August 27, 2020
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.
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:
- A sleep disorder that prevents quality sleep at night (narcolepsy, insomnia, sleep apnea); sleepiness secondary to a sleep disorder; modafinil addresses daytime sleepiness
- Sleep apnea treatment: continuous positive airway pressure machine (CPAP) machine
- Situational sleep disorders (nighttime work, newborn children, aging parents, etc.)
- Motivational daytime sleepiness (intentionally restricting nighttime sleep)
- A sleep disorder that prevents quality sleep at night (narcolepsy, insomnia, sleep apnea); sleepiness secondary to a sleep disorder; modafinil addresses daytime sleepiness
- 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, berberine, California 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:
– Gear and supplements:
- Morozko Forge (use code BENFORGE to save $150)
- Blue light blocking glasses
- Melatonin
- Grapefruit seed extract
- Bacopa
- Berberine
- California poppy
- Theanine
- Marshmallow root
- Inulin
– Other studies and articles:
- Modafinil Studies
- Mechanisms of modafinil: A review of current research
- Effects of acute modafinil ingestion on exercise time to exhaustion
- The safety of modafinil in combination with oral Δ9-tetrahydrocannabinol in humans
Episode sponsors:
–Kion Creatine: Fuel your performance, energy, and strength with Kion Creatine, made with 100% Creapure®. You can grab your own Kion Creatine now at getkion.com and save 10% off your first order with discount code BEN10.
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I’m really intrigued – I didn’t know that alcohol was such a bad combo but makes sense if they’re both processed by the liver. Thanks for sharing
i have been put on tamoxifen and have subsequently been sleeping about 12 hours a night. would this be a good option for me in that scenario?
What are your thoughts on Adrafinil? It is legal to buy in the US and since it is a precursor to modafinil it achieves the same effects.
Is there a possibility that Modafinil causes ED? Also, does it decrease appetite? TY
Armodafinil makes me hard and Horny as a jack rabbit. And always toward the second half of the cycle (last 5 hours, or so).
Most likely due to the up-regulation of Histamine
Hey Ben,
Enjoyed the podcast. My doctor gave me a prescription for Modafinil a few years back and I have taken it off and on throughout that time and have definitely seen the positive side of it when taken properly. One thing of note that you discussed in the podcast was the Modafinil + L-Theanine stack. I did some research into this when I first started taking the Modafinil for cognition.
Modafinil + coffee gave me a feeling of anxiousness so I wanted to find a way around that. I had used L-Theanine to counteract the occasional jitters I would get from coffee so I figured it would be helpful with Modafinil as well. Upon doing some research around this specific area I learned that is it possible that Modafinil + L-Theanine is counterproductive. L-Theanine boosts your GABA production to provide that calming sensation that you get when taking it. I found that Modafinil on the other hand blocks your GABA receptors. So taking these two together reduces the effect of Modafinil’s wakefulness.
Wanted to see if you have seen anything in this area. Thanks!
@Anna Kungxat To clarify, I am the second ‘Ben’ (the one that used the word superfluous) and was replying to the original ‘Ben’ (an likely ‘Anna’s Miserable Husband’, as I agree that his comment was completely unnecessary.
@Ben (the hateful one), why even post that crap? This podcast is for people that want to better themselves and help others do the same – nothing you’re writing is in line with this ethos so why are you a) posting and b) here? Go elsewhere and spread your hate.
**Allergic response to Nuvigil (R-modafinil) developed over time**
Hi Ben,
Great podcast–I personally used R-modafinil (nuvigil) in college, and I developed an allergic reaction to this compound over the course of a few months. I would develop a hive on my face in the same exact spot every time I took it, so I stopped as I was worried about a generalized inflammatory response (my whole body would also become a bit tingly and hot). Interestingly, two people very close to me who were also taking nuvigil ALSO developed an allergic (hive) response over the course of months! The one individual would develop a hive in the same exact spot every time on his hand, and the other individual formed a hive on his lower back. These hives also were accompanied by the warm/tingling sensation throughout the body that I had also experienced.
Given that 3 out of 3 people that I know (including myself) all developed allergic-type reactions to Nuvigil, it seems to me that it is likely a very common side effect. I have never taken Provigil (S-modafinil) so I can’t speak to the potential of allergic responses in this case.
Anyone else have a similar experience? Does anyone know if this reaction is less common with Provigil?
Alexis,
That is what I have.
I started to take it two months ago, 1/2 pill, 3-4 times a week. After about a month I started the hives and they itch to the point that I bleed. I stopped immediately. I still have the scars, in my elbows and my legs, a total of 4 places. I want to use something else because I was able to accomplish so much. Qualia doesn’t do it for me, I need to take 8-10 for the same effect of 1/2pill.
This is a pretty common side effect with Modafinil unfortunately. IIRC from research done a couple years ago, it is just an allergic reaction in your body and there isn’t really a way around. I haven’t taken rModaf, just normal Modaf and did not have a problem, YMMV.
Ben, interested in how you would compare/contrast Modafinil and Qualia? Is the difference in effectiveness worth the added hassle of trying to get Modafinil?
I just got my shipment of Lucy gum using your discount code. Though I am already brighter than most crayons in the box, I’m excited for the cognitive benefits, especially since I am taking physiology in college this year. I have listened to every podcast of yours that I’ve been able to get my hands on for the last 3 years, I look forward to every Thursday and Saturday morning and I never feel let down as I learn and am empowered to love a more enjoyable, adventurous and fulfilling life each time.. anyways I am concerned about feeling nauseous with nicotine, I eat nothing but organic whole foods, largely carnivorous (“bastardized”). I am in the best condition of my life. I do quarterly 100hr fasts and daily time restricted eating about 8hrs, and I do cold exposure everyday and exercise everyday except when honoring the sabbath on which days I just stretch and yoga and facia release (I’m sure you recall my last comment about calling you to be a fisher of men) My point is I’m doing right, and I just chewed a half a piece of Lucy gum, not even vigorously, parked it in my lip most of the time, and I already feel nauseous. All that to preface my question, even after doing all of that I feel nauseous from a tiny bit of nicotine, what ELSE can I do to help my nausea? Besides this lemon ginger tea that is working wonders
You’re making this too complicated. Take less gum.
1/4ths or 1/8ths. If you are that nicotine sensitive then you need to buy 2mg gum and do the same thing. Start with a 1/4 of a 2mg
Duh really? How rude, I’d like to get the cognitive benefit that surely won’t come with .25mg. Idk who says human physiology isn’t complicated, I’d like for my brain to be sensitive to it without my stomach being as sensitive
‘Duh’ is not being rude. Nicotine sensitivity is not in the ‘stomach’ or in the ‘brain’, it is in the entire body. So you if you are getting nauseous, then take less. You can get a cognitive benefit from .25mg, particularly if you are sensitive to it. Additionally, once you get used to a smaller dose, you can work your way up as sensitivity decreases.
Don’t default to think people are attacking you, ‘Duh’ is giving you good advice.
Peace.
I mean just the fact that he said “duh ug” seemed rather rude, thanks, and is I’ve taken that advise and also spit out my saliva instead of swallowing it I’ve had no more issues. And I definitely feel the cognitive benefits now that I can better tolerate the half stick. Thank you and God bless you all, one love
My name is Doug. Duh-ug
Thanks for this super interesting episode.
I personally feel like Modafinil is most effective on a day after a solid night’s sleep to really amplify one’s productivity/performance, best stacked with caffeine.
Also wouldn’t recommend taking it with too much regularity.
Thanks again!
Hi Ben,
I started to use it 4 weeks ago, I read and informed myself of all the side effects, and I took the risk. I took 1/2 a pill for 3 weeks 3-4 times a week as needed. The first week the days I didn’t take it, I was very depressed. Then in the last two weeks, I have big massive rashes in my arms and behind my legs. I stopped it a week ago but still have the rashes. Any advice?
I have heard that allergy medicines and time are the only solutions for this reaction – its an allergy reaction – either change the amount or discontinue – my friend was able to adapt taking half pill every other day
Thank you, I only took half the pill as mentioned, never a full doze. I will try the allergy meds.
If you’re referring to anti-histamines, I think that is an imperfect bandaid solution. Anti-histamines reduce acetylcholine and lower cognition. Probably better off just finding a different compound than Moda.
Also, 3-4x per week is frequent. What happens if you cut back to 1-2x per week?
Alex,
That is what I have.
I started to take it two months ago, 1/2 pill, 3-4 times a week. After about a month I started the hives and they itch to the point that I bleed. I stopped immediately. I still have the scars, in my elbows and my legs, a total of 4 places. I want to use something else because I was able to accomplish so much. Qualia doesn’t do it for me, I need to take 8-10 for the same effect of 1/2pill.
I did that for two weeks, still the same. I have completely stopped.
What do you suggest?
Hi Ben, one question that I wished was asked was if a user takes modafinil but still monitors their sleep with an oura ring and gets the required 8-9 hours each night – are there still potential down sides to supplementing with modafinil? Any insight here would be greatly appreciated.
Probably. I wouldn’t classify modafinil as a supplement. The more often you use it, the more potential downside. Considering that all pharmaceuticals have side effects (at least at the cellular level), moda does too. Acetaminophen has been around forever, and yet we are still discovering new side effects all the time. In 50 years we will probably know more about modafinil.
where does one even purchase this product?
https://modafinilxl.com
You will need a paypal account to purchase it, your bank will not approve it and decline it each time.
The safest place is a pharmacy with a Dr. prescription.
Really you’re bringing up Modafinil again? Fucking retarded.
This is not an appropriate word and response.
Anna stop being a cunt, Ben can say retard if he wants.
Really you’re contradicting your own opinion of a superfluous podcast by posting an even more superfluous comment? .
Is this Ben greenfield ? 👆🏻
Nope.
Dude, work on your choice of words, attitude and manners. The “R” word should never be used in that manner and purpose again. This is a decent site and using the thesaurus for the word “superflous’ doesn’t make you any smarter either. Good luck with your life.