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Opioids Codeine Megathread v. What's Your CYP2D6 Genotype?

kleinerkiffer

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Codeine​

1. What is codeine?
2. Codeine Metabolism
3. Pharmacology of Codeine
4. Routes of administration
5. Side effects
6. Potentiating and CYP2D6 genotypes
7. Interactions
8. Cold water extraction

1. What is codeine?
Codeine is classified as an opioid agonist, as it binds to opioid receptors (mu, delta and kappa that is) and as opiate, as it's one of the alkaloids of the poppy plant papaver somniferum (around 1-3% in latex).
The poppy plant has been cultivated and utilized for its medical effects for a long time.
Today codeine is still used for moderate pain and sometimes for its cough suppressant effects and of course is used recreational.


2. Codeine metabolism
This graph sums up the metabolic pathway of codeine pretty good:

https://s3.pgkb.org/pathway/PA146123006.png?versionId=G06iuDDals07ejfe11cB14JlXTiIRNfT
Most codeine, around 50-70%, is metabolized into codeine-6-glucuronide (C6G) via Phase-II metabolism catalyzed by UGT2B7. Around 10-15% of codeine is metabolized into norcodeine via CYP3A4 and around 0-15% (depending on your genotype) is metabolized into morphine via Phase-I metabolism catalyzed by CYP2D6.
A few sources suggest that codeine has a ceiling effect at around 400 mg meaning that taking anything over 400 mg won't increase the effects but only increase the duration of action.
For the metabolites morphine has the highest potency (around 10x more than codeine itself), but a few papers suggest that C6G is the main active metabolite. This is an ongoing debate and the final word hasn't been spoken yet afaik, but either way codeine is a prodrug.

Norcodeine:
In single doses of 75 mg/80 kg orally, both codeine and norcodeine induced mild to moderate morphine-like effects, and as compared to a placebo, both slightly depressed rectal temperature, respiratory rate, respiratory minute-volume, and constricted the pupils.
http://jpet.aspetjournals.org/content/129/2/172.long

C6G:
Intravenous administration of codeine-6-glucuronide resulted in approximately 60% of the analgesic response elicited by codeine itself. Analysis of plasma and brain showed that codeine-6-glucuronide is relatively stable in vivo, with only small amounts of morphine-6-glucuronide being detected in addition to unchanged codeine-6-glucuronide. The receptor affinity of codeine-6-glucuronide was similar to that of codeine. It is concluded that intravenously administered codeine-6-glucuronide possesses analgesic activity similar to that of codeine, and may have clinical benefit in the treatment of pain.
https://www.ncbi.nlm.nih.gov/pubmed/15102399


3. Pharmacology of Codeine
Codeine and especially its active metabolites morphine and codeine-6-glucuronide bind to and activate the mu-opioid-receptor. This receptor is a GPCR (GTP-binding-Protein coupled receptor), meaning that the effects are mediated via second messengers. The opioid receptor can be located on the pre synapse, in this case activation results in a decrease of Adenylycylase activity leading to a decrease in cAMP which in turn results in closing of Ca2+channels and thus inhibiting the release of glutamate and substance P. It can be located on the post synapse as well, in this case activation leads to K+channel opening, resulting in hyperpolarization meaning that it's harder to form an action potential.
The opioid receptors are located in different brain areas, spinal cord, as well as in the gut (this leads to one of the major side effects - constipation) and bladder (leading to problems peeing).
The main effects of opioids are analgesia (possible via all opioid receptors), respiratory depression in higher doses (mediated mostly via mu-2), sedation (mediated via mu-2, kappa-1 and kappa-3), euphoria (mu-1 and mu-2) and constipation (mediated via mu-2, kappa-1 and kappa-3).


4. Routes of administration
As codeine is a prodrug for morphine and C6D every RoA other than oral will decrease the metabolism, leading to lesser effects and the bioavailability is around 90% already, so stick to oral use with this one.
And for everyone thinking of injecting codeine, this can kill you as codeine i.v. can lead to non-immune mast-cell degranulation, leading to the release of histamine and other mediators. This in turn can lead to anaphylactoid reactions.
While codeine can be injected i.m. and s.c. it still will result in less effects and should only be done in a medical setting.


5. Side effects
Side effects include the usual like:
- drowsiness
- constipation (make sure to go to the toilet at least every other day, eating a lot of fibers can help as well as stool softeners, if that's not enough drugs like magnesium citrate, miralax, gylcerin enema or bisacodyl should do the trick)
- itching (for this an antihistamine, like cetirizine or desloratadine should work great)
- nausea and vomiting
- urinary retention
- miosis or excessive constriction of the pupil
- hypotension


6. Potentiating and CYP2D6 genotypes
CYP2D6 polymorphism:
As I said, the CYP450 family (this family includes a bunch of enzymes responsible for Phase-I metabolism) isozyme CYP2D6 is responsible for metabolizing codeine into morphine and given that morphine is way more potent you want as much codeine metabolized into morphine as possible.
You might remember the term allele. If not a quick recap on genetics. You have 46 chromosomes, 23 each from your father and mother respectively. Of those 46 44 chromosomes are called autosomes and the other 2 are called allosome. The two allosomes are responsible for your sex and the remaining 44 are homologue meaning the copy from your father and mother of say chromosome 1 are pretty much identical (they aren't identical to the base-pairs, but they each have the same genes on the same spot) so you have 2 so called alleles for each gene. Now this is important for the polymorphism. Your phenotype is determined by the genotype (the genes you have) and CYP2D6 has a lot of different genotypes.
I'll try to explain it with this graphic:

https://imgur.com/a/a6C6tTB


Here you can see the 4 important genotypes of CYP2D6.

1. Let's start with the poor metabolizer:
In this case you inherited an inactive/faulty allele each from your mother and father. This can happen in a few different ways. The CYP2D6*3 allele for example means that you miss the nucleotide in position 2549, because of this the reading frame shifts and you get a non-functioning enzyme. With this polymorphism your enzyme doesn't work at all (prevalence is around 1-4% in Caucasians). The CYP2D6*4 allele means that at position 1846 the base G was switched to A, this leads to problems with splicing which in turn leads to the loss of enzyme activity (prevalence is around 12-21% in Caucasians). The CYP2D6*5 allele means that the gene just isn't there at all, so no gene no enzyme (prevalence is around 1-7% in Caucasians).
With all these mutations your enzymes aren't working and inducing them will most likely fail to work at all.
2. Intermediate metabolizer:
In this case you either have one functioning and one non-functioning allele (see poor metabolizer for examples) or two mutated genes that have limited function. In this case inducing the enzyme will most likely help to a certain extend.
3. Extensive metabolizer:
This one is the one most people have. Here you have two functioning alleles, also called wild type alleles. This means that your enzymes are working as they should. In this case inducing your enzymes will help.
4. Ultrarapid metabolizer:
In this case you have more than the usual 2 functioning alleles, like 3 or even more. This genotype is called CYP2D6UM allele. In this case you have more functioning enzymes than normally. This can lead to problems as even a therapeutic dose of codeine might be metabolized into more morphine than you can take without risking an overdose. Because of that its advised to try a small dose of codeine first if it's your first time taking codeine, to rule out that you're an ultrarapid metabolizer. Here inducing your enzyme will only lead to more side effects and is really dangerous.

Now what's all the fuzz about inducing enzymes?
Normally your genes are expressed (not sure if that's the right term, in German it's called "exprimieren") at a set rate, let's call it the basal rate. So in a certain amount of time, an hour for example you produce 100 enzymes.
When you induce an enzyme by taking a drug you increase the basal rate. This will lead to more enzymes being produced in a set amount of time, like 200 enzymes instead of the 100 in an hour. Normally this isn't something you want as enzymes metabolize the drugs you take and will decrease the duration of action, so more enzymes = faster metabolism.
But in the case of codeine you want it as you want as much codeine metabolized into morphine as possible.
Drugs that induce CYP2D6 and thus increase the metabolism of codeine into morphine are:


- Glutethimide, this one is a strong inducer, meaning that a lot of CYP2D6 will be expressed leading to an increase of morphine production. But the drug itself is classified as a hypnotic sedative thus increasing the side effects and dangers of codeine. In the worst case this can lead to respiratory depression and death so proceed with caution and start with extremely low doses and have a friend around in case you overdose.

- Dexamethasone, this one has an unspecified potency, meaning that we don't know how strong it induces CYP2D6. The drug is classified as corticosteroid and imo that's a class of drug you shouldn't take if you don't have to as they come with a bunch of serious side effects.

- Rifampin, this one has an unspecified potency as well. Another drug you shouldn't fuck with as it's an antibiotic and popping antibiotics for fun will lead to nasty side effects and bacterial resistance (this is an important problem as we are currently running out of antibiotics, so please don't add to it!).

- Haloperidol, this one has an unspecified potency as well. It's an antipsychotic and imo another drug you shouldn't take if you don't have to as antipsychotics and especially strong ones like haloperidol come with serious and sometimes life threatening side effects (those are rare, but can happen, like torsade de pointes, a kind of arrhythmia that can lead to sudden death; neuroleptic malignant syndrome that can lead to high fever and can lead to your muscles breaking down etc.)

Now to conclude all this, if you really want to induce CYP2D6 the only way imo is with Glutethimide, but even this drug comes with dangers like increased respiratory depression and afaik is really hard to get. So really, there's not much you can do to increase the metabolism of codeine into morphine.
https://www.bluelight.org/vb/newreply.php?do=newreply&p=14479355

A CYP3A4 inhibition might prevent the metabolism into norcodeine, thus increasing the metabolism into morphine and C6G, but afaik no one has ever tried it and looking at the pharmacokinetics should only increase the effects by a maximum of 10-15% which isn't much and imo isn't worth the trouble.

CNS depressants will increase effects, but will also increase respiratory depression which can kill you so better be safe than sorry.

Antihistamines like promethazine and hydroxyzine will add to the sedation, but maybe decrease to metabolism into morphine


7. Interactions
As codeine is metabolized via CYP2D6 into morphine anything that inhibits this isozyme will lessen the effects of codeine. A list of CYP2D6 inhibitors includes:
- Antidepressants, i.e. fluoxetine, paroxetine, sertraline, duloxetine, citalopram and bupropion
- quinine and quinidine
- cimetidine
- antihistamines, i.e. promethazine, chlorphenamine, diphenhydramine, hydroxyzine

CNS depressants will synergize with codeine leading to more sedation, potentially more euphoria, but drastically increase respiratory depression!


8. Cold water extraction
Cold Water Extraction FAQ ? Mr Blonde

What is a Cold Water Extraction (CWE)?

In the context of this website, a Cold Water Extraction is a method used to separate compounds that are mixed together by using their difference of solubility in water. A Common example that this may be performed on is
Vicoden (hydrocodone, Acetaminophen).

Why do people perform a CWE?

Simple reason; they are taking large amounts of the medication in question for whatever reason to gain the effects/benefits of one active ingredient (e.g. hydrocodone), or taking this medication long-term in large amounts, however at the same time they are putting themselves at risk of physical harm through the ingestion of large amounts of the combo ingredient ,e.g. acetaminophen,. A cold water extraction is a simple way to separate the water soluble compound from the relatively non-water soluble compounds we do not want, e.g. hydrocodone will dissolve in room temperature water but acetaminophen won?t to the same extent, allowing us to easily separate them.

Is a CWE illegal?

In the case of hydrocodone or codeine containing preparations, in most jurisdictions this procedure is illegal. For example, in Australia codeine mixed with acetaminophen is either schedule II up to a 24-sized pack, schedule III for a 48-size pack or greater and schedule IV if the dose of codeine is 30mg. If the medication is codeine only, the schedule is VIII, the highest Rx schedule category in Australia. By performing a CWE, you are removing the combination ingredient and are left with mostly the codeine. This could then be considered a schedule VIII drug, and thus illegal to possess without a script.

So, why is discussion of this technique allowed?

Quite simple; a CWE is avoiding the harm that could come about where people to ingest large amounts of acetaminophen (APAP). Examples:

APAP: Overdose is associated with liver damage caused by the liver being unable to process the toxic metabolite of APAP, N-acetyl-p-benzo-quinone imine (NAPQI). When you ingest APAP, it normally gets converted to inactive metabolites with only a small amount becoming NAPQI. Usually this toxin is then conjugated by the liver tripeptide glutathione. When very large doses of APAP are taken, the liver is unable to process the amount of the drug and therefore more NAPQI is produced, and the liver is unable to conjugate it. This toxin causes liver failure. The antidote for NAPQI is acetylcysteine, however if you believe you have taken a toxic dose of APAP it is best to seek medical attention. A single dose of 10 grams or 200mg per kilogram of body mass can be toxic, and multiple smaller doses in a period of 24 hours can also be toxic. Using APAP in normal doses everyday has been shown to cause decreases in liver function tests of up to three fold.

Aspirin: Large doses or continuous use can cause gastrointestinal bleeding, ringing in the ears (tinnitus), nausea, vomiting, dizziness, hyperthermia, seizures, cerebral edema and comas. Most deaths from aspirin overdose are due to pulmonary edema. Aspirin can be toxic at 150mg/kg of body mass, and is considered lethal at above 500mg/kg. Although this sounds like a lot of aspirin, similar toxicity can occur with above-average-use spread out over a period of time. If you believe you may have overdosed, seek medical attention.

Ibuprofen: Overdose can cause nausea, stomach pains, dizziness, headaches, tinnitus and nystagmus (rapid eye-wobbles you may be familiar with if you have used MDMA), seizures, hypotension, tachycardia, hepatic and renal failure, cardiac arrest and death (though deaths from ibuprofen are relatively rare compared to APAP and aspirin). Toxic effects of this substance are considered to begin around 100mg/kg of body mass. If you believe you have overdosed on this substance, you should seek medical attention.

So, how do you perform a CWE?

There are a few different techniques used to perform a CWE; the aim of this thread is to collate them so that they aren?t all just floating around the place, and so that people can discuss their methods, viability, possible safety issues, etc.

*********************************

Solubility in Room Temperature:


APAP: Roughly 1 gram per 100ml at room temperature; around 0.1-0.5 grams per 100ml if the temperature is lowered to around 22C.


Mr Blonde?s Basic CWE

1) Normally, I will grind these in a coffee grinder; most other codeine combo meds dissolve quite quickly by themselves and these I will just drop into a glass of cool water. I use 50mL for 24 tablets of 10mg codeine/500mg APAP, for preparations known to be more ?sludgy? (e.g. N+, certain codeine/APAP brands), I will use 75-100mL of water. I try to use only 150-200ml of water maximum.

2) Once the tablets are dissolved, I stir them and then place an old shirt in a cup as a filter. I wet the shirt prior to using as a filter.

3) Pour the solution through the filter, and wait until the stream of filtered solution slows to droplets. I then squeeze the shirt to get the most liquid out.

4) That?s it! Dispose of the liquid by drinking, and dispose of the filtrate in your bin. Some people do second washes on the filtrate left over, I however do not.

Erowid?s CWE Technique

The Procedure
1. Obtain a quantity of tablets containing codeine, check to see if they contain anything other than codeine, caffeine, acetaminophen. If they do, and you don't know whether or not it will be a problem, your best bet is not to use them. Measure out your desired amount of codeine (ex. 64 mg = 8 tablets * 8mg/tablet). You may want to add 2 extra tablets as it is quite likely you will lose some codeine in the procedure. As you get more experience with the procedure you will be able to get approx. 95% of the codeine extracted.

2. Measure out some nice hot water, use approx. 40ml / 20 tablets or more if needed. I would suggest you don't go over 50ml for 20 tablets. I don't know if the use of boiling water would destroy any of the codeine but your best bet is not to use it. Use hot water but not boiling. Make sure the tablets dissolve completely. Some dissolve on contact with water while others need some help dissolving by crushing them. Note : not all of the tablet will dissolve, there are water-insoluble fillers in the tablet and not all of the A/A will dissolve either(which is what we want).

[Most sources recommend that codeine not be stored at temperatures in excess of 40C (104F), so its probably better to use warm, but not hot, water. I find that it is best to crash the tablets completely in a container, and then dissolve them in a glass with water.]

3. Place the solution in a cold bath, I just use some ice cubes in a container of water. Stir the mixture occasionally until the solution drops to about 15C or lower. You won't need a thermometer to measure the temperature, just make sure it's "cold". This will take about 30 min. If you wish to speed this up, you can use less water to dissolve the tablets, and add ice chips to cool the mixture faster. Just make sure you don't add so much ice that you drastically increase the volume of the mixture.

4. Filter the solution using whatever you have. Coffee filters work well, but lab filters work the best. Just make sure you don't end up with obvious solids in the filtered solution. This will take about 1 hr. You may also want to rinse the solids left over in the filter with minimal ice-water to extract any remaining codeine.

5. Drink and enjoy! The solution will be _very_ bitter, so I mix a little Kool-aid powder into the solution. The taste isn't really bad but it's similar to sucking on a lemon.

[One gets used to the taste after a while.:)]

6. Sit back and wait for the effects. Because the codeine is already in solution it only needs to be absorbed, while codeine in the tablet form must dissolve before being absorbed. Because of this, the effects will probably become noticeable within 15min.

Note : I don't suggest you evaporate the mixture unless you are willing to wait a while. The Merck index warns that codeine is sensitive to heat and light. For that reason if you wish to evaporate the mixture, do it without heat, and shield the solution from light.

*********************************

Can the solution be evaporated to be used for other purposes?

Yes, although the solution is going to contain some binders, fillers and some amount of the combo med we didn?t want. Hence, depending on the drug, the powder could be used for snorting, eating later or plugging, but would in no way be ideal for IV use. Most drugs that come in combo-med form are, as far as I know, not suited for smoking. To find out whether the drug you have separated can be used via a certain method of administration, use the search engine. ;)

Can every combo med be CWE?d?

No. Some combo meds also contain a third ingredient such as an anti-cholinergic. If this third ingredient is potentially dangerous and soluble in water, a CWE will not remove that risk.


Note that in some pills there is a binder named Titanium Dioxide that is used for making skim milk cloudy and milky white which could make your solution look unfiltered even if already has been rendered safer.

**********************************************************************

And that?s about it. Using this technique will help remove some of the dangers associated with overdoing a combo med, it?s simple to do and could save your health. If you have a technique you use or would like to discuss any aspects of the CWE, this is the thread to do it in.

Stay safe.
https://www.bluelight.org/vb/threads/548643-Cold-Water-Extraction-Mega-Thread-amp-FAQ-v2-0
 

CFC

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With thanks to KK and JA, we're unleashing a new Codeine Megathread for you peeps here at Bluelight.

Enjoy :)
 

Forever Changes

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I haven't had my genotype tested, but I'm pretty sure I don't metabolise codeine properly, as it does nothing for me, either analgesically or recreatonally

Surprisingly, Dihydrocodeine has no effect either
 

Jekyl Anhydride

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Thanks CFC! Although this is def 99% KleinerKiffer's work :)

I haven't had my genotype tested, but I'm pretty sure I don't metabolise codeine properly, as it does nothing for me, either analgesically or recreatonally

Surprisingly, Dihydrocodeine has no effect either
I think that's a ubiquitous stance seeing as codeine is weak and and tolerance rapid, but it's possible. Since DHC doesn't do anything for you either and doesn't rely on CYP2D6 as heavily for the bulk of it's effects it might just be this particular drug though.

CYP2D6 phenotype has no major impact on opioid receptor-mediated effects of a single 60 mg dihydrocodeine dose, despite the essential role of CYP2D6 in formation of highly active metabolites.
https://www.ncbi.nlm.nih.gov/pubmed/12665158
 

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Thanks CFC! Although this is def 99% KleinerKiffer's work :)


I think that's a ubiquitous stance seeing as codeine is weak and and tolerance rapid, but it's possible. Since DHC doesn't do anything for you either and doesn't rely on CYP2D6 as heavily for the bulk of it's effects it might just be this particular drug though.
well I can take 300mg of codeine with no tolerance and feel nothing - is it safe to assume it just doesn't work for me, whether it's an enzymatic issue or not?


As for DHC, I read recently that people with CYP2D6 deficiency may get the analgesic effects from DHC, but no recreational ones. So I guess the drug succeeds in its purpose, which was to be an alternative for those that can't use codeine
 

Jekyl Anhydride

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IMO Codeine loses rec. value very, very quickly if it actually has any to begin with, possibly, for those who've never used an opioid before or have 0 tolerance for some time. I think this is why it has the no prescription needed/ available upon chemist approval status in some countries. If codeine and promethazine or "Lean/ Purple Drank", didn't have the sedating and slight dissociative effects at high doses, there would be no cult following of it by some in the States.
 

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A theory taken from somewhere else:

Well, it doesn't seem to be all that simple. According to the below-mentioned article, dihydrocodeine relies on CYP2D6 to be metabolized to dihydromorphine, the substance that gives you that nice opiate buzz. The analgesic effects however seem to occur independent of that enzyme. So with poor CYP2D6 activity, you might get pain reduction, but not that much of a buzz.

"The O-demethylated DHC metabolites display greater affinity for opioid receptors and pharmacological activity in comparison to the parent compound, and CYP2D6 is crucial for DHM formation. In spite of their high pharmacological activity, DHM and DHM-6-G do not make a major contribution to the analgesic effects of DHC. Studies performed to date [56, 59–61] indicate that DHC analgesia is independent of CYP2D6 activity [64]."

Source:
https://www.karger.com/Article/PDF/326085
 

Pete556

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Does anyobe know how long i actually have to wait between codeine doses because ive looked around and some people say 4-12 hours others say 12-24 hour's id just like to know from someone who has actually got personal experience
 

Jekyl Anhydride

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A theory taken from somewhere else:
Well, it doesn't seem to be all that simple. According to the below-mentioned article, dihydrocodeine relies on CYP2D6 to be metabolized to dihydromorphine, the substance that gives you that nice opiate buzz. The analgesic effects however seem to occur independent of that enzyme. So with poor CYP2D6 activity, you might get pain reduction, but not that much of a buzz.

"The O-demethylated DHC metabolites display greater affinity for opioid receptors and pharmacological activity in comparison to the parent compound, and CYP2D6 is crucial for DHM formation. In spite of their high pharmacological activity, DHM and DHM-6-G do not make a major contribution to the analgesic effects of DHC. Studies performed to date [56, 59–61] indicate that DHC analgesia is independent of CYP2D6 activity [64]."

Source:
https://www.karger.com/Article/PDF/326085
CYP2D6 phenotype has no major impact on opioid receptor-mediated effects of a single 60 mg dihydrocodeine dose, despite the essential role of CYP2D6 in formation of highly active metabolites.
https://www.ncbi.nlm.nih.gov/pubmed/12665158
KK and myself have come across the same discrepancies with regards to codeine and CYP2D6. One school of though claims it's all C-6-G and another all demethylated morphine. In all honesty we both seem to think the truth lies somewhere in between but you bring up a good point that DHC + 2D6 might hold more weight than the 2D6 + codeine argument.
 

Pete556

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Right i last had my dose 9-10 hours ago (256mg) I shuld be ok to take my ext one and not waste it right?
 

Ne0

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Studies seems to say that african people metabolizes codeine the best so getting most morphine (miight be the reason why nigeria seems to have problem now with codeine syrup, most Europeans would say that is not strong enough), then europioid people then asian people so for them they get least amount of codeine. But of course there are individual differences.
 

Pete556

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I am mixed raced im on the whiter side but i defo got some african in me I used to be the fastest runner in my school
 

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KK and myself have come across the same discrepancies with regards to codeine and CYP2D6. One school of though claims it's all C-6-G and another all demethylated morphine. In all honesty we both seem to think the truth lies somewhere in between but you bring up a good point that DHC + 2D6 might hold more weight than the 2D6 + codeine argument.
what about Tramadol? Does that depend on 2D6 for analgesic and/or recreational effects?
 

Forever Changes

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^ I see. So if you don't metabolise codeine properly due to poor CYP2D6, it's likely Tramadol won't have any effect either?
 

Pete556

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Tramadol takes forever to kick in anyway though i never get bored of cwe as i take a big enough dose when i want to get high
 
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