How Modafinil Works on Neurotransmitters for its Nootropic Effects

By on July 25, 2014

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A while back I tried Modafinil for the purposes of a review, and shortly after uploaded a video on the matter to YouTube. This quickly became one of my most watched videos (it’s number one for ‘Modafinil’ on YouTube currently).

In the video I said that Modafinil was undoubtedly potent and impressive for increasing focus and attention, but that it also had side effects which led to me being unable to recommend it. Despite my warnings I’ve since been contacted by lots of people asking where they can get it… kind of missing the point but demonstrating just how interested people are in this particular study drug.

One of my concerns regarding Modafinil has always been the lack of long-term studies and the lack of information. We aren’t even sure how it affects the brain and most people seem happy to gulp it down without doing any research. That’s where this article comes in… Here I will look in more depth at precisely what Modafinil is and how it appears to affect the neurotransmitters in the brain to bring on its effects. I shall present the science and from there it is up to you to draw your own conclusions…

Let’s start with the formal introductions…

Introduction to Modafinil

Modafinil, also known as ‘Modalert’ or ‘Provigil’, is a prescription medication intended for use by narcoleptic patients who have trouble staying awake, or possibly shift workers and others who are forced to stick to unusual sleep regimes.

But this probably isn’t why you’ve heard of Modafinil, and it’s not the reason that a lot of people use it. Rather, Modafinil has become better known for its alleged ‘nootropic effects’ and ability to increase alertness, concentration and productivity. For this reason it has become popular among busy executive types and also students who compare it to the substance ‘NZT’ featured in the movie ‘Limitless’. It is also the nootropic of choice for DARPA and NASA apparently!

It is said to be safe and non-addictive, though some people come up in a skin rash. For my part, I experienced difficulty sleeping, sores in my mouth, bloodshot eyes, occasional headaches and a general ‘stariness’ – none of which I was a fan of. The focus it gives you though is undoubtedly impressive, and I definitely completed tasks I’d have struggled to finish as quickly or efficiently otherwise. Here’s my video review on the subject…

But how does it achieve these effects?

Orexin

The main mechanism of modafinil is to work on orexin and hypocretin. Neurons that respond to orexin can be found in the hypothalamus but project to numerous other parts of the brain – including several areas that are responsible for sleep and wakefulness. In short it appears that orexin is partly responsible for our sleep wake cycle and thus has been implicated in narcolepsy (this study).

When these neurons are activated, they increase dopamine and norepinephrine in those areas specifically, as well as increasing histamine. Animal studies show that defective orexin systems lead to narcolepsy-type symptoms. That said, studies on dogs and mice have found that modafinil could still be effective even when the orexin receptors were completely non-functional suggesting this to be only one explanation.

Using modafinil then may be like knocking out your sleep-wake cycle temporarily, thereby allowing you to work a little longer. However, many of our cycles are linked and this explains why modafinil also has effects on bowel movements and hunger – as anyone who has used it can attest. Modafinil makes you a bit pooey and disinterested in eating (I believe it probably has a secondary use as an appetite suppressant but wouldn’t recommend it to anyone on that basis…).

Dopamine

One of the other  main ways that modafinil appears to work is by increasing the amount of dopamine in the brain. Dopamine is the neurotransmitter that we most associate with ‘reward’ and is released whenever we perform an action we perceive as being ‘good’ (such as winning the lottery or eating a cake). Interestingly, dopamine isn’t required in order for us to feel good about our actions though, it simply strengthens the association to increase our likelihood of repeating those actions/seeking out the stimuli again in future. This can make us more motivated but also more impulsive. Also interesting, is that dopamine is produced as well when we have a ‘near miss’ and almost get a good outcome. Dopamine is also a stimulant of sorts, increasing communication generally between neurons.

When you take modafinil, it appears that it blocks the dopamine ‘transporters’ in the brain. These are molecules that act in order to remove dopamine from the synapses. Thus you increase the amount of dopamine available for action. Dopamine also likely increases as a result of increased wakefulness and activity in the brain – just as caffeine triggers a secondary increase in dopamine.

Dopamine was linked in this study to creativity – with highly creative types showing lower levels of D2 receptors in the thalamus. One of the roles of the thalamus is to ‘filter’ the information that gets taken to the cortex for higher thinking, so it’s possible that having fewer D2 receptors could lead to less filtering and more information – even somewhat ‘irrelevant’ information – making it to that part of the brain. Fewer D2 receptors though may also be responsible for schizophrenia, demonstrating a potential link between ‘madness’ and ‘creative genius’.

This would mean that, like caffeine, modafinil could potentially ‘blunt’ creativity by making us more focused and our brains more highly focussed but less inventive. This might suggest modafinil is more useful when you have a large but simple workload, rather than when you need to come up with a great new idea.

Histamine

Modafinil also elevates hypothalamic histamine levels. As a neurotransmitter histamine plays an important role in sleep/wake regulation. Histamine neurons can be found in the hypoathalamus and tuberomammilary nuclei, and protrude through the brain to the cortex and other regions. This is why antihistamines – which are capable of crossing the blood-brain barrier – will famously make users feel drowsy. Histamine can also impact on erections and sexual function, with the use of H2 antagonists (drugs that block some histamine receptors) potentially causing reduced testosterone uptake.

Norepinephrine

Norepinephrine (noradrenaline) is a substance similar to adrenaline that promotes wakefulness and attention and elevates the heartrate, though it may also lead to anxiousness. Norepinephrine is particularly increased in the hypothalamus and ventrolateral preoptic nucleus. As with many stimulants including caffeine, norepinephrine may be elevated as a response to the increased activity in other parts of the brain. In other words, the brain assumes that something important must be going on and thus triggers its ‘fight or flight’ response (though some research suggests an action on the norepinephrine transporters). This will probably also raise levels of other stress hormones like cortisol.

Serotonin

Serotonin is a feel good chemical that is responsible for balancing and regulating the mood. This too is elevated, particularly in the amygdala and frontal cortex – most likely as a response to increased stress hormones. Serotonin is considered useful for memory and plasticity both due to the role of emotion in learning, and due to its ability to stimulate neurogenesis (the birth of new neurons).

Some people have said that Modafinil improves their mood. Other have said it makes them generally less emotional. It’s possible that

GABA

This study shows that modafinil also reduces the amount of GABA in the ‘medial preoptic’ and ‘posterior hypothalamus’ areas in rats. GABA is also known to promote sleepiness and relaxation, so this can also partially account for the ‘vigilance’ effects of modafinil. It could also be the reduction in GABA that leads to the increase in histamines.

Glutamate

Glutatamate too is elevated when using Modafinil. Glutamate is another excitatory neurotransmitter which is once again similarly raised when we use caffeine. In fact, glutamate is the ‘main’ excitatory neurotransmitter and as such is involved in many aspects of normal cognitive function including attention and memory. It appears to play a vital role in ‘long term potentiation’ – meaning the creation of associations between neurons. This makes it critical for learning and brain plasticity.

Conclusions – Is Modafinil Safe?

The mechanisms of action for modafinil are not fully understood, but what we do know is that it increases the availability of dopamine, histamine, serotonin, glutamate, GABA and norepinephrine in the brain. This may be through the orexin systems and/or by reducing dopamine transporters.

Ultimately though, the lack of knowledge regarding the function of modafinil should be cause for concern. As with any neuroactive substances, it’s possible that regular use of modafinil could lead to tolerance – meaning that the brain could become less sensitive to the neurotransmitters it is experiencing in abundance. This could potentially result in the brain needing modafinil or something like it to experience normal effects from dopamine, histamine and noreadrenaline.

But then again we use caffeine every day and it appears to have similar actions… so it’s really up to you. Think of Modafinil as caffeine… on caffeine. But with a bit of mystery around it… Note that even caffeine can cause long-term negative changes in the brain (study) though, so if you want to dial that up to 11 then you should think about the consequences. Here’s a review that goes into everything I’ve discussed in detail. I can’t recommend using Modafinil personally (and there are definitely safer ways of boosting your focus), but if you’re going to then I would suggest using it in short bursts to avoid developing a tolerance and perhaps to increase attention, learning and plasticity while leaning a difficult new subject.

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About Adam Sinicki

Hi there! My name is Adam Sinicki, I'm an entrepreneur, psychology graduate and amateur bodybuilder interested in fitness, self improvement, technology and transhumanism. I run an online business (NQR Productions) which allows me to live the lifestyle I want: getting time to hit the gym and to work on my projects and apps. Stick around and I'll be sharing my experiments and adventures in brain training, bodybuilding, productivity, business and technology.
  • Zoe allan

    I’ve taken modafinil for ms fatigue for about 7 years 100mgevery morning. I had sleep issues initially, and still occasionally have sleep issues, but generally enough. I haveecently tarted Low Dose Naltrexone. Also morning dosing as im having major problems with insomnia. Apparently I shouldn’t be having theses issues with morning dosing. Do you know anything about LDN? I find if I stop taking the modafinil I’m floored and in bed all day, but if I take IT I do not sleep! Not sure which is worst. Life seems to Be passing Me by! Any advice?

  • alex

    Very nice review. Just saw your video on Youtube. Modafinil seems a lot less harmless than Adderrall. Thanks for your feedback!

    -Alex
    http://www.inertiawillhurtya.com

  • http://www.beulahgirl.com jenna

    Hi, I took Modafinil for a year for Narcolepsy. I develop severe arthritis (pain, heat, swelling) in my hands and feet that lasted from about 9 p.m. to roughly 11 a.m. I couldn’t walk or pick up my baby. I was weak, groggy, winded, and had vision problems. My muscles hurt. My head hurt. I kept getting hives. My memory got terrible. I saw several specialists; one determined that I had Rheumatoid Arthritis. The medication I was given for that sent me to the ER (Methotrexate). I became depressed, isolated, and anxious. None of my doctors thought that it could be my medication. I stopped taking it a few weeks ago. My symptoms vanished. I’m only 32 and lost a year of my life to this drug. I am not good with science, but I do think a histamine could cause inflammation… Right? Anyway, be careful please.

  • Kiera Carroll

    I have only seen positives from Modafinil and love it!

    Modafizone is where I get mine from. Sends directly to me and takes 5 days to the states. Very impressive service.

  • Howard

    Modafinil with Noopept is a fantastic stack. I got mine from rupharma.com, good if you live in EU.

  • Elizabeth Ross

    Modafinil’s results are 100% noticeable. I’ve been using it for
    quite some time now and I totally love how it keeps sleepiness away and
    keeps my Concentration on active mode for more than 18 hours at a
    stretch.

    I buy my Modafinil from https://simplymodafinil.com
    These guys offer Modalert and Waklert. They have Free shipping and 100%
    Refund guarantee if the product gets stuck in customs.

  • David Konnel

    Awesome article, Dave! It was after reading this post, that I had decided to try modafinil. I placed my very first order with MODAFINATOR dot COM and I must say, I took the right decision. The order placement is pretty simple & the payment is easy as well. Asked the customer support executive about any ongoing discount and they were more than happy to give me a 20% discount coupon code(BULLET20). Since they are shipping from India, I found the price fair enough. The packaging is very discreet, the products are original and the customer support staff is genuine.

    Currently, I’m taking the pill twice a day & I’m loving how it’s impacting my work. Three cheers to Modafinator!

  • Skizle

    I have Narcolepsy. It’s a very misunderstood disorder. I use Modafinal during the day and a medicine that forces me to sleep the right way at night. You are correct in that sleep is the best medicine…but Narcoleptics can’t get stage 3 and 4 sleep…they hover in REM (active) sleep, which is why they fall asleep during the day. It’s misdiagnosed as depression 95% of the time and the average diagnosis takes about 12 years because doctors don’t know how to screen for it.

    I don’t feel any crazy super thinking like you described…rather, I feel like someone who is able to focus a normal amount for about 7-8 hours a day. I was pretty blown away that it helped me, but I don’t feel any kind of addiction to it…probably because everyday I wake up feeling like a narcoleptic. There are days where I don’t take it because I feel like I’ll be napping during the day, and it’s hard for me to nap while on Modafinal. But again, definitely don’t feel addicted. My brother who does not have my disorder had co-workers taking it to increase job performance and for those people it really turbo charged them…but their bodies suffered because of it. They took too much and would go days without sleeping in order to be top performers. One guy got so bad that his body broke down and he tore everything in his right leg just walking down stairs because his body was so tired…I have never felt anything near that level of crazy. The lesson I’m learning here is that it’s for people who need it to function, and not for people who want to gain an edge in life.

    • Lurky Mysterioso

      >I use Modafinal during the day and a medicine that forces me to sleep the right way at night.

      Xyrem?

  • https://modafinator.com/ Peter Smith

    I placed an order of 80 pills with https://modafinator.com 6 days ago. Unfortunately, for the next couple of days, I got really caught up with work to bother about checking mails (related to my order) or tracking it. I was amazed to receive it so quickly. Totally unexpected!

    Modafinator folks, you just earned a loyal customer!!!!

  • Samuel Hunter

    No wonder people have many good things to say about modafinil. I’m really amazed with the results.
    It wasn’t easy to choose from so many modafinil vendors, but I finally chose https://modafinilmart.com The order placement is very convenient, the customer support is great and the product great. I like how they offer a sample pack, so that one has the option to try the various modafinil products. I bought their sample pack and after trying all the 4 products, I opted for Modalert 200.
    Totally worth it.

  • Alexander Ava

    My experience with https://modafinilmart.com has been pretty good. I’ve been regularly ordering from them. The packaging is very discreet, the products are 100% genuine and the customer support staff is helpful. Since they are shipping from India, I found the price fair too. Being in a creative field, I’d personally recommend Modalert 200 to people who have troubles brainstorming and have to work on complex projects.

  • Kyle Carr

    My experience with https://modafinilmart.com has been pretty good. I’ve been regularly ordering from them. The packaging is very discreet, the products are 100% genuine and the customer support staff is helpful. Since they are shipping from India, I found the price fair too. Being in a creative field, I’d personally recommend Modalert 200 to people who have troubles brainstorming and have to work on complex projects.

  • Aaron drury

    After having fatigue and brain fog for months, I finally decided to try modafinil. I took a pill on my first day after breakfast. I could feel it affecting me within 2 hours. It was definitely giving more motivation to work and helping me focus. Its effects stayed for about 10 hours and I was able to sleep by 12am.
    I feel much more efficient & I’m really happy with the results.
And for those who my be wondering who may supplier is….
    It’s AMAZINGMODAFINIL . COM cheers !!

  • Boris Denk

    I thought i was the only one having those problems; depression, anxiety and etc. To think that one can actually beat all of them just blowed my mind away. Thanks to modafinil! Bought some from modafinilworld . com and I couldn’t be any happier.

  • Chris Harrison

    After a few months using mod three days a week I’m noticing the effect is becoming less noticeable. Other than not being tired any enhanced concentration is mild at best.

    Taking a long break for a while…