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CYP2D6 Detox Enzyme: How it Affects The Brain

Written by Biljana Novkovic, PhD | Last updated:

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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.

What is CYP2D6?

CYP2D6 is one of the cytochrome P450 monooxygenases (CYPs). These are enzymes that eliminate most of the drugs and toxins from the human body [1].

Read more about CYPs here.

Function

Although it accounts for only 2-5 % of liver CYPs, CYP2D6 metabolizes 25% of all drugs [2, 3, 4].

This enzyme metabolizes:

  • Opioids: morphine [5], hydrocodone [3], codeine [6], oxycodone [7], tramadol [8].
  • Antidepressants: amitriptyline, nortriptyline, venlafaxine, and fluoxetine [8, 5, 9].
  • Antipsychotics: haloperidol [9], risperidone [10].
  • Atomoxetine (used to treat ADHD) [11].
  • Beta-blockers: carvedilol and metoprolol [12].
  • Antimalarials: primaquine and carboxy-primaquine [13].
  • Antiemetics: metoclopramide [14].
  • Antitumor agents: tamoxifen and gefitinib [15, 9].
  • Methamphetamine (MDMA) [8].

CYP2D6 also:

Because it metabolizes dopamine and serotonin, CYP2D6 is often associated with human behavior, personality, cognitive function, and psychiatric diseases [16].

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

  • ultra-rapid metabolizer
  • extensive metabolizer
  • intermediate metabolizer
  • poor metabolizer [12]

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 [6].

Location

Apart from the liver, this enzyme is also found in the brain [16].

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 [19].

CYP2D6 poor metabolizers (low enzyme activity) were significantly more anxiety prone. They were also less successful at socializing than extensive metabolizers [19, 16].

Further, those with reduced enzyme activity had a tendency to higher impulsivity (novelty seeking) [16].

CYP2D6 activity is beneficial against neurodegenerative disease. Poor CYP2D6 metabolizers are at higher risk of developing Parkinson’s (76 subjects) [17] and Alzheimer’s disease (2018 subjects) [20].

Low enzyme activity is also associated with autoimmune diseases (meta-analysis, 12 studies, 1,472 patients, and 3,328 controls) [21].

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) [16, 22].

Poor metabolizers also show better spatial working memory (144 subjects) [16, 22].

Poor metabolizers have higher conscientiousness/responsibility, orderliness, and the pursuit of achievement through perseverance [16].

Low CYP2D6 activity may decrease the risk of schizophrenia. A lower frequency of poor metabolizers has been observed in schizophrenia patients (270 subjects) [23].

High enzyme activity was associated with eating disorders. A higher frequency of CYP2D6 ultra-rapid metabolizers was found in people with bulimia [16].

Higher CYP2D6 activity was associated with heavier smoking. Poor metabolizers had a lower risk of becoming heavy smokers (1230 subjects) [24].

CYP2D6 ultra-rapid metabolism may increase suicidal tendencies (262 cases) [16]. However, these findings are controversial [25].

Suicide attempters carrying two or more active CYP2D6 genes were more likely to be diagnosed with one or more personality disorders (342 subjects) [26].

Gene Polymorphism

CYP_metabolizers

CYP2D6 gene has more than 100 known variants [27, 28]. These include:

  • Normal enzyme function variants (e.g. *1 and *2) [27, 28].
  • Reduced function variants (e.g. *9, *10, and *41) [27, 28].
  • Nonfunctional variants (e.g. ∗3, ∗4, ∗5, and ∗6) [27, 29].

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 [27].

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) [28].

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 [30].

If you are a poor metabolizer, you are more prone to adverse effects from taking antidepressants (46 studies) [8].

On the other hand, ultra-rapid metabolizers are more prone to the adverse effects of codeine and tramadol (46 studies) [8].

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%) [4].

  • RS3892097

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 [10].

This variant (A) increases the risk of developing systemic sclerosis (296 and 206 subjects) [31, 32], Alzheimer’s disease (2018 subjects) [20], and Parkinson’s disease (meta-analysis, 2629 patients, and 3601 controls ) [33].

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) [21].

The carriers of this variant are more susceptible to pesticide toxicity (59 subjects) [34].

This variant increases weight gain as a side effect of antipsychotics (81 patients) [35].

  • RS28371706

rs28371706 (CYP2D6*17) is the most frequent low activity variant in Africans (20%–35%). It is responsible for the intermediate metabolizer type [4, 10].

  • RS1065852

rs1065852 (CYP2D6*10) has a high frequency in Asia. It is especially common in Thai (50%) and East Asians (42%) [10, 4]. 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) [36].

Increasing or Decreasing CYP2D6

These increase CYP2D6:

These decrease CYP2D6:

  • Starfruit juice [38]
  • Aloe vera juice [39]
  • Kale [40]
  • St. John’s wort [41]
  • Goldenseal [42]
  • Fennel [43]
  • Garden cress seed extract [44]
  • Curcuma [45]
  • Asafetida [46]
  • Berberine [47, 48]
  • Quercetin [49, 50]
  • Caffeic acid [49]
  • Gallic acid and ellagic acid [51, 52]
  • The leaves of the lotus plant (Nelumbo nucifera) [53, 54]
  • Raspberry leaf [43]
  • Licochalcone A, a major compound in traditional Chinese herbal licorice [55]
  • Black pepper fruit and arylamides isolated from black pepper (Piper nigrum) [56, 57]
  • Paroxetine [58, 59], melperone [60], and sarpogrelate [61]
  • Tetrahydrocannabinol, cannabidiol (CBD), and cannabinol (found in marijuana) [62]
  • Chronic kidney disease [63]

About the Author

Biljana Novkovic

Biljana Novkovic

PhD
Biljana received her PhD from Hokkaido University.
Before joining SelfHacked, she was a research scientist with extensive field and laboratory experience. She spent 4 years reviewing the scientific literature on supplements, lab tests and other areas of health sciences. She is passionate about releasing the most accurate science and health information available on topics, and she's meticulous when writing and reviewing articles to make sure the science is sound. She believes that SelfHacked has the best science that is also layperson-friendly on the web.

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