In this post, I discuss:
- anecdotal reports of anxious modafinil users
- how common anxiety is as a side effect of modafinil
- other adverse effects of modafinil
- how modafinil causes anxiety in some people
- 5 tips to reduce modafinil-related anxiety
If you're most interested in tips to reduce anxiety on modafinil, skip down to the section Coping With Modafnil-Induced Anxiety. Also, please chime in if you have personal experience with modafinil and anxiety.
Anxious Modafinil Users
Look online and you'll find countless reports[^1][^2] of modafinil causing anxiety:
Hey, I've been taking Modalert since 2 months now. I take a dosage of 200mg twice in a week right after I wake up around 9am and start working at my home office. However today I got up late around 1pm and took one 200mg(last dose was 4 days ago) This is the first time I'm experiencing an anxiety attack after taking modalert, I tried calming myself down tried meditating but it keeps coming back. Right now this feeling is really shitty, I only feel like smoking cigarettes. Any of you'll had experience like this before? Any advice is appreciated.
New to modafinil. I've been experimenting with dosage of Modalert for the past week (currently at around 100mg a day but I will decrease). I find that a few hours after having some, my anxiety levels shoot up. When I'm anxious it's always been a nervous "butterfly" tingly type feeling in my chest (rather than the stomach, which I don't think I've ever felt). It gets quite intense with modalert that it's nearly unbearable at times.
There's no question that modafinil can cause anxiety. Until I learned how to manage it, modafinil made me anxious and once precipitated a full-blown panic attack.
Before diving in, let's take a look at modafinil's side effect profile:
In the study referenced in this graphic, 7% of participants on modafinil reported anxiety vs 5% with placebo.
I suspect that the frequency of anxiety with modafinil is much higher than 7%. This suspicion is based on my own experience and anecdotal reports from friends and internet strangers. Other studies[^13] also suggest a higher incidence of anxiety with modafinil.
Why Modafinil Causes Anxiety
The reason that modafinil causes anxiety in some people is straightforward.
Modafinil tends to increase:
- executive function
But too much of a good thing leads to a state of overstimulation and heightened anxiety.
Modafinil's Mechanism and Anxiety
How, mechanistically, does modafinil cause anxiety?
Modafinil stimulates specific circuits in the HPA axis to increase adaptive stress[^14]. If you've ever taken an anti-histamine like Benedryl, you know how drowsy antihistamines can make you. Modafinil has the opposite effect - it boosts histamine rather than blocking it - increasing wakefulness.
Besides histamine, modafinil also decreases GABA and increases glutamate, dopamine, and orexin.
Whether or not you'll experience anxiety on modafinil depends on many factors, like your baseline level of anxiety, your genotype, and the environment.
Baseline Level of Arousal
A big factor that affects whether modafinil makes you anxious is your baseline state.
If you tend to be low-energy, then modafinil is less likely to make you anxious. But if you're relatively energetic to begin with, modafinil can push you into overstimulated territory.
Anxiety is like a sliding scale; it's not continuous rather than discrete. Some people are already prone to anxiety to begin with. Adding modafinil to the mix just unmasks this latent tendency toward anxiety.
How Genetics and Metabolism Affect Response to Modafinil
Genetics play a big role in response to drugs. Pharmacogenomics is the budding field of medicine that deals with how genes affect a person's response to medications.
It's easy to imagine a future where doctors cheaply synthesize a patient's genome to help choose the best drug. This trend of tailored pharmacology is coming to fruition with products like 23andMe. But the field is still in its infancy and such a small fraction of the human genome is understood that the approach has limited value in its current form.
If you have single nucleotide polymorphisms (SNPs) in cytochrome P450 enzymes that metabolize a drug, your ability to clear the drug will be reduced. This can lead to higher than normal blood levels. Sex[^15], ethnicity[^16], and age also affect drug pharmacokinetics.
Slowed clearance of modafinil could result in a buildup of the drug in your system, exacerbating anxiety.
Modafinil is metabolized via the following mechanisms:
- amide hydrolysis (major mechanism)
A SNP in any of these enzymes could impair the rate at which modafinil is cleared from your body.
Philmore Robertson and colleagues characterize the metabolism of modafinil as follows[^10]:
Modafinil is primarily eliminated via metabolism, mainly in the liver, with subsequent excretion in the urine. Less than 10% of the dose is excreted as unchanged drug. Metabolism is largely via amide hydrolysis, with lesser contributions from cytochrome P450 (CYP)-mediated oxidative pathways. In patients who are renally or hepatically compromised, the elimination processes can be slowed, and in a similar manner (although to a lesser extent), elimination in the elderly may be reduced due to normal effects of aging.
The takeaway is that age, impairment in the kidneys or liver and mutations in CYP enzymes can all impede modafinil clearance. When modafinil excretion is slowed, it builds up in your system and can precipitate anxiety.
Drug-drug interactions can interfere with modafinil metabolism.
Any drug or substance that inhibits one of the six CYP enzymes mentioned above could make you feel more anxious on modafinil.
For example, grapefruit inhibits CYP3A4. Since modafinil is partially metabolized by CYP3A4, co-ingesting grapefruit could impair modafinil clearance.
Modafinil and Caffeine
You look online, you'll find anecdotal reports of modafinil and coffee precipitating panic attacks. Mixing stimulants can have this effect.
Coping With Modafnil-Induced Anxiety
Anxiety on modafinil can be unbearable. Sometimes getting more exercise, sleep, and mediating just won't cut it. I've personally experienced modafinil-induced panic attacks and I've found the following tips helpful.
1. Reduce Your Dose
This is a tried-and-tested method to dealing with modafinil-induced anxiety. If you take 200 mg modalert or modvigil you can reduce your dose to 100 mg and re-evaluate. Some people take as little as 50 mg and benefit.
2. Investigate other causes of anxiety
There are many conditions that can cause or exacerbate anxiety (in addition to modafinil).
If you address other anxiogenic (anxiety-promoting) factors in your life it can make a big difference. Here are some disease and factors that can contribute to anxiety:
- pheochromacytoma (tumor affecting the adrenals which secrete fight-or-flight hormones)
- heart disease[^3]
- vagus nerve dysfunction
- sleep restriction
- nutritional deficiencies, e.g., magnesium deficiency[^5]
Supplements and Nootropics For Anxiety
Another option worth exploring is adding a supplement to offset modafinil-induced anxiety.
This is not an ideal solution because you've fallen into the trap of taking additional things to treat the side effects of drugs.
But there are benign substances you can stack with modafinil that alleviate anxiety. Since the evidence for benefit of many supplements is often tentative at best, I try to stick with supplements with low downside risk.
These are a few of my favorites:
Kasper S et al. conducted a double-blind, randomized, placebo-controlled trial. The authors compared the efficacy of lavender oil to the SSRI paroxetine for the treatment of anxiety. The lavender oil group that received the highest dose showed improvement on the Hamilton Anxiety Scale by over 50%.
Even the scent of lavender seems to be beneficial. Maryam Kianpour and colleagues investigated the effect of lavender scent inhalation on the prevention of stress and anxiety in women. They reported that lavender scent reduced self-reported stress, anxiety, and depression at two weeks, 1 month, and three months compared to placebo.
Magnesium is an essential dietary mineral; over 300 enzymes require magnesium to catalyze reactions.
Jacka FN et al.[^6] reported an inverse association between magnesium intake and symptoms of depression and anxiety.
Magnesium may even be a nootropic in its own right.
Magnesium's endogenous function is to block the pore of NMDA-type glutamate receptors, which reduces hyper-excitability in the brain.
Valerian root has been used to treat anxiety in Europe for decades and has grown in popularity in the United States. According to one study, over 1% of the adult population in the United States used valerian in the last week [^8].
How does valerian reduce anxiety?
Valerian extract increases GABA in the synapse. GABA is a neurotransmitter that inhibits neural activity. Santos MS and colleagues[^9] showed that valerian extract induces GABA release from synaptosomes and then blocks GABA's uptake back into nerve cells. Valerian may also inhibit enzymes that degrade GABA.
There's no doubt that modafinil can increase your stress levels by modulating the hypothalamic-pituitary-adrenal (HPA) axis.
You can offset modafinil-related stress by creating an environment for yourself that facilitates relaxed concentration.
Here are a few of my favorite tips for reducing stress.
- Take baths or hit the sauna. One Finnish study found that sauna bathing is inversely related to dementia risk.[^11] Warm water may help help relieve modafinil-induced tension headaches.
- Air-cleaning plants. I'm a big fan of plants that may improve air quality. The main benefit is the psychological effect of seeing something green, alive, and reminiscent of the nature and the outdoors. (See: The great outdoors? Exploring the mental health benefits of natural environments).
- Aromatherapy. At first I thought aromatherapy was a joke and now I'm hooked and the joke's on me! I recommend using lavender oil, since lavender scent is evidently anxiolytic.
- Netflix and chill
- Turmeric tea. I'm always looking for ways to increase my curcumin consumption and drinking tea is a great way to unwind.
- Walking and immersion in nature.[^12]
- Decrease glycemic load. Chances are that you're eating too much sugar.
[^3]: Kapfhammer HP. The relationship between depression, anxiety and heart disease - a psychosomatic challenge. Psychiatr Danub. 2011;23(4):412-24.
[^4]: Collins MM, Corcoran P, Perry IJ. Anxiety and depression symptoms in patients with diabetes. Diabet Med. 2009;26(2):153-61.
[^5]: Sartori SB, Whittle N, Hetzenauer A, Singewald N. Magnesium deficiency induces anxiety and HPA axis dysregulation: modulation by therapeutic drug treatment. Neuropharmacology. 2012;62(1):304-12.
[^6]: Jacka FN, Overland S, Stewart R, Tell GS, Bjelland I, Mykletun A. Association between magnesium intake and depression and anxiety in community-dwelling adults: the Hordaland Health Study. Aust N Z J Psychiatry. 2009;43(1):45-52.
[^7]: Kasper S, Gastpar M, Müller WE, et al. Lavender oil preparation Silexan is effective in generalized anxiety disorder--a randomized, double-blind comparison to placebo and paroxetine. Int J Neuropsychopharmacol. 2014;17(6):859-69.
[^8]: Barnes PM, Powell-griner E, Mcfann K, Nahin RL. Complementary and alternative medicine use among adults: United States, 2002. Adv Data. 2004;(343):1-19.
[^9]: Santos MS, Ferreira F, Cunha AP, Carvalho AP, Macedo T. An aqueous extract of valerian influences the transport of GABA in synaptosomes. Planta Med. 1994;60(3):278-9.
[^10]: Robertson P, Hellriegel ET. Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet. 2003;42(2):123-37.
[^11]: Laukkanen T, Kunutsor S, Kauhanen J, Laukkanen JA. Sauna bathing is inversely associated with dementia and Alzheimer's disease in middle-aged Finnish men. Age Ageing. 2016;
[^12]: Warber SL, Dehudy AA, Bialko MF, Marselle MR, Irvine KN. Addressing "Nature-Deficit Disorder": A Mixed Methods Pilot Study of Young Adults Attending a Wilderness Camp. Evid Based Complement Alternat Med. 2015;2015:651827.
[^13]: Kuan YC, Wu D, Huang KW, et al. Effects of Modafinil and Armodafinil in Patients With Obstructive Sleep Apnea: A Meta-analysis of Randomized Controlled Trials. Clin Ther. 2016;38(4):874-88.
[^14]: Cohen S, Ifergane G, Vainer E, et al. The wake-promoting drug modafinil stimulates specific hypothalamic circuits to promote adaptive stress responses in an animal model of PTSD. Transl Psychiatry. 2016;6(10):e917.
[^15]: Soldin OP, Mattison DR. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2009;48(3):143-57.
[^16]: Johnson JA. Influence of race or ethnicity on pharmacokinetics of drugs. J Pharm Sci. 1997;86(12):1328-33.