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Modafinil

Discussion in 'Drug Articles' started by tripolar, Jan 26, 2010.

  1. tripolar

    tripolar Palladium Member

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    Male from U.K.
    [VAR]PAGENAME[/VAR] (Provigil, Modalert) - is a wakefulness-promoting agent, used to treat narcolepsy, shift work sleep disorder and excessive daytime sleepiness in obstructive sleep apnea (OSA) sufferers.


    [h="1"]Introduction to [VAR]PAGENAME[/VAR][/h]
    [imgr=white]https://drugs-forum.com/photopost/data/708/Modafinil_Ch_structure.jpg[/imgr]Modafinil (Provigil, Modalert) - is a wakefulness-promoting agent, used to treat narcolepsy, shift work sleep disorder and excessive daytime sleepiness in obstructive sleep apnea (OSA) sufferers. Modafini is primarily indicated to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder.


    [h="1"]Using [VAR]PAGENAME[/VAR][/h]
    [h="2"]Ways of Administration[/h]
    Modafinil (Provigil and generics) is available in 100 mg and 200 mg tablets for oral ingestion. Modafinil can also be crushed into a fine powder and insufflated, which produces a much quicker onset. Anecdotal reports indicate that the length of the main experience is not affected.

    [H="2"]Dose[/H]
    Column 1 Column 2
    0 Threshold mg
    1 Light mg
    2 Medium mg
    3 Strong mg

    [h="2"]Effects of [VAR]PAGENAME[/VAR][/h]
    The main effects of Modafinil are similar to those of more prominent stimulants such as amphetamines, but the effects are generally milder, as Modafinil is not known to have significant dopaminergic activity. produces wakefulness, increased locomotor activity, euphoric effects, alterations in mood, perception, and thinking similar to some stimulants.

    Modafinil usually has a length of about 5-10 hours total. Onset begins 20-60 minutes after ingestion, with a 10-30 minute come up. Onset can be delayed an hour or so if taken with food, but eating will not affect Modafinil's effectiveness once it begins. The effects will plateau for about 3.5-5 hours, and then gradually decrease during the comedown which lasts 1-3 hours. After effects (e.g. continued minor stimulation) may occur for 2-6 hours after the experience is over.

    Side effects can include but are not limited to:
    • head ache
    • dizziness
    • difficulty falling asleep or staying asleep
    • drowsiness
    • nausea
    • diarrhea
    • constipation
    • gas
    • heartburn
    • loss of appetite
    • unusual tastes
    • dry mouth
    • excessive thirst
    • nosebleed
    • flushing
    • sweating
    • tight muscles or difficulty moving
    • back pain
    • confusion
    • uncontrollable shaking of a part of your body
    • burning, tingling, or numbness of the skin
    • difficulty seeing or eye pain
    Serious side effects can occur, which are explained in the Dangers of Modafinil section.

    [h="2"][VAR]PAGENAME[/VAR] combinations[/h]
    [h="3"]Recreational drug combinations with [VAR]PAGENAME[/VAR][/h]
    No Recreational drug combinations with [VAR]PAGENAME[/VAR] have been added to this wiki yet.
    [h="3"]Dangerous interactions with [VAR]PAGENAME[/VAR][/h]
    No dangerous combinations with [VAR]PAGENAME[/VAR] have been added to this wiki yet.
    [h="3"]Medication interactions with [VAR]PAGENAME[/VAR][/h]
    No Medication combinations with [VAR]PAGENAME[/VAR] have been added to this wiki yet.
    [h="3"]Potentiators of [VAR]PAGENAME[/VAR][/h]
    No Potentiation combinations with [VAR]PAGENAME[/VAR] have been added to this wiki yet.

    [h="2"]Different Uses for [VAR]PAGENAME[/VAR][/h]
    In 2006 study showed that Modafinil had the potential to have efficacy in atypical depression (with features of hypersomnia, hyperphagia, anergia and rejection sensitivity); The results in the open-label part of the study suggested that Modafinil was safe and effective for this patient population. [footnote]Sandeep Vaishnavi, MD, PhD, Kishore Gadde, MD, Sayed Alamy, MD, Wei Zhang, MD, PhD, Kathryn Connor, MD and Jonathan R.T. Davidson, MD (2006). Modafinil for Atypical Depression: Effects of Open-label and Double-blind Discontinuation Treatment (Electronic version). Psychopharmacology, 26, 373-378.[/footnote]

    2004 study on effects of modafinil on working memory processes in non-sleep deprived humans showed that a single dose (200 mg) of Modafinil resulted in subtle improvements of performance in the difficult conditions of two working memory tasks ... [footnote]Ulrich Müller, Nikolai Steffenhagen, Ralf Regenthal, Peter Bublak (2004). Effects of modafinil on working memory processes in humans (Electronic version). Psychopharmacology, 177, 161-169.[/footnote]

    A helicopter simulator study, investigating the efficacy of Modafinil for sustaining the alertness and performance of aviators, demonstrated that modafinil attenuated a number of performance and mood-based problems associated with sleep loss. [footnote]John A. Caldwell Jr, J. Lynn Caldwell, Nicholas K. Smythe III, Kecia K. Hall (2000). A double-blind, placebo-controlled investigation of the efficacy of modafinil for sustaining the alertness and performance of aviators: a helicopter simulator study (Electronic version). Psychopharmacology, 150, 272-282.[/footnote]

    There is also some evidence that Modafinil has neuroprotective effects [footnote]Jenner, P; Zeng, B.-Y.; Smith, L.A.; Pearce, R.K.B.; Tel, B.; Chancharme, L.; Moachon, G. (July 2000). Antiparkinsonian and neuroprotective effects of modafinil in the mptp-treated common marmoset (Electronic version). Experimental Brain Research 133 (2): 178–188. [/footnote]

    In 2004, Guardian investigation has learned that over the previous six years, the Ministry of Defence has bought significant quantities of Provigil. According to figures released by the Defence Medical Supplies Agency, which provides medical items "to sustain UK military capability", the MoD has bought more than 24,000 tablets of Provigil between 1998 - 2004 [footnote]http://www.guardian.co.uk/education/...ighereducation[/footnote]
    [h="3"]Recreational use of [VAR]PAGENAME[/VAR][/h]

    [h="1"]Pharmacology of [VAR]PAGENAME[/VAR][/h]
    [h="2"]General[/h]
    Modafinil's mechanism of action has not been fully elucidated. It promotes wakefulness, and has a vaguely similar physiological profile to that of more powerful stimulants such as amphetamines and methylphenidate, but its pharmacological profile is not the same.
    Modafinil does not bind to noradrenaline, serotonin, dopamine, GABA, adenosine, histamine-3, melatonin, or benzodiazepine receptors. In addition, it does not inhibit MAO-B or phosphodiesterases II-V.

    [h="2"]Dopaminergic action[/h]
    Modafinil does not agonize dopamine receptors. In vitro, modafinil binds to the DRT and increases extracellular concentrations of dopamine, however, it does not modify dopamine release. In addition, modafinil's effects are not attenuated by dopamine antagonists such as haloperidol.

    [h="2"]Adrenergic action[/h]
    It has been proposed that modafinil acts via modification of the adrenergic system, however, it does not appear to be a direct or indirect alpha-1 agonist; interestingly, its effects are attenuated by alpha-1 receptor antagonists such as prazosin.

    [h="2"]Other pharmacodynamics[/h]
    In the cat, modafinil (at therapeutic doses) increases neuronal activation in much more discrete brain regions than amphetamine or methylphenidate. This finding's relevance to humans is unknown.

    Modafinil is reinforcing, and in rats has cocaine-like discriminative stimulus effects. In one study it produced up to a 67% increase in cocaine-lever responding and produced full substitution in four out of six rats tested.

    [h="2"]Pharmacokinetics[/h]
    Modafinil is a racemic compound. It's l-isomer has a half-life almost three times that of its d-somer. After steady-state has been achieved (usually 2-4 days of dosing), its trough concentration after once daily dosing consists of 90% l-modafinil and 10% d-modafinil. After multiple doses, effective half-life is 15 hours.

    [h="3"]Absorption and Distribution[/h]
    Rapid absorption, with peak plasma concentrations at 2-4 hours. Food does not affect modafinil bioavailability but it may delay absorption. Modafinil is distributed in body tissue with a V[sub]d[/sub] of 0.9L/kg.

    [h="3"]Metabolism and Elimination[/h]
    Approximately 90% is eliminated by liver and subsequent renal elimination of metabolites.

    Metabolism occurs through hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation, and glucuronide conjugation. Less than 10% is excreted unchanged. In one study the largest presence of the drug in the urine was in the form of modafinil acid (which has been shown to be inactive).

    Modafinil may have an inductive effect on its own metabolism at chronic doses of 400mg/day, via induction of CYP3A4. It is also a reversible inhibitor of CYP2C19.


    [h="2"]Targets, Enzymes, and Transporters[/h]
    [h="3"]Targets[/h]
    Target
    1
    Action


    [h="3"]Enzymes[/h]
    Enzyme
    1
    Action


    [h="3"]Transporters[/h]
    Transporter
    1
    Action



    [h="1"]Chemistry of Modafinil[/h]

    Column 1 Column 2
    0 Systematic (IUPAC) name: (RS)-2-[(diphenylmethyl)sulfinyl]-acetamide
    1 Synonyms: 2-(benzhydrylsulfinyl)acetamide, CRL-40476, Atenace, Provigil
    2 Molecular Formula: C[sub]15[/sub]H[sub]15[/sub]NO[sub]2[/sub]S
    3 Molar mass: 273.35 g/mol
    4 CAS Registry Number: 68693-11-8
    5 Melting Point: 164-168°C
    6 Boiling Point: no data
    7 Flash Point: no data
    8 Solubility: Sparingly soluble in methanol; sparingly to slightly soluble in acetone, slightly soluble in absolute alcohol; very slightly soluble in water; practically insoluble in cyclohexane
    9 Additionnal data: none
    10 Notes: white crystals from methanol
    [FOOTNOTE]Merck Index, fifteenth edition (2013)[/FOOTNOTE]

    [h="2"]Reagent test results of [VAR]PAGENAME[/VAR][/h]


    [h="1"]The Dangers of [VAR]PAGENAME[/VAR][/h]
    [h=“2”]General Warnings[/h]

    [h="2"]Side Effects and Interactions[/h]

    [h=“3”]Potential Side Effects[/h]
    In 2007 FDA advised on revised labeling updates safety information to include warnings regarding serious rash, including Stevens-Johnson Syndrome (SJS) and hypersensitivity reactions, and psychiatric symptoms. Rare cases of serious or life-threatening rash, including Toxic Epidermal Necrolysis, and Drug Rash with Eosinophilia and Systemic Symptoms have been reported in adults and children in worldwide postmarketing experience. Angioedema and multi-organ hypersensitivity reactions have also been reported in postmarketing experience.

    The use should be immediately discontinued if a rash or hypersensitivity reaction occurs.
    [h=“3”]Potential Drug Interactions[/h]

    Modafinil induces CYP 3A4 which is responsible for its own metabolism. CYP 3A4 is also responsible for methadone metabolism. Regular use of modafinil can cause the duration of methadone's action to be shortened significantly, thus causing the abstinence syndrome (i.e. withdrawal). It will also increase the metabolism of other drugs metabolized by CYP 3A4.

    [h=“3”]Potential Food Interactions[/h]

    [h="2"]Physical Health Risks[/h]
    [h="3"]Hypersensitivity and Serious Skin Reactions[/h]
    Rare cases of serious or life-threatening rash, including Toxic Epidermal Necrolysis, and Drug Rash with Eosinophilia and Systemic Symptoms have been reported in adults and children in worldwide postmarketing experience. Angioedema and multi-organ hypersensitivity reactions have also been reported in postmarketing experience.

    [h="2"]Mental Health Risks[/h]
    [h="3"]Psychosis[/h]
    There has been concern about the psychosis-inducing property of Modafinil. Psychiatric adverse experiences (including anxiety, mania, hallucinations, and suicidal ideation) have been reported in patients treated with Modafinil. Caution should be exercised when Modafinil is taken by patients with a history of psychosis, depression, or mania. [footnote]http://www.fda.gov/Safety/MedWatch/S.../ucm152701.htm[/footnote]

    There are documented reports of 2 cases of irritability and aggression related to modafinil use in bipolar disorder. [footnote]Sanjeev Ranjan, Prabha S. Chandra. Modafinil-induced irritability and Aggression? A report of 2 bipolar patients (Electronic version).
    Journal of Clinical Psychopharmacology, Volume 25, Number 6, December 2005[/footnote]

    [h="2"]Overdose[/h]
    [h="2"]Reported Deaths[/h]


    [h="1"]Producing [VAR]PAGENAME[/VAR][/h]

    Modafinil is a Schedule IV drug in the United States. However, a prodrug, called Adrafinil, is unscheduled and unregulated. The only difference between the two drugs is that Adrafinil has a hydroxyl group in place of one of the hydrogens of the amine. There is a thread about the conversion of Adrafinil to Modafinil here (requires chemistry forum access to view).

    [h="1"]Forms of [VAR]PAGENAME[/VAR] [/h]

    Modafinil is a white to off-white, crystalline powder that is practically insoluble in water and cyclohexane. It is slightly soluble in methanol and acetone. PROVIGIL (Cephalon, Inc.) tablets contain 100 mg or 200 mg of modafinil and the following inactive ingredients: lactose, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, povidone, and magnesium stearate.

    [​IMG] [​IMG]

    Alertec is a form of Modafinil available in Canada.
    [​IMG]
    Alertec (Shire Pharmaceuticals) pills contain 100mg of Modafinil. Alertec pills also contain the inactive ingredients lactose, maize starch, magnesium monosilicate, sodium croscarmellose polyvidone, magnesium stearate and talc. [footnote]http://www.antiaging-systems.com/a2z/modafinil.htm[/footnote]

    Modalert is available from Sun Pharmaceuticals in India in 200 mg pills.
    [​IMG]

    [h="1"] Legal status of[VAR]PAGENAME[/VAR] [/h]
    Modafinil is a controlled substance 21 CFR 1308.14


    [h="2"]United Nations[/h]


    [h="2"]USA[/h]
    Modafinil is a non-narcotic Schedule IV drug. This means it is illegal to sell without a DEA license and illegal to buy or possess without a license or prescription.

    [h="2"]Canada[/h]
    Modafanil is listed in Part I of Schedule F of Canada's Food and Drug Regulations, requiring a prescription for human use and for veterinary use.

    The form of modafinil that is scheduled is the racemic form of modafinil. Hence, armodafinil (i.e. the R-isomer of modafinil) can be purchased without a prescription.

    [h="2"]Australia[/h]
    Modafinil is available with a prescription under the name Modavigil.
    [h="2"]Italy[/h]
    Modafinil is available with a prescription under the name Provigil.
    [h="2"]Mexico[/h]
    Modafinil is sold in Mexico as Modiadal and it does not appear to be controlled.
    [h="2"]United Kingdom[/h]
    Available by prescription, unscheduled, and cleared for personal import from other countries.

    [h="1"]History of [VAR]PAGENAME[/VAR] [/h]
    Modafinil and its chemical precursor Adrafinil were developed by Lafon Laboratories, a French company acquired by Cephalon in 2001.

    [h="1"]Insights for [VAR]PAGENAME[/VAR][/h]
    [insights][VAR]PAGENAME[/VAR][/insights]
    [h="1"]More [VAR]PAGENAME[/VAR] Sections and Information[/h]

    Modafinil Experiences Post & read experiences with Modafinil.

    Modafinil File Archive

    Nootropics Forum Post and read about Modafinil.

    Modafinil Image Gallery Post and view pictures of Modafinil.



    [cat]Nootropics[/cat][CAT]Eugeroics[/CAT]
    [h="1"]References[/h]

    [REFLIST][/REFLIST]
     
    Last edited: Feb 8, 2010
  2. Emilita

    Emilita Titanium Member Donating Member

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    Female from earth
    Grammar and spelling corrections.

    No new information has been added.
     
  3. Phencyclidine

    Phencyclidine Silver Member

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    Male from Canada
    I have another change to make but my previous edit is still pending so I'm leaving this as a note. Also, I'm not sure how to cite properly in this wiki.

    The wiki states that l-modafinil has the longer half life. This may be confusing because R-modafinil is l-modafinil or (-)-modafinil (i.e. it is R-(-)-modafinil.

    I bring this up because I live in Canada and only racemic modafinil is scheduled as a prescription drug. I can purchase armodafini (i.e. (-)-modafinil or l-modafini) from a research chemical company in Canada without any worries. People unfamiliar with stereochemical nomenclature may be confused by this.

    Darwish, M., Kirby, M., Hellriegel, E. T., & Robertson Jr, P. (2009). Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives. Clinical drug investigation, 29(9), 613-623.
     
  4. aemetha

    aemetha V Silver Member Donating Member

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    40 y/o Male from Piloting the Rocinante through the slow zone
    You can cite using the [noparse][footnote]citation[/footnote][/noparse] tags. The citation will automatically be added to the reference list, and a link created at the location of the tags.
     
  5. Phencyclidine

    Phencyclidine Silver Member

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    Male from Canada
    Thanks.
    Apparently I am still waiting for my last minor edit to be approved before I can actually insert this.