Modafinil

It’s 2023—does it need any introduction? Introducing this new ‘smart pill’ that silicon-valley programmers and entrepreneurs are taking to get ahead! Does it really work?! Is this ethical?!

In any case, there’s considerable variation in how well different people respond to it, which is reflected in its rather ‘dirty’ pharmacology. It’s one of the most effective nootropics I’ve ever tried, yet some people are complete non-responders. So am I some days, when the heavens decide the time isn’t ripe, I guess.

Anyways, here we are. I won’t just proceed to tabulate every effect ever known and reiterate everything that’s on Wikipedia, since they said it better than I can. I’ll focus on the more obscure MOAs.

Pharmacology

• NDRI:

  • (This is in Rhesus monkeys. For the human equivalent dose, divide by ~3.1. So for a 75kg human, 5 on the graph corresponds ~120 mg.)

• Indeed, its wake-promoting effects are at least partly mediated via dopamine, considering:

  • Its wake-promoting effects were aboloished in DAT knckout mice: Dopaminergic Role in Stimulant-Induced Wakefulness
  • Its wake-promoting effects were enhanced in orexin knockout mice: Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates. This one confuses me a lot, and definitely doesn’t take orexin out of the equation, once you think about things like rs121912617, the infamous ‘short sleeper gene’ that increases orexin via weakening DEC2 repression of MyoD.
    • Orexin knockout also abolishes modafinil’s promotion of histamine¹ release (another major effect): Action of modafinil through histaminergic and orexinergic neurons though it’s also been shown (R) that modafinil inhibits GABAergic input in a 5-HT3 agonism-dependent manner from the ventrolateral preoptic nucleus → tuberomamillary nucleus also facilitates histamine release.

• α1B adrenergic agonist.

• Upregulates mGluR2/mGluR3, and downregulating mGluR1/5.

• Modafinil exerts anti-inflammatory and anti-fibrotic effects by upregulating adenosine A2A and A2B receptors granted this is in a model of liver fibrosis, which induces downregulation of A2A/A2B.

• Clinical pharmacokinetic profile of modafinil

  • Metabolism is largely via amide hydrolysis, with lesser contributions from cytochrome P450 (CYP)-mediated oxidative pathways.:
    • Induction of CYP1A2, CYB2B6 and CYP3A4.
    • Suppression/reversible inhibition of CYP2C9 and CYP2C19.

• Pharmacogenetics of Modafinil After Sleep Loss: Catechol-O-Methyltransferase Genotype Modulates Waking Functions But Not Recovery Sleep low COMT (thus high baseline dopaminergic signaling) can expect not to feel much from modafinil.

  • “Two‐time 100 mg modafinil potently improved vigor and well‐being, and maintained baseline performance with respect to executive functioning and vigilant attention throughout sleep deprivation in Val/Val genotype subjects but was hardly effective in subjects with the Met/Met genotype”
  • Effects of modafinil on the sleep EEG depend on Val158Met genotype of COMT

• The wakefulness promoting drug Modafinil causes adenosine receptor-mediated upregulation of receptor activator of nuclear factor κB ligand in osteoblasts: Negative impact of the drug on peak bone accrual in rats

  • Modafinil → A2A and A2B → RANKL expression, and a higher RANKL:OPG (osteoprotegerin) ratio results in increased osteoclast number per bone surface. Noradrenergic drugs are not favorable for bone health, ladies and gentlemen.

• Impact of Astroglial Connexins on Modafinil Pharmacological Properties

  • Flecainide (VGSC blocker; CYP2D6 inhibitor?) enhanced the wake-promoting and pro-cognitive effects of modafinil. Decreased number and duration of transitions to NREM, i.e. attenuated narcolepsy from orexin knockout.

• Modafinil shifts human locus coeruleus to low-tonic, high-phasic activity during functional MRI

Cognition

There are numerous reviews on its efficacy. Frankly I’m not sure how appreciated any annotations or spamming links would be. But anyways:

• Modafinil: A Review of Neurochemical Actions and Effects on Cognition

• Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review (2015)

• Stimulating meditation: a pre-registered randomised controlled experiment combining a single dose of the cognitive enhancer, modafinil, with brief mindfulness training

  • Modafinil acutely increased state mindfulness and improved sustained attention.. No effects on mind-wandering. Participants receiving modafinil engaged in more ‘strategy’ (mindfulness) practice across strategy conditions during follow-up. Modafinil acutely mimicked the effects of brief mindfulness training on state mindfulness but did not enhance the effects of this training.

• Cognitive enhancing effects of modafinil in healthy volunteers (2003)

  • Enhanced performance on tests of digit span, visual pattern recognition memory, spatial planning and stop-signal reaction time.
  • … no significant effects of drug on spatial memory span, spatial working memory, rapid visual information processing or attentional set-shifting. No effects on paired associates learning were identified.

• Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteers (2013)

  • Improvements under modafinil were seen on spatial working memory, planning and decision making at the most difficult levels, as well as visual pattern recognition memory following delay. Subjective ratings of enjoyment of task performance were significantly greater under modafinil compared with placebo, but mood ratings overall were not affected.

• Caffeine and Modafinil Ameliorate the Neuroinflammation and Anxious Behavior in Rats during Sleep Deprivation by Inhibiting the Microglia Activation

• Acute Effects of Modafinil on Brain Resting State Networks in Young Healthy Subjects

• Moral decision making under modafinil: a randomized placebo-controlled double-blind crossover fMRI study

• The Effects of Modafinil on Convergent and Divergent Thinking of Creativity: A Randomized Controlled Trial

Mechanism

• Modafinil (and bupropion, as well) binds to DAT in what is a safer/more sustainable way than cocaine, methylphenidate, monoamine releasing agents like amphetamine, etc. and is non-addictive: The Atypical Stimulant and Nootropic Modafinil Interacts with the Dopamine Transporter in a Different Manner than Classical Cocaine-Like Inhibitors There are 3 conformations that neurotransmitter sodium symporters (SLC6*) (which includes DAT, NET, SERT, usw.) may assume. Modafinil facilitates the ‘open-to-out’ conformation that accepts neurotransmitters from the extracellular space like usual, while amphetamines etc. facilitate the ‘open-to-in’ conformation of releasing substrate into the cytoplasm of the presynaptic neuron.

• Mass Spectrometry Imaging Shows Modafinil, A Student Study Drug, Changes the Lipid Composition of the Fly Brain (wtf is this image?)

  • They show that modafinil decreases the abundance of phosphatidylcholine and sphingomyelin, in favor of phosphatidylethanolamine and phosphatidylinositol. In other words, decreases cylindrical-shaped phospholipids in favor of the conical ones, which would elicit membrane curvature. Combined electrochemistry and mass spectrometry imaging to interrogate the mechanism of action of modafinil, a cognition-enhancing drug, at the cellular and sub-cellular level: This has numerous interesting effects, such as slowing exocytotic events, thereby incerasing the number of catecholamines in each. This potentiates the action of VMAT-2, which is significantly neuroprotective.
    • cf. bupropion, which may work in this way identical to modafinil: Bupropion increases striatal vesicular monoamine transport where interestingly they also noted: “bupropion-induced increase in vesicular DA uptake was prevented by pretreatment with eticlopride, a DA D2 receptor antagonist, but not by SCH23390, a DA D1 receptor antagonist.”
      • Indeed, as is mentioned on Wikipedia, armodafinil (but not esmodafinil) is a D2 partial agonist (R)—let alone functioning as a DRI along with facilitating the action of VMAT-2.
    • The work of Philipsen wrt. vesicular membrane composition is worth looking into: Mass Spectrometric Imaging of Plasma Membrane Lipid Alteration Correlated with Amperometrically Measured Activity-Dependent Plasticity in Exocytosis: “We found that increasing high-curvature lipid species and decreasing low-curvature lipids in the cell membrane favor the formation of a longer-lasting exocytotic fusion pore, resulting in higher release fraction for individual exocytotic events”.

• One would assume this membrane-stabilizing effect is downstream of α1A, 5-HT2A (themselves part of a feedback loop with the increased vesicular monoamine content), H1, etc. → Gαq → PLA2 (which could also potentially liberate choline for methylation)

Analogues

Armodafinil and Modafinil Have Substantially Different Pharmacokinetic Profiles Despite Having the Same Terminal Half-Lives

‘Armodafinil’, if you were unaware, is just the R-enantiomer. It has a longer half-life of ~12-15 hours and is generally more potent than ordinary racemic modafinil.

The action of S-Modafinil is pretty obscure. I was originally interested in it for recreational use (i.e. does not cause insomnia due to a long half life, considering its half life is ~3-5 hours) but there’s always the possibility that it’s actually pharmacologically inactive, and that the lower AUC is simply due to taking a lower effective dose of armodafinil. I haven’t seen anything to suggest the S enantiomer is in any way unique, especially considering there are no studies on it (all information being hidden in the context of studies on modafinil broadly), since why would you want a narcolepsy drug with a half life of only a couple hours, anyways?

Adrafinil seems to be retroactively obsoleted, beyond the fact it’s more legal due to being a prodrug. There are concerns (which frankly could be overblown) about liver toxicity (if for no other reason than the fact that the effective dose is 2x that of modafinil, which I think means your urine will smell of asparagus twice as much) so it’s advised to avoid. Fladrafinil is a similar deal.

Enter the halogenated analogues. Like adrafinil, these are nice because they’re not scheduled substances, and so can be purchased on research chemical sites like Alkonchem.

Elucidation of Structural Elements for Selectivity across Monoamine Transporters: Novel 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues shows that para-halogen substitution increases the affinity for DAT over NET and SERT (such that H < F < Br = Cl). From this, F-, 4F-, Cl-, 4-Cl, 3-Br—and maybe some others—enter the scene. But Fl-, 4Cl, and 3Br-Modafinil are probably the most popular:

Flmodafinil (aka CRL-40,940) Its dose is ~½ that of armodafinil. Again, one would assume it is a bit more dopaminergic. This is the most well-studied halogenated analogue, I believe.

3Br-Modafinil lacks NET affinity. The anecdotes I’ve read considered it to be underwhelming in terms of stimulation and wake-promotion, and is surpassed by 4Cl/Armoda. Dose is ~¾ of armodafinil.

4Cl-Modafinil has slight NET affinity, but still significantly lower than armodafinil. It still lasts 8-12 hours. Anecdotes include it not being as wakefulness-promoting as regular armodafinil, instead being more for ‘well-being’. Dose: ~¾ of armodafinil? Try 50-100 mg.

Heterocyclic Derivatives

• There are 3 main ones I’m aware of:
  • (S)-MK-26: currently undergoing clinical trials.
    • A Novel and Selective Dopamine Transporter Inhibitor, (S)-MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions
  • CE-158: A mere 1-2 hour half life.
  • CE-123, the most researched. Fucking Red Bull has a patent for it. Coming to a gas station near you?

Pragmatics

/r/modafinil and /r/afinil for most questions you may have. Not a lot of discussion of neuroscience or anything there, though. The former is mostly people who are being prescribed modafinil for legitimate reasons like narcolepsy, shift work disorder, etc. and the latter seems to be more about recreational usage.

Modafinil · Gwern.net is a classic. He also has a tag that’ll give you fair bit of studies.

As far as sourcing goes, /r/modareviewsnotbought used to be the go-to place, but it’s since been banned, and as far as I can tell, the entire modafinil sourcing scene on Reddit is heavily astroturfed. Your best bet is asking people who you know have it where they got it. And that being said, I’m 90% sure it’s legal for me here to vouch for ModafinilXL. I promise this post is not secretly one big advertisement for them. I’m spilling the beans about them because I can tell you right now that I’ve seen them being denounced on Reddit by highly questionable accounts in favor of this or that highly questionable vendor. It’s vicious out there.

What does it feel like? Cold and emotionless, usually. You sustain a bare (“clean” almost says too much) level of alertness and awareness. Whatever you want to do is doable and reduced to a list of actionable steps to grind through. Like the world is a field of data, wherever you aim your lance of vigilance subordinate to analysis. It’s usually slightly euphoric, especially when provding ‘event-induced’ reward at getting stuff done. At best, you feel like you could probably win the nobel prize if you felt like this for solid few years. But potentially dysphoric when there’s nothing to do and focus on.

Getting sidetracked, yet remaining 100% focused while doing so. Yet on the same side of the coin, tasks with multiple complex steps can be mentally coordinated more easily thanks to this, letting you jump ship to and from slightly different topics/contexts in service of a overarching goal.

Insomnia, and the potential virtues of intranasal administration

As I mentioned earlier, insomnia poses a serious problem with armodafinil’s ~12-15 hour half life. The wakefulness-promoting effect doesn’t seem to have a tolerance, unlike some of the other effects. This is perfectly beneficial for narcoleptics, medical students pulling all-nighters (working against their long-term health, of course) etc. but plenty of us out here only want a functional stimulant that noticeably lasts perhaps at most 8-10 hours? It’s a ridiculous experience having an insanely productive day thanks to taking a high dose of modafinil, then bedtime hits, and you damn near feel like you’re ready to start the day, not end it.

As is well known in the ‘drug world’, snorting something effectively compresses its duration of effects (and also bypasses first-pass metabolism, which could maybe be beneficial? Would have to research this though.)

Snorting powders is caustic, so clearly not sustainable for the long term. Modafinil is lipid soluble, hence: Google patents - Intranasal delivery of modafinil for potential formulation of a lipid microemulsion nasal spray. This uses extra virgin olive oil along with phosphatidlyserine, + sonicated sodium succinate for pH regulation. But perhaps simple caprylic acid is a candidate. 4Cl-modafinil is also soluble in propylene glycol.