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How Modafinil Works on Neurotransmitters for its Nootropic Effects
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?
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…).
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.
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 (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 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
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.
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.