Modafinil

links: Nootropics reference: https://www.gwern.net/docs/modafinil/index 5-6-2021

Modafinil #

Pharmacology #

• NET/DAT inhibitor.
  • Modafinil lacked wake-promoting activity in DAT knockout mice: Dopaminergic Role in Stimulant-Induced Wakefulness
  • Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice
    • Wake-promoting activity was not reduced by a dopamine receptor antagonist in rats, like it does for amphetamine.
  • α-methyl-p-tyrosine, a dopamine synthesis inhibitor, did not block modafinil-induced locomotor activity… like it does for amphetamine.
  • Modafinil Occupies Dopamine and Norepinephrine Transporters in Vivo and Modulates the Transporters and Trace Amine Activity in Vitro
    • In Rhesus monkeys, 5mg and 8mg/kg (~115 & 180 HED) occupied 16 $\pm$ 7.8 and 44 $\pm$ 12 % NET in the thalamus respectively. For DAT, 35 $\pm$ 12% and 54 $\pm$ 3% respectively:
• Increasing mGluR2 and mGluR3, and downregulating dose-dependently (low dose is ineffective) mGluR5 and mGluR1 impairs the abnormal neuroplasticity in addiction/dependency, inhibiting conditioned place preference (CPP).
• Has serotoninergic (via VMAT2 stuff) and acetylcholinergic effects.
• Partial α1B adrenergic receptor agonist.
  • Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals
• Clinical pharmacokinetic profile of modafinil
  • Metabolism is largely via amide hydrolysis, with lesser contributions from cytochrome P450 (CYP)-mediated oxidative pathways.
  • Small induction of CYP1A2 (upregulation), CYP2B6 and CYP3A4.
  • CYP2C9 suppression
    • https://old.reddit.com/r/Drugs/comments/1700jhu/modafinil_is_an_edible_activator_likely_to/
      • Since THC is metabolized in the liver by CY3A4 into the stronger 11-HO-THC, and CYP2C9 metabolizes it further into the inactive form, modafinil potentiates edibles!
  • In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil
    • CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5
  • Reversible inhibition of CYP2C19

• Modanifil activates the histaminergic system through the orexinergic neurons (2010)
  • Indeed: modafinil-induced increase histamine released is abolished in orexin neuron ablated mice.
• Action of modafinil through histaminergic and orexinergic neurons. (2012)
  • Orexin: increased by NE and decreased by GABA.
  • Presumably disinhibits histamine via blocking GABAergic input (from the ventrolateral preoptic nucleus of the Hypothalamus → TMN) to the histaminergic neurons as well as stimulating histamine directly via orexin.
    • Via: The vigilance promoting drug modafinil decreases GABA release in the medial preoptic area and in the posterior hypothalamus of the awake rat: possible involvement of the serotonergic 5-HT3 receptor looks like it’s 5-HT3 agonism that’s responsible since it was reversed by an antagonist.
    • https://en.wikipedia.org/wiki/Ventrolateral_preoptic_nucleus?useskin=vector there’s a good bit to read here.
  • Histamine release from modafinil is abolished in orexin neuron ablated mice.
    • But get this: Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates
• [Involvement of central histaminergic systems in modafinil-induced but not methylphenidate-induced increases in locomotor activity in rats]]
  • Depletion of neuronal histamine abolished an increase in locomotor activity.
• Possibl Vasodilation, due to the histamine.
• Lipolysis?
• Pharmacogenetics of Modafinil After Sleep Loss: Catechol-O-Methyltransferase Genotype Modulates Waking Functions But Not Recovery Sleep
  • Seems people with low COMT (thus high baseline dopaminergic signaling) don’t feel much.
  • Neither modafinil nor the Val158Met polymorphism affected distinct markers of sleep homeostasis in recovery sleep.
  • Bodenmann has a bunch of studies on wakefulness, including with adenosine stuff:
    • Later: Effects of modafinil on the sleep EEG depend on Val158Met genotype of COMT.
• Slightly hepatotoxic, probably because of the sulfur.
• Modafinil modulation of the default mode network deactivates.

Neurochemistry/Downstream #

• Modafinil shifts human locus coeruleus to low-tonic, high-phasic activity during functional MRI
  • NET inhibitors elevate NE at LC-NE cell bodies, leading to decreased baseline Locus Coeruleus activity, and this NET inhibitor effect also facilitates electrotonic coupling and synchronous activity between LC cells, which can resonate with PFC neurons… e reasoned that with systemic administration, NET inhibition by modafinil should increase NE levels at LC cell-body autoreceptors, leading to decreased baseline excitatory drive to LC cells, manifest as a task-independent pontine deactivation.
• Modafinil Elicits Sympathomedullary Activation
  • Increases resting heart rate and diastolic blood pressure.
• Caffeine and Modafinil Ameliorate the Neuroinflammation and Anxious Behavior in Rats during Sleep Deprivation by Inhibiting the Microglia Activation
  • 60mg/kg caffeine and 100mg/kg modafinil. Yeah - 1.1g modafinil definitely won’t kill you.
• Impact of Astroglial Connexin 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.
• Reduces CD19 expression. (So does Resveratrol, but caffeine attenuates it)

• Smoked Cocaine Self-Administration is Decreased by Modafinil
• Modafinil Abrogates Methamphetamine-Induced Neuroinflammation and Apoptotic Effects in the Mouse Striatum
• Attenuates CFS. Real nice blog post: Modafinil goes well beyond addressing fatigue.

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

  • Drug concentration over time AUC was 33% greater with armodafinil:
  • Plasma concentrations appeared to decline in a monophasic manner with armodafinil, but in a biphasic manner with modafinil due to the initial rapid elimination of its S-isomer.

• 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 increased serum type 1 pro-collagen N-terminal protein (P1NP) and collagen type 1 cross-linked C-telopeptide (CTX-1) indicating a high turnover bone loss.
  • The drug also increased RANKL to osteoprotegerin (OPG) ratio in serum which likely resulted in increased osteoclast number per bone surface..
    • modafinil signalled via A2A and A2B which resulted in increased RANKL expression.
    • ZM-241,385 (an A2AR inhibitor) and MRS 1754 (an A2BR inhibitor) suppressed modafinil-induced upregulation of RANKL/OPG ratio

Cognition #

• Modafinil: A Review of Neurochemical Actions and Effects on Cognition: (so much text) Depression, ADHD, and schizophrenia: improved cognition, working and episodic memory,.
• Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review (2015)
  • [Does modafinil enhance cognitive performance in young volunteers who are not sleep-deprived (2005)]

  • Modafinil and methylphenidate for neuroenhancement in healthy individuals: a systematic review (2010) #

• Modafinil: A Review of Neurochemical Actions and Effects on Cognition
  • Steady-state plasma concentrations are achieved between 2 and 4 days with repeated dosing
• 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.
  • These performance improvements were complemented by a slowing in latency on three tests: delayed matching to sample, a decision-making task and the spatial planning task.
  • In contrast to previous findings with methylphenidate, there were 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.
• Acute Effects of Methylphenidate, Modafinil, and MDMA on Negative Emotion Processing
  • 600 mg increased brain activation within a limbic-cortical-striatal-pallidal-thalamic circuit during fearful face processing, but not MDMA/Mph. also increased amygdala responses to fearful faces, compared to MDMA..
• 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
• Decreased power in delta/theta EEG bands in sleep-deprived subjects.

Mechanism/Kinetic/Physiology #

• The Atypical Stimulant and Nootropic Modafinil Interacts with the Dopamine Transporter in a Different Manner than Classical Cocaine-Like Inhibitors this will tell me everything I need to know
  • There’s a clear relationship between a drug’s ability to change DAT’s conformation and if it elicits cocaine-like effects and if it induces addiction. Mere binding doesn’t tell you anything, technically. Relationship between conformational changes in the dopamine transporter and cocaine-like subjective effects of uptake inhibitors
  • Slower onset of action also reduces addictive liability.
  • while β-CFT and methylphenidate stabilize an “open-to-out” conformation, binding of either modafinil or bupropion gives rise to a more closed conformation
  • They go into LeuT, a neurotransmitter/sodium symporter (NSS/SLC6) family, which includes SERT, NET, and DAT, and how they alternate between at least 3 dominant low-energy comformational states:
    • Open-to-out (outward facing) accepts substrate from the extracellular space.
      • Facilitated by Na+ binding to S1
    • Dually occluded (“closed-to-out”) intermediate (see the 2 blockages in the middle?)
      • Facilitated by substrate interaction with S1
      • This is what modafinil preferentiall interacts with.
    • Open-to-in (inward facing) releases substrate into the cytoplasm (of the cell/presynaptic neuron).
      • Facilitated by secondary substrate interacting with S2 (usually drugs, lol). But S2 ligands are also able to close, I think.
      • This is what’s characteristic of Amphetamine and whatnot.
    • There’s an S1 (primary substrate site) and S2 site: The LeuT-fold neurotransmitter:sodium symporter MhsT has two substrate sites (2018)
      • The electrochemical Na+ concentration gradient across the plasma membrane energizes the translocation of substrate and Na+.
      • 
        • Yeah for some reason, Tryptophan is
• Mass Spectrometry Imaging Shows Modafinil, A Student Study Drug, Changes the Lipid Composition of the Fly Brain (May 2021)
  • Mai H. Philipsen group has some previous work on vesicular Membrane composition:
    • Mass Spectrometry Imaging Shows Cocaine and Methylphenidate Have Opposite Effects on Major Lipids in Drosophila Brain (March 2018)
    • Mass Spectrometric Imaging of Plasma Membrane Lipid Alteration Correlated with Amperometrically Measured Activity-Dependent Plasticity in Exocytosis (Dec 2020)
      • “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”
    • Visualization of Partial Exocytotic Content Release and Chemical Transport into Nanovesicles in Cells (Feb 2022)
• 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 (Jul 2021)
  • 
    • reduces the cylindrical-shaped Phosphatidylcholine at the cellular membrane, while the high curvature lipids with conical structures such as phosphatidylethanolamine and phosphatidylinositol are elevated
      • Veganpermanently talked about how H1 → Gαq → PLA2 would facilitate this, and also 5-HT2A, as part of a feedback loop involving this increase of vesicular monoamine content.
  • Slows exocytosis, enhancing the number of catecholamines in each exocytotic event.
  • Possible upregulation of VMAT2? (It at least certainly potentiates it) Modafinil protects hippocampal neurons by suppressing excessive autophagy and apoptosis in mice with sleep deprivation showed that it increases intravesicular pH of organelles, in contrast to VMAT inhibitors like reserpine that increase intravesicular pH (wait, why is this a bad thing? I thought the low pH of the vesicle is what’s protective)
    • AKT activation
• HIGH POTENCY EUGEROICS— WAKE-PROMOTING AGENTS BEYOND MODAFINIL I feel like this was written in a single night by a guy on modafinil. Nice bachelor’s thesis though brah.
  • Increases electrical coupling between cortical interneurons implemented through a CAMK-II-dependent step: Modafinil enhances thalamocortical activity by increasing neuronal electrotonic coupling
  • Agonistic action at D2-like, since presynaptic D2 antagonist Sulpride abolished modafinil-induced inhibition of dopaminergic neurons (uhh, can you prove that’s not downstream of DAT?): Modafinil inhibits rat midbrain dopaminergic neurons through D2-like receptors

Dose/Protocol #

• Takes 1-2 weeks for tolerance to return to baseline. 50mg or so for 4-6 days a week is fine, while 100-200 is more like 2-3x/week.
• Supposedly the wakefulness-promoting effect has no tolerance (while the dopaminergic one does).
• 15 hour half-life for R-enatiomer; 4-6 hours for S-enantiomer. The racemic mixture is 50/50 that it’s sold as ends up with something like 9-14 hours:
  • 20-60 minute onset & come up, 3.5-5 hour peak, 1-3 hour offset, 2-6 hour after effect.
• 40-65% oral bioavailability.
• Blank said to take Na-R-Lipoic Acid for falling asleep as it’s a peripherally selective antihistamine.
• Could always do intranasal!! for a shorter half life.
  • Google patents - Intranasal delivery of modafinil specifically lipid microemulsion: patents are weird to read, so check it out. EVOO and phosphatidylserine with sonicated sodium succinate at pH 8 or something like that. 50/50 EVOO and phosphatidylserine sonicated in sodium succinate buffer at pH 8 for instance.
    • Intranasal hydrogel of armodafinil hydroxypropyl-β-cyclodextrin inclusion complex for the treatment of post-traumatic stress disorder why though? I do not know.
  • Not very water-soluble compared to something like cocaine hcl, ketamine, amphetamines, etc. This is apparently important for intranasal delivery?
  • Lasts about half as long. Needs about half the dose, considering the bioavailability of 40-65%.
• Snorting coarse powder is overall just kind of fucked up. Either I make a cool lipid emulsion (maybe even C8 works for all I know) or maybe mill/micronize it somehow

Sourcing #

AKA Wakalert, modvigil, modalert, provigil, modavinil, modafresh

• I’m gonna want some powder if I want intranasal usage.
• 30x100mg $50 https://bgpharmadrugs.com/product/modafinil-aspendos-tablets-100-mg-30/
• Modafinilxl (was pretty legit. The Modvigil and Armodavinil have been effective)
  • Modvigil: 50x200mg $80 or $200 Domestic https://modafinilxl.com/buy/modvigil-domestic-usa/ otherwise
  • Modalert: 50x200mg $100
  • Generic Provigil: 50x200mg $80
• Modafinia: 50x200mg $50~70. Sample pack is 40x175 (averaged) $70
• https://sharkmood.com/ 40x200mg $60

Derivatives/Analogues #

Armodafinil (R-Modafinil) #

AKA Nuvigil, Waklert, modaheal Enantiopure.

• Longer half-life than modafinil: 12-15 hours.

Adrafinil #

• Associated with elevated liver enzymes. The research on this is supposedly all in French.

• Effects take 45-60 minutes orally on an empty stomach.

• 80% bioavailability; 1-hour half-life (it converts to modafinil).

• Dose: ~2x that of modafinil.

Anecdote #

My stuff still works after like 2 years of chilling in the shoebox. ‘Vigilance promoting’ is definitely accurate. It just makes it effortless to sustain a bare (even “clean” almost says too much) alertness. It’s not that stimulating or anything like that. It just makes whatever you have to do doable, just slightly better than tolerable and it doesn’t even feel dopaminergic. It definitely increases self-control and generally seems to prevent novelty-seeking behavior.

Flmodafinil (CRL-40,940) #

• Dose: ~1/2 a modafinil dose. AKA Lauflumide, Bisfluoromodafinil, N-deshydroxyl Fladrafinil, bis-(p)-fluoromodafinil. It’s legal - I don’t think you have to go that grey market. https://www.99purity.com/flmodafinil https://www.flmodafinil.co.uk/collections/powder/products/flmodafinil-5g-powder tf?
• https://docs.google.com/document/u/0/d/1pwft7x6jn7INbogv92QU1JTHss6ru3c2dC2bxOJSfBw/mobilebasic
  • $10/1g from the polish guy. I might be missing something here, though, because higher doses cost way more.
• One would assume it has higher DAT affinity than vanilla. More noradrenergic than 4Cl-modafinil, though, according to anecdotes.
• Anecdote of it being… introspective?

Fladrafinil/Fluorafinil (CRL-40,941) #

• Metabolizes into Flmodafinil of course, which is 3-4x stronger than adrafinil, but needs more research; it’s not the same thing. science.bio, https://cziom.com/collections/all-products/products/fladrafinil. No approval necessary.

Fluorenol (Hydrafinil) #

Much shorter half life than any of them but who knows what it feels like in comparison. science.bio.

4-Chloromodafinil #

• Source: AlkonChem
• Slightly noradrenergic.
• Lasts plenty long; 8-12 hours with a long peak. Takes 1-2 hours to really start kicking in according to MattNZ
• Dose: 60-100mg or so.
• Relatively snortable - not caustic, just dry. Can supposedly make a nasal spray with propylene glycol (900mg/ml with heat)
• Apparently during synthesis it’s hard for halogenation to be selective for a certain ring.
• Anecdotes: not very wakefulness-promoting (at least not as much as modafinil). More stimulating than 3-Br. More for “well-being” than euphoria
• Chlorine is arguably a bit risky toxicity-wise… https://old.reddit.com/r/NooTopics/comments/16kr275/looking_for_fairly_legal_dopaminergic_substances/

3-BrModafinil #

• Lacks NET affinity!
• Source: AlkonChem
• Elucidation of Structural Elements for Selectivity across Monoamine Transporters: Novel 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues
  • DAT binding affinity: 550. Inactive at SERT and NET., with moda being 2600 at DAT and inactive at SERT and NET as well.
    • Structure-activity relationships at monoamine transporters for a series of N-substituted 3alpha-(bis[4-fluorophenyl]methoxy)tropanes: comparative molecular field analysis, synthesis, and pharmacological evaluation
      • *p-halogen substitution of the diphenylmethyl moiety of the (±)-1 structure gave analogues with improved binding affinities for the DAT over SERT and NET. *
• Potent and Selective Inhibitors of Monoamine Transporters; Method of Making; and Use Thereof - Google patents

Heterocylic Derivatives #

• 
• CE-123: the most researched.
• CE-158: does not cause motor behavioral sensitization, DESPITE increasing dopamine in the nucleus accumbens. Fully reverses motivation loss by TBZ’s depletion of dopamine.
  • Like a 1-2 hour half life, lmao.
• (S)-MK-26: clinical trials?
  • A Novel and Selective Dopamine Transporter Inhibitor, (S)-MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions