Modafinil Dosage – Complete Guide 2017

1. Modafinil Dosage – Complete Guide 2017 What is the optimal modafinil dosage? When is the best time to take modafinil? Which is better: one dose early in the morning or two smaller doses, taken throughout the day? There are many modafinil dosage "guides" out there. Some are more trustworthy than others, but most sources offer conflicting advice. In this article, I help you navigate through all of the information in order to select the best modafinil dosing schedule for you. Specifically, you will learn: Why you should start at a lower dosage and gradually increase the dosage Why some people are low-dose responders and others are high-dose responders How clinical trials determine which doses are appropriate for a given drug The ideal modafinil dosage for ADHD, narcolepsy, and other conditions The best time of day to take modafinil And more . . . As always, if you don't care to read the details, just skip to the TLDR section at the bottom of this post.

2. How the FDA Settled on 100/200 mg Dosage If you have ever bought modafinil online, you will have noticed that modafinil tablets come in two different sizes: 100 mg and 200 mg. The 200 mg tablets are most common, but even these can be broken in half to create 100 mg doses. How did the FDA decide that 100 and 200 mg were appropriate doses of modafinil? These decisions are usually made during phase 2 clinical trials. This means that the proper dose(s) are determined based on how patients (as opposed to healthy individuals) respond to the drug. An optimal dose is defined as: optimal dose (n.) - 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 dosage 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 from a phase 2, parallel dose comparison study by Nagaraja et al. in 2002. [1] The authors divided narcoleptic patients into three groups and treated them with 200 mg modafinil, 400 mg modafinil, or a placebo, respectively. Nagaraja et al. reported that after 200 mg modafinil per day for two weeks, the patients’ fatigue and attention levels improved considerably; however, the group treated with 400 mg were no different from the placebo group.

3. Apparently, the 200 mg modafinil dosage stuck. But recent evidence calls into question these results. For example, a 2003 study by Jonathan Schwartz and colleagues [2] found that 400 mg modafinil (in two 200 mg doses) was superior to single-dose 200 mg and 400 mg modafinil. Modafinil and Pharmacokinetic Variability As with any other drug, modafinil dosages are standardized; however, 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 and response. Researchers have characterized many genetic variants that contribute to pharmacokinetic variability, including: N-acetylation; CYP2D6 drug oxidation; CYP2C9; CYP2C19; Conjugation by sulfotransferases, glucuronosyltransferases; and other enzymes; and Cleavage by pseudocholinesterases. [3] To give you a sense of the number of variations we’re talking about, there are over 70 variants in the CYP2D6 gene, which has a significant impact on drug metabolism.

4. The takeaway, here, is that there are myriad of genetic factors that can influence your response to modafinil. So while modafinil is only prescribed in 100 mg and 200 mg doses, 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 to Consider When Deciding Modafinil Dosage Modafinil affects numerous neurotransmitters in the brain. It modulates orexin, histamine, norepinephrine, dopamine, adenosine, and other molecules. However, despite this seeming heterogeneity, modafinil’s effects converge on one thing: dialing up arousal. Modafinil increases neurophysiological arousal, which in turn, 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 have type B personalities. On the other end of the spectrum, other people are naturally anxious, insomnia-prone and easily agitated. The point is, 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. This is an excellent blog post on modafinil's use as an anti-depressant. The article touches on the link between arousal and dosage, and suggests that depressed people require higher doses of modafinil because depression is essentially under-stimulation – a fascinating topic! In short, don’t assume that 100mg or 200mg modafinil is the optimal dosage for you. Instead, you should experiment with a few different doses, beginning with the minimum effective dose (as low as 25-50 mg) and slowly titrate upwards. Modafinil Dose Titration: Finding Your Optimal Dose

5. In addition to pharmacokinetic variability, some people are low-dose responders and others are high-dose responders. There are even a small percentage of people who are entirely resistant to the effects of modafinil, but they are extremely rare. Finding your optimal dose should be treated like an experiment. Basically, you start at a very low dose (25 - 50mg) and titrate upwards until you reach a dose that maximizes the benefits of the drug while minimizing the side effects. I used this technique when I first started taking modafinil to find my optimal dosage. Here's how I did it: Day 1: Take 25 mg (approx. 1/4 100 mg tablet) once in the morning Day 2: Take 25 mg at the same time as on Day 1 Day 3: Take 25 mg at the same time as on Day 1 3-day break (no modafinil) Day 4: Take 50 mg (approx. 1/2 100 mg tablet or 1/4 200 mg tablet) once in the morning Day 5: Take 50 mg at the same time as on Day 4 Day 6: Take 50 mg at the same time as on Day 4 3-day break (no modafinil) Day 7: Take 75 mg (approx. 3/4 100 mg tablet) once in the morning Day 8: Take 75 mg at the same time as on Day 7 Day 9: Take 75 mg at the same time as on Day 7 3-day break (no modafinil) . . . and so on until I reached 150 mg I discovered that my ideal dosage is actually quite low: right around 65-70 mg (approx. 1/3 200 mg tablet). For me, the difference between 70 mg and 100 mg modafinil is noticeable. On the days when I take 100 mg in the morning, I have non-stop energy until around 2:00 or 3:00 p.m. – and then, I crash! I cannot focus for more than ten or twenty minutes at a time; it's as if my mind shuts off completely. But when I take 65-70 mg in the morning, I not only have higher mental energy levels but also significantly higher motivation – I become a working machine – and the energy doesn't stop at 2 or 3 p.m.; it goes all day. Sometimes, I have to drink two cups of chamomile tea and take a few milligrams of melatonin around 10 p.m. just to calm down.

6. Modafinil Dosage Timing The next question to consider is: when should you take modafinil? It is often said that the ideal time to take modafinil is in the morning, immediately upon waking up. When most people get up in the morning, their brains are sluggish. This sluggishness is called neural inertia: neural inertial (n.) - a tendency of the CNS [Central Nervous System] to resist behavioral state transitions between conscious andunconscious states.” The morning is a great time to take modafinil because it helps overcome neural inertia by modulating attentional networks. [4] [5] After dosing, it takes about 45-60 minutes for modafinil to “kick in.” So, if you want to give your attention a boost starting around 8:00 a.m., try to take modafinil at 7 a.m. It is important to note that modafinil has a half-life of 12-14 hours. This means that the effects will last, on average, about as long. In order to avoid interference with sleep quality, therefore, it is best to take modafinil as early in the day as possible. 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, however, FDA-approved for: Narcolepsy (200 mg), Obstructive sleep apnea (200 mg), and Shift work sleep disorder (SWSD) (200 mg) Despite the fact that modafinil lacks FDA approval for ADHD, there’s substantial evidence that modafinil confers important benefits for ADHD patients:

7. "Modafinil for the treatment of attention-deficit/hyperactivity disorder: a meta- analysis" [6] Wang et al. (2017) Biederman et al. (2008)"Modafinil improves symptoms of attention-deficit/hyperactivity disorder across subtypes in children and adolescents" [7] "Modafinil as a treatment for Attention-Deficit/Hyperactivity Disorder in children and adolescents: a double-blind, randomized clinical trial" [8] Amiri et al. (2008) Ultimately, the FDA committee rejected the ADHD use-case for modafinil because of concerns over Steven’s Johnson’s syndrome (SJS). [9] 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. Given the above evidence, it’s no surprise that psychiatrists nevertheless prescribe modafinil as an off-label treatment for ADHD. Modafinil has advantages over traditional psychostimulants. For example, unlike Adderall, modafinil is not neurotoxic and may even be neuroprotective. [10] [11] 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 deficiencysyndrome.” Low-dose modafinil (e.g., 25- 50 mg) is unlikely to benefit ADHD patients because at baseline they are understimulated and sluggish. That said, however, I remain a proponent of starting at the minimum possible effective dose and titrating upwards to find the “sweet spot," even if you suffer from ADHD. Modafinil Dosage for Narcolepsy "Some people suffering from narcolepsy may benefit from higher than usual modafinil dosages." That’s the punchline of Hughes et al.’s 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

8. superior to once-daily dosing for sustaining wakefulness in narcoleptic patients. 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. Therefore, it’s no surprise that people will be curious about which modafinil dosage facilitates studying. An excellent paper by Brem and Battleday, entitled "Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review" includes a helpful summary (in the form of a table) of the studies investigating the effects of modafinil on cognitive ability in healthy volunteers. Here’s an excerpt of that table: [table id=dosage /] You’ll notice that most of the above studies use a modafinil dosage of 200 mg. However, to reiterate, 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.

9. There’s no one-size-fits-all modafinil dosage; individual variability in drug response implies that the best way to find your optimal dosage is by trial and error (aka start low and titrate upwards). Titrate your modafinil dosage! 'Titrating' means starting with the minimum possible effective dose (e.g. 25-50 mg) and gradually increasing the dose until you've obtained the maximum benefit and the minimum side effects. If you’re prone to anxiety, you may benefit from lower doses, such as 50 or 75 mg. if you suffer from ADHD or narcolepsy, you may benefit from higher modafinil doses, such as 200 mg. 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 centrephase 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. Ikeda Y, Funayama T et al. Modafinil enhances alerting-related brain activity in attention networks. Psychopharmacology (Berl). 2017 Apr;3. 6. 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 7. 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

10. 8. 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 9. Ghoshal L, Sinha M. Fixed drug eruptions with modafinil. Indian J Pharmacol. 2015 Mar-Apr;47(2):224-6 10. 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. 11. Antonelli T, Ferraro L, et al. Modafinil prevents glutamate cytotoxicity in cultured cortical neurons. Neuroreport. 1998;9:4209–13.