Is This Wildly Popular Smart Drug Safe And Effective?

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Modafinil (also known as “Provigil”)…

It’s the darling of the smart drug industry and has been for quite some time.

With over 200 human clinical studies in the past 10 years, it is reported to have few to no side effects, to not be addictive, and to not be excessively stimulating.

It’s used by notable figures like Joe Rogan, Ray Kurzweil, Barack Obama, Hilary Clinton, Tim Ferriss, and many others.

It’s the entire inspiration behind the smart drug movie Limitless with Bradley Cooper.

It may increase resistance to fatigue and improve mood, reaction time, and vigilance, while simultaneously reducing bad decision making.

Laboratory studies have even shown that it may have potent antioxidative and neuroprotective effects.

It is of high interest to the US military for enhancing alertness and reducing battle fatigue.

Acute ingestion significantly increases exercise time to exhaustion.

So what could go wrong? Is this stuff too good to be true? Surely there must be some dark biological side of this supposed super-smart drug. On today’s podcast, I host a guest who knows more about the science of modafinil than anyone I’m aware of—and who, conveniently, happens to live just a few miles from my house: Dr. Jonathan Wisor.

Dr. Wisor received a bachelor of science degree in psychology from Pennsylvania State University, a Ph.D. in neuroscience from the University of California, Los Angeles, then served as a postdoctoral fellow and subsequently as a research associate at Stanford University School of Medicine. From 2004 through 2008 he was a staff scientist at SRI International, a non-profit research institute in Menlo Park, California. Dr. Wisor has served on the faculty of Washington State University and the WWAMI (Washington, Wyoming, Alaska, Montana, Idaho) Medical Education Program since December of 2008.

During this discussion, you’ll discover:

-How Jonathan became interested in sleep and neuroscience…8:05

  • Professor at WSU teaching cell biology of the nervous system, muscles, immune system, etc.
  • Worked at a bakery as an undergraduate, which caused erratic sleep patterns; This spawned an interest in neuroscience and sleep
  • Sleep and neuroscience are recurring themes in his research and teaching
  • Immune system and nervous system are connected
  • Stress hormones, glucose utilization, etc. are influenced by the quality of sleep

-What exactly modafinil is…13:40

  • “Small molecule therapeutic”
  • Enters through the digestive system into the bloodstream, then into the brain
  • Binds to the “dopamine transmitter” in the brain
  • We associate dopamine with motivational states (focus on a single task)
  • Cells’ release of dopamine is highly regulated; stimulates a receptor on the other cells
    • Cells that release dopamine have a mechanism that allows to keep them to keep the concentration at a certain level, then take back the dopamine
  • Modafinil is a “selective dopamine reuptake inhibitor” (not a precise scientific term)
    • It blocks dopamine when it attempts to reenter the cell from which it originated

-How various neurotransmitters respond to modafinil…19:30

  • Norepinephrine is affected by modafinil indirectly
    • Central mediator of the sympathetic (fight or flight) response
  • Histamine promotes alertness (anti-histamine drugs put you in a fog)
    • All these neurotransmitters talk with each other and, for better or worse, trying to selectively activate one is messing with all of them, which may be therapeutic or may not be
    • Histamine is associated with arousal, cognitive enhancement
  • Modafinil has the opposite effect
  • Orexin promotes wakefulness in the hypothalamus; modafinil helps fill in the gaps with an orexin shortage
    • People with narcolepsy are lacking the orexin signal


-Antioxidant and neuroprotective effects of modafinil…23:20

  • Modafinil prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an impurity in synthetic opioids, from being taken up by the dopamine transporter into the dopamine-producing cells; a metabolic process that produces a toxin that kills those dopamine-producing cells
  • Need to make a distinction between a cognitive effect and being neuroprotective (slows progression of a disease)
  • For Parkinson’s disease, a condition with a known degeneration of the dopamine-producing cells, data is weak as to whether modafinil protects those cells
    • Parkinson’s is not only a motor disorder, it also has a cognitive aspect as well
  • Data does not support modafinil as being neuroprotective
  • Nicotine and caffeine can act as a neuroprotective (stacked with modafinil)

-How modafinil use can go wrong…31:15

  • Modafinil is FDA approved for excessive daytime sleepiness
  • 3 situations that cause daytime sleepiness:
    1. A sleep disorder that prevents quality sleep at night (narcolepsy, insomnia, sleep apnea); sleepiness secondary to a sleep disorder; modafinil addresses daytime sleepiness
      1. Sleep apnea treatment: continuous positive airway pressure machine (CPAP) machine
    2. Situational sleep disorders (nighttime work, newborn children, aging parents, etc.)
    3. Motivational daytime sleepiness (intentionally restricting nighttime sleep)
  • Very few people can sustain excessive daytime sleepiness for long
  • Physiological effects of sleep deprivation (even with modafinil):
    • Lose insulin sensitivity (resistance)
    • Muscles lose the ability to store glucose for athletic performance
    • Staying awake with modafinil does not mitigate this negative effect
    • Cortisol levels get screwed up (inhibits the response of muscles to insulin)
  • Ben reports an enhanced workout with modafinil, but much more soreness the morning after, as well as low amounts of deep sleep
  • Growth hormone surge occurs at night
  • Melatonin increase is blunted by lack of sleep
  • You pay a physiological and hormonal price
  • Cycling modafinil use may regulate dopamine transporters such as Tari and D2

-Whether or not genetics determine a response to modafinil…47:05

  • Modafinil is processed in the liver; some people have higher CYP genes (which affect the liver)
  • People with certain enzymes break down modafinil quicker and feel its effects less
  • High CYP inhibitors: Grapefruit, bacopa, berberineCalifornia poppy
  • Take these with modafinil and perhaps assess your body’s response to it
  • Obviously use caution when toying with liver enzymes

-How modafinil affects sleep cycles…49:50

  • Ben reports that he woke up significantly earlier 1-2 days after using it
  • Perhaps has to do with the change in orexin levels and wake drive being shifted
  • Our circadian clock is responsive to neurotransmitters discussed earlier (dopamine, serotonin, melatonin, cortisol, etc.)
  • Other factors such as exposure to light, the time you exercise will also affect the circadian clock
  • Sunlight exposure will help reset the circadian clock during multiple time zone changes
  • Blue light blocking glasses
  • Limit exposure to light until the time you want to wake up

-How long modafinil stays in the bloodstream after taking it…54:15

  • Modafinil molecules are enantiomers, molecules that are a mirror image of itself (like two opposing hands)
  • R and S enantiomers are metabolized differently
  • R enantiomer (Armodafinil) metabolizes slower (much longer half-life) than S enantiomer
  • Theanine is used to take the edge off a stimulant like modafinil or coffee
  • Prebiotics such as marshmallow root and inulin slow the uptake of modafinil
  • Onset or duration of a standard 100~200mg dose:
    • Onset is 45 min to 2 hrs
    • Time to peak effect is 1-2 hours (before it becomes effective)
    • Peak effect is 2-4 hours
    • Tapering is 12-16 hrs
    • Total duration of the cycle is ~16 hours
  • Modafinil can remain in the body for 4 days

-Effects of combining modafinil with alcohol and drugs…57:55

  • Both alcohol and modafinil are synthesized by the liver
  • Modafinil itself is not harmful to the liver; a combination of the two may be
  • Tweak your liver enzymes at your own risk
  • The typical euphoric effect of THC may be down-regulated when combined with modafinil
  • Similarities and differences between the effects of modafinil and cocaine on neurotransmitters
    • Cocaine blocks more than just the dopamine transporter, also the serotonin and noradrenaline transporters while modafinil blocks only the dopamine transporter
    • The pharmacokinetic response is slower in modafinil than cocaine
    • Snorting, smoking, injecting cocaine into veins brings on euphoria
    • How you use cocaine makes a difference in its effect on the body
    • No way to change the pharmacokinetics of modafinil (no direct shot to the brain)

-Why Jonathan has never used modafinil personally…1:05:50

-And much more!


Click here for the full written transcript of this podcast episode.

Resources from this episode:

Jonathan Wisor

BGF podcast with Dan Pardi

– Gear and supplements:

– Other studies and articles:

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Do you have questions, thoughts, or feedback for Jonathan or me? Leave your comments below and one of us will reply!

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