Oral Drug Metabolism Enhancement SUPER THREAD! Learn how to make your drugs work better for YOU!
by /u/StarScream999 Harm Reduction Guy
DISCLAIMER: The author of this article is not responsible for any liver or other organ damage that may be caused by using this protocol. Please take care of your liver by getting regular blood tests to ensure there is no liver damage. You can purchase a "Hepatic Function Panel (ALB, AST, ALT, TP) Liver Profile" blood test from Health Tests Direct for only $38, then you print out a sheet, take it into a Qwest lab location, have your blood drawn and they will email you your results the next day. You will have to do some basic research to ensure what you're looking at on your blood tests make sense to you and are not in a dangerous range. You can also protect yourself by taking supplements such as SNS Liver Assist XT which contain liver boost ingredients such as NAC (N-Acetyl-Cystine) and Milk Thistle. TUDCA (Tauroursodeoxycholic Acid) would also be a wise choice, as it helps clear the bile ducts of the liver. This would be a required part of the kit as it's necessary to function.
This combination is not for freshmen drug users, this is for individuals who have been using drugs for years and the liver has become so efficient at breaking them down, steps like this need to be taken to get the best result from the drug. SO BE CAREFUL WHEN USING THIS PROTOCOL! IF ANYTHING, TRY ONE COMPOUND I RECOMMEND AT A TIME SO YOU CAN SEE HOW IT INTERACTS WITH YOU AND THE DRUG YOU'RE TAKING!
Health Tests Drug: https://www.health-tests-direct.com/ordering-page
SNS Liver XT: https://a1-supplements.com/sns-liver-assist-xt
TUDCA: https://a1-supplements.com/competitive-edge-labs-tudca
Understanding Basic Oral Drug Metabolism
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TL;DR Recipe
1) We're going to either drink an 8oz glass of grapefuit juice or take 600mg of Grapefruit Extract Capsules. https://amzn.to/3o5W55J
2) We're going to take at least 10mg of Bioperine https://amzn.to/3wm53zG
3) 200mg-400mg of Cimetidine. https://amzn.to/3onN7km
4) We're going to wait 30-45 minutes.
5) We take the drugs we want to take.
6) Add 1 half a teaspoon of HPBC and pour it on your tongue, then swallow it with some water. Bioperine
Better when crushed and mixed with oil and used sublingually.
When you take any drug orally, it has to pass through the GI (gastrointestinal) tract, which can destroy part of the drug due to it's acidity, then it has to pass through the liver, where it has to pass through Cytochrome P450 (CYP) which a variety of enzymes in the liver that work to breakdown those drugs even more and make them even more less potent.
https://en.wikipedia.org/wiki/Cytochrome_P450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases.[1][2][3] In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown. In plants, these proteins are important for the biosynthesis of defensive compounds, fatty acids, and hormones.
There are dozens of CYP Enzymes in the human liver that work to break down various compounds. This is because your liver wasn't evolutionary developed to ingest drugs, it's meant to break down foods. Every human has different levels of CYP enzymes in their body that can metabolize drugs in different ways. That's why you might have a preference for a certain drug over another, because it might hit you harder because you have less of that particular CYP enzyme that breaks it down as much, or it could have a CYP enzyme that keeps it hanging out in the liver and slowly metabolize over a long period, keeping the high up longer.
CYP Enzymes: https://en.wikipedia.org/wiki/Cytochrome_P450#CYP_families_in_humans
When I first went to my psychiatrist, I took a DNA test to determine which CYP enzymes I have more of than others and which drugs would work best based on my liver's metabolism.
How to Bypass These CYP Enzymes and Sneak Drugs Through the Liver
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There are essentially four chemicals, sold OTC as dietary supplements and one drug that will help you bypass the liver and absorb your drugs more efficiently by using these techniques.
1) Grapefruit Juice
The effect is most studied with grapefruit and grapefruit juice, but similar effects have been observed with certain other citrus fruits. A 2005 medical review advised patients to avoid all citrus juices until further research clarifies the risks. It was reported in 2008 that similar effects had been observed with apple juice.
One whole grapefruit, or a small glass (200 mL, 6.8 US fl oz) of grapefruit juice, can cause drug overdose toxicity. Fruit consumed three days before the medicine can still have an effect. The relative risks of different types of citrus fruit have not been systematically studied. Affected drugs typically have an auxiliary label saying "Do not take with grapefruit" on the container, and the interaction is elaborated upon in the package insert. People are also advised to ask their physician or pharmacist about drug interactions.
The effects are caused by furanocoumarins (and, to a lesser extent, flavonoids). These chemicals inhibit key drug metabolizing enzymes, such as cytochrome P450 3A4 (CYP3A4). CYP3A4 is a metabolizing enzyme for almost 50% of drugs, and is found in the liver and small intestinal epithelial cells. As a result, many drugs are affected. Inhibition of enzymes can have two different effects, depending on whether the drug is either metabolized by the enzyme to an inactive metabolite, or activated by the enzyme to an active metabolite.
In the first instance, inhibition of drug-metabolizing enzymes results in elevated concentrations of an active drug in the body, which may cause adverse effects. Conversely, if the medication is a prodrug, it needs to be metabolised to be converted to the active drug. Compromising its metabolism lowers concentrations of the active drug, reducing its therapeutic effect, and risking therapeutic failure.
Low drug concentrations can also be caused when the fruit suppresses drug absorption from the intestine
Source: https://en.wikipedia.org/wiki/Grapefruit–drug_interactions
The main compounds we are looking for in the grapefruit juice are bergamottin and 6',7'-dihydroxybergamottin, as these are the main components that inactivate CYP3A4, the main CYP compound that breaks down drugs. Although I have seen supplements containing bergamottin and 6',7'-dihydroxybergamottin, I have been unable to find a source for it directly. So you have two options. You can go to the grocery store and buy yourself some bottles of Grapefruit Juice (try and get white or ruby 100% pure with NO SUGAR). Ideally, you want to buy it where it's been chilled during storage. If you're feeling a little bit reckless, some gin and my favorite, Campari, can help the grapefruit juice go down and now you're mixing alcohol and drugs so welcome to the wonderful world of drug abuse. NOTE: If you're taking heavy sedatives or opioids, adding alcohol might not be the best idea. But you want to drink an 8oz glass of grapefruit juice 30-45 minutes prior to your drug intake.
The second option is to buy Grapefruit Extract Capsules standardized for Naringin but with the full spectrum of other enzymes in them. These claim to aid weight loss, but that's a lot of bullshit. You want to take 600mg (2 capsules) 30-45 minutes prior to your drug intake.
Grapefruit Extract Capsules: https://amzn.to/3o5W55J
Naringin inhibits some drug-metabolizing cytochrome P450 enzymes, including CYP3A4 and CYP1A2, which may result in drug-drug interactions.Ingestion of naringin and related flavonoids can also affect the intestinal absorption of certain drugs, leading to either an increase or decrease in circulating drug levels. To avoid interference with drug absorption and metabolism, the consumption of citrus (especially grapefruit) and other juices with medications is advised against.
Now, all this stuff about so called "drugs". these substaneces have miracle properties and should be allowed to everyone might sound scary, we're not taking dangerous stuff here than can cause fatal interactions or anything like that. The fact that it can inhibit these CYP enzymes is actually good for us drug abusers.
2) Bioperine: https://amzn.to/3wm53zG
The next supplement in our toolkit to bypass the liver is Bioperine, a derivative of Black Pepper.
Black Pepper is a source of piperine, a molecule that does not do much on its own but can inhibit enzymes that would attack other molecules. Due to this, it is ingested alongside some supplements to increase their absorption rates and is almost always consumed with curcumin.
[...]
Caution Notice
If using any drugs or pharmaceuticals, check with your MD before supplementing anything with Piperine in it in high quantities.
Piperine inhibits drug detoxifying enzymes. This typically increases bioavailability of any compound which would normally be attacked by said enzymes. This can be good (ie. curcumin, EGCG) or it can be bad by stopping a protective measure against toxic xenobiotics.
[...]
Piperine is known for changing metabolism of various drugs and supplements, most notably increasing curcumin bioavailability by 2000%. It affects metabolism by both intestinal absorption as well as downregulating or inhibiting phase II detoxification enzymes and the glucuronidation process in the liver. It may also contribute to increase absorption by slowing intestinal transit rate and thus prolonging the time said compounds are exposed to the potential uptake.
Source: https://examine.com/supplements/black-pepper/research/#enterohepatic-effects
Bioperine 10mg | 120 Capsules | Non-GMO & Gluten Free | Sourced from Black Pepper Extract (only $9 for 120 caps): https://amzn.to/3wm53zG
You want to take 10mg of Bioperine 30-45 minutes prior to your drug intake.
3) Cimetidine: https://amzn.to/3onN7km
Second to last, in our cocktail of drugs that help metabolism is Cimetidine, also known as Tagamet HB, which is an antacid of the H2 histamine class. Meanining it blocks histamine release from your liver. The study below quotes take 1g/day, but we're going to be a little more safety consious and only take 1-2 tablet of 200mg to 400mg. (I usually just take 200mg)
Abstract
Cimetidine has been shown to impair elimination of a number of drugs metabolized by the hepatic mixed-function oxidase enzymes. It is uncertain whether this is related to its histamine H2-receptor antagonism or to its intrinsic structure. Ranitidine is a more potent H2-receptor antagonist and has a completely different structure. Cimetidine (1 gm/day for 7 days) induced a 23% and 35% fall in mean systemic clearance of antipyrine and theophylline, whereas ranitidine (300 mg/day 7 days) had no significant effect on the clearance of either drug. Our data suggest that the inhibition of drug metabolism by cimetidine is not related to histamine H2-receptor antagonism.
K J Breen, R Bury, P V Desmond, M L Mashford, B Morphett, B Westwood, R G Shaw. Effects of cimetidine and ranitidine on hepatic drug metabolism. Clin Pharmacol Ther. 1982 Mar;31(3):297-300. doi: 10.1038/clpt.1982.36.: https://pubmed.ncbi.nlm.nih.gov/6120774/
Abstract
Cimetidine has been reported to decrease the biotransformation of drugs metabolized by the MFOE system. Additionally, cimetidine decreases liver blood flow and increases the bioavailability of drugs with high hepatic extraction ratios. Patients receiving cimetidine in conjunction with drugs known to interact with cimetidine in conjunction with drugs known to interact with cimetidine are at risk of experiencing toxicity. When appropriate, reducing the dosage of these agents or switching to an alternative drug will minimize the incidence of side effects. Clinicians should be suspicious if patients experience exaggerated drug effects when cimetidine therapy is begun.
J H Bauman, B J Kimelblatt. Cimetidine as an inhibitor of drug metabolism: therapeutic implications and review of the literature. Drug Intell Clin Pharm. 1982 May;16(5):380-6. doi: 10.1177/106002808201600504.: https://pubmed.ncbi.nlm.nih.gov/6123423/
Interactions
Due to its non-selective inhibition of cytochrome P450 enzymes, cimetidine has numerous drug interactions. Examples of specific interactions include the following:
Cimetidine affects the metabolism of methadone, sometimes resulting in higher blood levels and a higher incidence of side effects, and may interact with the antimalarial medication hydroxychloroquine.[25]
Cimetidine can also interact with a number of psychoactive medications, including tricyclic antidepressants and selective serotonin reuptake inhibitors, causing increased blood levels of these drugs and the potential of subsequent toxicity.[citation needed]
Following administration of cimetidine, the elimination half-life and area-under-curve of zolmitriptan and its active metabolites were roughly doubled.
[...]
Like several other medications (e.g. erythromycin), cimetidine interferes with the body's metabolization of sildenafil, causing its strength and duration to increase (therefore also its side effects to be more likely and prominent).[citation needed]
Clinically significant drug interactions with the CYP1A2 substrate theophylline, the CYP2C9 substrate tolbutamide, the CYP2D6 substrate desipramine, and the CYP3A4 substrate triazolam have all been demonstrated with cimetidine, and interactions with other substrates of these enzymes are likely as well.[28]
Cimetidine has been shown clinically to reduce the clearance of mirtazapine, imipramine, timolol, nebivolol, sparteine, loratadine, nortriptyline, gabapentin, and desipramine in humans.[29]
Cimetidine inhibits the renal excretion of metformin and procainamide, resulting in increased circulating levels of these drugs.
Interactions of potential clinical importance with cimetidine include warfarin, theophylline, phenytoin, carbamazepine, pethidine and other opioid analgesics, tricyclic antidepressants, lidocaine, terfenadine, amiodarone, flecainide, quinidine, fluorouracil, and benzodiazepines.
Cimetidine may decrease the effects of CYP2D6 substrates that are prodrugs, such as codeine, tramadol, and tamoxifen.
Cimetidine reduces the absorption of ketoconazole and itraconazole (which require a low pH).[20] [EDITOR'S NOTE: IF YOU ARE TAKING EITHER OF THESE TWO DRUGS ORALLY - YOU DO NOT WANT TO TAKE CIMETIDINE IN YOUR COMBINATION AS IT INHIBITS ABSORPTION OF THESE - I BELIEVE THE SAME IS TRUE WITH ITRACONAZOLE AND GRAPEFRUIT JUICE]
Cimetidine has a theoretical but unproven benefit in paracetamol toxicity.[23] This is because N-acetyl-p-benzoquinone imine (NAPQI), a metabolite of paracetamol (acetaminophen) that is responsible for its hepatotoxicity, is formed from it by the cytochrome P450 system (specifically, CYP1A2, CYP2E1, and CYP3A4).
Used in cancer metastasis research as a blocker of E-selectin.
Numerous other drug interactions.
Source: https://en.wikipedia.org/wiki/Cimetidine#Interactions
As with our other compounds, we want to take 200-400mg of Cimetidine 30-45 minutes for our drug intake.
5) Hydroxypropyl Beta Cyclodextrin (HPBC)
Now, for the final concoction in our witch's brew. This is an old drug delivery system that has been virtually forgotten by drug connoisseurs. It's a compound called a cyclodextrin.
Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds. Cyclodextrins are produced from starch by enzymatic conversion. They are used in food, pharmaceutical, drug delivery, and chemical industries, as well as agriculture and environmental engineering.
Now, if that sounds like a bunch of gibberish, that's because it is. So, let me explain. Cyclodextrins are a sugar like molecule (hence the saccharides) that are formed in a donut like shape. Here is a picture of what one looks like, this is the beta-cyclodextrin, the one we're going to focusing on. They look like:
Image One of Beta Cyclodextrin Molecule
https://ibb.co/rffmPpR
As you can see, in the middle where it says B-CD and it surrounded by the ring made of glucose (aka dextrose aka the most simple sugar your body breaks down from other carbohydrates). The B-CD is the middle part where the drug molecule is going to get trapped in and then stuck to like a spider's web.
Abstract
The purpose of this review is to discuss and summarize some of the interesting findings and applications of cyclodextrins (CDs) and their derivatives in different areas of drug delivery, particularly in protein and peptide drug delivery and gene delivery. The article highlights important CD applications in the design of various novel delivery systems like liposomes, microspheres, microcapsules, and nanoparticles. In addition to their well-known effects on drug solubility and dissolution, bioavailability, safety, and stability, their use as excipients in drug formulation are also discussed in this article. The article also focuses on various factors influencing inclusion complex formation because an understanding of the same is necessary for proper handling of these versatile materials. Some important considerations in selecting CDs in drug formulation such as their commercial availability, regulatory status, and patent status are also summarized. CDs, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different novel drugs through different delivery routes.
Rajeswari Challa, Alka Ahuja,corresponding author Javed Ali, and R. K. Khar. Cyclodextrins in drug delivery: An updated review. AAPS PharmSciTech. 2005 Jun; 6(2): E329–E357. Published online 2005 Oct 14. doi: 10.1208/pt060243 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750546/
Here is a very interesting image I found of a side view of a cyclodextrin molecule. You can see how the drug molecule can get trapped in the "donut" center and make for better absorption.
Image Two of Beta Cyclodextrin Molecule
https://ibb.co/GnznJJD
I tried to find a layman's guide explaining exactly how cyclodextrins enhance the effects of drugs, I was unable to find one, so you'll just have to take my word for it. On bluelight.org if you do a Google site search you can find a receipe to make an liquid heroin solution for oral or plugging using cyclodextrins for maximum absorption.
https://www.bluelight.org/xf/threads/optimising-a-heroin-nasal-spray-avoiding-hydrolysation-to-morphine.464301/
Here's a little bit more from another study
Cyclodextrins are cyclic oligosaccharides that have been recognized as pharmaceutical adjuvants for the past 20 years. The molecular structure of these glucose derivatives, which approximates a truncated cone, bucket, or torus, generates a hydrophilic exterior surface and a nonpolar interior cavity. Cyclodextrins can interact with appropriately sized drug molecules to yield an inclusion complex. These noncovalent inclusion complexes offer a variety of advantages over the noncomplexed form of a drug. Cyclodextrins are primarily used to enhance the aqueous solubility, physical chemical stability, and bioavailability of drugs. Their other applications include preventing drug–drug interactions, converting liquid drugs into microcrystalline powders, minimizing gastrointestinal and ocular irritation, and reducing or eliminating unpleasant taste and smell. Here, we discuss the physical chemical properties of various cyclodextrins, including the effects of substitutions on these properties. Additionally, we report on the regulatory status of their use, commercial products containing cyclodextrins, toxicological considerations, and the forces involved in complex formation. We also highlight the types of complex formed and discuss the methods used to determine the types of complex present.
Sunil S. Jambhekar1 and Philip Breen2. Cyclodextrins in pharmaceutical formulations I: structure and physicochemical properties, formation of complexes, and types of complex (PDF). ECOM Bradenton School of Pharmacy, Bradenton, FL 34211, USA 2Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA - http://csmres.co.uk/cs.public.upd/article-downloads/Cyclodextrins-in-pharmaceutical-formulations-I.pdf
So, for our purposes, we're going to be using a more advanced form of beta-cyclodextrin called Hydroxypropyl Beta Cyclodextrin (HBPC). I haven't been able to find any cyclodextrins for sale except on research sites for years. The fact that it's available in a small amount & reasonable price and is 99.5% pure is amazing.
HBPC: https://amzn.to/3F6M3Zb
So, what you do with the HBPC is add about half a teaspoon (or more depending on how many orals your taking) to the final amount of oral drug you're taking.
Next, you want to search Google and find out if the drug you're taking is fat soluble. Most are. Just Google "is [drug name] fat soluble". If it is, we're in business.
Directions for Ethanol Absorption
If the drug you're using is only soluble in ethanol, then you're probably not going to want to hold it into your mouth very long due to the burning. Just add the powder under your tongue, and take a shot of good quality vodka. I recommend Tito's vodka as it is triple distilled and some of the best on the market. If you can't stand keeping it under your tongue, swirl it around in your mouth for awhile like it's Listerine and then swallow it. You can add some BHPC to it to help it absorb in the stomach lining, but you don't want to be adding any CBD oil or vegetable glycerin.
You're just going to mix it with a shot of vodka (which should be fine, unless it still doesn't dissolve, then you're going to need Everclear. *shudders*)
With an alcohol solution, it doesn't involve into your mucous membranes as well as a fat soluble drug, but it will still work, So here are the directions for suspending drugs in an alcohol solution
Directions to follow for oral sublingual absorption
The best way to do this is as follows. First, we're going to follow the same instructions as above. Take the grapefruit juice or Grapefruit Extract Capsules, 10mg of Bioperine, 200-400mg of Cimetidine 30-45 minutes before we start.
Next, we're going to take our pills and grind them up in the Pill Mill Pill Crusher - Crushes Multiple Tablets to a Fine Powder - Metal Pill Grinder. These has a crank on top with fine gears in the middle that will turn a large amount of pills into a fine powder. Even if some comes out as a little chunky, don't worry about it. You can pour it back in the Pill Mill and crush run it through again if you want, but it isn't necessary. Add the HBPC into the pill mill before you grind it up. This will ensure a consistent blend into the powder mixture.
The Pill Mill - Master of Turning Pills into Fine Powder (Image)
Once the pills have been ground up, open your mouth and put your tongue back to the back of your mouth. Pour the powder in (note: if it's a lot of powder, you might have to do this twice). I HIGHLY recommend you add 2ml of Full Spectrum 2500mg CBD Oil fom CBDisterlly. If you use this link, you will get a 30% off coupon. However, you may have to open the link in an in private/incognito window as it's very finicky with adblockers and the like. The CBD oil will enhance the high of whatever you're taking and provide some anti-anxiety benefits (which are especially good if you're using benzos). After that, add some Vegetable Glycerin. You don't really need to measure it out if you don't want to, I just take a sip of it until I feel its blended into the powder. Swirl the powder around under your tongue for a bit and let it sit there for awhile as it absorbs into the mucous membranes under your tongue. Once it's dissolved, you can swirl it around into the rest of your mouth, getting it into your gumline and eventually swallow it.
CBDisterllry 2500mg Bottle which is $130 for 30ml. Note: I use about the highest priced CBD oil they offer. However, if you can't afford that, that is understandable. But studies have shown that 300mg of CBD anti-anxiety effects. However, they sell cheaper amounts such as 500mg for $35. They also sell CBD isolate powder as "Full Spectrum CBD Powder - CBDelicious Formulation Powder - 1 gram" for $30. You could add the same amount of HBPC (1/2 teaspoon) to your blend. Note, I haven't tried the isolate powder myself, but it makes since that it would work. If you simply can't afford CBD at all I would get some high quality coconut cooking oil and add about a regular teaspoon (the kind you eat cereal with) or any other kind of cooking oil, such as olive oil, corn, canola, or whatever you have on hand.
