P450 enzyme CYP2D6 is of importance in medicinal chemistry, pharmacology and medicine. It belongs to one of the major group of liver enzymes that metabolize drugs (and other crap) that float around your system. For several reasons, CYP2D6 is especially troublesome for scientists working with discovering new drugs.

To name one such reason, the individual variation of CYP2D6 expression among the human population is very high. In other words, a certain drug that is primarily eliminated by CYP26D may have a half-life of say 4 hours in one patient, but 0.5 hours in the other, at the same dose and route of administration. The pharmaceutical industry hates these things. So do doctors. They want complete control. In this case, I take their side.


One of the most classic CYP2D6 substrates is codeine, an opiate used in managing mild to moderate pain. Most often, it is used in combination with an NSAID or acetaminophen (paracetamol), because of their synergistic effects. Such combination medications are available in almost every country in the world.

Whether codeine is a drug or a prodrug is debated. Long story short: When you ingest codeine and it enters your blood stream, the first thing your liver tries to do is breaking it down via so called first-passage metabolism (if taken orally).

Now, here comes the funny part, where your body gets a little more action than it was aiming for. In trying to protect you from codeine, the evil intruder, your liver decides to chop the molecule in pieces. Armed and loaded with CYP2D6, the liver knocks off a methyl group (vide ninja). But the result is, as you know, morphine – an opiate 5-10 times stronger than codeine itself. Dang.

Presumably, the pain relief — and the not completely unpleasant buzz — that you get from codeine is due to the fact that your body partly (5-10 %) converts it into morphine, which enters your central nervous system, finds opiod μ-receptors and yada, yada…

10-15 % of the population, however, report no positive effect whatsoever from taking codeine. This is consistent with findings that roughly the same number of people have significantly diminished levels of active CYP2D6 enzymes. In other words, 1 in 8-10 people have little or no use of codeine. A major hassle for this patient group is that the typical physician is quite reluctant to prescribing anything stronger for everyday pain conditions. Hence, these poor souls risk suffering more pain in life than necessary.

I happen to be at the very other end of the spectrum. Hehe. We select 1-2 % go under the name ultrarapid CYP2D6 metabolizers. (And it sounds cool too!) I haven’t had my genes mapped, so I cannot be entiery sure, but still I feel fairly certain.

For reasons I will not go into, I have been prescribed both codeine and morphine, separately, at several occasions. I know what 10 milligrams of morphine feels like. I also know what 60 milligrams of codeine feels like. The latter is the standard dose used to treat for instance toothache, migraine and other half-decent pain conditions. You don’t get morphine for these. But I do. Sort of.

Because — believe it or not — 60 milligrams of codeine has in my experience and body much more oomph in it than 10 milligrams of morphine. I would even go so far as to say peroral codeine is stronger than intravenous morphine. In me. So yeah, I am pretty sure my liver is unusually loaded with CYP2D6, and that it is damn active too.

Finally, I hope my doctor never read this. “Hi. My name is Fredrik, and I am an ultrarapid CYP2D6 metabolizer.”


24 Responses to Life as an ultrarapid CYP2D6 metabolizer

  1. I’m sad to say, I prefer the morphine. Codeine doesn’t touch me.

  2. Toad says:

    Atomoxetine (Strattera in the U.S.) is another drug significantly metabolized via CYP2D6. It is used primarily in children with ADD/ADHD, who are typically started at a low dose, then that dose is increased in increments until an effective dose is found for the child. However, those kids that are “slow metabolizers”, which is a substantial percentage of at least the Caucasian population, are at risk of developing severe (usually cardiovascular) side effects. Once the concentration of parent drug saturates the capacity of the 2D6 enzyme to remove it, the drug concentration continues to build up rapidly over time. The problem is, if CV effects are not noticed quick enough, even taking the child off the drug does not immediately remove the systemic drug concentration until additional 2D6 is made by the body; and, this can take some time. I’ve seen it take a good 2-3 weeks for the side effects to dissipate. The wide variety of 2D6 mutations and heterogeneity in their substrate binding and instance and severity in the population make this a more difficult issue to deal with – a simple test wouldn’t necessarily tell you much.

    • drfreddy says:

      Interesting. I didn’t know that. A close friend of mine has his kid on Strattera (maximum dose), but nothing unusual there, knock on wood.

      Another fascinating aspect with codeine that didn’t make it into the main post is that it is also a potent CYP2D6 inhibitor (even at therapeutic doses), which means that you could say that it has a built in safety system. A second dose after 2 hours usually has little or no effect. You have to wait the full 4-6 hours until you take it again, or it won’t work.

  3. Jayde says:

    So what on earth does it mean when nothing works, no codeine, no morphine, no Tylenol, no Advil, no dental freezing ( or any other kind of freezing), I can drink several shots of espresso and fall asleep. My dentist called me an alien when neither freezing, nor “conscious sedation” had any effect whatsoever at the legal limit. Fortunately I only get sick once every 20 years, unfortunately I get wicked migraines, for which I have no solution. Whatever my liver enzymes are doing, they aren’t helping me. Modern medicine has no ideas, and I’ve been a lab rat for too long.

    • claude says:

      I’ve been searching the internet around the subject of migraines and
      cyp2d6 ultra extensive metabolizer variant obviously in such a case codeine should be overly potent as a pain killer but most standard longterm treatments should be negatively impacted propanolol amitryptiline flunarizine all seem to be processed by cyp2d6 have you had any novel insight since ?

    • amanda says:

      I know this thread is old, but are you RH negative by chance?

  4. Susan says:

    UNfortunately for me, my CYP2D6 is so compromised that NO pain medications I take orally works for me AT ALL. Worse, the only route(s) by which I can get any opioid relief, say, from acute post-surgical pain, is by IM injection or IV infusion. Needless to say, walking into an ED and saying, “HI! I need 2 mg of dilaudid (standard adult dose)and 4 mg of Zofran” doesn’t usually go over very well!!. I have been labeled a “liar,” “malingerer” – although I don’t know how anyone who has just had their ulnar shortened and had the block wear off in four hours could be said to be malingering – a “drug-seeker,” and several other impolite names by physicians in various emergency departments. And it’s always someone else’s “job” to figure this thing out. Frankly, ED physicians haven’t done their homework with regard to individual patient response to opioid treatment needed for acute pain experiences. They have no clue about the differences of metabolic issues which can cause patients to respond to IV/IM medications and NOT respond to oral administration. And, from my own experiences, I think I can state that they really don’t care. It is simply easier to, as I said, say it’s someone else’s “job” or suspect drug abuse. I’m allergic to the adhesive used in the patches too, so that’s out as well. I’d much prefer the pain in the A#$ injection than what I have to deal with from pain in the A$# emergency department physicians!

  5. Debra says:

    I have been swab tested by my therapist/MD because he was trying to treat me for ADHD and I told him I was not feeling anything from the Adderall dosage even after he had increased it to the highest recommended. I told him when we first started my treatment that I had a super high tolerance to all pain killers, alcohol, Novocain… At the time I did not know why, I just knew I did. My swab was conclusive that I am a CYP2D6*2xN (UM-Ultrarapidmetabolizer). CYP2D6 is responsible for the metabolism and elimination of approximately 25% of clinically used drugs. Ultrarapid metabolizer – multiple copies of the CYP2D6 gene are expressed, and therefore greater-than-normal CYP2D6 function. In my genotype, *2xN the N stands for the number of alleles and could be anywhere from 2 copies up to 13 (that they know of.)

    Interesting fact about depression and CYP2D6 UMs: we have statistically lower than normal levels of Dopamine, a neurotransmitter that helps control the brain’s reward and pleasure centers. And serotonin, many researchers believe that an imbalance in serotonin levels may influence mood in a way that leads to depression. What is really sad is that the instances of failed therapies from antidepressants is extremely high in CYP2D6 UMs because the drugs have no effect unless administered at super high doses and most physicians are not aware of the CYP2D6 UM anomalies thus are not willing to administer remedies in the high doses necessary.

    These gene tests seem to be gaining popularity, so there is hope for us UMs although, I don’t like the side effects from the super high doses that are necessary… I may need to stick with natural remedies… and do like I have done all my life, just don’t get sick and or have a super high tolerance to pain and learn to live with it, in lieu of being called a drug monger, or addict. Even the dentists have called me a lier, saying there is “no way” you still feel that… Honestly, why would I lie to the dentist? It would have been nice to have these test results to stick in the A** H*** nurses face after I woke up the morning after a serious car accident from which I had a compound fracture repaired the night before. I was in SEVERE pain and the nurse told me to shut up and that I was on a morphine drip so could not have pain… Funny thing is, Morphine might as well be water to a UM. And don’t give us Codine… it very possibly could kill us as it turns to super high doses of morphine. Go figure…

    I hope this was helpful, your not crazy…

  6. julie says:

    Thinking I may be a high metabolizer but not sure. I can’t take any type of opiate (I’ve had several surgeries to come to this conclusion) morphine made me hallucinate(I was told I was quite hilarious of course I have no recollection) and pass out so that pca pump was not needed, hydro’s, vicodin, percocets they all make me deathly ill talking instant puke. I was on straterra at a pediatric dose for my adhd and it knocked me out, couldn’t stand up, had to hold the wall to walk to bed. Dextromomethorphan (DM in cough suppressants) causes me to vomit like a person who just drank while on antabuse. Claritin makes me look like I am on cocaine (I’m a psych nurse I’ve seen it all). I would presume since all side effects occur in 30minutes or so I am an ultra-metabolizer? However Benadryl has no ill effects on me. I can take it and it helps allergies but doesn’t knock me out. Background- White living in North America, 5ft2in, 110lbs. So what medications do I need to avoid if an ultrametabolizer? Substrates, inhibitors? Any info appreciated.

  7. Glenda Alexander says:

    Ijust found out that I am a Ultra Rapid METABILIZER, after years of nothing working on me for pain and other disorders.I have had a Thoracotomy with a lung removed and ribs.I have been on everything you can name to no prevail.I worked in the medical field most of my life.There is no use to go to the ER BECAUSE THEY DO NOT UNDERSTAND.it took years for my doctor to figure this out.He did a DNA and found it out.I have a pain pump in with Fentanyl in it and also take Percocet.I might as well take a baby aspirin.Maybe some day they will be able to do something about it,meanwhile I guess we will have to live with the hand we were dealt.

    • drfreddy says:

      Ask your doctor for a written certificate, unless you haven’t already. To show the staff in the ER for example. It is quite rare, and must be horrible, to be “immune” to all kinds of pain medication. Are you sure your current pain is nociceptive (traditional), and not neuropathic? Sufferers of neuropathic pain often get little or no relief even from strong opiates. Have you tried Lyrica (pregabalin), for example? I am not a medical doctor, so don’t take this as medical advice, but in your shoes I would ask my doctor for a neuropathic pain evaluation. Nerve damage is not unheard of after major surgery.

  8. Jonny C says:

    I was a pain patient in Pittsburgh for 22 years and was on 390mg of methadone after taking blood tests to prove that I could metabolize 200 in under 4 hours. Codiene doesn’t work for me, I’ve been given
    12x10mg tabs with no effect. Right now I’m on 120mg of morphine 3x and 120mg of roxycodone every 4. I still feel pain, and I’m not remotely feeling these meds (not that I want to I just want to be out of pain) I do take 4 x 500mg of the most powerful nsaid, with some help. I’m called a super metabolizer, by the docs I’ve seen, but I can’t get into another pain place.

    It’s unfair that we have to live with pain beside of pressure on doctors to not write for us. I guess
    If we are all ultra rapid metabolizer, we should join together and protestor our cause.

    • Glenda says:

      I’m with you Mr! None of my Doctors understand or want to even try…. they make you feel like you’re only trying to seek out drugs, only because of all the drug abusers out there. so the rest of us that aren’t seeking them for their reasons (just to get high)We are in serious cronic pain, as for my self I have a pain pump in my back and had taking just about all you can take for pain that would killll a normal person. I had a DNA ran under my Doctors order not mine. I AM a URM. My liver eats up not only pain meds, but just about anything I take. No wonder people like us get so depressed. These Doctors need to do more research on this!!!!! We need HELP with our pain!”just saying”

  9. George says:

    Ultra rapid metabolisers will get more pain relief and more chance of euphoria from the oral medication. The clue is in the name, if you metabolise something you are breaking it down. Codeine needs to be broken down to work. And it’s broken down into morphine. This is what provides the euphoria and pain relief. If these pills have no effect, you have a CYP2D6 enzyme deficiency. This is why you get no pain relief.

  10. Glenda Alexander says:

    Morphine or Lyrica neither one work on me and tobacco makes things worse. I am trying to quit, but it is about the only thing I can do when I get anxious from the pain. The m.d. said it breaks the medicine down too fast. Good luck everyone.

  11. Anial says:

    In reply to Debra,
    Funnily enough, I have substantial reason to believe that I am a extremely poor metablizer. I get intended and side effects from various mental health and pain medications (which are notoriously involved in CDY2DS), even at the lowest available doses, sometimes in under an hour. These have included some serious effects such as palpitations and extreme nosebleeds (from citalopram) and a hysterical cry-laugh-cry state from amitriptyline which felt like I had just drunk 50 coffees. The result is ultimately the same; I can’t have medication. Full stop. Some GPs have accused me of making it up. Others have been very understanding (to be fair you can’t fake many of the side effects so they all should be understanding). I think it basically boils down to whether the GPs are informed or ignorant about the vast variation (up to 1000 fold in some cases) in metabolizer ability for certain drugs derived from certain genes.
    However, I just wanted to voice on here that us under and over metabolizers are essentially in the same boat, because medicine still only caters for the average.

  12. Anial says:

    P.s. George it depends on drug action.
    Metabolism (which is defined in science as the sum of all chemical reactions in an organism; including both anabolism building molecules, and catabolism breaking down molecules).

    Further, some drugs are activated by breaking down, whereas some are inactivated by breaking down, and some are make more removeable (e.g. easier to excrete) by breaking down, whereas some are made less so.

    So being an ultra/poor metabolizer has different effects on different drugs. Please don’t over simplify it, as you may actually confuse people reading this, who have problems they are trying to understand.

  13. Anial says:

    Sorry for typos no glasses on.

  14. Liam says:

    I’m completely unresponsive to Paracetamol, Ibuprofen, Aspirin, Naproxen, Amitriptyline and Cyclizine. I go into respiratory depression if I’m given opiates such as Tramadol, Morphine, Fentanyl and Codeine, and the former two make me extremely physically sick and give me headaches unlike any cluster I have ever had. My mum is the same. I swear we must be Ultrarapid CYP2D6 metabolisers but I’ve only just found out about this so I haven’t had a chance to ask my doctor yet.

    Needless to say, I have had some weird experiences. In the ER last week, I got a disbelieving look when I said that I don’t respond to any ‘normal’ painkillers (they probably thought I was looking for a high) but then I was faced with a look of confusion when I rejected opiates! They gave me Entonox but I felt like I was losing control of my body and worst of all my breathing so I quickly put an end to that. They tried IV Paracetamol in a drip which had no effect at all, and then resorted to Codeine which worked (of course) until my BP and RR fell and I began to feel very sick.

    I don’t know…should I get checked for CYP2D6 ultrarapid metabolism or is it just me?

  15. Bronwyn Maddison says:

    Hi!Am from Australia & have not heard of anyone else with this problem,just that my dr says I have it,& have actually felt really victimised & traumatised by the attitudes,as described above,by ignorant medical staff.So am pleased to connect with some others…..however it would be good to hear from anyone from down here,especially re ANYWHERE that does understand the problem?I suppose the first step is getting the test done.Am just about to have surgery & feel a bit scared re how “the mix” is going to go!

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