Scientists involved in the clinical trials published articles warning of birth defects at the same time the drug was launched in the US, but isotretinoin was taken up quickly and widely, both among dermatologists and general practitioners. Cases of birth defects showed up in the first year, leading the FDA to begin publishing case reports and to Roche sending warning letters to doctors and placing warning stickers on drug bottles, and including stronger warnings on the label. Lawsuits against Roche started to be filed. In 1983 the FDA's advisory committee was convened and recommended stronger measures, which the FDA took and were at that time unprecedented: warning blood banks not to accept blood from people taking the drug and adding a warning to the label advising women to start taking contraceptives a month before starting the drug. However, the use of the drug continued to grow, as did the number of babies born with birth defects. In 1985 the label was updated to include a  boxed warning . In early 1988 the FDA called for another advisory committee, and FDA employees prepared an internal memo estimating that around 1,000 babies had been born with birth defects due to isotretinoin, that up to around 1,000 miscarriages had been caused, and that between 5,000 and 7,000 women had had abortions due to isotretinoin. The memo was leaked to  The New York Times [ 97 ]  a few days before the meeting, leading to a storm of media attention. In the committee meeting, dermatologists and Roche each argued to keep the drug on the market but to increase education efforts; pediatricians and the  Centers for Disease Control and Prevention  (CDC) argued to withdraw the drug from the market. The committee recommended restricting physicians who could prescribe the drug and requiring a second opinion before it could be prescribed. The FDA, believing it did not have authority under the law to restrict who had the right to prescribe the drug, kept the drug on the market but took further unprecedented measures: it required Roche to make warnings yet more visible and graphic, provide doctors with  informed consent  forms to be used when prescribing the drug, and to conduct follow up studies to test whether the measures were reducing exposure of pregnant women to the drug. Roche implemented those measures, and offered to pay for contraception counseling and pregnancy testing for women prescribed the drug; the program was called the "Pregnancy Prevention Program".


A CDC report published in 2000, [ 98 ]  showed problems with the Pregnancy Prevention Program and showed that the increase in prescriptions was from off-label use, and prompted Roche to revamp its program, renaming it the "Targeted Pregnancy Prevention Program" and adding label changes like requirements for two pregnancy tests, two kinds of contraception, and for doctors to provide pharmacists with prescriptions directly; providing additional educational materials, and providing free pregnancy tests. The FDA had another advisory meeting in late 2000 that again debated how to prevent pregnant women from being exposed to the drug; dermatologists testified about the remarkable efficacy of the drug, the psychological impact of acne, and demanded autonomy to prescribe the drug; others argued that the drug be withdrawn or much stricter measures be taken. In 2001 the FDA announced a new regulatory scheme called SMART (the System to Manage Accutane Related Teratogenicity) that required Roche to provide defined training materials to doctors, and for doctors to sign and return a letter to Roche acknowledging that they had reviewed the training materials, for Roche to then send stickers to doctors, which doctors would have to place on prescriptions they give people after they have confirmed a negative pregnancy test; prescriptions could only be written for 30 days and could not be renewed, thus requiring a new pregnancy test for each prescription. [ 99 ]


In February 2002, Roche's patents for isotretinoin expired, and there are now many other companies selling cheaper generic versions of the drug. On 29 June 2009,  Roche Pharmaceuticals , the original creator and distributor of isotretinoin, officially discontinued both the manufacture and distribution of their  Accutane  brand in the  United States  due to what the company described as business reasons related to low market share (below 5%), coupled with the high cost of defending personal injury lawsuits brought by some people who took the drug. [ 100 ]  Roche USA continues to defend Accutane and claims to have treated over 13   million people since its introduction in 1982. F. Hoffmann-La Roche Ltd. apparently will continue to manufacture and distribute  Roaccutane  outside of the United States. [ 101 ]


Among others, actor  James Marshall  sued Roche over allegedly Accutane-related disease that resulted in the removal of his  colon . [ 102 ]  The jury, however, decided that James Marshall had a pre-existing bowel disease. [ 103 ]


Several trials over inflammatory bowel disease claims have been held in the United States, with many of them resulting in multimillion-dollar judgments against the makers of isotretinoin. [ 104 ]


As of 2017, isotretinoin was marketed under many brand names worldwide: A-Cnotren, Absorica, Accuran, Accutane, Accutin, Acne Free, Acnecutan, Acnegen, Acnemin, Acneone, Acneral, Acnestar, Acnetane, Acnetin A, Acnetrait, Acnetrex, Acnogen, Acnotin, Acnotren, Acretin, Actaven, Acugen, Acutret, Acutrex, Ai Si Jie, Aisoskin, Aknal, Aknefug Iso, Aknenormin, Aknesil, Aknetrent, Amnesteem, Atlacne, Atretin, Axotret, Casius, Ciscutan, Claravis, Contracné, Curacne, Curacné, Curakne, Curatane, Cuticilin, Decutan, Dercutane, Effederm, Epuris, Eudyna, Farmacne, Flexresan, Flitrion, I-Ret, Inerta, Inflader, Inotrin, Isac, Isdiben, Isoacne, Isobest, Isocural, Isoderm, Isoface, IsoGalen, Isogeril, Isolve, Isoprotil, Isoriac, Isosupra, Isosupra Lidose, Isotane, Isotina, Isotinon, Isotren, Isotret, Isotretinoin, Isotretinoina, Isotretinoína, Isotretinoine, Isotretinoïne, Isotrétinoïne, Isotretinoinum, Isotrex, Isotrin, Isotroin, Izotek, Izotziaja, Lisacne, Locatret, Mayesta, Medinac, Myorisan, Neotrex, Netlook, Nimegen, Noitron, Noroseptan, Novacne, Oralne, Oraret, Oratane, Piplex, Policano, Procuta, Reducar, Retacnyl, Retin A, Roaccutan, Roaccutane, Roacnetan, Roacta, Roacutan, Rocne, Rocta, Sotret, Stiefotrex, Tai Er Si, Teweisi, Tretin, Tretinac, Tretinex, Tretiva, Tufacne, Zenatane, Zerocutan, Zonatian ME, and Zoretanin. [ 1 ]


The topical  combination drug   erythromycin/isotretinoin  combines the antibiotic  erythromycin  with isotretinoin and has been marketed under the brand names Isotrex Eritromicina, Isotrexin, and Munderm. [ 1 ]


Isoxicam  is a  nonsteroidal anti-inflammatory drug  (NSAID) that was taken or applied to reduce  inflammation  and as an  analgesic  reducing pain in certain conditions. The drug was introduced in 1983 by the  Warner-Lambert Company . Isoxicam is a chemical analog of  piroxicam  (Feldene) which has a pyridine ring in lieu of an isoxazole ring. In 1985 isoxicam was withdrawn from the French market, due to adverse effects, namely  toxic epidermal necrolysis  resulting in death. Although these serious side effects were observed only in France, the drug was withdrawn worldwide. [ 1 ] [ 2 ]


Lamotrigine , sold under the brand name  Lamictal  among others, is a  medication  used to treat  epilepsy  and stabilize mood in  bipolar disorder . [ 5 ] [ 8 ]  For epilepsy, this includes  focal seizures ,  tonic-clonic seizures , and seizures in  Lennox-Gastaut syndrome . [ 8 ]  In bipolar disorder, lamotrigine has not been shown to reliably treat acute  depression  in any groups except for the severely depressed; but for patients with bipolar disorder who are not currently symptomatic, it appears to reduce the risk of future episodes of depression. [ 9 ]


Common side effects include  nausea ,  sleepiness ,  headache ,  vomiting ,  trouble with coordination , and  rash . [ 8 ]  Serious side effects include  excessive breakdown of red blood cells , increased risk of  suicide , severe skin reaction ( Stevens–Johnson syndrome ), and  allergic reactions , which can be fatal. [ 8 ]  Lamotrigine is a  phenyltriazine , [ 5 ]  making it chemically different from other  anticonvulsants . [ 8 ]  Its mechanism of action is not clear, but it appears to inhibit release of excitatory neurotransmitters via  voltage-sensitive sodium channels  and  voltage-gated calcium channels  in neurons. [ 8 ] [ 10 ] [ 11 ]


Lamotrigine was first marketed in Ireland in 1991, [ 12 ]  and approved for use in the United States in 1994. [ 8 ] [ 13 ]  It is on the  World Health Organization's List of Essential Medicines . [ 14 ]  In 2022, it was the most commonly prescribed  mood stabilizer  and 58th most commonly prescribed medication in the United States, with more than 11   million prescriptions. [ 15 ] [ 16 ]


Lamotrigine is considered a first-line drug for primary generalized  tonic-clonic seizures  (includes simple partial, complex partial, and secondarily generalized seizures such as focal-onset tonic-clonic seizures). It is also used as an alternative or adjuvant medication for partial seizures, such as  absence seizure ,  myoclonic seizure , and  atonic seizures . [ 17 ] [ 18 ]  The evidence supporting the use of lamotrigine as an add-on therapy for drug-resistant generalized tonic-clonic seizures is not clear enough to inform clinical practice. [ 19 ]  Although low-certainty evidence suggests that it reduces generalized tonic-clonic seizures by 50% the level of uncertainty indicates that the actual findings could be significantly different. [ 19 ]  Evidence supporting the use of lamotrigine as an add-on therapy for  drug-resistant focal epilepsy  found that it is likely effective for reducing seizure frequency and is generally well tolerated. [ 20 ]  Lamotrigine has some side effects including a risk of dizziness, nausea, ataxia, or visual disturbances such as  diplopia . [ 20 ]  The long-term effects of lamotrigine have not been investigated. [ 20 ]


Lamotrigine is one of a small number of FDA-approved therapies for the form of  epilepsy  known as  Lennox–Gastaut syndrome . [ 21 ]  It reduces the frequency of LGS seizures, and is one of two medications known to decrease the severity of drop attacks. [ 22 ]  Combination with  valproate  is common, but this increases the risk of lamotrigine-induced severe skin reaction  Stevens–Johnson syndrome , and necessitates reduced dosing due to the interaction of these drugs. [ 23 ]


Lamotrigine is approved in the US for maintenance treatment of  bipolar I disorder  and  bipolar II disorder . [ 24 ]  While the anticonvulsants  carbamazepine  and  valproate  are predominantly  antimanics , lamotrigine has demonstrated efficacy only in preventing or reducing the risk of recurrent depressive episodes of bipolar disorder. The drug seems ineffective in the treatment of current rapid-cycling, acute mania, or acute depression in bipolar disorder. [ 25 ]  Lamotrigine has been shown to be as effective as  lithium , the standard treatment for bipolar disorder. [ 26 ]


Lamotrigine has not demonstrated clear efficacy in treating acute mood episodes, either mania or depression. It has not demonstrated effectiveness in treating acute mania, [ 27 ]  and there is controversy regarding the drug's effectiveness in treating acute bipolar depression. [ 28 ]  A paper written in 2008 by Nassir et al. reviewed evidence from trials that were unpublished and not referenced in the 2002 APA guidelines, and it concludes that lamotrigine has "very limited, if any, efficacy in the treatment of acute bipolar depression". [ 25 ]  A 2008 paper by Calabrese et al. examined much of the same data, and found that in five  placebo-controlled studies , lamotrigine did not significantly differ from placebo in the treatment of bipolar depression. [ 29 ]   However, in a meta-analysis of these studies conducted in 2008, Geddes, Calabrese, and Goodwin found that lamotrigine was effective in individuals with bipolar depression, with a  number needed to treat  (NNT) of 11, or 7 in severe depression. [ 30 ]


A 2013 review concluded that lamotrigine is recommended in bipolar maintenance when depression is prominent and that more research is needed regarding its role in the treatment of acute bipolar depression and unipolar depression. No information to recommend its use in other psychiatric disorders was found. [ 31 ]


Lamotrigine, as a monotherapy, is not substantially effective against  schizophrenia . However, various publications [ 32 ] [ 33 ]  and textbooks [ 34 ] [ 35 ]  have expressed that lamotrigine could be added to  clozapine  as augmentation therapy against partial or non-responding patients with schizophrenia. Patients had statistically significant improvements in positive, negative and affective symptoms. Lamotrigine does not have a statistically significant effect with  antipsychotics  other than  clozapine , such as:  olanzapine ,  risperidone ,  haloperidol ,  zuclopenthixol , etc. [ 36 ]


Off-label uses  include the treatment of  peripheral neuropathy ,  trigeminal neuralgia ,  cluster headaches ,  migraines ,  visual snow , and reducing  neuropathic pain , [ 37 ] [ 38 ] [ 39 ] [ 40 ]  although a systematic review conducted in 2013 concluded that well-designed clinical trials have shown no benefit for lamotrigine in  neuropathic pain . [ 41 ]  Off-label psychiatric usage includes the treatment of treatment-resistant  obsessive-compulsive disorder , [ 42 ]   depersonalization derealization disorder , [ 43 ]   hallucinogen persisting perception disorder , [ 44 ]   schizoaffective disorder , [ 45 ]  and  borderline personality disorder . [ 46 ]  It has not been shown to be useful in  post-traumatic stress disorder . [ 47 ]


GlaxoSmithKline  investigated lamotrigine for the treatment of  ADHD  with inconclusive results. No detrimental effects on  cognitive function  were observed; however, the only statistical improvement in core ADHD symptoms was an improvement on a  Paced Auditory Serial Addition Test  that measures auditory processing speed and calculation ability. [ 48 ]  Another study reported that lamotrigine might be a safe and effective treatment option for adult ADHD  comorbid  with bipolar and recurrent depression. [ 49 ]


Side effects such as rash, fever, and fatigue are very serious, as they may indicate incipient SJS, TEN, DRESS syndrome, or  aseptic meningitis . [ 50 ]


Lamotrigine prescribing information has a  black box warning  about life-threatening skin reactions, including  Stevens–Johnson syndrome  (SJS),  DRESS syndrome , and  toxic epidermal necrolysis  (TEN). [ 5 ]  The manufacturer states that nearly all cases appear in the first two to eight weeks of therapy. [ 5 ]  Patients should seek medical attention for any unexpected skin rash, as its presence is an indication of a possible serious or even deadly side effect of the drug. Not all rashes that occur while taking lamotrigine progress to SJS or TEN. Between 5 and 10% of patients will develop a rash, but only one in a thousand patients will develop a serious rash. Rash and other skin reactions are more common in children, so this medication is often reserved for adults. For patients whose lamotrigine has been stopped after the development of a rash, rechallenge with lamotrigine is also a viable option. Usually, rechallenge is done by reinstating lamotrigine at a smaller dose (5mg/day). However, it does not apply to very serious cases. [ 51 ]  The incidence of these eruptions increases in patients who are currently on, or recently discontinued a  valproate -type anticonvulsant drug, as these medications interact in such a way that the clearance of both is decreased and the effective dose of lamotrigine is increased. [ 5 ]


In 2018, the FDA required a new warning for the risk of  hemophagocytic lymphohistiocytosis . This serious reaction can occur between days to weeks after starting the treatment. [ 52 ]


Other side effects include  alopecia  (hair loss), loss of balance or coordination,  double vision ,  crossed eyes ,  pupil constriction ,  blurred vision ,  dizziness  and  lack of coordination ,  drowsiness ,  insomnia ,  anxiety , vivid dreams or  nightmares ,  dry mouth ,  mouth ulcers ,  memory  problems,  mood changes ,  itchiness ,  runny nose ,  cough ,  nausea ,  indigestion ,  abdominal pain ,  weight loss , missed or painful  menstrual periods , and  vaginitis . The side-effects profile varies for different patient populations. [ 50 ]  Overall adverse effects in treatment are similar between men, women, geriatric, pediatric, and racial groups. [ 5 ]


Lamotrigine has been associated with a decrease in white blood cell count ( leukopenia ). [ 53 ]  Lamotrigine does not prolong  QT/QTc  in TQT studies in healthy subjects. [ 54 ]


In people taking antipsychotics, cases of lamotrigine-precipitated  neuroleptic malignant syndrome  have been reported. [ 55 ] [ 56 ]


Women are more likely than men to have side effects. [ 5 ]


Some evidence shows interactions between lamotrigine and female hormones, which can be of particular concern for women on estrogen-containing  hormonal contraceptives .  Ethinylestradiol , an ingredient of such contraceptives, has been shown to decrease serum levels of lamotrigine. [ 57 ]  Women starting an estrogen-containing oral contraceptive may need to increase the dosage of lamotrigine to maintain its level of efficacy. Likewise, women may experience an increase in lamotrigine side effects upon discontinuation of birth control pills. This may include the "pill-free" week where lamotrigine serum levels have been shown to increase twofold. [ 5 ]


Many studies have found no association between lamotrigine exposure  in utero  and birth defects, while those that have found an association have found only slight associations with minor malformations such as  cleft palates . [ 58 ]  Review studies have found that overall rates of congenital malformations in infants exposed to lamotrigine  in utero  are relatively low (1–4%), which is similar to the rate of malformations in the general population. [ 59 ] [ 60 ]  It is known that lamotrigine is a weak inhibitor of human  dihydrofolate reductase  (DHFR) and other, more powerful, human DHFR inhibitors such as  methotrexate  are known to be  teratogenic . [ 58 ]


Lamotrigine is expressed in  breast milk ; the manufacturer recommends carefully weighing the benefits and risks of taking lamotrigine while  breastfeeding . [ 61 ]  However, some studies suggest that lamotrigine is safe to use while breastfeeding. [ 62 ]   A frequently updated review of scientific literature rates lamotrigine as L3: moderately safe. [ 63 ]


Lamotrigine binds to  melanin -containing tissues such as the iris of the eye or melanin-rich skin. The long-term consequences of this are unknown. [ 64 ]


Lamotrigine is known to affect sleep. Studies with small numbers of patients (10–15) reported that lamotrigine increases the duration of  REM sleep , decreases the number of phase shifts, and decreases the duration of  slow-wave sleep , [ 65 ]  and that there was no effect on  vigilance , [ 66 ]  daytime somnolence and cognitive function. [ 67 ]  However, a retrospective study of 109 patients' medical records found that 6.7% of patients experienced an "alerting effect" resulting in intolerable  insomnia , for which the treatment had to be discontinued. [ 68 ]


Lamotrigine can induce a type of seizure known as a  myoclonic jerk , which tends to happen soon after the use of the medication. [ 69 ]  When used in the treatment of myoclonic epilepsies such as  juvenile myoclonic epilepsy , lower doses (and lower plasma levels) are usually needed, as even moderate doses of this drug can induce seizures, including tonic-clonic seizures, which can develop into  status epilepticus , which is a medical emergency. It can also cause myoclonic status epilepticus. [ 5 ]


In overdose, lamotrigine can cause uncontrolled seizures in most people. Reported results in overdoses involving up to 15 g include increased seizures, coma, and death. [ 5 ]


Lamotrigine is a member of the  sodium channel blocking  class of antiepileptic drugs. [ 70 ]  This may suppress the release of  glutamate  and  aspartate , two dominant excitatory neurotransmitters in the central nervous system. [ 5 ]  It is generally accepted to be a member of the sodium channel blocking class of  antiepileptic drugs , [ 71 ]  but it could have additional actions, since it has a broader spectrum of action than other sodium channel antiepileptic drugs such as  phenytoin  and is effective in the treatment of the depressed phase of bipolar disorder, whereas other sodium channel-blocking antiepileptic drugs are not, possibly on account of its  sigma receptor  activity. In addition, lamotrigine shares few side effects with other, unrelated anticonvulsants known to inhibit sodium channels, which further emphasizes its unique properties. [ 72 ]


It is a  triazine  derivate that inhibits  voltage-sensitive   sodium channels , leading to  stabilization of neuronal membranes . It also blocks L-, N-, and P-type  calcium channels  and weakly inhibits the serotonin  5-HT 3  receptor . [ 73 ]  These actions are thought to inhibit release of  glutamate  at cortical projections in the  ventral striatum   limbic areas , [ 74 ]  and its  neuroprotective  and antiglutamatergic effects have been pointed out as promising contributors to its mood stabilizing activity. [ 75 ]  Observations that lamotrigine reduced  GABA A  receptor -mediated neurotransmission in rat amygdala suggest that a  GABAergic  mechanism may also be involved. [ 76 ]  It appears that lamotrigine does not increase GABA blood levels in humans. [ 77 ]


Lamotrigine does not have pronounced effects on any of the usual neurotransmitter receptors that anticonvulsants affect ( adrenergic ,  dopamine   D 1  and  D 2 ,  muscarinic ,  GABA ,  histaminergic   H 1 ,  serotonin   5-HT 2 , and  N-methyl-D-aspartate ). Inhibitory effects on  5-HT ,  norepinephrine , and dopamine transporters are weak. [ 78 ]  Lamotrigine is a weak inhibitor of  dihydrofolate reductase , [ 5 ]  but whether this effect is sufficient to contribute to a mechanism of action or increases risk to the fetus during pregnancy is not known. Early studies of lamotrigine's mechanism of action examined its effects on the release of endogenous amino acids from rat cerebral cortex slices  in vitro . As is the case for antiepileptic drugs that act on voltage-dependent sodium channels, lamotrigine thereby inhibits the release of  glutamate  and  aspartate , which is evoked by the sodium-channel activator  veratrine  and was less effective in the inhibition of  acetylcholine  or  GABA  release. At high concentrations, it did not affect spontaneous or  potassium -evoked amino acid release. [ 5 ]


These studies suggested that lamotrigine acts presynaptically on voltage-gated sodium channels to decrease glutamate release. Several electrophysiological studies have investigated the effects of lamotrigine on voltage-gated sodium channels. For example, lamotrigine blocked sustained repetitive firing in cultured mouse spinal cord neurons in a concentration-dependent manner, at concentrations that are therapeutically relevant in the treatment of human seizures. In cultured hippocampal neurons, lamotrigine reduced sodium currents in a voltage-dependent manner, and at depolarised potentials showed a small frequency-dependent inhibition. These and a variety of other results indicate that the antiepileptic effect of lamotrigine, like those of phenytoin and  carbamazepine , is at least in part due to use- and voltage-dependent modulation of fast voltage-dependent sodium currents. However, lamotrigine has a broader clinical spectrum of activity than phenytoin and carbamazepine and is recognized to be protective against generalized  absence epilepsy  and other generalized epilepsy syndromes, including primary generalized tonic-clonic seizures, juvenile myoclonic epilepsy, and Lennox-Gastaut syndrome.


The basis for this broader spectrum of activity of lamotrigine is unknown but could relate to actions of the drug on  voltage-gated calcium channels . Lamotrigine blocks T-type  calcium channels  weakly, if at all. However, it does inhibit native and recombinant high voltage-gated calcium channels (N- and P/Q/R-types) at therapeutic concentrations. Whether this activity on calcium channels accounts for lamotrigine's broader clinical spectrum of activity in comparison with phenytoin and carbamazepine remains to be determined.


It  antagonizes  these receptors with the following IC 50  values: [ 5 ]


The  pharmacokinetics  of lamotrigine follow  first-order kinetics , with a  half-life  of 29 hours and volume of distribution of 1.36   L/kg. [ 79 ]  Lamotrigine is rapidly and completely absorbed after oral administration. Its absolute  bioavailability  is 98% and its plasma  C max  occurs from 1.4 to 4.8 hours. Available data indicate that its bioavailability is not affected by food. Estimate of the mean apparent volume of distribution of lamotrigine following oral administration ranges from 0.9 to 1.3   L/kg. This is independent of dose and is similar to following single and multiple doses in both patients with epilepsy and in healthy volunteers. [ 80 ]


Lamotrigine is inactivated by  glucuronidation  in the  liver . [ 81 ]  Lamotrigine is metabolized predominantly by  glucuronic acid   conjugation . Its major metabolite is an inactive 2-n-glucuronide conjugate. [ 82 ]


Lamotrigine has fewer drug interactions than many  anticonvulsant  drugs, although pharmacokinetic interactions with  carbamazepine ,  phenytoin  and other hepatic enzyme-inducing medications may shorten  half-life . [ 83 ]  Dose adjustments should be made on clinical response, but monitoring may be of benefit in assessing compliance. [ 5 ]


The capacity of available tests to detect potentially adverse consequences of  melanin  binding is unknown. Clinical trials excluded subtle effects and optimal duration of treatment.  There are no specific recommendations for periodic ophthalmological monitoring. Lamotrigine binds to the eye and melanin-containing tissues which can accumulate over time and may cause toxicity. Prescribers should be aware of the possibility of long-term ophthalmologic effects and base treatment on clinical response.  Patient compliance should be periodically reassessed with lab and medical testing of liver and kidney function to monitor progress or side effects. [ 5 ]


The first synthesis of lamotrigine was disclosed in a patent file by the  Wellcome Foundation  in 1980. [ 84 ] [ 85 ]
2,3-Dichlorobenzoyl chloride is treated with  cuprous cyanide  to form an  acyl cyanide . This is then reacted with the  nitrate  salt of  aminoguanidine  to give an intermediate which is cyclised to the diamino  triazine  of the drug product. [ 86 ]


Lamotrigine is sold under the original brand name Lamictal [ 5 ]  and it is available in generic form under many brand names worldwide. [ 1 ] [ 89 ]


In March 2021, the United States Food and Drug Administration (FDA) issued a warning regarding the potential for  cardiac arrhythmias  in people with pre-existing structural or conduction heart defects. [ 90 ] [ 91 ]  The warning provoked consternation and controversy within the professional community. [ 92 ]  An in-vitro study conducted in 2011 predicted Class IB antiarrhythmic activity at therapeutic concentrations of lamotrigine, due to its sodium channel-blocking activity. [ 93 ]  Thus, lamotrigine use in at-risk populations could prolong the QRS interval on the electrocardiogram, and increase the risk of arrhythmias and sudden death. No references to human studies or postmarket data in at-risk populations (i.e., people with structural heart disease) were cited to support the warning. A study in dogs is mentioned in the prescribing information brochure by the manufacturer. [ 90 ]  A rapid systematic review concluded that "there is insufficient evidence to support or refute that lamotrigine is associated with sudden death or electrocardiogram changes..." [ 94 ]  The FDA has recommended that further studies are conducted with lamotrigine and other sodium-channel blocking antiseizure medications. [ 91 ]


In March 2023, an  FDA Adverse Event Reporting System  analysis demonstrated signals of  cardiac arrest , but not of  tachyarrhythmia  or  bradyarrhythmia  nor their clinical manifestation as fainting in lamotrigine. The study stratified the epileptic and psychiatric indications, explaining that the nature of the signal for cardiac arrest seems to be confounded by the psychiatric indication, which included 2.5 times more concomitant medications with cardiac adverse events, such as QT-prolonging drugs. Additionally, a 1.5-fold greater reports on  overdose  and  suicide attempts  was recorded in the psychiatric reports. Although lamotrigine blocks the cardiac sodium channels at therapeutically relevant concentrations, owing to its short-fast kinetics at the channel level, this blockage did not translate into a disproportional signal in this study. [ 95 ]


Though lamotrigine has been used to treat seizures in infants, as of 2023, its effectiveness in this age group has been evaluated in only one study. Adverse effects were rarely severe enough for the medication to be discontinued in this age group, however, its effectiveness in reducing seizures was inconclusive. [ 96 ]


Lornoxicam , also known as  chlortenoxicam , is a  nonsteroidal anti-inflammatory drug  (NSAID) of the  oxicam  class with  analgesic  (pain relieving),  anti-inflammatory  and  antipyretic  (fever reducing) properties. It is available in  oral  and  parenteral  formulations.


It was patented in 1977 and approved for medical use in 1997. [ 1 ]  Brand names include  Xefo  and  Xefocam  among others.


Lornoxicam is used for the treatment of various types of pain, especially resulting from inflammatory diseases of the joints,  osteoarthritis , surgery,  sciatica , and other inflammations. [ 2 ]


The drug is contraindicated in patients who must not take other NSAIDs, possible reasons including  salicylate sensitivity , gastrointestinal bleeding and  bleeding disorders , and severe impairment of heart, liver or kidney function. Lornoxicam is not recommended during pregnancy and breastfeeding and is contraindicated during the last third of pregnancy. [ 2 ]


Lornoxicam has side effects similar to other NSAIDs, most commonly mild ones like gastrointestinal disorders ( nausea  and  diarrhea ) and  headache . Severe but seldom side effects include bleeding,  bronchospasms  and the extremely rare  Stevens–Johnson syndrome . [ 2 ]


Interactions with other drugs are typical of NSAIDs. Combination with  vitamin K antagonists  like  warfarin  increases the risk of bleeding. Combination with  ciclosporin  can lead to reduced kidney function, and to  acute kidney injury  in rare cases. Lornoxicam can also increase the adverse effects of  lithium ,  methotrexate  and  digoxin  and its derivatives. The effect of  diuretics ,  ACE inhibitors  and  angiotensin II receptor antagonists  can be reduced, but this is only relevant in patients with special risks like  heart failure . As with  piroxicam ,  cimetidine  can increase plasma levels but is unlikely to cause relevant interactions. [ 3 ]


Modafinil , sold under the brand name  Provigil  among others, is a  central nervous system  (CNS)  stimulant  and  eugeroic  ( wakefulness  promoter) medication used primarily to treat  narcolepsy , [ 3 ] [ 8 ] [ 15 ]  a  sleep disorder  characterized by  excessive daytime sleepiness  and sudden  sleep attacks . [ 16 ]  Modafinil is also approved for stimulating wakefulness in people with  sleep apnea  and  shift work sleep disorder . [ 3 ]  It is taken  by mouth . [ 3 ] [ 8 ]  Modafinil is not approved by the US  Food and Drug Administration  (FDA) for use in people under 17 years old. [ 8 ]


Common side effects of Modafinil include  anxiety ,  insomnia ,  dizziness , and  headache . Modafinil has potential for causing severe  allergic reactions ,  psychiatric  effects, [ 3 ]   hypersensitivity ,  adverse   interactions  with  prescription drugs , and misuse or  abuse . [ 3 ] [ 8 ] [ 15 ]  Modafinil may harm the  fetus  if taken during or two months prior to  pregnancy . [ 17 ]


While modafinil is used as a  cognitive enhancer , or "smart drug," among healthy individuals seeking improved focus and productivity, [ 18 ] [ 19 ]  its use outside medical supervision raises concerns regarding potential misuse or abuse. [ 3 ] [ 8 ] [ 20 ]  Research on the cognitive enhancement effects of modafinil in non-sleep deprived individuals has yielded mixed results, with some studies suggesting modest improvements in attention and executive functions, while others show no significant benefits or even a decline in cognitive functions at high doses. [ 21 ] [ 22 ]


Modafinil, a  eugeroic  or  wakefulness-promoting drug , is primarily used for treating narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and sudden sleep attacks. [ 16 ]  Being a  central nervous system  (CNS)  stimulant  itself, [ 23 ]  modafinil has lower addictive potential than classical stimulants such as  amphetamine ,  cocaine , or  methylphenidate , [ 13 ] [ 24 ] [ 25 ]  but still produces  psychoactive  and subjective effects typical of classical stimulants. [ 3 ] [ 8 ] [ 20 ]


Narcolepsy causes a strong urge to sleep during the day and can include symptoms like  cataplexy  (sudden muscle weakness),  sleep paralysis  (inability to move or speak while falling asleep or waking up), and  hallucinations . Narcolepsy is linked to a lack of the brain chemical  hypocretin  ( orexin ), primarily produced in the  hypothalamus . [ 26 ] [ 27 ]  Modafinil is not a cure for narcolepsy, but it can help manage the symptoms. While modafinil is primarily used to treat excessive sleepiness, it may also help reduce the frequency and severity of cataplexy attacks in some people. Modafinil is approved for management of narcolepsy with or without cataplexy. However, it is not specifically approved for the treatment of cataplexy. [ 28 ] [ 29 ]


Modafinil is also prescribed for  shift work sleep disorder . [ 8 ]


Modafinil performs moderately (but better than  armodafinil  or  solriamfetol ) [ 30 ]  as a drug to overcome  excessive daytime sleepiness  caused by  obstructive sleep apnea , [ 31 ]  though it is recommended that people with apnea use  continuous positive airway pressure  (CPAP) therapy, that is a sleep breathing apparatus to prevent apnea, before starting modafinil. [ 8 ] [ 22 ] [ 32 ]  When obstructive sleep apnea is comorbid with narcolepsy, modafinil is an effective drug to reduce the associated excessive daytime sleepiness. [ 33 ]


Modafinil's use varies by region. In the US, it is approved for adult narcolepsy, shift work sleep disorder, and obstructive sleep apnea, but not for children. [ 20 ]  In the UK and the EU, since 2014, it is approved solely for narcolepsy, including in children ( pediatric narcolepsy ), with its use for other conditions restricted by the European Medicines Agency. [ 28 ] [ 34 ]


As of 2024, [update]  both the French and the American Academy of Sleep Medicine strongly recommend modafinil as the first-choice treatment for narcolepsy. [ 35 ]  In Europe, modafinil is considered one of the primary drugs recommended for treating narcolepsy according to the guidelines. [ 36 ]


The  National Institute for Health and Care Excellence  (NICE) in the UK, along with various non-governmental organizations focused on  multiple sclerosis  (MS), endorse the off-label use of modafinil to alleviate fatigue associated with MS. [ 20 ] [ 37 ] [ 38 ]


MS-related fatigue is a common and often debilitating symptom experienced by people with multiple sclerosis. [ 39 ] [ 40 ] [ 41 ] [ 42 ]  It can significantly impact their daily functioning,  quality of life , and ability to perform everyday activities. When prescribed for MS-related fatigue management, modafinil works by promoting wakefulness and increasing  alertness  without causing drowsiness or disrupting nighttime sleep. People with multiple sclerosis often report increased energy levels, reduced feelings of tiredness, improved cognitive function, and an overall improvement in their quality of life when taking modafinil. [ 43 ]  While modafinil can provide relief from MS-related fatigue symptoms, [ 43 ]  it does not treat the underlying cause or cure MS itself. The primary goal of using modafinil in MS is symptom management and improving daily functioning. [ 41 ] [ 42 ] [ 44 ] [ 45 ]  The effects of modafinil on other aspects of MS-related fatigue, such as severity and cognitive function, are less clear. [ 45 ] [ 43 ]


While modafinil has been shown to be effective in managing fatigue in people with MS, [ 43 ] [ 41 ]  optimal dosing and treatment schedules are not well established. [ 41 ] [ 42 ] [ 44 ] [ 45 ]


Modafinil is occasionally prescribed  off-label  for individuals with attention deficit hyperactivity disorder (ADHD). [ 46 ] [ 47 ] [ 48 ]  It has not consistently shown efficacy in treating adult ADHD, [ 49 ]  especially when compared to other treatments such as  lisdexamfetamine . [ 50 ] [ 51 ]  In children, modafinil is efficient in treating ADHD symptoms. [ 52 ] [ 53 ]


Given its approved status in the US to treat narcolepsy, physicians can also prescribe modafinil for off-label uses, such as treating ADHD in both children and adults. [ 54 ] [ 55 ] [ 56 ]


The Canadian Network for Mood and Anxiety Treatments (CANMAT) suggests modafinil as a second-line choice for ADHD, after the first-line choices such as  bupropion  are exhausted. [ 57 ]


Modafinil is used off-label as an  adjunctive treatment  (i.e., in combination therapy) for the acute depressive phase in bipolar disorder. [ 58 ] [ 59 ] [ 60 ] [ 61 ]  The depressive phase of  bipolar disorder  may feature excessive sleepiness and fatigue. Adjunctive treatment with modafinil can be used as an augmentation for the main treatment to increase its effect and is safe and effective, especially for people who do not respond well to standard antidepressants. [ 62 ] [ 63 ] [ 49 ]  Modafinil does not significantly increase the risk of mood switch to mania or suicide attempts in people with bipolar disorder. [ 64 ] [ 62 ]  Modafinil may also have cognitive benefits in people with bipolar disorder who are in a remission state. [ 65 ] [ 66 ] [ 49 ]


Whereas modafinil and armodafinil are approved for narcolepsy, they have been repurposed as  adjunctive treatments  to alleviate symptoms of acute depressive phase in people with bipolar disorder. [ 67 ]  Drug repurposing in psychiatry is a strategy for discovering new uses for drugs that have already been approved or tested in clinical trials for other illnesses. As such, drug repurposing is a rapid, cost-effective, and reduced-risk strategy for the development of new treatment options for psychiatric disorders. [ 67 ]  2021  meta-analysis  concluded that add-on modafinil and armodafinil were more effective than placebo on response to treatment, clinical remission, and reduction in depressive symptoms, with only minor side effects, but the effect sizes are small and the quality of evidence is therefore low, limiting the clinical relevance of the evidence. [ 67 ] [ 68 ]  Very low rates of mood swing (a change in mood from one extreme to another) [ 64 ] [ 69 ]  have been observed with modafinil and armodafinil in depressive phase of bipolar disorder. [ 60 ] [ 70 ]


Modafinil was used during the  Gulf War  by the  French Foreign Legion , [ citation needed ]  the  US Air Force , [ 71 ] [ 72 ]  and  US Marine [ 73 ]  infantry to enhance "operational tempo" (a term that denotes the speed and intensity at which military operations or activities are executed), aiming to optimize the overall performance and efficiency of the units. [ 72 ] [ 74 ] [ 75 ]


Armed forces in various countries, including the United States, the United Kingdom, India, and France, have considered modafinil as an alternative to traditional  amphetamines  for managing sleep deprivation in combat or extended missions. [ 76 ]  The US military approved modafinil for specific Air Force missions, replacing amphetamines for fatigue management. [ 77 ]  The use of modafinil in military contexts without sleep deprivation is not recommended due to inconclusive evidence on its cognitive enhancement benefits and potential risks of adverse effects. [ 71 ]


Modafinil is also available to astronauts aboard the International Space Station for the management of fatigue caused by circadian dyssynchrony in orbit. [ 78 ]


Modafinil has been used non-medically as a "smart drug" [ 18 ] [ 19 ]  by various groups, including students, [ 79 ] [ 80 ] [ 81 ]  office workers,  transhumanists , [ 82 ] [ 83 ]  and professionals in various sectors. Its use is attributed by these individuals to its potential for enhancing attention, cognitive capabilities, and  alertness . [ 84 ] [ 85 ]


The effectiveness of modafinil as a cognitive enhancer is still debated. Some studies suggest significant increases in cognitive abilities, while others indicate mild to nonexistent cognitive improvements. [ 86 ] [ 87 ] [ 58 ] [ 88 ]  In some cases, it has even been associated with impairments in certain cognitive functions. [ 21 ] [ 22 ] [ 89 ]  It has been shown that modafinil's positive impact on cognitive abilities is more noticeable on sleep-deprived individuals. [ 90 ]  Therefore, in people who are not sleep-deprived, the potential of modafinil as a cognitive enhancer may be limited. [ 91 ]


Modafinil is generally well-tolerated but can have potential risks and side effects. Common adverse effects of modafinil, experienced by less than 10% of users, include  headaches ,  nausea , and  reduced appetite . [ 92 ] [ 93 ] [ 20 ]   Anxiety ,  insomnia ,  dizziness ,  diarrhea , and  rhinitis  are also reported in 5% to 10% of users. [ 20 ]  Psychiatric reactions have occurred in individuals with and without a preexisting psychiatric history. [ 94 ]


No significant changes in body weight have been observed in clinical trials, although decreased appetite and weight loss have been noted in children and adolescents. [ 95 ]  Modafinil can cause a slight increase in  aminotransferase enzymes , indicative of liver function, but there is no evidence of serious liver damage when levels are within reference ranges. [ 96 ]


Rare but serious adverse effects include severe skin rashes and allergy-related symptoms. Between December 1998 and January 2007, the FDA received reports of six cases of severe cutaneous adverse reactions, including  erythema multiforme ,  Stevens–Johnson syndrome ,  toxic epidermal necrolysis , and  DRESS syndrome . The FDA has issued alerts regarding these risks and also noted reports of angioedema and multi-organ hypersensitivity reactions in  postmarketing surveillance . [ 97 ] [ 98 ]  In 2007, the FDA required Cephalon to modify the Provigil leaflet to include warnings about these serious conditions. The long-term safety and effectiveness of modafinil have not been conclusively established. [ 99 ]


The FDA does not endorse modafinil for children's medical conditions due to an increased risk of rare but serious dermatological toxicity, manifested as  Stevens–Johnson syndrome  which is a type of severe skin reaction. [ 100 ] [ 65 ] [ 101 ]  However, in Europe, modafinil may be prescribed for treating narcolepsy in children. [ 102 ]


Modafinil is commercially available in  100 mg  and  200 mg  oral tablet forms. [ 8 ]  Additionally, it is offered as the ( R )- enantiomer , known as  armodafinil , and as a  prodrug  named  adrafinil . [ 103 ]


Modafinil is contraindicated during pregnancy and 2 months before getting pregnant. [ 104 ]  Women who take modafinil should not become pregnant, and, additionally, should be aware that modafinil reduces effectiveness of hormonal contraceptives, increasing chances of getting pregnant. [ 8 ] [ 15 ] [ 105 ]  Modafinil therapy during pregnancy increases the risk of birth defects, [ 17 ] [ 106 ] [ 107 ] [ 104 ]  such as with  congenital torticollis ,  hypospadias , and  congenital heart defects . [ 106 ]


Modafinil is contraindicated for individuals with known  hypersensitivity  to either modafinil or armodafinil. [ 8 ] [ 13 ]


Modafinil is also contraindicated in certain cardiac conditions, including uncontrolled moderate to severe  hypertension ,  arrhythmia ,  cor pulmonale , [ 108 ] [ 109 ]  and in cases with signs of CNS stimulant-induced  mitral valve prolapse  or  left ventricular hypertrophy . [ 110 ] [ 111 ]  The package insert in the United States cautions about using modafinil in people with a documented medical history of left ventricular hypertrophy or those diagnosed with mitral valve prolapse who have previously exhibited symptoms associated with the mitral valve prolapse syndrome while undergoing treatment involving central nervous system stimulants. [ 112 ]  The reasons why modafinil is contraindicated in certain cardiac conditions are because modafinil affects the autonomic nervous system and, in particular, exerts significant effects on autonomic cardiovascular regulation, leading in some people to notable increases in heart rate and blood pressure. These substantial changes in the autonomic system warrant careful consideration when prescribing modafinil to people with pre-existing cardiovascular conditions. [ 113 ]  The increase in heart rate and blood pressure can worsen the symptoms of such pre-existing conditions as hypertension, arrhythmia, and cor pulmonale. These changes in the autonomic system induced by modafinil can increase the risk of heart attack, stroke, and heart failure. Modafinil can stimulate the release of norepinephrine and epinephrine, hormones that activate the sympathetic nervous system. This can cause  vasoconstriction , which is the narrowing of blood vessels, and increase the heart's workload, which is not desired in people with pre-existing heart conditions. In particular, modafinil can worsen the consequences of mitral valve prolapse or left ventricular hypertrophy, which are structural abnormalities of the heart. These can affect the blood flow and oxygen delivery to the heart and other organs. [ 114 ]


Modafinil is also contraindicated in people with congenital problems like  galactose  intolerance,  lactase deficiency , or  glucose-galactose malabsorption . [ 115 ] [ 108 ] [ 109 ]


Extensive clinical research has not demonstrated  drug tolerance  as a common adverse effect, even with therapeutic use extending up to 40 weeks. [ 116 ] [ 117 ] [ 99 ]  Drug tolerance in this context is defined as a reduction in response, to wakefulness-promoting and  anti-fatigue  properties of modafinil. [ 116 ]


While modafinil is generally found to be safe and significant adverse effects are rare, including in pediatric narcolepsy cases (sleep disorders in children), there is evidence that long-term usage can lead to tolerance in some individuals. [ 22 ]  This necessitates higher doses to maintain the same level of cognitive enhancement or relief from sleepiness. [ 22 ]


People with current or past substance addictions and those with a family history of addiction are particularly at risk for developing tolerance. [ 22 ] [ 102 ] [ 118 ]


The mechanisms driving tolerance to modafinil, which may involve its impact on  dopamine  and  norepinephrine  levels in the brain, are not fully understood. [ 22 ] [ 102 ] [ 118 ]


Repeated administration of modafinil for off-label use, such as increased  alertness  and cognitive-enhancing effects in sleep deprivation, can lead to drug tolerance, which means that the effectiveness of the drug may decrease over time. Still, modafinil therapy as a  eugeroic  agent to treat narcolepsy does not typically lead to drug tolerance, i.e., the effectiveness does not usually decrease on prolonged use, although individual responses may vary. [ 22 ] [ 102 ] [ 118 ]


Despite being a  CNS stimulant , the addiction and  dependence  liabilities of modafinil are considered low. [ 8 ] [ 2 ] [ 25 ] [ 119 ]  The exact mechanisms of action of modafinil are not known, [ 120 ]  and it is believed that pharmacological profile of modafinil is different from that of the classical stimulants such as  cocaine  or  amphetamine . [ 13 ]  Although modafinil shares biochemical mechanisms with stimulant drugs, it is less likely to have  mood-elevating properties . [ 8 ]  The similarities in effects with  caffeine  are not clearly established. [ 13 ] [ 121 ]  Unlike other stimulants, modafinil does not induce a strong subjective  feeling of pleasure or reward , which is commonly associated with  euphoria , an intense feeling of well-being. [ 22 ]  Euphoria may be an indicator of a drug's potential to be abused. Substance abuse is a compulsive and excessive use of the substance despite adverse consequences. [ 122 ]  In comparison to classical stimulants, modafinil exhibits a low propensity for abuse, as it lacks significantly expressed pleasurable or euphoric effects. [ 22 ]  Albeit to a lower degree than classical stimulants, modafinil still can produce psychoactive, euphoric, and subjective effects typical for abused stimulants. [ 8 ] [ 3 ]


Modafinil was not observed to promote overuse or misuse, even in people who have a history of cocaine addiction. [ 123 ]  Despite the initial belief that modafinil carried no abuse potential, emerging evidence suggests that it works at the same neurobiological mechanisms as other addictive stimulants. Consequently, there exists a potential risk of modafinil abuse, necessitating prudent consideration and caution when prescribing or using this medication. [ 91 ]  Modafinil exhibits a lower response on the amphetamine scale of the addiction research center inventory, suggesting reduced propensity for abuse compared to amphetamine. [ 124 ]


The US  Drug Enforcement Administration  has classified modafinil as a  Schedule IV controlled substance ; [ 2 ] [ 8 ]  the medicine is recognized for having valid medical uses with low addiction potential. [ 119 ] [ 54 ]  The  International Narcotics Control Board  does not classify it as a narcotic or a psychotropic substance. [ 125 ] [ 126 ]


An  overdose  of modafinil can lead to a range of symptoms and complications. Psychiatric symptoms may include  psychosis ,  mania ,  hallucinations , and suicidal ideation, which can occur even in individuals without a history of mental illness and may persist after discontinuation of the drug. [ 127 ]  Neurological complications, such as seizures, tremors,  dystonia , and  dyskinesia , may arise from modafinil's interaction with various neurotransmitter systems. [ 127 ]


Allergic reactions such as rash,  angioedema ,  anaphylaxis , and  Stevens–Johnson syndrome  may rarely be triggered by an immunological response to modafinil or its metabolites. [ 128 ] [ 129 ]  Cardiovascular complications like hypertension,  tachycardia , chest pain, and  arrhythmias  may also be observed due to modafinil's sympathomimetic action. [ 127 ]


In animal studies, the median lethal dose (LD 50 ) of modafinil varies among species and depends on the route of administration. In mice and rats, the LD 50  is approximately  1250 mg/kg  if administered via an injection, but the oral LD 50  for rats is  3400 mg/kg . [ 130 ] [ 131 ]  The LD 50  value for humans have not been established. Human clinical trials have involved total daily doses up to  1200 mg/d  for 7–21 days. Acute one-time total overdoses up to  4500 mg  have not been life-threatening but resulted in symptoms like  agitation ,  insomnia ,  tremor ,  palpitations , and  gastrointestinal disturbances . [ 8 ] [ 132 ]


The management of modafinil overdose involves supportive care, monitoring of vital signs, and treatment of specific complications. In cases of recent consumption,  activated charcoal ,  gastric lavage , or  hemodialysis  may be used. [ 127 ]  There is no specific antidote for modafinil overdose. [ 132 ] [ 133 ] [ 134 ]  The main way to deal with modafinil overdose is supportive care, which includes sedating the patient and stabilizing their blood pressure, and muscle activity in case of manifestations such as agitation or tremor. [ 132 ]


Some of the drugs that frequently interact with modafinil include  aripiprazole  (an antipsychotic),  amphetamine  (including its enantiomers and salts; stimulants),  aspirin ,  diphenhydramine  (an  antihistamine ), and others. [ 135 ]


Modafinil is a weak to moderate  inducer  of  CYP3A4 [ 105 ] [ 136 ] [ 137 ]  and a weak inhibitor of  CYP2C19 , [ 11 ]  enzymes of the  cytochrome P450  group of enzymes. [ 20 ]  Modafinil also induces or inhibits other cytochrome P450 enzymes. [ 105 ]  One  in vitro  study predicts that modafinil may  induce  the cytochrome P450 enzymes  CYP1A2 , CYP3A4, and  CYP2B6 , as well as may inhibit  CYP2C9  and  CYP2C19 . [ 14 ]  However, other in-vitro studies find no significant inhibition of  CYP2C9 . [ 11 ] [ 138 ]  Modafinil may induce  P-glycoprotein , which may affect drugs transported by P-glycoprotein, such as  digoxin . [ 139 ]
It was clinically found that modafinil affects  pharmacodynamics  of drugs which are metabolized by CYP3A4 and other enzymes of the cytochrome P450 family so that interactions of modafinil with these drugs were observed in real people, rather than being predicted in a lab setting. [ 105 ] [ 136 ]  For instance, it was observed that induction of CYP3A4 by modafinil affects metabolism of the following  medications  and  endogenous  substances: [ 140 ]


Hypertensive crises  have been reported when  armodafinil  (one of modafinil's  enantiomers ) has been taken with  monoamine oxidase inhibitors  (MAOIs) like  tranylcypromine . [ 145 ]


The precise  mechanism of action  of modafinil for narcolepsy and other sleep disorders remains unclear. [ 3 ] [ 120 ] [ 151 ] [ 152 ]  Although modafinil may have interactions with neurotransmitter systems, its exact mode of action is not fully understood. [ 120 ] [ 153 ]


From laboratory research, modafinil has little to no affinity for  serotonin  or  norepinephrine transporters  and does not directly interact with these systems. [ 20 ] [ 152 ]  However, studies have shown that elevated concentrations of norepinephrine and serotonin can occur as an indirect effect following modafinil administration due to increased extracellular dopamine activity. [ 152 ] [ 20 ]  Unlike traditional psychostimulant drugs, [ 23 ]  such as  cocaine  or  amphetamine , modafinil shows low potential for causing euphoria due to differences in how it interacts with dopamine transporters at a cellular level. [ 120 ] [ 152 ] [ 153 ]


In addition to its influence on  dopaminergic pathways , modafinil may impact other neurotransmitter systems, such as  orexin  ( hypocretin ). [ 152 ]  Orexin neurons are involved in promoting wakefulness and regulating arousal states. Modafinil may increase signaling within hypothalamic orexin pathways, potentially contributing to its wake-promoting effects. [ 20 ] [ 152 ]


C max  (peak levels) occurs approximately 2 to 3 hours after modafinil administration. [ 11 ]  Food slows the absorption of modafinil but does not affect the total  area under the curve  (AUC).  In vitro  measurements indicate that 60% of modafinil is bound to  plasma proteins  at clinical concentrations of the drug. This percentage changes very little when the concentration of modafinil is varied. [ 154 ]


Renal excretion of unchanged modafinil usually accounts for less than 10% of an oral dose. This means that when modafinil is taken by mouth, that is the only approved route of administration, less than 10% of the drug is eliminated from the body through the urine without being metabolized by the liver or other organs. The rest of the drug is either metabolized or excreted through other routes, such as feces or bile. [ 11 ]


The two major circulating  metabolites  of modafinil are  modafinil acid  (CRL-40467) and  modafinil sulfone  (CRL-41056). Both of these metabolites have been described as inactive, and neither appears to contribute to the wakefulness-promoting effects of modafinil. [ 65 ] [ 155 ]  However, modafinil sulfone does appear to possess  anticonvulsant  effects, a property that it shares with modafinil. [ 65 ] [ 156 ]


Elimination half-life  is in the range of 10 to 12 hours, [ 11 ] [ 154 ]  subject to differences in sex, [ 105 ]  in cytochrome P450  genotypes , liver function and renal function. Modafinil is metabolized mainly in the liver, [ 11 ]  and its inactive metabolites are excreted in the urine. Urinary excretion of the unchanged drug is usually less than 10% but can range from 0% to as high as 18.7%, depending on the factors mentioned. [ 154 ]


Modafinil exhibits sex-specific pharmacokinetic differences. [ 105 ]  It demonstrates higher  bioavailability  in women compared to men. The mean C max  is higher in women than in men,  5.2  mg/L  vs.  4.2  mg/L  (p < 0.05), following a single  200 mg  oral dose of modafinil. [ 105 ]  This difference persists even after adjusting for body weight ( 0.88 ml/min/kg  vs.  0.72 ml/min/kg ). [ 105 ]  The clearance of modafinil is 30% higher in men than in women, and plasma concentrations after a single dose are significantly higher in women than in men. These sex-specific pharmacokinetic differences may have implications for the efficacy and safety of modafinil. [ 105 ]


Modafinil is a  racemic mixture  of two  enantiomers ,  armodafinil  (( R )-modafinil) and  esmodafinil  (( S )-modafinil). [ 157 ]


Modafinil and/or its major metabolite, modafinil acid, may be quantified in plasma, serum, or urine to monitor dosage in those receiving the drug therapeutically, to confirm a diagnosis of poisoning in hospitalized patients, or to assist in the forensic investigation of a vehicular traffic violation. [ 158 ]  Instrumental techniques involving gas or liquid chromatography are usually employed for these purposes. [ 88 ] [ 159 ] [ 160 ]  In 2011, modafinil was not tested for by common  drug screens  (except for anti-doping screens) and is unlikely to cause false positives for other chemically unrelated drugs such as  substituted amphetamines . [ 149 ] [ 157 ] [ 161 ]


Reagent testing  can screen for the presence of modafinil in samples. [ 162 ] [ 163 ]


Many  derivatives  and  structural analogs  of modafinil have been synthesized. [ 24 ] [ 164 ] [ 165 ]  Examples include  adrafinil ,  CE-123 ,  fladrafinil  (CRL-40941; fluorafinil),  flmodafinil  (CRL-40940; bisfluoromodafinil, lauflumide),  RDS03-94 ,  JJC8-088 ,  modafiendz  and  modafinil sulfone  (CRL-41056). [ 166 ] [ 24 ]


Modafinil was developed in France by  neurophysiology  professor  Michel Jouvet  and Lafon Laboratories. It is part of a series of benzhydryl sulfinyl compounds, including  adrafinil , initially used as a treatment for narcolepsy in France in 1986. [ 167 ]  Modafinil, the primary metabolite of  adrafinil , [ 168 ]  has been prescribed in France since 1994 under the name Modiodal, [ 167 ]  and in the United States since 1998 as Provigil. [ 8 ]  Unlike modafinil, adrafinil does not have FDA approval and was withdrawn from the French market in 2011. [ 169 ]


The FDA approved modafinil in 1998 for  narcolepsy  treatment, and later for  shift work sleep disorder  and  obstructive sleep apnea  in 2003. [ 8 ] [ 170 ] [ 171 ]  It was approved in the UK in December 2002. In the United States, modafinil is marketed by  Cephalon , [ 172 ]  who acquired the rights from Lafon and purchased the company in 2001. [ 172 ]


Cephalon introduced armodafinil, the ( R )-enantiomer of modafinil, in the United States in 2007. Generic versions of modafinil became available in the US in 2012 after extensive patent litigation. [ 173 ] [ 174 ]


Modafinil is not approved for use by children in multiple jurisdictions. [ 1 ] [ 175 ] [ 7 ] [ 8 ] [ 176 ]


In Australia, modafinil is considered to be a  Schedule 4   prescription-only medicine . This means that it is a drug with a perceived low potential for abuse and low risk of dependence; still, the use of Schedule 4 drugs in Australia is restricted to those who have a valid prescription from a medical practitioner; import from abroad is illegal. [ 177 ]


In Canada, modafinil is not specifically included in the lists of controlled drugs and substances specified within the  Controlled Drugs and Substances Act . [ 178 ]  However, it is classified as a Schedule F prescription drug. [ 179 ] [ 180 ] [ 181 ]  This means that modafinil can only be obtained legally with a valid prescription from a licensed health care practitioner in Canada, and the import of modafinil to Canada from other countries is subject to restrictions: importing prescription drugs without an import permit may result in the seizure of the drugs at the border, the refusal of entry of the drugs into Canada, or prosecution. [ 182 ]


In mainland China, modafinil is strictly controlled like other stimulants such as amphetamines and  methylphenidate . It is classified as Class I psychotropic drug. This classification means that modafinil is considered to have a high potential for abuse and dependence, and is therefore subject to strict regulation and control. As a result, modafinil is only available by prescription and cannot be purchased over the counter. In order to obtain a prescription for modafinil, a patient must have a valid medical reason for using the drug, such as  narcolepsy  or  obstructive sleep apnea . Additionally, the prescription must be written by a licensed physician and filled at a  licensed pharmacy . The use of modafinil for non-medical purposes, such as with the aim to improve cognitive performance or to stay awake for long periods of time, is strictly prohibited and can result in legal consequences. [ 183 ] [ 184 ]


In Denmark, modafinil is a prescription drug but not listed as a controlled substance. According to the  Danish Medicines Agency , modafinil is approved for use in the treatment of narcolepsy, still, importing modafinil to Denmark is considered illegal without a valid prescription. [ 185 ] [ 186 ] [ 187 ] [ 188 ]


In Finland, modafinil is a prescription drug but not listed as a  controlled substance . Finland is a member of the European Union, and it is illegal to import prescription medicine from outside the European Union unless the person has a valid prescription. [ 189 ] [ 190 ] [ 191 ]


In the Republic of Moldova, modafinil is classified as a psychotropic drug (included in table III list 3 which is the list of psychotropic substances as defined by the  Government of Moldova ) [ 192 ]  and is available by prescription. [ 192 ]  Importation of modafinil may be considered illegal and subject to severe penalties, even if you have a prescription. [ 193 ]  For example, on June 29, 2017,  Moldovan postal officers  discovered 60 tablets of Modalert (200 mg modafinil tablets) in a parcel sent from India to a resident in  Chișinău , Moldova. The prohibited substance was detected during a routine scan and was seized as illegal. The authorities were notified of the incident and the recipient was charged with criminal penalties. [ 194 ] [ 195 ]  In the  Transnistria  region of Moldova, modafinil is completely prohibited, due to application of the legislation similar to that of Russia where modafinil is completely prohibited and is in the same list as narcotics. Possession or an attempt to bring modafinil to Transnistria potentially leads to imprisonment. [ 196 ]


In Romania, modafinil is classified as a stimulant doping agent and is prohibited in sports competitions. [ 197 ]  In 2022, laws were passed making its importation or sale a felony, punishable by three to seven years in jail. [ 198 ]  Simple possession for personal use may result in a fine and confiscation. [ 198 ]


In Sweden, modafinil is classified as a schedule IV substance, which means that it is considered to have a low potential for abuse and a low risk of dependence. Still, possession is illegal without a prescription. [ 199 ]


In the United Kingdom, it is not listed in  Misuse of Drugs Act , so possession is not illegal, but a prescription is required. [ 200 ]


In Mexico, modafinil is not listed as a controlled substance, in the National Health Law, and can be purchased in pharmacies without prescription. [ 201 ]


In Japan, modafinil is Schedule I psychotropic drug. This means that it is considered to have a high potential for abuse and dependence, and is therefore subject to strict regulations. The use of Schedule I drugs in Japan is generally prohibited, except under certain circumstances, such as for medical purposes. It can only be prescribed by a doctor. It cannot be imported or exported without a permit. It cannot be used while driving or operating machinery. [ 202 ] [ 203 ]   Cephalon  licensed Alfresa Corporation to produce, and  Mitsubishi Tanabe Pharma  to sell modafinil products under the trade name Modiodal in Japan. [ 204 ]  There have been arrests of people who imported modafinil for personal use. [ 205 ] [ 206 ]


In Russia, starting from May 18, 2012, modafinil is Schedule II controlled substance. Being classified as a Schedule II controlled substance in Russia means that it is seen as a drug with a high potential for abuse and dependence. This classification imposes strict regulations on the production, distribution, and use of modafinil. Possession of a few modafinil pills can lead to three to ten years imprisonment. Modafinil is not approved for medical use in Russia and cannot be bought even in pharmacies. It also cannot be imported from abroad, even if you have a prescription issued outside Russia. [ 196 ] [ 207 ]  There are multiple cases of criminal proceedings initiated against Russian residents who tried to import modafinil by mail from abroad. [ 208 ] [ 209 ]


In South Africa, modafinil is Schedule V substance, which means that it is legal to use modafinil in South Africa, but only with a valid prescription from a licensed medical practitioner. [ 210 ]


In the United States, modafinil is classified as a  schedule IV controlled substance [ 2 ]  under US federal law. [ 8 ] [ 211 ]  This means that the drug has a low potential for abuse and dependence compared to other controlled substances. However, it still requires a prescription from a  licensed healthcare provider  to obtain. [ 211 ]


It is illegal to import modafinil to the United States without a  Drug Enforcement Administration  ( DEA )–registered importer and a prescription. [ 212 ]  Individuals may legally bring modafinil into the US from a foreign country for personal use, limited to 50 dosage units, with a prescription and proper declaration at the border. [ 213 ]  Under the  Pure Food and Drug Act , marketing drugs for off-label uses is prohibited. [ 214 ]  Cephalon, the manufacturer of Provigil, faced legal issues for promoting off-label uses and paid significant fines in 2008. [ 215 ]


Modafinil is sold under a variety of brand names worldwide, including Alertec, Alertex, Altasomil, Aspendos, Bravamax, Forcilin, Intensit, Karim, Mentix, Modafinilo, Modalert, Modanil, Modasomil, Modvigil, Modiodal, Modiwake, Movigil, Provigil, Resotyl, Stavigile, Vigia, Vigicer, Vigil, Vigimax, Waklert, and Zalux. [ 216 ]


Originally developed in the 1970s by French neuroscientist Michel Jouvet and Lafon Laboratories, modafinil has been prescribed in France since 1994, [ 167 ] [ 36 ]  and was approved for medical use in the United States in 1998. [ 8 ] [ 36 ]


Concerns have been raised about the growing use of modafinil as a "smart drug" or cognitive enhancer among healthy individuals who use it with the aim to improve concentration and memory. [ 217 ] [ 218 ]  In 2003, modafinil sales were skyrocketing, with some experts concerned that it had become a tempting pick-me-up for people looking for an extra edge in a productivity-obsessed society. [ 217 ]  The cost of modafinil varied depending on factors such as location and insurance coverage; [ 217 ] [ 218 ] [ 219 ]  still, in 2004, the price of modafinil in the US was around $120 or more per monthly supply. [ 217 ]  However, the availability of generic versions has increased since then and may have driven down prices. [ 217 ] [ 218 ] [ 219 ]


In 2020, modafinil was the 302nd most commonly prescribed medication in the United States, with just over 1,000,000 prescriptions. [ 220 ]


As of 2024, [update]  the global sales figures for modafinil are not known. Still, modafinil sold under the brand name Provigil accounted for over 40% of  Cephalon 's global turnover for several years, according to the information published in 2020. [ 221 ]


Modafinil's patent history involves several key developments. The original patent,  U.S. patent 4,927,855 , was granted to Laboratoire L. Lafon in 1990, covering the chemical compound of modafinil. This patent expired in 2010. [ 222 ]  In 1994, Cephalon filed a patent for modafinil in the form of particles of a defined size, represented by  U.S. patent 5,618,845 , which expired in 2015. [ 223 ]


Following the nearing expiration of marketing rights in 2002, generic manufacturers, including Mylan and Teva, applied for FDA approval to market a generic form of modafinil, leading to legal challenges by Cephalon regarding the particle size patent. [ 224 ]  The patent RE 37,516 was declared invalid and unenforceable in 2011. [ 225 ]


In addition, Cephalon entered agreements with several generic drug manufacturers to delay the sale of generic modafinil in the US. These agreements were subject to legal scrutiny and antitrust investigations, culminating in a ruling by the Court of Appeals in 2016, which found that the settlements did not violate antitrust laws. [ 226 ]


The regulation of modafinil as a  doping agent  has been controversial in the sporting world, with high-profile cases attracting press coverage since several prominent American athletes tested positive for the substance. Some athletes who used modafinil protested that the drug was not on the prohibited list at the time of their offenses. [ 227 ]  However, the  World Anti-Doping Agency  (WADA) maintains that modafinil was related to already-banned substances. The Agency added modafinil to its list of prohibited substances on August 3, 2004, ten days before the start of the  2004 Summer Olympics . [ 161 ]


Several athletes, such as sprinter  Kelli White  in 2003, [ 228 ]  cyclist  David Clinger [ 229 ]  and basketball player  Diana Taurasi [ 230 ]  in 2010, and rower Timothy Grant in 2015, [ 231 ]  were accused of using modafinil as a performance-enhancing  doping  agent. Taurasi and another player—Monique Coker, tested at the same lab—were later cleared. [ 232 ]  Kelli White, who tested positive after her 100m victory at the 2003 World Championships in Paris, was stripped of her gold medals. [ 233 ]  She claimed that she used modafinil to treat narcolepsy, but the  International Association of Athletics Federations  (IAAF) ruled that modafinil was a performance-enhancing drug. [ 233 ]


The  BALCO  scandal brought to light an unsubstantiated (but widely published) account of Major League Baseball's all-time leading home-run hitter  Barry Bonds ' supplemental chemical regimen that included modafinil in addition to  anabolic steroids  and  human growth hormone . [ 234 ]


The use of modafinil as a supposed cognitive enhancer may be considered as cheating, unnatural, or risky. [ 235 ]  The  University of Sussex  explained that it is a prescription drug and the decision should be made by the  doctor  on whether to prescribe modafinil to a student. [ 236 ]  As a matter of  bioethics , the US  President's Council on Bioethics  argued that excellence achieved through the use of drugs like modafinil is "cheap" as it obviates the need for hard work and study, and is not fully authentic because the excellence is partly attributable to the drug, not the individual. [ 237 ]  Alternately, people in environments like  Wall Street trading  may not view the use of modafinil as cheating, believing that if modafinil can give them an edge and they are aware of the risks involved, it should not be considered as cheating. [ 238 ]  Due to such varying views, modafinil users for narcolepsy may cope with stigma by hiding, denying, or justifying their use, or by seeking support from others who share their views or experiences. [ 239 ] [ 240 ]


Modafinil has been studied in the treatment of  major depressive disorder . [ 241 ] [ 242 ] [ 243 ]  In a 2021  systematic review  and meta-analysis of  randomized controlled trials  of  psychostimulants  for depression, modafinil and other stimulants such as  methylphenidate  and amphetamines improved depression in traditional meta-analysis. [ 243 ]  However, when subjected to  network meta-analysis , modafinil and most other stimulants did not significantly improve depression, with only methylphenidate remaining effective. [ 243 ]  Modafinil and other stimulants likewise did not improve  quality of life  in the meta-analysis, although there was evidence for reduced fatigue and sleepiness with modafinil and other stimulants. [ 243 ]  While significant effectiveness of modafinil for depression has been reported by particular trials, [ 70 ] [ 242 ] [ 244 ]  reviews and meta-analyses note that the effectiveness of modafinil for depression is limited, the quality of available evidence is low, and the results are inconclusive. [ 243 ] [ 245 ] [ 246 ]


Modafinil was considered for the treatment of ADHD because of its lower  abuse potential  than conventional psychostimulants [ 23 ]  like methylphenidate and amphetamines. [ 55 ] [ 247 ]  In 2008, an application to market modafinil for pediatric ADHD was submitted to the  Food and Drug Administration  in the US. [ 92 ] [ 49 ]


However, evidence of modafinil for treatment of adult ADHD is mixed, and a 2016 systematic review of alternative drug therapies for adult ADHD did not recommend its use in this context. [ 51 ]  In a later large  phase 3  clinical trial of modafinil for adult ADHD, modafinil was not effective in improving symptoms, there was also a high rate of side effects (86%) and discontinuation (47%). [ 248 ]  The poor  tolerability  of modafinil in this study was possibly due to the use of high doses ( 210–510 mg/d ). [ 248 ]  Another reason for the denial of the approval was due to concerns about rare but serious dermatological toxicity in  Stevens–Johnson syndrome . [ 92 ]


The research on the use of modafinil for treating individuals with Autism Spectrum Disorder (ASD) who also exhibit ADHD symptoms is currently in its early stages with no results delivered. [ 249 ]


Modafinil was studied for the treatment of  stimulant dependence , but the results are mixed and inconclusive. [ 24 ] [ 250 ]  Modafinil is not a  controlled substance  in some countries, unlike other medications, such as  bupropion , which is also used to treat  depression  and  nicotine dependence . [ 251 ]  The clinical trials that have tested modafinil as a treatment for stimulant abuse have failed to demonstrate its efficacy and the optimal dose and duration of modafinil treatment remain unclear, and modafinil is not a recommended treatment for stimulant abuse. [ 251 ]  2024 reviews found that modafinil was ineffective for treating individuals with  amphetamine-type stimulant use disorder [ 252 ]  or  methamphetamine use disorder [ 253 ]  from these dependencies. [ 253 ] [ 252 ]


Modafinil and armodafinil were studied as a complement to  antipsychotic  medications in the treatment of  schizophrenia . They showed no effect on positive symptoms or cognitive performance. [ 254 ] [ 255 ]  A 2015  meta-analysis  found that modafinil and armodafinil may slightly reduce negative symptoms in people with acute schizophrenia, though they do not appear useful for people with the condition who are stable, with high negative symptom scores. [ 255 ]  Among medications demonstrated to be effective for reducing negative symptoms in combination with antipsychotics, modafinil, and armodafinil are among the smallest  effect sizes . [ 256 ]


Modafinil is researched to determine whether it might improve abstinence in people with  cocaine addiction . [ 257 ]


Modafinil has been found to reverse  tetrabenazine -induced  motivational deficits  in animals and hence can produce  pro-motivational  effects. [ 258 ] [ 259 ] [ 260 ]  Novel modafinil  analogs  with greater  potency , including  CE-123 ,  CE-158 ,  JJC8-088 ,  MK-26 , and  RDS03-94 , have also been developed and have shown pro-motivational effects in animals. [ 258 ] [ 261 ]  These agents are of potential interest in the treatment of  motivational disorders  in humans. [ 258 ] [ 261 ]


A 2019 review conducted on the potential nootropic effects of modafinil in healthy, non-sleep-deprived individuals revealed the following: [ 262 ]  a) while studies using basic testing paradigms demonstrated that modafinil enhances  executive function , only half of these studies showed improvements in attention, learning, and memory, with a few studies even reporting impairments in divergent creative thinking; b) modafinil displayed small levels of enhancement in attention, executive functions, and learning abilities; c) no substantial side effects or mood changes were observed; d) the available evidence showed limited evidence for modafinil as a cognitive enhancer outside of its use for sleep-deprived populations.


A 2020 review reported that modafinil has a modest effect on memory updating, but the effect is small and may not accurately reflect the perception that it is useful as a cognitive enhancer, as there is insufficient evidence to support such a claim. [ 263 ]


General anesthesia  is required for many  surgeries , but may cause lingering fatigue, sedation, and/or drowsiness after surgery that lasts for hours to days. [ 264 ] [ 265 ]  In  outpatient surgery  the  sedation ,  fatigue , and occasional  dizziness  is problematic. [ 266 ] [ 267 ]  Modafinil was tested as a potential remedy to alleviate these symptoms. [ 54 ]  For example, it was expected that modafinil would help people recover quicker from general anesthesia after a short surgery, [ 92 ]  but the results were uncertain and the inconclusive studies could not reliably verify the expectation. [ 54 ]  The use of modafinil to relieve post-anesthesia sedation is investigational. [ 92 ]


Caution should be exercised in people who have narcolepsy in  comorbidity  with  postural orthostatic tachycardia syndrome  (POTS). [ 268 ]


Modafinil is being researched as a potential remedy for excessive daytime sleepiness in  myotonic dystrophy  (DM), an inherited condition characterized by progressive muscle loss, weakness, and  myotonia.  Myotonia is a condition where muscles cannot relax after they contract. [ 269 ]  Myotonic dystrophy has two main types: DM1 (Steinert disease) and DM2 (proximal myotonic myopathy). Both types can cause excessive daytime sleepiness. Studies suggest that modafinil may be a promising drug that can reduce both daytime sleepiness and myotonia itself, without significant cardiac conduction effects. These presumed property of modafinil is of particular interest for evntual treatment of pepole with myotonic dystrophy who often have underlying cardiac issues. [ 269 ]  Still, modafinil is not approved by the FDA for use in myotonic dystrophy, and the value and role of modafinil in DM remain the subject of debate. [ 269 ]


Modafinil has been studied for its potential therapeutic effects in patients with  disorders of consciousness . [ 270 ]  Researchers are investigating whether modafinil can stimulate  neurotransmitters  such as  histamine ,  norepinephrine ,  serotonin ,  dopamine , and  orexin , and whether modafinil has potential  anti-oxidative effects . [ 270 ]


Disorders of consciousness are states characterized by impaired arousal and awareness. [ 270 ]  These states include  coma ,  vegetative state / unresponsive wakefulness syndrome  (VS/UWS),  minimally conscious state  (MCS),  cognitive motor dissociation , and  covert cortical processing . [ 270 ]  Brain injuries can impair consciousness through  neuroanatomic lesions  involving the  bilateral cerebral hemispheres ,  rostral brainstem ,  diencephalon , or  basal forebrain . [ 270 ]


Neuroimaging  studies have shown that modafinil increases  cerebral blood flow  in several brain regions, such as the  thalamus ,  locus coeruleus ,  limbic system , and  insular cortex ; [ 270 ]  still, observational reports on the use of modafinil in patients with disorders of consciousness have produced mixed results, indicating that its effectiveness may vary among individuals. [ 270 ]


A possible link between  inflammatory processes  and depressive disorders [ 271 ]  has stimulated preliminary research on modafinil for its potential anti-inflammatory effects. [ 272 ]


Mustard gas  or  sulfur mustard  are names commonly used for the  organosulfur   chemical compound   bis(2-chloroethyl) sulfide , which has the chemical structure S(CH 2 CH 2 Cl) 2 , as well as other  species . In the wider sense, compounds with the substituents  −SCH 2 CH 2 X or −N(CH 2 CH 2 X) 2  are known as  sulfur mustards  or  nitrogen mustards , respectively, where X = Cl or Br. Such compounds are potent  alkylating agents , making mustard gas acutely and severely toxic. [ 3 ]  Mustard gas is a  carcinogen . [ 3 ]  There is no preventative agent against mustard gas, with protection depending entirely on skin and airways protection, and no  antidote  exists for mustard poisoning. [ 4 ]


Also known as mustard agents, this family of compounds comprises infamous  cytotoxins  and  blister agents  with a long history of use as  chemical weapons . [ 4 ]  The name  mustard gas  is technically incorrect; the substances, when  dispersed , are often not gases but a fine mist of liquid droplets that can be readily absorbed through the skin and by inhalation. [ 3 ]  The skin can be affected by contact with either the liquid or vapor. The rate of penetration into skin is proportional to dose, temperature and humidity. [ 3 ]


Sulfur mustards are viscous liquids at room temperature and have an odor resembling  mustard plants ,  garlic , or  horseradish , hence the name. [ 3 ] [ 4 ]  When pure, they are colorless, but when used in impure forms, such as in warfare, they are usually  yellow-brown . Mustard gases form  blisters  on exposed skin and in the lungs, often resulting in prolonged illness ending in death. [ 4 ]


Sulfur mustard is a type of chemical warfare agent. [ 5 ]  As a chemical weapon, mustard gas was first used in  World War I , and has been used in several armed conflicts since then, including the  Iran–Iraq War , resulting in more than 100,000 casualties. [ 6 ] [ 7 ]  Sulfur-based and  nitrogen-based  mustard agents are regulated under  Schedule 1  of the 1993  Chemical Weapons Convention , as substances with few uses other than in  chemical warfare . [ 4 ] [ 8 ]  Mustard agents can be deployed by means of  artillery shells ,  aerial bombs ,  rockets , or by spraying from aircraft.


Mustard gases have powerful  blistering  effects on victims. They are also  carcinogenic  and  mutagenic   alkylating agents . [ 3 ]  Their high  lipophilicity  accelerates their absorption into the body. [ 2 ]  Because mustard agents often do not elicit immediate symptoms, contaminated areas may appear normal. [ 4 ]  Within 24 hours of exposure, victims experience intense  itching  and skin irritation. If this irritation goes untreated, blisters filled with  pus  can form wherever the agent contacted the skin. [ 4 ]  As  chemical burns , these are severely debilitating. [ 3 ] [ 4 ]


If the victim's eyes were exposed, then they become sore, starting with  conjunctivitis  (also known as pink eye), after which the eyelids swell, resulting in temporary blindness. Extreme ocular exposure to mustard gas vapors may result in  corneal ulceration , anterior chamber scarring, and  neovascularization . [ 9 ] [ 10 ] [ 11 ] [ 12 ]  In these severe and infrequent cases,  corneal transplantation  has been used as a treatment. [ 13 ]   Miosis , when the pupil constricts more than usual, may also occur, which may be the result of the cholinomimetic activity of mustard. [ 14 ]  If inhaled in high concentrations, mustard agents cause bleeding and blistering within the  respiratory system , damaging  mucous membranes  and causing  pulmonary edema . [ 4 ]  Depending on the level of contamination, mustard agent burns can vary between  first  and  second degree burns . They can also be as severe, disfiguring, and dangerous as  third degree burns . Some 80% of sulfur mustard in contact with the skin evaporates, while 10% stays in the skin and 10% is absorbed and circulated in the blood. [ 3 ]


The carcinogenic and mutagenic effects of exposure to mustard gas increase the risk of developing  cancer  later in life. [ 3 ]  In a study of patients 25 years after wartime exposure to chemical weaponry, c-DNA microarray profiling indicated that 122 genes were significantly mutated in the lungs and airways of mustard gas victims. Those genes all correspond to functions commonly affected by mustard gas exposure, including  apoptosis , inflammation, and stress responses. [ 15 ]  The long-term ocular complications include burning, tearing, itching,  photophobia ,  presbyopia , pain, and foreign-body sensations. [ 4 ] [ 16 ] [ 17 ]


In a rinse-wipe-rinse sequence, skin is decontaminated of mustard gas by washing with liquid soap and water, or an absorbent powder. [ 4 ]  The eyes should be thoroughly rinsed using saline or clean water. A topical analgesic is used to relieve skin pain during decontamination. [ 4 ]


The blistering effects of mustard gas can be neutralized by decontamination solutions such as "DS2" (2%  NaOH , 70%  diethylenetriamine , 28%  2-methoxyethanol ). [ medical citation needed ]  For skin lesions, topical treatments, such as  calamine lotion , steroids, and oral  antihistamines  are used to relieve itching. [ 4 ]  Larger blisters are irrigated repeatedly with saline or soapy water, then treated with an antibiotic and petroleum gauze. [ 4 ]


Mustard agent burns do not heal quickly and (as with other types of burns) present a risk of  sepsis  caused by  pathogens  such as  Staphylococcus aureus  and  Pseudomonas aeruginosa . The mechanisms behind mustard gas's effect on endothelial cells are still being studied, but recent studies have shown that high levels of exposure can induce high rates of both  necrosis  and  apoptosis . In vitro tests have shown that at low concentrations of mustard gas, where apoptosis is the predominant result of exposure, pretreatment with 50 mM  N-acetyl-L-cysteine  (NAC) was able to decrease the rate of apoptosis. NAC protects  actin  filaments from reorganization by mustard gas, demonstrating that actin filaments play a large role in the severe burns observed in victims. [ 18 ]


A British nurse treating soldiers with mustard agent burns during  World War I  commented: [ 19 ]


They cannot be bandaged or touched. We cover them with a tent of propped-up sheets. Gas burns must be agonizing because usually the other cases do not complain, even with the worst wounds, but gas cases are invariably beyond endurance and they cannot help crying out.


Sulfur mustards readily eliminate  chloride  ions by intramolecular  nucleophilic substitution  to form cyclic  sulfonium  ions. These very reactive intermediates tend to permanently  alkylate   nucleotides  in  DNA  strands, which can prevent cellular division, leading to  programmed cell death . [ 2 ]  Alternatively, if cell death is not immediate, the damaged DNA can lead to the development of cancer. [ 2 ]   Oxidative stress  would be another pathology involved in mustard gas toxicity.


In the wider sense, compounds with the structural element BC 2 H 4 X, where X is any  leaving group  and B is a  Lewis base , are known as  mustards . [ citation needed ]  Such compounds can form cyclic  "onium" ions  (sulfonium,  ammonium , etc.) that are good  alkylating agents . Other such compounds are bis(2-haloethyl)ethers ( oxygen mustards ), the (2-haloethyl)amines ( nitrogen mustards ), and  sesquimustard , which has two α-chloroethyl thioether groups (ClC 2 H 4 S−) connected by an ethylene bridge (−C 2 H 4 −). [ citation needed ]  These compounds have a similar ability to alkylate DNA, but their physical properties vary.


In its history, various types and mixtures of mustard gas have been employed. These include:


Mustard gases were possibly developed as early as 1822 by  César-Mansuète Despretz  (1798–1863). [ 23 ]  Despretz described the reaction of  sulfur dichloride  and  ethylene  but never made mention of any irritating properties of the reaction product. In 1854, another French chemist, Alfred Riche (1829–1908), repeated this procedure, also without describing any adverse physiological properties. In 1860, the British scientist  Frederick Guthrie  synthesized and characterized the mustard agent compound and noted its irritating properties, especially in tasting. [ 24 ]  Also in 1860, chemist  Albert Niemann , known as a pioneer in  cocaine  chemistry, repeated the reaction, and recorded blister-forming properties. In 1886,  Viktor Meyer  published a paper describing a synthesis that produced good yields. He combined  2-chloroethanol  with  aqueous   potassium sulfide , and then treated the resulting  thiodiglycol  with  phosphorus trichloride . The purity of this compound was much higher and consequently the adverse health effects upon exposure were much more severe. These symptoms presented themselves in his assistant, and in order to rule out the possibility that his assistant was suffering from a mental illness (psychosomatic symptoms), Meyer had this compound tested on laboratory  rabbits , most of which died. In 1913, the English chemist  Hans Thacher Clarke  (known for the  Eschweiler-Clarke reaction ) replaced the phosphorus trichloride with  hydrochloric acid  in Meyer's formulation while working with  Emil Fischer  in  Berlin . Clarke was hospitalized for two months for burns after one of his flasks broke. According to Meyer, Fischer's report on this accident to the  German Chemical Society  sent the  German Empire  on the road to chemical weapons. [ 25 ]


Mustard gas can have the effect of turning a patient's skin different colors, including shades of red, orange, pink, and in unusual cases, blue. The  German Empire  during  World War I  relied on the Meyer-Clarke method because  2-chloroethanol  was readily available from the German dye industry of that time.


Mustard gas was first  used in World War I  by the German army against British and Canadian soldiers near  Ypres , Belgium, on July 12, 1917, [ 26 ]  and later also against the  French Second Army .  Yperite  is "a name used by the French, because the compound was first used at Ypres." [ 27 ]  The Allies did not use mustard gas until November 1917 at  Cambrai , France, after the armies had captured a stockpile of German mustard shells. It took the British more than a year to develop their own mustard agent weapon, with production of the chemicals centred on  Avonmouth Docks  (the only option available to the British was the Despretz–Niemann–Guthrie process). [ 28 ] [ 29 ]  This was used first in September 1918 during the breaking of the  Hindenburg Line .


Mustard gas was originally assigned the name LOST, after the scientists Wilhelm Lommel and  Wilhelm Steinkopf , who developed a method of large-scale production for the  Imperial German Army  in 1916. [ 30 ]


Mustard gas was dispersed as an  aerosol  in a mixture with other chemicals, giving it a yellow-brown color. Mustard agent has also been dispersed in such munitions as  aerial bombs ,  land mines ,  mortar rounds ,  artillery shells , and  rockets . [ 1 ]  Exposure to mustard agent was lethal in about 1% of cases. Its effectiveness was as an  incapacitating agent . The early countermeasures against mustard agent were relatively ineffective, since a soldier wearing a  gas mask  was not protected against absorbing it through his skin and being blistered. A common countermeasure was using a urine-soaked mask or facecloth to prevent or reduce injury, a readily available remedy attested by soldiers in documentaries (e.g.  They Shall Not Grow Old  in 2018) and others (such as forward aid nurses) interviewed between 1947 and 1981 by the British Broadcasting Corporation for various World War One history programs; however, the effectiveness of this measure is unclear.


Mustard gas can remain in the ground for weeks, and it continues to cause ill effects. If mustard agent contaminates one's clothing and equipment while cold, then other people with whom they share an enclosed space could become poisoned as contaminated items warm up enough material to become an airborne toxic agent. An example of this was depicted in a British and Canadian documentary about life in the trenches, particularly once the "sousterrain" (subways and berthing areas underground) were completed in Belgium and France. Towards the end of World War I, mustard agent was used in high concentrations as an  area-denial weapon  that forced troops to abandon heavily contaminated areas.


Since World War I, mustard gas has been used in several wars and other conflicts, usually against people who cannot retaliate in kind: [ 31 ]


The use of toxic gases or other chemicals, including mustard gas, during warfare is known as  chemical warfare , and this kind of warfare was prohibited by the  Geneva Protocol of 1925 , and also by the later  Chemical Weapons Convention of 1993 . The latter agreement also prohibits the development, production, stockpiling, and sale of such weapons.


In September 2012, a US official stated that the rebel militant group  ISIS  was manufacturing and using mustard gas in Syria and Iraq, which was allegedly confirmed by the group's head of chemical weapons development, Sleiman Daoud al-Afari, who has since been captured. [ 47 ] [ 48 ]


As early as 1919 it was known that mustard agent was a suppressor of  hematopoiesis . [ 49 ]  In addition, autopsies performed on 75 soldiers who had died of mustard agent during  World War I  were done by researchers from the  University of Pennsylvania  who reported decreased counts of  white blood cells . [ 39 ]  This led the American Office of Scientific Research and Development (OSRD) to finance the biology and chemistry departments at  Yale University  to conduct research on the use of chemical warfare during World War II. [ 39 ] [ 50 ]


As a part of this effort, the group investigated  nitrogen mustard  as a therapy for  Hodgkin's lymphoma  and other types of  lymphoma  and  leukemia , and this compound was tried out on its first human patient in December 1942. The results of this study were not published until 1946, when they were declassified. [ 50 ]  In a parallel track, after the  air raid on Bari  in December 1943, the doctors of the U.S. Army noted that white blood cell counts were reduced in their patients. Some years after World War II was over, the incident in Bari and the work of the Yale University group with nitrogen mustard converged, and this prompted a search for other similar  chemical compounds . Due to its use in previous studies, the nitrogen mustard called "HN2" became the first cancer  chemotherapy  drug,  chlormethine  (also known as mechlorethamine, mustine) to be used. Chlormethine and other mustard gas molecules are still used to this day as an chemotherapy agent albeit they have largely been replaced with more safe chemotherapy drugs like  cisplatin  and  carboplatin . [ 51 ]


In the United States, storage and incineration of mustard gas and other chemical weapons were carried out by the U.S. Army Chemical Materials Agency. [ 52 ]  Disposal projects at the two remaining American chemical weapons sites were carried out near  Richmond, Kentucky , and  Pueblo, Colorado .


New detection techniques are being developed in order to detect the presence of mustard gas and its metabolites. The technology is portable and detects small quantities of the hazardous waste and its oxidized products, which are notorious for harming unsuspecting civilians. The  immunochromatographic  assay would eliminate the need for expensive, time-consuming lab tests and enable easy-to-read tests to protect civilians from sulfur-mustard dumping sites. [ 53 ]


In 1946, 10,000 drums of mustard gas (2,800 tonnes) stored at the production facility of Stormont Chemicals in  Cornwall, Ontario , Canada, were loaded onto 187 boxcars for the 900 miles (1,400 km) journey to be buried at sea on board a 400 foot (120 m) long barge 40 miles (64 km) south of  Sable Island , southeast of  Halifax , at a depth of 600 fathoms (1,100 m). The dump location is 42 degrees, 50 minutes north by 60 degrees, 12 minutes west. [ 54 ]


A large British stockpile of old mustard agent that had been made and stored since World War I at  M. S. Factory, Valley  near  Rhydymwyn  in  Flintshire , Wales, was destroyed in 1958. [ 55 ]


Most of the mustard gas found in Germany after  World War II  was dumped into the  Baltic Sea . Between 1966 and 2002, fishermen have found about 700 chemical weapons in the region of  Bornholm , most of which contain mustard gas. One of the more frequently dumped weapons was "Sprühbüchse 37" (SprüBü37, Spray Can 37, 1937 being the year of its fielding with the German Army). These weapons contain mustard gas mixed with a  thickener , which gives it a tar-like viscosity. When the content of the SprüBü37 comes in contact with water, only the mustard gas in the outer layers of the lumps of viscous mustard  hydrolyzes , leaving behind amber-colored residues that still contain most of the active mustard gas. On mechanically breaking these lumps (e.g., with the drag board of a fishing net or by the human hand) the enclosed mustard gas is still as active as it had been at the time the weapon was dumped. These lumps, when washed ashore, can be mistaken for amber, which can lead to severe health problems.  Artillery shells  containing mustard gas and other toxic ammunition from World War I (as well as conventional explosives) can still be found in France and Belgium. These were formerly disposed of by explosion undersea, but since the current environmental regulations prohibit this, the  French government  is building an automated factory to dispose of the accumulation of chemical shells.


In 1972, the  U.S. Congress  banned the practice of disposing of chemical weapons into the ocean by the United States. 29,000 tons of nerve and mustard agents had already been dumped into the ocean off the United States by the  U.S. Army . According to a report created in 1998 by William Brankowitz, a deputy project manager in the  U.S. Army Chemical Materials Agency , the army created at least 26 chemical weapons dumping sites in the ocean offshore from at least 11 states on both the  East Coast  and the  West Coast  (in  Operation CHASE ,  Operation Geranium , etc.). In addition, due to poor recordkeeping, about one-half of the sites have only their rough locations known. [ 56 ]