Introduction to Modafinil

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.

Using Modafinil

Ways of Administration

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.

Dose

Column 1	Column 2
Threshold	mg
Light	mg
Medium	mg
Strong	mg

Effects of Modafinil

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.

Modafinil combinations

Recreational drug combinations with Modafinil

No Recreational drug combinations with Modafinil have been added to this wiki yet.

Dangerous interactions with Modafinil

No dangerous combinations with Modafinil have been added to this wiki yet.

Medication interactions with Modafinil

No Medication combinations with Modafinil have been added to this wiki yet.

Potentiators of Modafinil

No Potentiation combinations with Modafinil have been added to this wiki yet.

Different Uses for Modafinil

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. [1]

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 ... [2]

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. [3]

There is also some evidence that Modafinil has neuroprotective effects [4]

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 [5]

Recreational use of Modafinil

Pharmacology of Modafinil

General

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.

Dopaminergic action

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.

Adrenergic action

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.

Other pharmacodynamics

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.

Pharmacokinetics

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.

Absorption and Distribution

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_d of 0.9L/kg.

Metabolism and Elimination

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.

Targets, Enzymes, and Transporters

Targets

Target​
	Action​

Enzymes

Enzyme​
	Action​

Transporters

Transporter​
	Action​

Chemistry of Modafinil

Column 1	Column 2
Systematic (IUPAC) name:	(RS)-2-[(diphenylmethyl)sulfinyl]-acetamide
Synonyms:	2-(benzhydrylsulfinyl)acetamide, CRL-40476, Atenace, Provigil
Molecular Formula:	C15H15NO2S
Molar mass:	273.35 g/mol
CAS Registry Number:	68693-11-8
Melting Point:	164-168°C
Boiling Point:	no data
Flash Point:	no data
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
Additionnal data:	none
Notes:	white crystals from methanol

[6]

Reagent test results of Modafinil

The Dangers of Modafinil

General Warnings

Side Effects and Interactions

Potential Side Effects

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.

Potential Drug Interactions

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.

Potential Food Interactions

Physical Health Risks

Hypersensitivity and Serious Skin Reactions

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.

Mental Health Risks

Psychosis

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. [7]

There are documented reports of 2 cases of irritability and aggression related to modafinil use in bipolar disorder. [8]

Overdose

Reported Deaths

Producing Modafinil

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).

Forms of Modafinil

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.

Alertec is a form of Modafinil available in Canada.

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.

Modalert is available from Sun Pharmaceuticals in India in 200 mg pills.

Legal status ofModafinil

Modafinil is a controlled substance 21 CFR 1308.14

United Nations

USA

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.

Canada

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.

Australia

Modafinil is available with a prescription under the name Modavigil.

Italy

Modafinil is available with a prescription under the name Provigil.

Mexico

Modafinil is sold in Mexico as Modiadal and it does not appear to be controlled.

United Kingdom

Available by prescription, unscheduled, and cleared for personal import from other countries.

History of Modafinil

Modafinil and its chemical precursor Adrafinil were developed by Lafon Laboratories, a French company acquired by Cephalon in 2001.

Insights for Modafinil

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