Modafinil is a wakefulness-promoting drug used for narcolepsy but also by some for cognitive enhancement. You need a prescription for it.
I’ve experimented with Modafinil and had negative results. I realize that this is because I am dopamine dominant as a result of a mutation in my COMT V158M gene (A/G allele).
I became interested in the primary mechanism by which it promotes wakefulness and how I can substitute it with other biological substances when sleep deprived.
If you have the COMT GG allele based on your 23andme data then that means you will do much better with modafinil.
What are The Mechanisms of Action of Modafinil?
1) Increases Histamine
Modafinil elevates hypothalamic histamine levels [R], a known wakefulness mechanism.
Substitutes:: Fermented foods, Kombucha
2) Increases Dopamine
Modafinil seems to inhibit the reuptake action of the dopamine transporter, thus leading to an increase in extracellular and thus synaptic concentrations of dopamine [R]. Specifically, it increases dopamine in the striatum and nucleus accumbens [R, R].
Specifically, Modafinil works on the D1 dopamine receptors and this causes orexin neurons in the hypothalamus to activate [R].
Forskolin increases cyclic AMP in the whole body, including in the area where orexin neurons are. This causes these neurons to activate (long-term potentiation) and the result is we’re more wakeful [R].
3) Increases Norepinephrine
Substitutes:: Lactate, Caffeine, Synephrine, Adrenal Glandular
4) Increases Glutamate, Inhibits GABA
5) Increases Orexin
Modafinil increases orexin, but some studies have shown that this doesn’t account for its wakefulness.
Orexin neurons are found in the hypothalamus but project to many different parts of the brain, including several areas that regulate wakefulness.
Activation of these neurons increases dopamine and norepinephrine in these areas and excites histaminergic tuberomammillary neurons increasing histamine levels there.
There are two orexin receptors, namely orexin receptor 1 and orexin receptor 2. Animals with defective orexin systems exhibit signs and symptoms similar to narcolepsy.
However, modafinil is also able to promote wakefulness with similar efficacy to amphetamine in dogs with complete loss-of-function mutations in orexin receptor 2 [R], suggesting that orexin activation is not required for these effects of modafinil. Additionally, a study of orexin knockout mice found that not only did modafinil promote wakefulness in these mice, but that it did so even more effectively than in wild-type mice [R].
6) Enhances Effectiveness of Gap Junctions
Most neurons are separated by synapses, and communication between cells is accomplished via the release of neurotransmitters. However, some neurons are directly connected to one another via gap junctions, and it is proposed that modafinil influences the effectiveness of these connections [R].
Modafinil increases electric coupling (meaning the electrical connections or diffusion of current across neurons) in various cells of the brain such as the reticular activating system, which is important for arousal. It is thought to enhance arousal via cholinergic inputs to the thalamus [R].
Gap junctions permit the diffusion of current across linked cells and result in higher resistance to action potential induction since excitatory post-synaptic potentials must diffuse across a greater membrane area. This means, however, that when action potentials do arise in coupled cell populations, the entire populations tend to fire in a synchronized manner. Thus enhanced electrotonic coupling results in the lower tonic activity of the coupled cells while increasing rhythmicity.
Greater neuronal coupling theoretically could enhance gamma band rhythmicity, a potential explanation for modafinil’s nootropic effects [R].
7) Increases Serotonin
Modafinil increases serotonin in the amygdala and frontal cortex [R]. This influences mood rather than wakefulness.
Health Tools I Wish I Had When I Was Sick
At SelfHacked, it’s our goal to offer our readers all the tools possible to get optimally healthy. When I was struggling with chronic health issues I felt stuck because I didn’t have any tools to help me get better. I had to spend literally thousands of hours trying to read through studies on pubmed to figure out how the body worked and how to fix it.
That’s why I decided to create tools that will help others cut down the guesswork:
- Lab Test Analyzer – a software tool that will analyze your labs and tell you what the optimal values are for each marker — as well as provide you with actionable tips and personalized health and lifestyle recommendations to help you get there.
- SelfDecode – a software tool that will help you analyze your genetic data from companies such as 23andme and ancestry. You will learn how your health is being impacted by your genes, and how to use this knowledge to your advantage.
- SelfHacked Secrets – an ebook where we examine and explain the biggest overlooked environmental factors that cause disease. This ebook is a great place to start your journey if you want to learn the essential steps to optimizing your health.
- SelfHacked Elimination Diet course – a video course that will help you figure out which diet works best for you
- Selfhacked Inflammation course – a video course on inflammation and how to bring it down
- Biohacking insomnia – an ebook on how to get great sleep
- Lectin Avoidance Cookbook – an e-cookbook for people with food sensitivities
- BrainGauge – a device that detects subtle brain changes and allows you to test what’s working for you
- SelfHacked VIP – an area where you can ask me (Joe) questions about health topics
The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.
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