Login

Modafinil Dosage

 

The Ultimate Modafinil Dosage Guide: Have You Been Taking The Wrong Dose?

What’s the optimal modafinil dosage? In this post, you’ll learn:

  • Why you should start at low modafinil dosages and titrate upwards
  • The ideal modafinil dosage for ADHD, narcolepsy, and other conditions
  • The best time of day to take modafinil
  • How clinical trials determine what doses of a drug are appropriate
  • Why some people are low-dose responders and others are high dose-responders

I’m writing about this topic because I’ve thought a great deal about the ideal modafinil dosage and have years of experience taking modafinil under my belt.

 

Modafinil Dosage

 

The Story of How The FDA Settled on 100/200 mg Modafinil

Modafinil comes in two strengths: 100 mg and 200 mg. Armodafinil, the related drug that superseded modafinil, is available in four strengths: 50 mg, 150 mg, 200 mg, and 250 mg.

How did the FDA decide that 100/200 mg were appropriate dosages of modafinil? These decisions are usually made in phase 2 clinical trials.

The optimal dose of a drug is:

“A dose that is high enough to demonstrate effectiveness in the target population, yet low enough to minimize safety concerns and adverse effects.”

The most common dose finding study designs are cross-over, dose titration, parallel dose comparison, and dose escalation.

The fact that 200 mg is the most commonly prescribed dose of modafinil likely comes frorm a phase 2 study of modafinil’s efficacy and safety by Nagaraja and colleauges in 2002[1]. The authors enrollled patients with narcolepsy and treated them 200 mg, 400 mg or placebo. Nagaraja et al. reported that after 200 mg/day modafinil for two weeks, patients’ fatigue improved. But the group treated with 400 mg did not separate from placebo.

This 200 mg modafinil dosage stuck. But recent evidence calls into question these results. For example, Schwartz’s group found that 400 mg modafinil (in two divided doses) was superior to single-dose 200 mg and 400 mg modafinil[2].

Modafinil and Pharmacokinetic Variability

Like any drug, modafinil dosages are standardized. But just because modafinil is only available in 100 mg and 200 mg tablets does not mean that you’re restricted to these doses.

People vary widely in their response to drugs. “Pharmacokinetic variability” describes the intra-patient variability in drug delivery. Researchers have characterized many genetic variants that contribute to pharmacokinetic variability[3]:

  • N-acetylation
  • CYP2D6 drug oxidation
  • CYP2C9
  • CYP2C19
  • Conjugation by sulphotransferaes, glucuronosyltransferases and other enzymes
  • Cleavage by pseudocholinesterases

To give you a sense of the level of variation we’re talking about, there are over 70 variants in the CYP2D6 gene, which influences drug metabolism.

The take home message is that there are myriad of genetic factors that contribute to inter-individual variability in drug response. So while modafinil is only prescribed in 100 mg and 200 mg dosages, that doesn’t mean that these are the ideal doses for you. I’ll develop this concept in greater detail in the section on Modafinil Titrations.

Factors That Affect Your Target Modafinil Dosage

Modafinil affects many neurotransmitter systems. It modulates, orexin, histamine, norepinephrine, dopamine, adenosine and other molecules. But despite this seeming heterogeneity, modafinil’s effects converge on one thing: dialing up arousal. Modafinil increases neurophysiological arousal which improves cognitive performance.

Some people at baseline are under-stimulated and prone to hypoarousal. They’re lethargic, inattentive, and lack a sense of urgency. Such people tend to be type B. On the other end of the spectrum, you’ll find naturally anxious, insomnia-prone and agitated people.

People have different baseline levels of arousal. Since modafinil modulates arousal, a 100 mg dosage might be too much for an already-anxious person. But if you suffer from narcolepsy, you might need a 400 mg dose to derive any therapeutic benefits from modafinil [2].

To cut to the chase: don’t assume that 100mg or 200mg modafinil is your ideal dosage.

Modafinil Dose Titration

Apart from pharmacokinetic variability, some people are low-dose responders and others are high-dose responders. There’s even a handful of people are entirely resistant to the effects of modafinil. Finding the right dose should be treated like an experiment. Under the guidance of a physician, you start at low doses (25 – 50mg) and titrate upwards until you reach a dose that maximizes the benefits of the drug while minimizing the side effects.

Modafinil Dosage Timing

When should you take modafinil? The ideal time to take modafinil is in the morning, upon waking.

When most people wake up in the morning they’re cognitively sluggish. This sluggishness is called neural inertia or “a tendency of the CNS to resist behavioral state transitions between conscious and unconscious states.”[4] The morning is a great time to take modafinil because it helps overcome neural inertia by modulating attentional networks.

One downside of modafinil is its long half-life of 12-14 hours. The pharmacokinetics of modafinil are unideal because the modafinil that lingers in your body at night can interfere with sleep quality. It’s therefore best to take modafinil as early in the day as possible to reduce modafinil blood levels at night.

After dosing, it takes about 45 – 60 minutes for modafinil to “kick in.”

Modafinil Dosage for ADHD

What’s the ideal modafinil dosage for ADHD?

This answer to this question is likely to be controversial because modafinil is not an FDA-approved treatment for ADHD. Modafinil is FDA-approved for:

  • Narcolepsy (200 mg)
  • Obstructive sleep apnea (200 mg)
  • Sleep work disorder (200 mg)

Despite the fact that modafinil lacks FDA-approval for ADHD, there’s substantial evidence for benefit:

At the end of the day, the FDA committee rejected the ADHD use-case for modafinil because of concerns over Steven’s Johnson’s syndrome (SJS)[8]. SJS is an extremely rare, life-threatening rash that can develop over the course of modafinil treatment. The FDA was understandably concerned about granting modafinil approval for ADHD because most of the patient population is comprised of children and adolescents. From NPR’s report on the subject: “Based on the known mortality associated with […] Steven-Johnson, we would expect from 25 to over 400 deaths to occur.”

Given the above evidence, it’s no surprise that psychiatrists sometimes prescribe modafinil off-label for ADHD. Modafinil has advantages over traditional psychostimulants. For example, unlike Adderall, modafinil is not neurotoxic and may even be neuroprotective[9][10].

The ideal modafinil dosage for ADHD is likely to fall within the typically prescribed 100 – 200 mg range.

ADHD is characterized by inattention and sluggish cognitive tempo. Hence, ADHD was originally described as a “reward deficiency syndrome.” Low-dose modafinil (e.g., 25-50 mg) is unlikely to benefit ADHD patients because at baseline they are understimulated and sluggish. However, I remain a big proponent of starting at the minimum possible effective dose and titrating upwards to find the “sweet spot.”

Modafinil Dosage for Narcolepsy

Some people suffering from narcolepsy may benefit from higher than usual modafinil dosages.

That’s the punchline of Hughes and colleagues’ study[2] that compared single-dose 200 mg, single-dose 400 mg and divided dose 400 mg in patients with narcolepsy. The authors found that a split-dose 400 mg regimen was superior to once-daily dosing for sustaining wakefulness throughout the entire waking day. Here’s an excerpt from the abstract:

The 400-mg split-dose regimen improved wakefulness significantly in the evening compared with the 200-mg and 400-mg once-daily regimen (both P < 0.05). The percentage of patients rated as “much improved” or “very much improved” with respect to evening sleepiness was 27%, 82%, and 80% in the 200-mg, 400-mg once-daily, and 400-mg split-dose groups, respectively. Adverse events were mild to moderate in nature and included headache, nausea, nervousness, dyspepsia, pain, and vomiting (all 6%). Some patients may benefit from 400-mg doses of modafinil taken once daily compared with 200-mg doses. A split-dose 400-mg regimen may be superior to once-daily dosing for sustaining wakefulness throughout the entire waking day.

Modafinil Dosage for Studying

Modafinil is the quintessential study drug. Thus it’s no surprise that people will be curious about what modafinil dosage facilitates studying.

A great paper by Brem and Battleday, entitled Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review has a great table on the studies investigating the effects of modafinil on cognitive ability in healthy volunteers. Here’s an excerpted version of that table:

NameDoseNotes
Baransky et al., 20144 mg/kgImproved accuracy on DRN; faster reaction time on SRT. No effect on other domains.
Esposito et al., 2013100 mgNo effect of group. Individuals taking modafinil demonstrated significant improvement on medium difficulty trials, whereas those on placebo did not.
Finke et al., 2010400 mgImprovement in visual attention of low baseline performers: more objects processed, and increased visual short-term memory storage capacity.
Geng et al., 2013200 mgIncreased successful selective spatial attention in low probability conditions; increased attention/vigilance in combination with enhanced cognitive control mechanisms.
Gilleen et al., 2014200 mgFaster improvements in early training period of language learning task; superior performance maintained over ten day training period and at two week follow up. Performance of high IQ group improved to a greater extent than low IQ. No effect on other measures.
Liepert and Weiller, 2004200 mgNo effect found.
Makris et al., 20071.75, 3.5, and 7 mg/kgImproved performance on DSS and RA. Decreased reaction time on SNR.
Marchant et al., 2009200 mgIncreased accuracy on complex attentional set shifting task. No effect on DSS, PM, or FR.
Minzenberg et al., 2008200 mgNo effect on POP when whole group analysed; subgroup with sub-ceiling performance exhibited improved accuracy.
Minzenberg et al., 2011200 mgTrend towards faster reaction time on arousal task.
Minzenberg et al., 2014200 mgNo effect.
Mohamed, 2014200 mgMarginally significant improvement on GEF. No main effect on ReA (but participants low in creativity personality trait scored significantly higher than those high in creativity personality trait in modafinil group only). Reduced performance on flexibility scores on the AT. No effect on other tasks.
Mohamed and Lewis, 2014200 mgNo effect on accuracy of HSC (slower reaction times in inhibition section).
Müller et al., 2004200 mgFewer errors on NWM when difficult manipulation required only; “poor” baseline manipulators benefitted more than “good”. Decrease in error rates after long delays only in DMTS. No effect on DC or TMT-A.
Müller et al., 2013200 mgImproved performance on SOC, SWM, and PRM (delayed only). No effect on other tasks.
Pringle et al., 2013100 mgEnhanced learning rate in complex learning task (rule acquisition and set shifting): reflects executive function (working memory and cognitive flexibility). No effect on DS.
Randall et al., 2003100 / 200 mgNo effect found on any task.
Randall et al., 2004100 / 200 mg200 mg group scored better on CD. 200 mg were faster on congruent Stroop task (i.e., to name colour); No effect on TMT-A, RVIP, SOC, TMT B, DMTS.), LoM, or COWA. 200 mg scored worse on IEDSS.
Randall et al., 2005a, 2005b100 / 200 mgImproved performance on PRM (200 mg were slower during accurate trials). 200 mg more accurate and sensitive on RVIP. 100 mg showed improved digit span. 200 mg group faster on congruent Stroop trials. No effect on other trials, although drug group were faster on easy trials, and slower on harder trials in the SOC.
Rasetti et al., 2010100 mgNo effect.
Rycroft et al., 2007200 mgFaster correct movements on an antisaccade task, did not decrease (incorrect) prosaccades.
Theunissen et al., 2009200 mgFaster reaction time on MC. No effect on other tests.
Turner et al., 2003100 / 200 mgImproved performance on SOC, SST, and DS, PRM. Longer latency/deliberation time in DMTS and CGT, with similar accuracy. No effect on other tests.
Winder-Rhodes et al., 2010300 mgFewer moves required on hardest difficulty of SOC. No difference on other measures.

You’ll notice that most studies use a modafinil dosage of 200 mg. However, even though most published papers use a 200 mg dose for cognitive enhancement, you may benefit from lower or higher doses based on your individual neurophysiology.

TLDR

  • The FDA-approved doses of modafinil are 100 and 200 mg
  • If you’re prone to anxiety, you may benefit from lower doses
  • There’s no one-size-fits-all modafinil dosage; inter-individual variability in drug response implies that the best way to find the best modafinil dose is through trial and error
  • Some people benefit from modafinil doses as low as 25 mg (e.g., low-dose responders)
  • Sufferers of narcolepsy may benefit from higher modafinil dosages

References


  1. Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatr. 2002;72(2):179-83.
  2. Schwartz JR, Feldman NT et al… Dosing regimen effects of modafinil for improving daytime wakefulness in patients with narcolepsy. Clin Neuropharmacol. 2003 Sep-Oct;26(5):252-7
  3. Roden DM, George AL Jr. The genetic basis of variability in drug responses. Nat Rev Drug Discov. 2002 Jan;1(1):37-44
  4. Friedman EB, Sun Y et al… A conserved behavioral state barrier impedes transitions between anesthetic-induced unconsciousness and wakefulness: evidence for neural inertia. PLoS One. 2010 Jul 30;5(7):e11903
  5. Wang SM, Han C et al… Modafinil for the treatment of attention-deficit/hyperactivity disorder: A meta-analysis. J Psychiatr Res. 2017 Jan;84():292-300
  6. Biederman J, Pliszka SR. Modafinil improves symptoms of attention-deficit/hyperactivity disorder across subtypes in children and adolescents. J Pediatr. 2008 Mar;152(3):394-9
  7. Amiri S, Mohammadi MR et al… Modafinil as a treatment for Attention-Deficit/Hyperactivity Disorder in children and adolescents: a double blind, randomized clinical trial. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Jan 1;32(1):145-9
  8. Ghoshal L, Sinha M. Fixed drug eruptions with modafinil. Indian J Pharmacol. 2015 Mar-Apr;47(2):224-6
  9. Jenner P, Zeng BY, et al. Antiparkinsonian and neuroprotective effects of modafinil in the mptp-treated common marmoset. Exp Brain Res. 2000;133:178–88.
  10. Antonelli T, Ferraro L, et al. Modafinil prevents glutamate cytotoxicity in cultured cortical neurons. Neuroreport. 1998;9:4209–13.