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7 Modafinil Mechanisms + Natural Alternatives

Written by Joe Cohen, BS | Last updated:
Jonathan Ritter
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology) | Written by Joe Cohen, BS | Last updated:

Modafinil is a wakefulness-promoting drug used for narcolepsy but also by some for cognitive enhancement. This post describes some major mechanisms of action.

Joe’s Experience With Modafinil

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 SelfDeocde data then that means you will do much better with modafinil.

Modafinil Mechanisms of Action

1) Increases Histamine

Modafinil elevates hypothalamic histamine levels, a known wakefulness mechanism [1].

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 [2]. Specifically, it increases dopamine in the striatum and nucleus accumbens [34].

Specifically, Modafinil works on the D1 dopamine receptors and this causes orexin neurons in the hypothalamus to activate [5].

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 [5].

Substitutes: Mucuna, Amphetamines, L-dopa, Tyrosine, SAM-e

3) Increases Norepinephrine

Modafinil increases norepinephrine in the hypothalamus and ventrolateral preoptic nucleus [67].

Substitutes: Lactate, Caffeine, Synephrine, Adrenal Glandular

4) Increases Glutamate, Inhibits GABA

Alternative mechanisms of action that have been proposed include the activation of glutamatergic circuits while inhibiting GABAergic neurotransmission [89].

Substitutes: Panax Ginseng?, Ginkgo (GABA antagonist)

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.

Modafinil seems to activate these orexin neurons in animal models, which would be expected to promote wakefulness [10, 11].

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 [12], 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 [13].

Substitutes: Lactate (via Kombucha or Exercise) and GLP-1 agonists. See a comprehensive list on increasing orexin.

6) Enhances the 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 [14].

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 [15].

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 [16].

7) Increases Serotonin

Modafinil increases serotonin in the amygdala and frontal cortex [17]. This influences mood rather than wakefulness.

Substitutes: 5-HTP, St John’s Wort, SAM-e

About the Author

Joe Cohen, BS

Joe Cohen, BS

Joe Cohen flipped the script on conventional and alternative medicine…and it worked. Growing up, he suffered from inflammation, brain fog, fatigue, digestive problems, insomnia, anxiety, and other issues that were poorly understood in traditional healthcare. Frustrated by the lack of good information and tools, Joe decided to embark on a learning journey to decode his DNA and track his biomarkers in search of better health. Through this personalized approach, he discovered his genetic weaknesses and was able to optimize his health 10X better than he ever thought was possible. Based on his own health success, he went on to found SelfDecode, the world’s first direct-to-consumer DNA analyzer & precision health tool that utilizes AI-driven polygenic risk scoring to produce accurate insights and health recommendations. Today, SelfDecode has helped over 100,000 people understand how to get healthier using their DNA and labs.
Joe is a thriving entrepreneur, with a mission of empowering people to take advantage of the precision health revolution and uncover insights from their DNA and biomarkers so that we can all feel great all of the time.


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