples with levels ranging from 0.04 to 2.0 g kg(-1). Additionally, an aflatoxigenic A. flavus strain from ATTC and an A. parasiticus strain isolated from MT herb powder were found to produce high amounts of aflatoxins (11,200 and 49,100 g kg(-1), respectively) when cultured in MT seed powder. This is the first study reporting on aflatoxin contamination of MT botanical supplements and identifying methodology for AF analysis of these commodities."
http://www.ncbi.nlm.nih.gov/pubmed/22439650

Another good review article on Silymarin, although much of it isn't particularly relevant to the thread... It's just interesting :):

SILYBIN AND SILYMARIN – NEW EFFECTS AND APPLICATIONS
http://mefanet.upol.cz/BP/2005/1/29.pdf [Full Text .PDF]

mrflowers00
08-08-2012, 08:14
i tried milk thistle 500mg than 1000 and it did nothing for me

endlessnameless
08-08-2012, 08:40
i tried milk thistle 500mg than 1000 and it did nothing for me

It'll tend not to, unless you take it with a narcotic; milk thistle isn't a psychoactive substance.

mrflowers00
09-08-2012, 00:17
nah i meant with oxycodone and as well with xanax and nothing

Aporia
15-12-2012, 11:39
Hey all. I don't mean to hijack a thread but I didn't want to start a whole new one when the topic has been covered already, in away. So here's my question. I'm on 4-6 lortabs a day for chronic pain. I told my doc that I was concerned about my liver and constantly tells me I have nothing to worry about. I asked him about milk thistle today at my appointment and he told me he wouldn't say he was for nor against it. I've been taking them for about three months. The information I have gotten on BL is contradictory saying that if taken with apap it could increase the toxicity..but then I come across the post above and it seems that I ought to be taking it daily along with my meds. Could anyone give advice on whether it is helpful to take while taking medication with apap and maybe what doses I ought to be looking into taking? Thank you so much everyone!

Fire&Water
15-12-2012, 20:06
Normally oxy will always grind up his 80's with a hose clamp and snort them because he finds the effects much stronger than any other method. However, after repeated use, tolerance has lead to in many cases absolutely no high from doing as much as 50 - 60mg. He's looked at potentiators, but there's always a counter argument for every argument for things such as grapefruit juice and others like it. This milk thistle seems very promising so oxy thinks he'll try it tomorrow. Since it peaked his interest, he discovered this article http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2010.03653.x/abstract, which interestingly tested exactly what we're all interested in, whether or not inhibiting the enzymes CYP 2D6 (milk thistle) and 3A4 would increase the potency of oxycodone. Skipping to the conclusion, he found the results to state that inhibiting just CYP 2D6 made minor changes, but the metabolization of oxycodone mostly just shifted to the other enzyme CYP 3A4. But, if the test subjects inhibited both CYP 2D6 and 3A4 there were significant increases in potency. Significant increases sounds good to oxy :) So he promptly went and found a product called biaxin purchasable without a prescription with the active ingredient clarithromycin, which is known to be a strong inhibitor of CYP 3A4.

So, today oxy will hunt down some milk thistle and biaxin and see what improvements this will have. Although he doesnt have much to go on because he has only once or twice ground up some ox to place under his tongue and has never ingested it, besides drips. He doesn't have a very good reference then, but the plan is to pop some milk thistle (750mg) with biaxin (750mg) and half an hour later, buck a 60 of ox and then drop another 40 or so.

Its hard for oxy to eat it because it feels like such a waste, but nowadays so is putting it up his nose so he'll give it a try for the sake of science. Oxy will return to the forum with results later.

Thank you Oxychem for sharing this fantastic information!

Does "oxy" always talk about himself as the 3rd person ?

HYDRO_CHRONIC
15-12-2012, 21:40
I take milk thistle all the time just the other day I ate 56mg of oxy and had 1000mg of mt before it and never notice any affect on the high