Is the nootropic drug modafinil likely to work for you?

modafinil genes

Modafinil is being used as a nootropic drug that increases alertness and gives a sense of well being — to some users. Like most drugs, individual results seem to vary.  One reason for the variation is a common genetic variation in the COMT gene.

Modafinil is a prescription medication (in the US) for decreasing daytime drowsiness in narcolepsy patients.  Off-label, it is a popular drug for neuroenhancement. Does it work? Clinical trials have shown that it is effective for cognitive enhancement, but the trials didn’t differentiate between genotypes and show a range of effectiveness.

Modafinil is thought to work by increasing dopaminergic neurotransmission, which depends on the activity of the gene, COMT (catechol-O-methyltransferase).  COMT is the enzyme that breaks down neurotransmitters (including dopamine, epinephrine, and norepinephrine), and the rate at which it metabolizes the neurotransmitters affects their levels in the brain.

When investigating modafinil’s effectiveness in people with different genotypes, research results showed that those with the COMT Val/Val genotype had a much better response than those with the Met/Met genotype in terms of sustained vigilant attention. In fact, the study says that modafinil “was hardly effective in subjects with the Met/Met genotype”. For both genotypes, modafinil worked in keeping the subjects from feeling sleepy, so the difference in genotype was on the cognitive benefits rather than wakefulness.

Check your 23andMe results for rs4680 (v.4 and v.5):

  • G/G: (Val/Val) higher COMT activity, better response to modafinil
  • A/G: intermediate COMT activity
  • A/A: (Met/Met) lower COMT activity, not as much response to modafinil


Another study looked at the effects of modafinil on REM and non-REM sleep and found that it varied by COMT genotype. This sleep deprivation study found that modafinil increased specific EEG activity in those with the Val/Val genotype during sleep recovery (after modafinil and sleep deprivation for 40 hours).  The study concludes: ” in NREM sleep, the drug increased EEG activity in 3.0-6.75 and > 16.75 Hz frequencies exclusively in Val/Val allele carriers. Taken together, the data show that the promotion of wakefulness by pharmacological interference with dopaminergic and adenosinergic mechanisms differently affects sleep EEG markers of sleep homeostasis.”


If you’ve ever tried modafinil and wonder why it didn’t have much of an effect on you, perhaps the reason is in your genes.

I’m not going to weigh in on whether or not you should take modafinil… or where to buy it. You can go read about it on Reddit for that type of info.

If you have histamine intolerance, mast cell problems, or anorexia, please note that modafinil may increase histamine levels in the brain.

If you are interested in other effects of the COMT gene, check out my article: COMT – Genetic Connections to Neurotransmitter Levels

If you are wondering about the metabolism of other drugs, I suggest starting with checking your phase I detoxification genes (CYP450’s) through my  Phase I Detox report or by reading about it here.


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7 Comments on “Is the nootropic drug modafinil likely to work for you?

  1. This is a good look at COMT and modafinil.
    I would add that, like everything in genetics and biology, it’s complicated. Two examples are that COMT works by methylation, so its function will be diminished if there is a lack of methyl groups available.
    Another factor is diet. A diet high in catechols can overwhelm COMT enzymes and green tea, Rhodiola, and quercitin suppress COMT activity.

    This is a great example of why prescribing drugs and natural compounds in the outmoded manner of X is good for Y should be discarded. Yes, coffee (as an example) may be beneficial to the majority of people, but because of genetic variations, some will not be affected by it and others harmed. Our knowledge of genetics has opened up a more efficient, personalized way of improving health.

    Tom Ballard, ND

  2. I have my 23andme data but I’m just too ill to go through it. I know I have the highest COMT activity, very low dopamine, very low norepinephrine, very low choline and very high glutamate. I’ve been diagnosed with EDS, PCOS, mast cell problems, herniation of my cerebellum tonsils, methylation issues, sleep disorders, circadian rhythm disorder, metabolic issues (so far I know about thiamin), POTS, inattentive ADHD ETC. I was put on a pretty vague methylation protocol that when I looked into it didn’t fit properly with my mutations, and didn’t take into account CBS mutation and glutamate / ammonia. It hasn’t helped.
    The only thing that has enabled me to move or have any mental energy is Modafinil but in very high amounts, 400mg but 600mg is better. I’ve been taking it for less than a year, but have had most of my problems for all my life. I’ve had blocked ears for 8 years, and recently developed itching in my ears and throat, possibly due to the Modafinil, and very recently have tried diosmin and hesperidin, which has helped reduce the edema and the itching a bit, but only in large amounts. As flavonoids, do these reduce the effectiveness of Modafinil? Also, I thought supplements like quercetin, fisetin, EGCG, luteolin, rutin, resveratrol were supposed to be good for you,especially for inflammation. So would these also reduce the effectiveness of Modafinil even if I have high COMT activity? Due to PCOS, my straight up and down body shape and my genetics, I would have thought that I have much lower levels of dopamine than the average woman, and nothing I’ve taken seems to improve my executive functioning (l-dopa, tyrosine, vitamin c, even Selegiline), and physical energy. Anything to do with acetylcholine I think adds to the itching, but taking it has given me strength in my muscles for the first time in my life. I was put on Ritalin and then Concerta 8 years ago but it did nothing. A couple of very high doses gave me alertness for a few hours and then nothing – weirdly it did nothing to my heart rate, which when lying down never budged above 56 beats/minute, same with ephedrine. Nothing gets me going. Genetically, it turns out I am a poor responder to methylphenidate, and I don’t seem to produce the needed neurotransmitters to begin with. I know I have a D2 transporter gene mutation and I feel it is the lack of norepinephrine that I feel the most. Adderall isn’t available in the U.K and nothing I’ve tried helps. Even if I’ve slept, my entire life my brain just never wakes up, maybe briefly if I get an unpleasant shock, but only sometimes. And the inflammation / mast cell issue has made the hope of ever getting better seem impossible. As everything that seems to stimulate the CNS, also seems to aggravate the itching.

    I’m sorry this is so long. Do you have any advice? I would be interested in you personal profile service. There’s really no help for all this in the U.K at this time.

    • Hi Lisa,
      I would be happy to help you out with a Genetic Lifehacks Cheat Sheet and Report to see if that sheds any light on your issues.
      To be honest, I’m not sure if quercetin, rutin, etc would impact Modafinil metabolism with the faster COMT enzyme.
      It sounds like you have a lot more going on that just needing methylation supplements or due to lower dopamine from the COMT variant. You say that there is no help in the UK at this time — have you tried reaching out to any online doctors in the US or elsewhere who specialize in getting to the root of difficult cases?

  3. If someone is a nonresponder to modafinil would they also be nonresponders to armodafinil?

    • Good question, and the answer is ‘I think so’… While I can’t find any studies that directly answer it, the mechanism should still be the same for armodafinil and the COMT gene should still impact response to it.
      Thanks for reading and commenting.

    • Hi Jessica – good question :-) It varies depending on ethnic background, but for most population groups the ‘slow’ COMT allele is found in around 10-20% of people.
      Thanks for reading and commenting,

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