Modafinil Side Effects

Modafinil is one of the most popular smart drugs in the world. Officially classified as a eugeroic, it’s a powerful substance which promotes wakefulness and alertness, as well as enhances overall cognition.

Thanks to those benefits, it is commonly used as a nootropic by a wide range of the population, starting at university students, and ending high-performing executives.

Modafinil’s ability to boost efficiency and overall output is second to none.

But, as is the case with any drug, there are several modafinil side effects anyone considering using it should be aware of.

This article will address what those potential adverse effects are, what causes them, and the steps you can take to avoid them.

How Modafinil Works

To understand why specific side effects of modafinil happen and what you can do to avoid them, it’s necessary first to know how modafinil works behind the scenes. Its mechanism of action is centered around the brain’s dopamine, norepinephrine, histamine, and orexin systems (1).

Dopamine

A very important neurotransmitter (and perhaps one of the better-known ones), dopamine is a vital part of your brain’s reward center (2). It can better your mood (3), increase your focus (4), and give you a boost in motivation (5).

Modafinil makes more dopamine available for your brain by blocking the receptors which normally remove it (6). This method is in stark contrast to traditional stimulants which increase dopamine levels by stimulating its release (and often do so very quickly) (7).

By using a more gentle approach, modafinil avoids the type of euphoria typically seen with stimulant addiction (8). It’s an important distinction and a big part of its appeal.

Norepinephrine

Norepinephrine is another neurotransmitter whose levels modafinil increases (1). It’s a stimulant neurotransmitter responsible for your fight or flight response that heightens alertness and promotes wakefulness (9).

While it is not fully understood how modafinil increases the availability of norepinephrine, the mechanism is believed to be the same as with dopamine (1). The reason for this belief is that dopamine is a precursor for norepinephrine and eventually converts to it (10).

There are several effects that a boost in norepinephrine and a triggering of the fight or flight system have on your body. They include:

• A widening of the airways, which allows more oxygen to enter your system.
• An increased heart rate, which results in faster movement of blood.
• The tightening of blood vessels, which raises your blood pressure.
• The shutting down of your digestive and immune systems, which allows other parts of your body, specifically your muscles and brain, to use more energy.

All these effects are important to note since they’re big contributors to many of modafinil’s side effects.

Histamine

Histamine is most often associated with immune responses and allergies. However, it is also responsible for regulating your sleep and wake cycles (11).

The latter is the reason why antihistamine, a common treatment for certain allergy symptoms, can make you drowsy. It blocks histamine production, which leaves your brain unable to stimulate itself as well as it should, and results in you feeling tired.

Boosting histamine levels is yet another way in which modafinil heightens alertness and wakefulness (1). It’s very effective at it too. Research has shown that it can increase this important neurotransmitter by as much as 150% (12).

Orexin

Another neurotransmitter affected by modafinil (1), orexin is released by the hypothalamus (13).

The hypothalamus is located at the very center of your brain. Its role is like that of a foreman at a construction site. Using different hormones, it controls and assigns work to organs all over your body. It focuses on the big picture and manages things from a very high level.

Orexin is the neurotransmitter the hypothalamus uses to dictate arousal and wakefulness to other parts of your brain (14). Modafinil increases its levels by stimulating the neurons that release it (1).

As an aside, this is the reason why modafinil is such an effective treatment for the most common form of narcolepsy, the root cause of which is insufficient amounts of orexin.

Common Side Effects of Modafinil

With a better understanding of how modafinil works, it’s time to take a closer look at its most common side effects and, more importantly, how to avoid them.

Insomnia

By far, the most frequently reported side effects of taking modafinil is insomnia (15)(16). It’s root cause is the combined increase of the neurotransmitters norepinephrine, histamine, and orexin.

Given that modafinil is a wakefulness-promoting agent and keeping you awake is what it was created for, this should come as no surprise. For as long as its levels are high in your system, it will do its job, and sleep will not come easily.

How to Avoid Insomnia

The main reason you may experience insomnia as a side effect of using modafinil is simply not getting the timing right.

Modafinil has a long half-life of about 12 hours (17). Rule number one is you need to take it at least that far ahead before your planned bedtime. Ideally, this will be in the morning, right after having a good breakfast.

Beside accurate timing, there are also a few other things you should do to makes sure you get a good night’s sleep after taking modafinil.

For example, avoid using other stimulants on the same day. Modafinil potentiates and dramatically increases the effects of any other such substance (18). In other words, unless you know how to do it correctly, modafinil and coffee together is a no-go.

Headaches

The second most commonly reported side effects of modafinil use is a headache (19). And indeed, no matter how much they try, some individuals just can’t avoid it.

It ultimately boils down to your unique brain chemistry.

Headaches, in this case, are most likely caused by an increase of another neurotransmitter called glutamate (20). While modafinil does not do so directly, elevated glutamate levels are a byproduct of the production of dopamine and orexin (21), two neurotransmitters whose production modafinil does stimulate.

Some people have high levels of glutamate, to begin with, and taking modafinil only makes matters worse. It pushes glutamate levels to a point where it starts causing headaches.

That said, glutamate is not always too blame.

Another common cause of experiencing modafinil headaches is dehydration (22). This usually has to do with the fact that after taking modafinil you become so focused, you simply forget to drink. A dozen or so hours of not taking in any liquids will surely have its effects.

How to Avoid Headaches

Because headaches can be caused by one of two things, if you do experience them, you’ll have to do a bit of investigating to figure out if glutamate levels or dehydration is the culprit.

Start by making sure you drink enough water throughout the day. Have at least eight glasses. That’s about two liters or half a gallon.

The easiest to make sure it happens is to gulp down two glasses just before taking modafinil. Then, every time you go to the bathroom, have two more.

If you stay hydrated but still find yourself experiencing headaches, then you know too much glutamate is the most likely cause. You need to bring it under control.

Supplementing with l-theanine is an effective and safe way of lowering your glutamate levels (23). L-theanine is an amino acid found most often in tea leaves and has been proven to have precisely that effect.

Anxiety

Anyone suffering from anxiety has higher levels of certain neurotransmitters in the brain (24). These include norepinephrine and glutamate, both of which modafinil boost either directly or indirectly.

If you are generally anxious, odds are using modafinil will make matters worse.

How to Avoid Increased Anxiety

There are four categories of brain waves: alpha, beta, theta, and delta. Anxiety typically correlates with low alpha wave activity, which is strongest during a state of relaxation.

The neurotransmitters that modafinil boosts certainly do not promote a state of relaxation. Quite the opposite. That leads to a decrease in alpha waves, which in turn results in more anxiety (25).

There are two ways in which you can try to address this issue.

You can use a supplement to increase alpha wave activity. L-theanine has been scientifically proven to do just that (26). It also lowers the levels of the neurotransmitter glutamate (23). Both those effects can lead to reduced anxiety.

If you do end up supplementing with l-theanine, be sure to take it before using modafinil. Don’t wait until your anxiety increases.

The other way you can attempt to lower anxiety while taking modafinil is to use various breathing techniques. This is doable as you go along, anytime you notice symptoms.

Slow and rhythmic breathing can work surprisingly well to reduce anxiety (27). Often, only a few seconds of it is necessary to reach a much calmer state of mind.

The video below shows one technique of doing it.

Do note however that managing anxiety after you take modafinil will be harder than usual. It increases your focus, and just like you may forget to hydrate properly, you may have issues breaking away to perform a breathing technique.

Diarrhea

Gastrointestinal discomfort or diarrhea during modafinil use is typically rooted by one of two factors (or a combination of both).

The first is an irritation of your intestinal tissue. It’s caused by the relatively slow process of your digestive system breaking down the drug (1).

Diarrhea or intestinal discomfort can also be caused by the fight or flight response, which can have a stimulating effect on your intestines. Norepinephrine, one of the neurotransmitters boosted by modafinil, is what causes that system to trigger (9).

How to Avoid Diarrhea

The only way to avoid diarrhea or gastrointestinal discomfort is to eat before using modafinil. It should be a meal that contains plenty of healthy fats. Foods like avocados, olive oil, butter, or other types of animal fat are excellent choices.

Modafinil is a fat-soluble compound. Introducing good dietary fats along with it will reduce irritation to your digestive system.

While eating after taking modafinil can have a similar effect, in practice, it can be challenging to pull off. As is the case with drinking liquids, the increased focus modafinil gives you may make it hard to break away from your task.

No Appetite

While not a big problem for casual modafinil users, a lack of appetite becomes more serious if you use the drug regularly.

By increasing levels of norepinephrine, modafinil at least partially triggers your fight or flight response (9), which shuts down your digestive system.

It’s not uncommon to hear about modafinil users going a full day without eating anything but not realizing they’re hungry until well after the drug has worn off (28).

Some may see this as a benefit. People have even gone as far as trying to take advantage of this side effect in an attempt to lose weight.

However, your body needs proper nutrition to function correctly. Without it, over time, more severe problems may start to appear.

How to Avoid Poor Appetite

Unfortunately, there is no good way to avoid this side effect. It’s your body’s natural response to increased levels of some of the neurotransmitters modafinil acts on (29).

What you can avoid, however, are the prolonged effects of malnutrition.

Understandably, it’s hard to know you need to eat when you both have no appetite and are super focused on your task.

For starters, always make sure you have a large, healthy meal before you take modafinil. You’ll be giving your body at least some fuel to use throughout the day.

You can also try to prepare ahead of time and have within arm’s reach a nutritionally rich shake or snack. Set an alarm that will be hard to miss and as soon as it goes off, reach for what you have prepared.

Although you won’t feel hungry, eat anyways. And make sure you do so immediately. You’ll be surprised how quickly your focus shifts back to your task, making you forget about your snack. That’s just modafinil doing its work.

Dry Mouth

A not so serious but frustrating potential side effect of modafinil is dry mouth. Here, once again, the neurotransmitter norepinephrine is the root cause.

Modafinil increases your norepinephrine levels. By doing so, it triggers your fight or flight response (9) and results in the temporary shutdown of your digestive system.

The logic behind this mechanism is that it allows your body’s energy to divert where it is needed more to handle imminent danger, like your muscles or the brain.

Saliva is very much a part of your digestive system. Its function is to moisten food, making it easier to chew and swallow. Once your body stops producing it, you can get dry mouth.

How to Avoid Dry Mouth

You can reduce the chances of developing dry mouth from modafinil by applying the same methods used to lower anxiety. Those methods include supplementing with l-theanine or practicing breathing exercises or other relaxation techniques.

By keeping your system in a state of greater calm, you can prevent your body from overreacting to the triggering of your fight or flight system. This should dampen its effects.

Serious Modafinil Side Effects

Though the vast majority of modafinil users will either not develop any side effects or will only experience the common easy to manage ones already described, there is a small risk of more serious problems.

These side effects are rare, but anyone taking modafinil needs to be aware of them. Should you experience any, see a doctor immediately.

Chest Pains

Reports of chest pains caused by modafinil use are very uncommon. But, should they occur, they need to be looked into as soon as possible.

Modafinil stimulates the central nervous system (1). Though modafinil causing a heart attack has never been documented, it is a theoretical possibility (especially if you’ve had one in the past or suffer from poor cardiovascular health).

Fever

In rare cases, modafinil use may cause a fever. If the hypothalamus, a part of the brain modafinil targets, partially loses control of the delicate balance it maintains between the body’s various system (also known as homeostasis), an elevated temperature may be the result.

The best way to ensure you don’t develop a fever is by not exceeding modafinil’s recommended dosage, and by staying well hydrated.

If you do develop a temperature, you should stop using modafinil and talk to your physician. Uncontrolled, the loss of homeostasis may lead to more severe issues, including enzyme breakdown, blood pH level changes, and even seizures.

Hallucinations

If modafinil causes you to experience hallucinations, a more serious neurological problem is likely at play. By itself, modafinil should not be triggering this side effect.

Stop using the drug immediately and see your doctor as soon as you can.

Severe Depression

Though modafinil is sometimes prescribed as a treatment for depression, in the odd case, it may lead to a worsening of the condition (30)(31).

As the effects of modafinil wear off, dopamine levels in your brain begin to fall. In some cases, they may end up dropping too far.

The best way to avoid this potential modafinil side effect is to ensure you’re in good mental health before using it. If you already experience depression, talk with your doctor first. You should also avoid mixing modafinil with alcohol or any other medications.

Skin Reaction

As is the case with all the other serious side effects of modafinil, this issue, while very rare, is possible.

The name for this condition is the Stevens-Johnson syndrome (or SJS). It’s a severe an allergic skin reaction that modafinil has been known to trigger (32). The symptoms can range from rashes to blisters and ulcers.

If you experience anything like this, stop modafinil use immediately and seek medical help.

Conclusion

There is a potential for side effects with any drug or medication. Modafinil is no different. Issues are, however, rare and the more common ones are fairly easy to avoid. This is one of the reasons why modafinil has become as popular as it is.

By far, the most frequent problems are headaches and bouts of insomnia. They can be managed with the responsible use of the drug and proper hydration. Supplementing with a relaxation promoting agent like l-theanine or practicing breathing exercises can go a long way towards avoiding any other common issues too (on the odd chance they come up).

While extremely rare, there are also more severe modafinil side effects. You should be aware of them and understand their symptoms before any use. Should they appear, stop using modafinil immediately and see a doctor as soon as possible.

References

1. Paul Gerrard, Robert Malcolm. Mechanisms of modafinil: A review of current research. Neuropsychiatr Dis Treat. 2007 Jun; 3(3): 349–364.
2. Oscar Arias-Carrión, et al. Dopaminergic reward system: a short integrative review. Int Arch Med. 2010; 3: 24.
3. Diehl DJ, Gershon S. The role of dopamine in mood disorders. Compr Psychiatry. 1992 Mar-Apr; 33(2): 115-20.
4. Nieoullon A. Dopamine and the regulation of cognition and attention. Prog Neurobiol. 2002 May; 67(1): 53-83.
5. Salamone JD, Correa M. The mysterious motivational functions of mesolimbic dopamine. Neuron. 2012 Nov 8; 76(3): 470-85.
6. Nora D. Volkow, et al. Effects of Modafinil on Dopamine and Dopamine Transporters in the Male Human Brain: Clinical Implications. JAMA. 2009 Mar 18; 301(11): 1148–1154.
7. Ike dela Peña, et al. Psychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms. Eur J Pharmacol. 2015 Oct 5; 764: 562–570.
8. Center for Substance Abuse Treatment. How Stimulants Affect the Brain and Behavior. Treatment Improvement Protocol (TIP) Series, No. 33. 1999; Chapter 2.
9. David S Goldstein. Adrenal Responses to Stress. Cell Mol Neurobiol. 2010; 30(8): 1433–1440.
10. Mostafa El Mansari, et al. Relevance of Norepinephrine–Dopamine Interactions in the Treatment of Major Depressive Disorder. CNS Neurosci Ther. 2010 Jun; 16(3): e1–e17.
11. Mahesh M Thakkar. Histamine in the Regulation of Wakefulness. Sleep Med Rev. 2011 Feb; 15(1): 65–74.
12. Ishizuka T, et al. Modafinil increases histamine release in the anterior hypothalamus of rats. Neurosci Lett. 2003 Mar 20; 339(2): 143-6.
13. I O Ebrahim, et al. The hypocretin/orexin system. J R Soc Med. 2002 May; 95(5): 227–230.
14. Thomas E Scammell, Christopher J Winrow. Orexin Receptors: Pharmacology and Therapeutic Opportunities. Annu Rev Pharmacol Toxicol. 2011 Feb 10; 51: 243–266.
15. u/throwawaytoday12345. Having trouble sleeping after modafinil. Retrieved January 23, 2019, from https://www.reddit.com/r/Nootropics/comments/1doywn/having_trouble_sleeping_after_modafinil/
16. u/catwithbenefits. Insomnia from Modafinil. Retrieved February 15, 2019, from https://www.reddit.com/r/askdrugs/comments/7j26ol/insomnia_from_modafinil/
17. C. Ballas, D.F. Dinges. Stimulant and Wake-Promoting Substances. Encyclopedia of Neuroscience. 2009.
18. Maddalena Mereu, et al. The Unique Psychostimulant Profile of (±)-Modafinil: Investigation of Behavioral and Neurochemical Effects in Mice. Eur J Neurosci. 2017 Jan; 45(1): 167–174.
19. u/browndude97. Modafinil Headache. Retrieved February 15, 2019, from https://www.reddit.com/r/afinil/comments/55avk6/modafinil_headache/
20. C F Gasparini, L R Griffiths. The Biology of the Glutamatergic System and Potential Role in Migraine. Int J Biomed Sci. 2013 Mar; 9(1): 1-8.
21. John Broussard. Co-transmission of dopamine and glutamate. J Gen Physiol. 2012 Jan; 139(1): 93–96.
22. Blau JN, et al. Water-deprivation headache: a new headache with two variants. Headache. 2004 Jan; 44(1): 79-83.
23. Kimura K, et al. L-Theanine reduces psychological and physiological stress responses. Biol Psychol. 2007 Jan; 74(1): 39-45.
24. Howells FM, Russell VA. Glutamate-stimulated release of norepinephrine in hippocampal slices of animal models of attention-deficit/hyperactivity disorder (spontaneously hypertensive rat) and depression/anxiety-like behaviours (Wistar-Kyoto rat). Brain Res. 2008 Mar 20; 1200: 107-15.
25. Mohsen Dadashi, et al. Effects of Increase in Amplitude of Occipital Alpha & Theta Brain Waves on Global Functioning Level of Patients with GAD. Basic Clin Neurosci. 2015 Jan; 6(1): 14–20.
26. Russ Mason. 200 mg of Zen: L-Theanine Boosts Alpha Waves, Promotes Alert Relaxation. Alternative and Complementary Therapies. April 2001; 7(2): 91-95.
27. Xiao Ma, et al. The Effect of Diaphragmatic Breathing on Attention, Negative Affect and Stress in Healthy Adults. Front Psychol. 2017; 8: 874.
28. u/sleepisbane. Has anyone had trouble eating while on modafinil/armodafinil? Retrieved February 15, 2019, from https://www.reddit.com/r/afinil/comments/4r8w0x/has_anyone_had_trouble_eating_while_on/
29. Perez GA, et al. Modafinil decreases food intake in humans subjected to simulated shift work. Pharmacol Biochem Behav. 2008 Oct; 90(4): 717-22.
30. Goss AJ, et al. Modafinil augmentation therapy in unipolar and bipolar depression: a systematic review and meta-analysis of randomized controlled trials. J Clin Psychiatry. 2013 Nov; 74(11): 1101-7.
31. Price CS, Taylor FB. A retrospective chart review of the effects of modafinil on depression as monotherapy and as adjunctive therapy. Depress Anxiety. 2005; 21(4): 149-53.