|Summary sheet: Modafinil|
|Common names||Modafinil, Alertec, Modavigil, Modiodal, Provigil, Modalert|
|Routes of Administration|
|Hormonal Birth Control|
Modafinil (also known by the brand names Provigil, Alertec, Modavigil, and others) is a eugeroic substance of the benzhydryl class that produces 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. However, studies have shown that modafinil may also be useful off-label for alleviating the symptoms of depression,, bipolar disorder, Parkinson's disease, seasonal depressive disorder, ADHD, 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 physical stimulation. It has recently gained mainstream popularity for its use as a "smart drug" to improve memory, counteract the desire or need for sleep, and increase general productivity.
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, 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.
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 R2, 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.
Although the exact mechanisms by which modafinil and its R-enantiomer, armodafinil, decrease sleepiness are not fully understood, evidence suggests that these agents promote wakefulness by acting directly or indirectly on many components of the sleep / wake circuit. Modafinil and armodafinil are hypothesized to inhibit GABA and promote dopamine, norepinephrine, histamine, and hypocretin / orexin.
Modafinil and its R-enantiomer, armodafinil, increase both norepinephrine (NE) and dopamine (DA), possibly via their blockade of both the NE and DA reuptake transporters (NET and DAT, respectively). The actions of NE at alpha-adrenergic receptors and DA at dopamine D2 receptors are thought to contribute to the wake-promoting properties of modafinil. Orexin is a key component of the arousal system; thus, the hypothesized action of modafinil on the orexinergic system may help increase alertness. Additionally, modafinil may indirectly increase histamine, either by reducing GABAergic inhibition of histaminergic neurons or via actions at orexinergic neurons. The increase in histamine may contribute to both the wake-promoting effects of modafinil as well as the potential of modafinil to increase alertness.
In genetically engineered mice lacking the dopamine transporter (DAT), modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not reduced by the dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, an inhibitor of dopamine synthesis, blocks the action of amphetamine but does not block locomotor activity induced by modafinil.
In comparison to traditional stimulants such as amphetamine, methylphenidate or cocaine, this compound induces an experience which is far less forceful, euphoric, and recreational. It instead emphasizes general wakefulness and motivation enhancement.
Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), a research literature based on anecdotal reports and the personal experiences of PsychonautWiki contributors. As a result, they should be regarded with a healthy degree of skepticism. It is worth noting that these effects will not necessarily occur in a predictable or reliable manner, although higher doses are more liable to induce the full spectrum of effects. Likewise, adverse effects become much more likely with higher doses and may include addiction, serious injury, or death.
- Stimulation - In terms of its effects on the user's physical energy levels, modafinil is commonly considered to be stimulating and energetic, but can be considered as much less stimulating when compared to amphetamine. This stimulation encourages physical movement and activities such as running, playing sports, socializing, and/or exercising. The particular style of stimulation which modafinil presents can result in jaw clenching, teeth grinding, or other involuntary movements comparable to that of traditional stimulants at high doses, but are manifested much less consistently and intensely when compared to amphetamine or cocaine.
- Increased heart rate
- Appetite suppression - The above components are also accompanied by a suppression of appetite which is usually less intense in strength in comparison to the appetite suppression experienced with amphetamine.
- 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.
- 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.
- 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.
- Pupil dilation
- Photophobia - Although uncommon, modafinil can cause a temporary visual intolerance to light.
- Focus enhancement
- Thought acceleration
- Memory enhancement
- Motivation enhancement
- Time distortion
- Emotion enhancement or Emotion suppression
- 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.
There are currently no anecdotal reports which describe the effects of this compound within our experience index. Additional experience reports can be found here:
Toxicity and harm potential
The long-term safety and effectiveness of modafinil as a drug of regular usage have not been determined.
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).
It is worth noting that as this compound is a commonly prescribed pharmaceutical, it is considerably less likely to have unpredictable adverse health effects than the typical research chemical. Nevertheless, it is strongly recommended that one use harm reduction practices if using this substance.
The median lethal dose at which 50% of participants die (LD50) 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. After overdosing on 5000mg of modafinil in a suicide attempt, a fifteen-year-old female reported a severe headache, nausea, and tachycardia, but did not appear to have any lethal or long-term effects.
Tolerance and addiction potential
The chronic use of modafinil can be considered as not addictive with a low potential for abuse. It does not seem to be capable of causing psychological dependence among most users.
Tolerance to many of the effects of modafinil develops with prolonged and repeated use. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the absence of further consumption). Modafinil may present a cross-tolerance with all benzhydryl nootropics, meaning that after the consumption of modafinil, all related eugeroic compounds such as armodafinil and adrafinil will display a reduced effect.
Although many psychoactive substances are reasonably safe to use on their own, they can suddenly become dangerous or even life-threatening when combined with other substances. The following list includes some known dangerous combinations (although it is not guaranteed to include all of them). Independent research (e.g. Google, DuckDuckGo) should always be conducted to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions have been sourced from TripSit.
- 25x-NBOMe & 25x-NBOH - Members of the 25x family are highly stimulating and physically straining. Combinations with stimulants should be avoided due to the risk of excessive stimulation. This can result in panic attacks, thought loops, seizures, increased blood pressure, vasoconstriction, and heart failure in extreme cases.
- Alcohol - Alcohol can be dangerous to combine with stimulants due to the risk of accidental over-intoxication. Stimulants mask the sedative effects of alcohol, which is the main factor people use to assess their degree of intoxication. Once the stimulant wears off, the depressant effects of alcohol are left unopposed, which can result in blackouts and respiratory depression. If combined, one should strictly limit themselves to only drinking a certain amount of alcohol per hour.
- DXM - Combinations with DXM should be handled with extreme care due to DXM's effects on serotonin and norepinephrine reuptake. This can lead to panic attacks, hypertensive crisis, or serotonin syndrome with stimulants that increase levels of serotonin (MDMA, methylone, mephedrone, etc.). Monitor blood pressure carefully and avoid strenuous physical activity.
- MDMA - The neurotoxic effects of MDMA may be increased when combined with other stimulants. There is also a risk of excessive heart strain.
- MXE - Combinations with MXE may dangerously elevate blood pressure and increase the risk of psychosis.
- Stimulants - Modafinil can be potentially dangerous in combination with other stimulants like cocaine as they can increase one's heart rate and blood pressure to dangerous levels.
- Tramadol - Tramadol lowers the seizure threshold. Combinations with stimulants may further increase this risk.
- MAOIs - This combination may increase the amount of neurotransmitters such as dopamine to dangerous or even fatal levels. Examples include syrian rue, banisteriopsis caapi, and some antidepressants.
- MDMA - The neurotoxic effects of MDMA may be increased when combined with other stimulants.
- 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. Notably, the same enzyme is inhibited by grapefruit juice.
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.
- Canada: Modafinil is listed as a Schedule F prescription drug in Canada and can be prescribed for human and veterinary use.
- Germany: Modafinil is a prescription medicine, according to Anlage 1 AMVV.
- Russian Federation: Modafinil is classed as a Schedule II substance. 
- Switzerland: Modafinil is listed as a "Abgabekategorie B" pharmaceutical, which requires a prescription.
- United Kingdom: Modafinil is a licensed prescription-only medicine (POM) in the United Kingdom. It is not a criminal offence to possess this medicine without a valid prescription. This medicine can legally be obtained with a valid prescription or through legal import of the medicine for personal use as outlined in Section 13 of the Medicines Act 1968.
- United States: In the United States, modafinil is a Schedule IV controlled substance. It is illegal to buy, sell, or possess the drug without a prescription or DEA license.
- Provigal (Manufacturer's Website) | http://www.provigil.com/
- Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/17729016
- A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/17671288
- Neuroprotective effects of modafinil in a marmoset Parkinson model: behavioral and neurochemical aspects (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/16940766
- PubMed - Modafinil treatment in patients with seasonal affective disorder/winter depression: an open-label pilot study (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/15306145
- Modafinil improves symptoms of attention-deficit/hyperactivity disorder across subtypes in children and adolescents (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/18280848
- Modafinil: past, present and future - https://www.tandfonline.com/doi/abs/10.1586/14737188.8.131.529
- Efficient synthesis and biological evaluation of two modafinil analogues - https://www.sciencedirect.com/science/article/abs/pii/S0968089608009772
- Morrissette, D. A. (2013). Twisting the night away: a review of the neurobiology, genetics, diagnosis, and treatment of shift work disorder. CNS Spectrums, 18(s1), 42–54. https://doi.org/10.1017/S109285291300076X
- Touitou, Y., & Bogdan, A. (2007). Promoting adjustment of the sleep-wake cycle by chronobiotics. Physiology and Behavior, 90(2–3), 294–300. https://doi.org/10.1016/j.physbeh.2006.09.001
- Darwish, M., Kirby, M., D'Andrea, D. M., Yang, R., Hellriegel, E. T., & Robertson, P. (2010). Pharmacokinetics of armodafinil and modafinil after single and multiple doses in patients with excessive sleepiness associated with treated obstructive sleep apnea: A randomized, open-label, crossover study. Clinical Therapeutics, 32(12), 2074–2087. https://doi.org/10.1016/j.clinthera.2010.11.009
- Erman MK, Yang R, Seiden DJ. The effect of armodafinil on patient-reported functioning and quality of life in patients with excessive sleepiness associated with shift work disorder: a randomized, double-blind, placebo-controlled trial. Prim Care Companion CNS Disord. 2012;14(4) . doi:10.4088/pcc.12m01345. PMID: 23251870; PMCID: PMC3505139.
- He, B., Peng, H., Zhao, Y., Zhou, H., & Zhao, Z. (2011). Modafinil treatment prevents REM sleep deprivation-induced brain function impairment by increasing MMP-9 expression. Brain Research, 1426, 38–42. https://doi.org/10.1016/j.brainres.2011.09.002
- Udert, K. M., Larsen, T. A., & Gujer, W. (2006). Fate of major compounds in source-separated urine. Water Science and Technology, 54(11–12), 413–420. https://doi.org/10.2166/wst.2006.921
- Pharmacotherapy for excessive daytime sleepiness | http://www.smrv-journal.com/article/S1087-0792(04)00024-3/abstract
- The National Library of Medicine - PROVIGIL | http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=fd75a8a7-a8ab-4141-9af9-989a220b9c19
- Journal of Clinical Sleep Medicine - Unsuccessful Suicide Attempt of a 15 Year Old Adolescent with Ingestion of 5000 mg Modafinil http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725258
- Talaie, H.; Panahandeh, R.; Fayaznouri, M. R.; Asadi, Z.; Abdollahi, M. (2009). "Dose-independent occurrence of seizure with tramadol". Journal of Medical Toxicology. 5 (2): 63–67. doi:10.1007/BF03161089. eISSN 1937-6995. ISSN 1556-9039. OCLC 163567183.
- Gillman, P. K. (2005). "Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity". British Journal of Anaesthesia. 95 (4): 434–441. doi: . eISSN 1471-6771. ISSN 0007-0912. OCLC 01537271. PMID 16051647.
- Robertson, P (2002). "Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers". Clinical Pharmacology & Therapeutics. Springer Nature. 71 (1): 46–56. doi:10.1067/mcp.2002.121217. ISSN 0009-9236.
- Bailey, D. G.; Dresser, G.; Arnold, J. M. O. (2012-11-26). "Grapefruit-medication interactions: Forbidden fruit or avoidable consequences?". Canadian Medical Association Journal. Joule Inc. 185 (4): 309–316. doi:10.1503/cmaj.120951. ISSN 0820-3946.
- Modafinil Wikipedia | https://en.wikipedia.org/wiki/Modafinil
- 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
- MHRA (April 3, 2013). "MHRA license for Modafinil in UK" (PDF). MHRA.
- "Medicines Act 1968 Section 13".
- Placement of Modafinil Into Schedule IV - U.S. Department of Justice | http://www.deadiversion.usdoj.gov/fed_regs/rules/1999/fr0127.htm