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CYP2D6 is one of the most important detox enzymes. It is responsible for the clearance of 20% of clinical drugs, including opioids (codeine, tramadol), antitumor drugs (tamoxifen), antidepressants (fluoxetine), and antipsychotics (haloperidol). In addition, this enzyme also metabolizes dopamine and serotonin. Therefore, it doesn’t come as a surprise that the activity of this enzyme can be associated with human personality, behavior traits, and psychiatric disease susceptibility. Read on to find out more about CYP2D6 function, gene variants, and supplements that increase or decrease enzyme activity.

CYP2D6

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CYP2D6 is one of the cytochrome P450 monooxygenases (CYPs). These are enzymes that eliminate most of the drugs and toxins from the human body (R).

Read more about CYPs here.

CYP2D6 Function

Although it accounts for only 2-5 % of liver CYPs, CYP2D6 metabolizes 25% of all drugs (R, R, R).

This enzyme metabolizes:

CYP2D6 also:

Because it metabolizes dopamine and serotonin, CYP2D6 is often associated with human behavior, personality, cognitive function and psychiatric diseases (R).

Four metabolizer types are used to describe CYP2D6 activity in individuals:

  • ultra-rapid metabolizer
  • extensive metabolizer
  • intermediate metabolizer
  • poor metabolizer (R).

The activity of your CYP2D6 should be taken into account when administering a number of drugs. For example, a poor metabolizer should not be given codeine since the drug would have no effect. Conversely, an ultra-rapid metabolizer would likely suffer side effects from a normal dose (R).

CYP2D6 Location

Apart from the liver, this enzyme is also found in the brain (R).

CYP2D6 The Good

This enzyme influences dopamine and serotonin levels in the brain. That explains why the activity of CYP2D6 has been associated with different personality traits (R).

CYP2D6 poor metabolizers (low enzyme activity) were significantly more anxiety prone. They were also less successful at socializing than extensive metabolizers (R, R).

Further, those with reduced enzyme activity had a tendency to higher impulsivity (novelty seeking) (R).

CYP2D6 activity is beneficial against neurodegenerative disease. Poor CYP2D6 metabolizers are at higher risk of developing Parkinson’s (76 subjects) (R) and Alzheimer’s disease (2018 subjects) (R).

Low enzyme activity is also associated with autoimmune diseases (meta-analysis, 12 studies, 1,472 patients and 3,328 controls) (R).

CYP2D6 The Bad

CYP2D6 activity affects cognitive function. People with less active CYP2D6 (poor metabolizers) perform better in tasks that demand sustained attention or vigilance (144 subjects) (R, R).

Poor metabolizers also show better spatial working memory (144 subjects) (R, R).

Poor metabolizers have higher conscientiousness/responsibility, orderliness, and the pursuit of achievement through perseverance (R).

Low CYP2D6 activity may decrease the risk of schizophrenia. A lower frequency of poor metabolizers has been observed in schizophrenia patients (270 subjects) (R).

High enzyme activity was associated with eating disorders. A higher frequency of CYP2D6 ultra-rapid metabolizers was found in people with bulimia (R).

Higher CYP2D6 activity was associated with heavier smoking. Poor metabolizers had a lower risk of becoming heavy smokers (1230 subjects) (R).

CYP2D6 ultra-rapid metabolism may increase suicidal tendencies (262 cases) (R). However, these findings are controversial (R).

Suicide attempters carrying two or more active CYP2D6 genes were more likely to be diagnosed with one or more personality disorders (342 subjects) (R).

CYP2D6 Gene Polymorphism

CYP_metabolizers

CYP2D6 gene has more than 100 known variants (R, R). These include:

  • Normal enzyme function variants (e.g. *1 and *2) (R, R).
  • Reduced function variants (e.g. *9, *10, and *41) (R, R).
  • Nonfunctional variants (e.g. ∗3, ∗4, ∗5, and ∗6) (R, R).

It gets more complicated, however, because this gene can also be missing, or multiplied. This means that you can have 0, 1, 2, or more than 2 copies of the gene. Therefore, most clinical laboratories also report the copy number (R).

CYP2D6*5 represents a gene deletion (no gene present). Gene duplications and multiplications are denoted by “xN” (e.g., CYP2D61xN with xN representing the number of gene copies) (R).

How often do people have more or less of the usual two copies of this gene?

In a set of over 30 000 clinical samples, 12.6% had zero, one, or three or more copies of the CYP2D6 gene (R).

If you are a poor metabolizer, you are more prone to adverse effects from taking antidepressants (46 studies) (R).

On the other hand, ultra-rapid metabolizers are more prone to the adverse effects of codeine and tramadol (46 studies) (R).

People with ultra-rapid metabolism are less frequent in Northern Europe, North America and Asia (1–5%). They are more common in the Mediterranean (7–12%), Saudi-Arabia (21%) and Ethiopia (29%) (R).

rs3892097 is also known as the CYP2D6*4 variant. This is the most frequent variant in Europeans and North Americans (18.0%). It accounts for 70%–90% of all nonfunctional enzyme cases (R).

This variant (A) increases the risk of developing systemic sclerosis (296 and 206 subjects) (R, R), Alzheimer’s disease (2018 subjects) (R) and Parkinson’s disease (meta-analysis, 2629 patients and 3601 controls ) (R).

It was also associated with autoimmune diseases: systemic lupus erythematosus (SLE) and ankylosing spondylitis (meta-analysis, 12 studies, 1,472 patients and 3,328 controls) (R).

The carriers of this variant are more susceptible to pesticide toxicity (59 subjects) (R).

This variant increases weight gain as a side effect of antipsychotics (81 patients) (R).

rs28371706 (CYP2D6*17) is the most frequent low activity variant in Africans (20%–35%). It is responsible for the intermediate metabolizer type (R, R).

rs1065852 (CYP2D6*10) has a high frequency in Asia. It is especially common in Thai (50%) and East Asians (42%) (R, R). This variant is responsible for the intermediate metabolizer type.

The T/T was associated with lower incidence of lung cancer in a Chinese population (9 studies, 1,516 cases and 1,950 controls) (R).

Increasing or Decreasing CYP2D6

These increase CYP2D6:

  • Common valerian (R).
  • Ginkgo biloba (R).
  • Age (R).

These decrease CYP2D6:

FDA Compliance

The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.

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5 COMMENTS

  • Marina

    This article is utterly fascinating. Years ago, I took Paxil (Paroxetene) for 2 days, then stopped. I then began to have muscle twitching that made it nearly impossible to sleep for up to one year, and that came intermittently for 6 years following.

    Years later, I had genetic testing done, and found that, indeed, I have two defective alleles of CYP2D6.

    I have no doubt that my poor CYP2D6 metabolism was the cause of my adverse reaction to Paxil, which no doctor at the time could understand.

    What I am likewise amazed by, however, reading your article, is the further correlation to personality traits.

    I totally identify with these:

    – increased anxiety (was the reason why I was prescribed Paxil in the first place)
    – higher impulsivity
    – performing well in tasks that demand sustained attention – have always been able to focus for long hours
    – “high conscientiousness/responsibility, orderliness, and the pursuit of achievement through perseverance.”

    Also, you mention a correlation to autoimmune disease. Indeed, I was diagnosed with Hashimoto’s hypothyroidism at the age of 12.

    Thank you so much for your research, and for making it so easily accessible.

    Blessings.

  • Sam

    “…the activity of mitochondrial CYP2D6 can be high, and there have been correlations between these variants and the incidence of Parkinson’s disease.”

    “If we add MPTP to dopamine-sensitive neurons and also add a CYP2D6 inhibitor, we see marked protection of the neuronal function,” Avadhani said. “We believe this is a paradigm shift in how we think about the mechanism of Parkinson’s.”

    [neurosciencenews]

  • Sam

    and here is a whole textbook of “all” plants, tea, gfj, Schisandra, resveratrol,

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477257/

  • Sam

    Andrographolide, curcumin, and lycopene produced no significant induction effects on CYP1A2, CYP2D6, and CYP3A4.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237480/

  • Sam

    Nice to know, But what’s your point? It seems you want to increase CYP2D6 activity to avoid developmental /psychological diseases and flush toxins. So don’t take onions, apples, no kale, and no spices? and broccoli?
    it seems every Hindu/Indian lives on all of these spices, yet there is no mental disease and the consensus you do want to take these spices all the time to induce detox.

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