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Proper Modafinil Use and Dose
By: Road2HardCoreIron Date: June 29, 2021, 3:25 pm
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OPTIMAL DOSE MODAFINIL?
Modafinil Dosage
December 6/16/2021
The Ultimate Modafinil Dosage Guide: Have You Been Taking The
Wrong Dose?
[toc]
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 FDA Settled on 100/200 mg
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Armodafinil, the related drug that superseded modafinil, is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 & 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 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:
Modafinil for the treatment of attention-deficit/hyperactivity
disorder: A meta-analysis (2017) [5]
Modafinil improves symptoms of attention-deficit/hyperactivity
disorder across subtypes in children and adolescents (2008) [6]
Modafinil as a treatment for Attention-Deficit/Hyperactivity
Disorder in children and adolescents: a double blind, randomized
clinical trial (2008) [7]
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:
NAME DOSE NOTES
Baransky et al., 2014 4 mg/kg Improved accuracy on DRN; faster
reaction time on SRT. No effect on other domains.
Esposito et al., 2013 100 mg No effect of group. Individuals
taking modafinil demonstrated significant improvement on medium
difficulty trials, whereas those on placebo did not.
Finke et al., 2010 400 mg Improvement in visual attention of low
baseline performers: more objects processed, and increased
visual short-term memory storage capacity.
Geng et al., 2013 200 mg Increased successful selective spatial
attention in low probability conditions; increased
attention/vigilance in combination with enhanced cognitive
control mechanisms.
Gilleen et al., 2014 200 mg Faster 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, 2004 200 mg No effect found.
Makris et al., 2007 1.75, 3.5, and 7 mg/kg Improved performance
on DSS and RA. Decreased reaction time on SNR.
Marchant et al., 2009 200 mg Increased accuracy on complex
attentional set shifting task. No effect on DSS, PM, or FR.
Minzenberg et al., 2008 200 mg No effect on POP when whole group
analysed; subgroup with sub-ceiling performance exhibited
improved accuracy.
Minzenberg et al., 2011 200 mg Trend towards faster reaction
time on arousal task.
Minzenberg et al., 2014 200 mg No effect.
Mohamed, 2014 200 mg Marginally 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, 2014 200 mg No effect on accuracy of HSC
(slower reaction times in inhibition section).
Müller et al., 2004 200 mg Fewer 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., 2013 200 mg Improved performance on SOC, SWM, and
PRM (delayed only). No effect on other tasks.
Pringle et al., 2013 100 mg Enhanced 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., 2003 100 / 200 mg No effect found on any task.
Randall et al., 2004 100 / 200 mg 200 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, 2005b 100 / 200 mg Improved 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., 2010 100 mg No effect.
Rycroft et al., 2007 200 mg Faster correct movements on an
antisaccade task, did not decrease (incorrect) prosaccades.
Theunissen et al., 2009 200 mg Faster reaction time on MC. No
effect on other tests.
Turner et al., 2003 100 / 200 mg Improved 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., 2010 300 mg Fewer 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
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. ↩
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
↩ ↩ ↩
Roden DM, George AL Jr. The genetic basis of variability in drug
responses. Nat Rev Drug Discov. 2002 Jan;1(1):37-44 ↩
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 ↩
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 ↩
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
↩
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
↩
Ghoshal L, Sinha M. Fixed drug eruptions with modafinil. Indian
J Pharmacol. 2015 Mar-Apr;47(2):224-6 ↩
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. ↩
Antonelli T, Ferraro L, et al. Modafinil prevents glutamate
cytotoxicity in cultured cortical neurons. Neuroreport.
1998;9:4209–13. ↩
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