Opioids Is it an oddity that Milk Thistle RADICALLY potentiates Oxycodone?

[avcpl]

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]

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]

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]

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]

which is the better inhibitor of the CYP3A4 enzyme, tagamet or milk thistle?

 

[smackcraft]

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]

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]

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]

will give it a try tomorrow and report back

 

[k20]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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!]

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:

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). NAC is an important precursor to Glutathione (GSH) 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) 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:doi/10.1371/journal.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