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Modafinil: Difference between revisions
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'''Modafinil''' (also known by the brand names '''Provigil''', '''Alertec''', '''Modavigil''', and others) is a [[psychoactive class::eugeroic]] substance of the [[chemical class::benzhydryl]] class that produces [[wakefulness|wakefulness-promoting]] and [[stimulant]] effects when [[administered]]. It is commonly used to enhance cognition, reduce fatigue, and increase alertness in both medical and non-medical contexts. | '''Modafinil''' (also known by the brand names '''Provigil''', '''Alertec''', '''Modavigil''', and others) is a [[psychoactive class::eugeroic]] substance of the [[chemical class::benzhydryl]] class that produces [[wakefulness|wakefulness-promoting]] and [[stimulant]] effects when [[administered]]. It is commonly used to enhance cognition, reduce fatigue, and increase alertness in both medical and non-medical contexts. | ||
Modafinil is approved by the U.S. Food and Drug Administration for the treatment of obstructive sleep apnea, shift work sleep disorder and narcolepsy.<ref>Provigal (Manufacturer's Website) | http://www.provigil.com/</ref> However, studies have shown that modafinil may also be useful off-label for alleviating the symptoms of depression,<ref>Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness | Modafinil is approved by the U.S. Food and Drug Administration for the treatment of obstructive sleep apnea, shift work sleep disorder and narcolepsy.<ref>Provigal (Manufacturer's Website) | http://www.provigil.com/</ref> However, studies have shown that modafinil may also be useful off-label for alleviating the symptoms of depression,<ref>{{cite journal | vauthors=((Fava, M.)), ((Thase, M. E.)), ((DeBattista, C.)), ((Doghramji, K.)), ((Arora, S.)), ((Hughes, R. J.)) | journal=Annals of Clinical Psychiatry: Official Journal of the American Academy of Clinical Psychiatrists | title=Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness | volume=19 | issue=3 | pages=153–159 | date= September 2007 | issn=1040-1237 | doi=10.1080/10401230701464858}}</ref> bipolar disorder,<ref>{{cite journal | vauthors=((Frye, M. A.)), ((Grunze, H.)), ((Suppes, T.)), ((McElroy, S. L.)), ((Keck, P. E.)), ((Walden, J.)), ((Leverich, G. S.)), ((Altshuler, L. L.)), ((Nakelsky, S.)), ((Hwang, S.)), ((Mintz, J.)), ((Post, R. M.)) | journal=The American Journal of Psychiatry | title=A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression | volume=164 | issue=8 | pages=1242–1249 | date= August 2007 | issn=0002-953X | doi=10.1176/appi.ajp.2007.06060981}}</ref> Parkinson's disease,<ref>{{cite journal | vauthors=((Vliet, S. A. M. van)), ((Vanwersch, R. A. P.)), ((Jongsma, M. J.)), ((Gugten, J. van der)), ((Olivier, B.)), ((Philippens, I. H. C. H. M.)) | journal=Behavioural Pharmacology | title=Neuroprotective effects of modafinil in a marmoset Parkinson model: behavioral and neurochemical aspects | volume=17 | issue=5–6 | pages=453–462 | date= September 2006 | issn=0955-8810 | doi=10.1097/00008877-200609000-00011}}</ref> seasonal depressive disorder,<ref>{{cite journal | vauthors=((Lundt, L.)) | journal=Journal of Affective Disorders | title=Modafinil treatment in patients with seasonal affective disorder/winter depression: an open-label pilot study | volume=81 | issue=2 | pages=173–178 | date= August 2004 | issn=0165-0327 | doi=10.1016/S0165-0327(03)00162-9}}</ref> ADHD,<ref>{{cite journal | vauthors=((Biederman, J.)), ((Pliszka, S. R.)) | journal=The Journal of Pediatrics | title=Modafinil improves symptoms of attention-deficit/hyperactivity disorder across subtypes in children and adolescents | volume=152 | issue=3 | pages=394–399 | date= March 2008 | issn=1097-6833 | doi=10.1016/j.jpeds.2007.07.052}}</ref> and various other conditions which have fatigue as a symptom. | ||
Modafinil has also been used as a doping agent by various athletes due to its ability to produce [[Stimulation|physical stimulation]]. | Modafinil has also been used as a doping agent by various athletes due to its ability to produce [[Stimulation|physical stimulation]].<ref>https://www.cyclingnews.com/news/clinger-given-two-year-suspension-for-doping</ref><ref>https://web.archive.org/web/20120122061356/http://sportsillustrated.cnn.com/2006/baseball/mlb/03/06/news.excerpt/1.html</ref><ref>https://journals.lww.com/acsm-msse/fulltext/2004/06000/effects_of_acute_modafinil_ingestion_on_exercise.23.aspx</ref> It has recently gained mainstream popularity for its use as a [[nootropic|"smart drug"]] to [[Memory enhancement|improve memory]], counteract the desire or need for sleep, and increase general productivity.<ref>https://pubmed.ncbi.nlm.nih.gov/34632515</ref> | ||
==History and culture== | ==History and culture== | ||
Modafinil was originally developed in France by neurophysiologist professor Michel Jouvet and Lafon Laboratories. Modafinil originated with the late 1970s invention of a series of benzhydryl sulfinyl compounds, including adrafinil, which was first offered as an experimental treatment for narcolepsy in France in 1986. Modafinil is the primary metabolite of adrafinil, lacking the polar -OH group on its terminal amide,<ref>Modafinil: past, present and future | Modafinil was originally developed in France by neurophysiologist professor Michel Jouvet and Lafon Laboratories. Modafinil originated with the late 1970s invention of a series of benzhydryl sulfinyl compounds, including adrafinil, which was first offered as an experimental treatment for narcolepsy in France in 1986. Modafinil is the primary metabolite of adrafinil, lacking the polar -OH group on its terminal amide,<ref>{{cite journal | vauthors=((Ballas, C. A.)), ((Kim, D.)), ((Baldassano, C. F.)), ((Hoeh, N.)) | journal=Expert Review of Neurotherapeutics | title=Modafinil: past, present and future | volume=2 | issue=4 | pages=449–457 | date=1 July 2002 | url=https://doi.org/10.1586/14737175.2.4.449 | issn=1473-7175 | doi=10.1586/14737175.2.4.449}}</ref> and has similar activity to the parent drug but is much more widely used. It has been prescribed in France since 1994 under the name Modiodal, and in the US since 1998 as Provigil. | ||
==Chemistry== | ==Chemistry== | ||
Modafinil is a synthetic molecule of the benzhydryl class. Benzhydryl compounds are comprised of two benzene rings attached to a single carbon molecule. Modafinil is classified as a sulphinyl benzhydryl molecule, as it also contains a sulfinyl group, a sulphur molecule double-bonded to an oxygen molecule, attached to the carbon of the benzhydryl group. From this sulphur group at R<sub>2</sub>, an acetamide group is bound at its free carbon through a carbonyl group to a terminal amine group. Modafinil is structurally analogous to fluorafinil, another benzhydryl stimulant. | Modafinil is a synthetic molecule of the benzhydryl class. Benzhydryl compounds are comprised of two benzene rings attached to a single carbon molecule. Modafinil is classified as a sulphinyl benzhydryl molecule, as it also contains a sulfinyl group, a sulphur molecule double-bonded to an oxygen molecule, attached to the carbon of the benzhydryl group. From this sulphur group at R<sub>2</sub>, an acetamide group is bound at its free carbon through a carbonyl group to a terminal amine group. Modafinil is structurally analogous to fluorafinil, another benzhydryl stimulant. | ||
While modafinil is a racemic mixture, a similar medication, [[armodafinil]], consists of only the (−)-(R)-enantiomer of modafinil. Modafinil is a highly researched compound, with many derivatives created and studied<ref>Efficient synthesis and biological evaluation of two modafinil analogues | While modafinil is a racemic mixture, a similar medication, [[armodafinil]], consists of only the (−)-(R)-enantiomer of modafinil. Modafinil is a highly researched compound, with many derivatives created and studied<ref>{{cite journal | vauthors=((De Risi, C.)), ((Ferraro, L.)), ((Pollini, G. P.)), ((Tanganelli, S.)), ((Valente, F.)), ((Veronese, A. C.)) | journal=Bioorganic & Medicinal Chemistry | title=Efficient synthesis and biological evaluation of two modafinil analogues | volume=16 | issue=23 | pages=9904–9910 | date=1 December 2008 | url=https://www.sciencedirect.com/science/article/pii/S0968089608009772 | issn=0968-0896 | doi=10.1016/j.bmc.2008.10.027}}</ref>. | ||
==Reagent Testing Color Results== | |||
To find out whether a substance is likely to be Modafinil, reagent testing kits can be used. Application of different reagents to the same substance may cause specific colors changes to appear. The expected color changes for Modafinil with their respective reagent tests (Marquis, Mecke, Mandelin, Liebermann and Froehde) are shown in the following image. Exposing substances to reagents may cause a color change which is indicative of the substance under test <ref>{{cite web |url = https://app.testdrugs.info/substances/564|title = Modafinil Testdrugs.info Website|date = September 7, 2022|author = Testdrugs|publisher = Testdrugs}}</ref> . Reagent tests do not guarantee that a substance is pure. To test purity of a substance, consider thin layer chromatography (TLC) or even more elaborate tests like gas chromatography. | |||
[[File:Modafinil-reagent-colors-psychonautwiki.svg|800px|thumb|center|Expected color changes for Modafinil]] | |||
{{Modafinil/Pharmacology}} | {{Modafinil/Pharmacology}} | ||
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{{Preamble/SubjectiveEffects}} | {{Preamble/SubjectiveEffects}} | ||
{{effects/base | {{effects/base | ||
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*'''[[Effect::Dehydration]]''' - Dehydration and dry mouth commonly occur due to an increase in motivation to engage in physical activities as well as an increased sense of focus which causes one to forget to drink water. | *'''[[Effect::Dehydration]]''' - Dehydration and dry mouth commonly occur due to an increase in motivation to engage in physical activities as well as an increased sense of focus which causes one to forget to drink water. | ||
*'''[[Effect::Headaches]]''' - In terms of physical discomfort, modafinil can cause headaches especially if dehydrated, if you have not eaten food, or if you have been sitting in an awkward position for an extended period of time focused intensely on a task. | *'''[[Effect::Headaches]]''' - In terms of physical discomfort, modafinil can cause headaches especially if dehydrated, if you have not eaten food, or if you have been sitting in an awkward position for an extended period of time focused intensely on a task. | ||
*'''[[Effect::Body odor alteration]]''' - Modafinil can leave a very distinct smell of sulfur in one's urine. This is likely because modafinil, being a member of the sulphinyl benzhydryl chemical class, contains sulfur in its chemical makeup.<ref>Udert, K. M., Larsen, T. A., | *'''[[Effect::Body odor alteration]]''' - Modafinil can leave a very distinct smell of sulfur in one's urine. This is likely because modafinil, being a member of the sulphinyl benzhydryl chemical class, contains sulfur in its chemical makeup.<ref>{{cite journal | vauthors=((Udert, K. M.)), ((Larsen, T. A.)), ((Gujer, W.)) | journal=Water Science and Technology | title=Fate of major compounds in source-separated urine | volume=54 | issue=11–12 | pages=413–420 | date=1 December 2006 | url=https://iwaponline.com/wst/article/54/11-12/413/13916/Fate-of-major-compounds-in-sourceseparated-urine | issn=0273-1223 | doi=10.2166/wst.2006.921}}</ref> | ||
*'''[[Effect::Pupil dilation]]''' | *'''[[Effect::Pupil dilation]]''' | ||
*'''[[Effect::Photophobia]]''' - Although uncommon, modafinil can cause a temporary visual intolerance to light. | *'''[[Effect::Photophobia]]''' - Although uncommon, modafinil can cause a temporary visual intolerance to light. | ||
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*'''[[Effect::Wakefulness]]''' | *'''[[Effect::Wakefulness]]''' | ||
*'''[[Effect::Focus enhancement]]''' | *'''[[Effect::Focus enhancement]]''' | ||
*'''[[Effect::Depression reduction]]''' | |||
*'''[[Effect::Thought acceleration]] | *'''[[Effect::Thought acceleration]] | ||
*'''[[Effect::Memory enhancement]]''' | *'''[[Effect::Memory enhancement]]''' | ||
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*'''[[Effect::Time distortion]]''' | *'''[[Effect::Time distortion]]''' | ||
*'''[[Effect::Emotion enhancement]]''' or '''[[Effect::Emotion suppression]]''' | *'''[[Effect::Emotion enhancement]]''' or '''[[Effect::Emotion suppression]]''' | ||
*'''[[Effect::Anxiety]]''' | *'''[[Effect::Anxiety]]''' or '''[[Effect::Anxiety suppression]]'''{{citation needed}} | ||
*'''[[Effect::Increased music appreciation]]''' - While modafinil is capable of producing this effect, it does not do so as reliably as it does with traditional [[stimulants]] or [[entactogens]]. | *'''[[Effect::Increased music appreciation]]''' - While modafinil is capable of producing this effect, it does not do so as reliably as it does with traditional [[stimulants]] or [[entactogens]]. | ||
}} | }} | ||
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==Toxicity and harm potential== | ==Toxicity and harm potential== | ||
The long-term safety and effectiveness of modafinil as a drug of regular usage have not been determined.<ref>Pharmacotherapy for excessive daytime sleepiness | | The long-term safety and effectiveness of modafinil as a drug of regular usage have not been determined.<ref>{{cite journal | vauthors=((Banerjee, D.)), ((Vitiello, M. V.)), ((Grunstein, R. R.)) | journal=Sleep Medicine Reviews | title=Pharmacotherapy for excessive daytime sleepiness | volume=8 | issue=5 | pages=339–354 | date=1 October 2004 | url=https://www.sciencedirect.com/science/article/pii/S1087079204000243 | issn=1087-0792 | doi=10.1016/j.smrv.2004.03.002}}</ref> | ||
Anecdotal reports from people who have tried modafinil suggest that there do not seem to be any negative health effects attributed to simply trying this substance at low to moderate doses by itself or using it sparingly (but nothing can be completely guaranteed). | Anecdotal reports from people who have tried modafinil suggest that there do not seem to be any negative health effects attributed to simply trying this substance at low to moderate doses by itself or using it sparingly (but nothing can be completely guaranteed). | ||
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===Lethal dosage=== | ===Lethal dosage=== | ||
[[Toxicity::The median lethal dose at which 50% of participants die ([[LD50|LD<sub>50</sub>]]) from modafinil for human beings has never been reached]]. No life-threatening effects have taken place in clinical trials involving the administration of 1000mg to 1600mg of modafinil per day for 7 to 21 consecutive days. Intentional acute overdoses of 4500mg and 4000mg in two adult subjects and an accidental ingestion of 800mg by a three-year-old child did not result in any life-threatening effects or death.<ref>The National Library of Medicine - PROVIGIL | http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=fd75a8a7-a8ab-4141-9af9-989a220b9c19</ref> After overdosing on 5000mg of modafinil in a suicide attempt, a fifteen-year-old female reported a severe [[Headaches|headache]], [[Nausea|nausea]], and [[Abnormal heartbeat|tachycardia]], but did not appear to have any lethal or long-term effects.<ref>Journal of Clinical Sleep Medicine | [[Toxicity::The median lethal dose at which 50% of participants die ([[LD50|LD<sub>50</sub>]]) from modafinil for human beings has never been reached]]. No life-threatening effects have taken place in clinical trials involving the administration of 1000mg to 1600mg of modafinil per day for 7 to 21 consecutive days. Intentional acute overdoses of 4500mg and 4000mg in two adult subjects and an accidental ingestion of 800mg by a three-year-old child did not result in any life-threatening effects or death.<ref>The National Library of Medicine - PROVIGIL | http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=fd75a8a7-a8ab-4141-9af9-989a220b9c19</ref> After overdosing on 5000mg of modafinil in a suicide attempt, a fifteen-year-old female reported a severe [[Headaches|headache]], [[Nausea|nausea]], and [[Abnormal heartbeat|tachycardia]], but did not appear to have any lethal or long-term effects.<ref>{{cite journal | vauthors=((Neuman, G.)), ((Shehadeh, N.)), ((Pillar, G.)) | journal=Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine | title=Unsuccessful Suicide Attempt of a 15 Year Old Adolescent with Ingestion of 5000 mg Modafinil | volume=5 | issue=4 | pages=372–373 | date=15 August 2009 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725258/ | issn=1550-9389}}</ref> | ||
===Tolerance and addiction potential=== | ===Tolerance and addiction potential=== | ||
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{{DangerousInteractions/MAOI|nt=dopamine}} | {{DangerousInteractions/MAOI|nt=dopamine}} | ||
*'''[[DangerousInteraction::Hormonal Birth Control]]''' - Modafinil reduces the effectiveness of hormonal birth control for up to a month after use by increasing the activity of the enzyme CYP3A4/5.<ref>{{cite journal | last=Robertson | first=P | title=Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers | journal=Clinical Pharmacology & Therapeutics | publisher=Springer Nature | volume=71 | issue=1 | year=2002 | issn=0009-9236 | doi=10.1067/mcp.2002.121217 | pages=46–56}}</ref> Notably, the same enzyme is inhibited by grapefruit juice.<ref>{{cite journal | last=Bailey | first=D. G. | last2=Dresser | first2=G. | last3=Arnold | first3=J. M. O. | title=Grapefruit-medication interactions: Forbidden fruit or avoidable consequences? | journal=Canadian Medical Association Journal | publisher=Joule Inc. | volume=185 | issue=4 | date=2012-11-26 | issn=0820-3946 | doi=10.1503/cmaj.120951 | pages=309–316}}</ref> | *'''[[DangerousInteraction::Hormonal Birth Control]]''' - Modafinil reduces the effectiveness of hormonal birth control for up to a month after use by increasing the activity of the enzyme CYP3A4/5.<ref>{{cite journal | last=Robertson | first=P | title=Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers | journal=Clinical Pharmacology & Therapeutics | publisher=Springer Nature | volume=71 | issue=1 | year=2002 | issn=0009-9236 | doi=10.1067/mcp.2002.121217 | pages=46–56}}</ref> Notably, the same enzyme is inhibited by grapefruit juice.<ref>{{cite journal | last=Bailey | first=D. G. | last2=Dresser | first2=G. | last3=Arnold | first3=J. M. O. | title=Grapefruit-medication interactions: Forbidden fruit or avoidable consequences? | journal=Canadian Medical Association Journal | publisher=Joule Inc. | volume=185 | issue=4 | date=2012-11-26 | issn=0820-3946 | doi=10.1503/cmaj.120951 | pages=309–316}}</ref> | ||
*'''[[DangerousInteraction::CYP2C19-substrates]]''' - Modafinil may prolonge the elimation of some anxyolitics like diazepam, propranolol and clomipramine, resulting in higher systemic exposure to those drugs.<ref name="rxlist">https://www.rxlist.com/provigil-drug.htm</ref> | *'''[[DangerousInteraction::CYP2C19-substrates]]''' - Modafinil may prolonge the elimation of some anxyolitics like diazepam, propranolol and clomipramine, resulting in higher systemic exposure to those drugs.<ref name="rxlist">https://www.rxlist.com/provigil-drug.htm</ref> | ||
Although Modafinil may cause nausea and acid reflex, it should not be taken together with omeprazole (which is a CYP2C19-substrate).<ref name="rxlist"/> | Although Modafinil may cause nausea and acid reflex, it should not be taken together with omeprazole (which is a CYP2C19-substrate).<ref name="rxlist" /> | ||
==Legal status== | ==Legal status== | ||
Modafinil is legally approved for medical purposes worldwide. However, it is illegal to sell and possess in most countries without a prescription. | Modafinil is legally approved for medical purposes worldwide. However, it is illegal to sell and possess in most countries without a prescription. | ||
*'''Australia:''' Modafinil is listed as a Schedule 4 (prescription only) drug in Australia and it can be prescribed sleep apnea and narcolepsy.<ref>Modafinil | *'''Australia:''' Modafinil is listed as a Schedule 4 (prescription only) drug in Australia and it can be prescribed for sleep apnea and narcolepsy.<ref>{{Citation | title=Modafinil | url=https://en.wikipedia.org/w/index.php?title=Modafinil&oldid=1100020692}}</ref> | ||
*'''Austria:''' Modafinil is classed as NR (prescription only, repeated dispense prohibited) <ref>Rezeptverordnung | https://www.ris.bka.gv.at/GeltendeFassung.wxe?Abfrage=Bundesnormen&Gesetzesnummer=10010358</ref> | |||
*'''Canada:''' Modafinil is listed as a Schedule F prescription drug in Canada and can be prescribed for human and veterinary use.<ref>National Association of Pharmacy Regulatory Authorities - Regulations Amending the Food and Drug Regulations (1184 — Modafinil) | http://napra.ca/Content_Files/Files/FDR-Project1184-Modafinil-Oct122006.pdf</ref> | *'''Canada:''' Modafinil is listed as a Schedule F prescription drug in Canada and can be prescribed for human and veterinary use.<ref>National Association of Pharmacy Regulatory Authorities - Regulations Amending the Food and Drug Regulations (1184 — Modafinil) | http://napra.ca/Content_Files/Files/FDR-Project1184-Modafinil-Oct122006.pdf</ref> | ||
*'''Germany:''' Modafinil is a prescription medicine, according to Anlage 1 AMVV.<ref>https://www.gesetze-im-internet.de/amvv/BJNR363210005.html</ref> | *'''Germany:''' Modafinil is a prescription medicine, according to Anlage 1 AMVV.<ref>{{Citation | title=AMVV - Verordnung über die Verschreibungspflicht von Arzneimitteln | url=https://www.gesetze-im-internet.de/amvv/BJNR363210005.html}}</ref> | ||
*'''Russian Federation:''' Modafinil is classed as a Schedule II substance. <ref>{{cite web |url = http://www.consultant.ru/cons/cgi/online.cgi?req=doc;base=LAW;n=142882;fld=134;dst=4294967295;rnd=0.8965571122244;from=141820-563|title = Narcotics}}</ref> | *'''Russian Federation:''' Modafinil is classed as a Schedule II substance. <ref>{{cite web |url = http://www.consultant.ru/cons/cgi/online.cgi?req=doc;base=LAW;n=142882;fld=134;dst=4294967295;rnd=0.8965571122244;from=141820-563|title = Narcotics}}</ref> | ||
*'''Switzerland:''' Modafinil is listed as a "Abgabekategorie B" pharmaceutical, which requires a prescription.{{citation needed}} | *'''Switzerland:''' Modafinil is listed as a "Abgabekategorie B" pharmaceutical, which requires a prescription.{{citation needed}} | ||
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*[https://www.erowid.org/smarts/modafinil/ Modafinil (Erowid Vault)] | *[https://www.erowid.org/smarts/modafinil/ Modafinil (Erowid Vault)] | ||
*[https://isomerdesign.com/PiHKAL/explore.php?id=2978 Modafinil (Isomer Design)] | *[https://isomerdesign.com/PiHKAL/explore.php?id=2978 Modafinil (Isomer Design)] | ||
*[https://go.drugbank.com/drugs/DB00745 Modafinil (DrugBank)] | |||
*[https://drugs-forum.com/wiki/Modafinil Modafinil (Drugs-Forum)] | |||
==References== | ==References== | ||