Provigil vs Adderall XR: Combining the Two (Rationale + Risk)

What each drug is approved to treat

Provigil (modafinil tablets, 100 and 200 mg) is approved for excessive sleepiness in adults with narcolepsy, obstructive sleep apnea or shift work disorder [1]. The label dose is 200 mg once daily in the morning, or 200 mg about an hour before the work shift in shift work disorder, and the label halves the dose in severe hepatic impairment [1]. In sleep apnea it treats the sleepiness, not the airway obstruction, and the label says a maximal effort with CPAP should be made before and during treatment [1]. It is not approved for any pediatric use [1].

Adderall XR (extended-release mixed amphetamine salt capsules, 5 to 30 mg) is approved for ADHD in adults and children 6 and older, and is not recommended under age 6 [2]. The label dose for adults is 20 mg once daily in the morning; for children 6 to 12 it starts at 10 mg with a maximum of 30 mg a day; for adolescents 13 to 17 it starts at 10 mg and may go to 20 mg after a week [2]. The label says afternoon doses should be avoided because of insomnia [2].

One detail matters for the combined-use question: Adderall XR is approved only for ADHD, whereas the immediate-release Adderall tablet is indicated for both ADHD and narcolepsy.

Is there a pharmacological rationale for combining them?

There is a plausible rationale, but it rests on mechanism, not on trial data. Both drugs promote wakefulness, and the Provigil label says modafinil's wake-promoting actions are similar to those of sympathomimetics including amphetamine and methylphenidate, though its pharmacologic profile is not identical [1]. In vitro, modafinil binds the dopamine transporter and inhibits dopamine reuptake, activity that has been linked in animals to higher extracellular dopamine in some brain regions [1]. Amphetamines are thought to block reuptake of norepinephrine and dopamine and to increase their release.

Two caveats come from the Provigil label. The mechanism by which modafinil promotes wakefulness is unknown [1]. And modafinil is not a direct- or indirect-acting dopamine receptor agonist, and it lacked wake-promoting activity in mice engineered without the dopamine transporter [1].

What the trials show for each drug on its own

Adderall XR in adults: a 4-week randomized, double-blind, placebo-controlled, dose-escalation study of 255 adults with ADHD tested 20, 40 and 60 mg a day. Mean ADHD Rating Scale scores at endpoint were 18.5, 18.4 and 18.5 in the three dose groups (P=.001 or lower), the mean effect size was 0.8, and improvement began in the first week [3].

Across the class: a network meta-analysis of 133 double-blind randomized trials found amphetamines, including lisdexamfetamine, reduced clinician-rated ADHD symptoms with a standardized mean difference of -1.02 in children and adolescents and -0.79 in adults versus placebo, larger than methylphenidate [4]. In head-to-head comparisons amphetamines were more efficacious than methylphenidate, atomoxetine and modafinil by clinician ratings, although confidence in most indirect comparisons was low or very low [4].

Modafinil in narcolepsy: an 18-center, 9-week, double-blind, placebo-controlled trial in 283 people with narcolepsy tested 200 or 400 mg daily. Modafinil reduced sleepiness on the Epworth Sleepiness Scale, the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test and improved clinical global impression, with adverse experiences that were few, dose-dependent and mostly mild to moderate [5].

Modafinil in healthy adults: a meta-analysis of 14 studies of acute doses in healthy, non-sleep-deprived adults found a small overall effect on cognition (standardized mean difference 0.12) and a larger effect on memory updating (0.28); the authors concluded that the popular belief these drugs are effective cognitive enhancers is not supported by the evidence so far [6].

Modafinil in ADHD is off-label and comes with a caution. In pediatric trials of modafinil, rash led to discontinuation in about 0.8% of patients (13 of 1,585), including one possible Stevens-Johnson syndrome, and the drug is not approved for ADHD or for children [1].

Risks of using both

Cardiovascular. The Adderall XR label says CNS stimulants raise blood pressure by a mean of about 2 to 4 mm Hg and heart rate by about 3 to 6 bpm, with larger rises in some patients, and says to avoid the drug in people with known structural cardiac abnormalities, cardiomyopathy, serious arrhythmia, coronary artery disease or other serious cardiac disease, where sudden death has been reported at recommended ADHD doses [2]. The Provigil label reports that a larger share of modafinil patients needed new or increased blood pressure medication than placebo patients (2.4% vs 0.7%, and 3.4% vs 1.1% in the sleep apnea studies), and says to consider increased monitoring in known cardiovascular disease [1].

Psychiatric. Adderall XR can worsen pre-existing psychosis, induce mania in bipolar disorder, and cause new psychotic or manic symptoms at recommended doses in about 0.1% of stimulant-treated patients versus 0% on placebo in pooled short-term trials [2]. In the Provigil trials, psychiatric symptoms leading to discontinuation included anxiety (1%), nervousness (1%) and, under 1%, insomnia, confusion, agitation and depression; postmarketing reports include mania, delusions, hallucinations, suicidal ideation and aggression, and many but not all of those patients had a prior psychiatric history [1].

A separate observational claims study of 337,919 people aged 13 to 25 starting a stimulant found a new psychosis diagnosis with an antipsychotic prescription within 60 days in 0.21% of amphetamine users versus 0.10% of methylphenidate users (hazard ratio 1.65); absolute risk was low [7].

Serious rash with modafinil. The Provigil label describes Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS and multi-organ hypersensitivity, with nearly all serious rash cases appearing 1 to 5 weeks after starting, and says to discontinue at the first sign of rash unless it is clearly not drug-related [1].

Abuse and misuse. Adderall XR has a boxed warning: high potential for abuse and misuse, which can lead to a substance use disorder including addiction, with overdose and death risk that rises with higher doses or unapproved routes such as snorting or injection [2]. Modafinil is Schedule IV, not uncontrolled: in an inpatient study in people experienced with drugs of abuse, modafinil 200, 400 and 800 mg produced psychoactive and euphoric effects consistent with other scheduled stimulants [1]. The label says physicians should follow patients closely, especially those with a history of drug or stimulant abuse, and watch for misuse such as increasing doses or drug-seeking [1].

Sleep timing. Modafinil peaks 2 to 4 hours after a dose and has an effective elimination half-life of about 15 hours after multiple doses [1]. Adderall XR peaks at about 7 hours, roughly 4 hours later than the immediate-release tablet, and d-amphetamine has a mean half-life of about 10 hours in adults [2]. In the Provigil placebo-controlled trials, insomnia occurred in 5% of patients compared with 1% receiving placebo [1]; in the Adderall XR adult trial it occurred in 27% versus 13% [2].

What each label lists for interactions

The Provigil interactions section covers four areas: induction of CYP3A4/5, which can lower exposure to steroidal contraceptives, cyclosporine, midazolam and triazolam, with the label recommending alternative or additional contraception during treatment and for one month after stopping; inhibition of CYP2C19, raising exposure to drugs such as phenytoin, diazepam, propranolol, omeprazole and clomipramine; more frequent INR monitoring with warfarin; and caution with MAO inhibitors [1].

The Adderall XR table of clinically important interactions lists MAO inhibitors (contraindicated during use and within 14 days of stopping, because of hypertensive crisis), serotonergic drugs, CYP2D6 inhibitors, alkalinizing agents such as antacids and sodium bicarbonate, acidifying agents such as ascorbic acid, and tricyclic antidepressants. The label says coadministration of Adderall XR with gastrointestinal or urinary alkalinizing agents should be avoided, and that acidifying agents lower blood levels and efficacy [2].

Sport and anti-doping rules

Both drugs are on the WADA Prohibited List. Amfetamine and modafinil are both named in section S6.A, non-specified stimulants, prohibited in competition, and a prescription requires a Therapeutic Use Exemption in WADA-governed sport [8][9].

Which drug for which problem

If the problem is ADHD, Adderall XR is the approved drug of the two and the amphetamine class has the stronger comparative efficacy data [2][4]. If the problem is sleepiness from narcolepsy, sleep apnea or shift work, Provigil is the approved drug and Adderall XR is not approved for any of those indications [2][1]. For patients already taking divided immediate-release Adderall doses, the XR label states they may be switched to the same total daily dose taken once daily [2].