Is Modafinil the Next Cocaine? Probably Not

Ugh, I’m sorry guys, the intertubes ate the last half of my post last night. I’m not at all sure what happened. Here’s what I can remember.
First of all, a quick reminder to please take my survey on condom breakage! I may have to make another survey eventually, I am now realizing a whole bunch of questions I missed. But please take it! I’m going to try my best to present the data on Friday.
So here’s Sci, pondering away about what to present for her Journal Club presentation next week, when BEHOLD! Dr. Pal drops this little article right in my inbox. Right on cue, Dr. Pal. Unfortunately, I’m not the first to get to this article (shakes fist momentarily at the Corpus Callosum, but he did a good job of it, so I can’t be mad), but I’ve got my own thoughts. So here we have the first one in a series of papers I could present for Journal Club. As a new addendum to help me make up my mind, I’ll be listing the pros and cons of each paper at the end of my article coverage. And I would welcome any votes! Volkow et al. “Effects of modafinil on dopamine and dopamine transporters in the male human brain”. JAMA, 2009.
never sleep.jpg

So first off, what IS modafinil? Right now, modafinil is marketed as Provigil, a drug used primarily in the treatment of narcolepsy. Up until recently, it was thought that modafinil was a non-dopamine stimulant. Most stimulants, such as cocaine and amphetamine, have their mechanism of action by increasing the amounts of dopamine present in the synapses between neurons (for more on dopamine, check out my previous post on it. I also have a post on cocaine, if you’re curious. Yeah, you know you are).
But modafinil was thought to be different, and instead of stimulating and promoting wakefulness via interactions with the dopamine transporter, like cocaine, it was thought to have its effects on other neurotransmitters, such as histamine, epinephrine, GABA, and glutamate. Recent studies, however, have shown that modafinil probably has some dopaminergic properties, just like other stimulants, by interacting with the dopamine transporter.
Studies in rodents have shown that modafinil can increase dopamine in the brain, specifically in an area called the nucleus accumbens. This is not only one of the main focuses for psychostimulant action, it is ALSO thought to be an important area for the initial rewarding effects of drugs like cocaine and amphetamine. In other words, the nucleus accumbens is thought to be where you get your hit, and increases in dopamine may initially represent the hit.
These findings in rodents, that modafinil increased dopamine in the nucleus accumbens, were kind of a cause for worry. Modafinil is not only prescribed to large numbers of people, it is also being used illicitly for cognitive enhancement, and there are some people out there who want to promote it as a safe, cognitive enhancing alternative to stimulants such as Ritalin and Adderall, which have higher abuse potential. But, if modafinil increases dopamine in the nucleus accumbens, it’s possible that IT could have abuse potential as well.
So in this study, the authors looks at the effects of modafinil on dopamine levels in the brains of humans. They ran 10 men through a PET study with two different levels of modafinil. They found that modafinil, at the doses prescribed, DOES in fact increase dopamine in the brain, specifically in the nucleus accumbens and in other brain regions closely connected with it (such as the caudate and putamen). Not only that, it increases dopamine about the same amount as methylphenidate would. Methylphenidate is also known as Ritalin, and is known to have some abuse potential. They concluded that we may have to re-evaluate whether or not we hand out modafinil like candy. If modafinil can increase dopamine in the nucleus accumbens, it could have addictive potential.
Unfortunately, the media kind of took this and ran with it, and the next time I know I’m seeing headlines like this:

My first thought on seeing this was “whoa, people, let’s not get our panties all in a twist”. Everyone seems to be fixating on one thing in the paper, that modafinil increased dopamine in the nucleus accumbens. What they’re MISSING is that they also took behavioral measures of all the people as they were being scanned. These measures look for things like changes in heart rate, but they ALSO ask questions like “how high do you feel right now?” “how euphoric do you feel right now?”
And you know what? None of the study subjects felt a thing. Because this turned out to be nonsignificant, it was relegated to a small sentence in the first paragraph of the results section. But it’s not insignificant at all. Modafinil may increase dopamine levels in the nucleus accumbens, and so may have abuse potential, but this is not taking into account that, at the doses used, people did NOT find it rewarding. It didn’t get them high. And if it doesn’t get you high, what are the odds you’re going to do it?
The major way that pharmacologists decide whether or not a drug is addictive is NOT whether it increases dopamine in the nucleus accumbens. Rather, it is whether or not you can get an animal to hit a lever for it. Results with modafinil are mixed. Some reports with rats show no administration of modafinil, while other reports in monkeys show administration taking place in animals previously trained with cocaine. So the odds are, it is reinforcing. But not much.
On the other hand, people DO take modafinil for its cognitive enhancement effects, regardless of whether it gives them a high. This, coupled with increases in dopamine in the nucleus accumbens, could make modafinil a problem to those who do it often. So maybe we shouldn’t hand it out like candy. On the other OTHER hand, other drugs, such as Ritalin, ALSO increase dopamine in the nucleus accumbens, without providing effects of “drug liking” (at least not when taken orally in pill form), and we certainly hand them out like candy. So while I wouldn’t want to take medication away from narcoleptics, I am not a fan of handing out cognitive enhancers that might have stimulant properties to any and all comers.
Basically, I think we need more studies. A couple of contradictory self-administration studies and some studies on dopamine effects in the brain, in this case, just isn’t enough to prove the drug “addictive”. And is modafinil the next cocaine? Probably not. It just doesn’t have the powerful reinforcing and rewarding effects. Not only that, it’s usually taken as a pill, and so highs resulting from it are more unlikely. Still, the authors of the study may be right. We should step back and take some more data before we pass final judgement.

17 Responses

  1. [… P]eople DO take modafinil for its cognitive enhancement effects, regardless of whether it gives them a high. This, coupled with increases in dopamine in the nucleus accumbens, could make modafinil a problem to those who do it often.

    Personally, given how much I enjoy using my cognitive functions, I would expect any cognitive enhancer to increase dopamine in my nucleus accumbens. I wonder how the subjects of this study felt about abstract thinking (ie do they enjoy it)?

  2. I suffer from excessive daytime drowsiness (EDD) and was on Provigil for year. It kept me alert and focused during the day and I only used it on days I had to go to work. No high what-so-ever. Also I would not say that I felt addicted to it. Sometimes it did make me feel like I was having panic attacks. I no longer use it, but still suffer from EDD.

  3. I’ve been using low does (i.e. 10mg of adderall) to help with my mild sleep apnea. It helps a lot. My doc perscribed provigil — I took it… it did nothing. Normally I react quickly to caffeen or adderall– but with provigil it was like I took a sugar pill. I even got another perscription and went to a different pharmacy. Even after taking it for 10 days– it didn’t make me feel alert or even not tired.
    Any thoughts why? What would make provigil work for certain people? As for me, I’m going in for surgery soon to get my tonsils removed. Should clear up the whole mess.

  4. John: I can safely say that I have no idea. Adderall is a dopamine, serotonin, and norepinephrine releasing agent, while modafinil works…well…we’re not entirely sure how it works, there are implications with histamine, epinephrine, norepinephrine, dopamine, etc. So it could just be that you were insensitive to the way modafinil works, while the straight up stimulant helps. Incidentally, I’ve never heard of a stimulant being prescribed for sleep apnea. That’s really interesting! Good luck with your tonsil removal! Eat many popsicles.
    And Danimal, your EDD certainly has never hampered your ability to make lucid comments! I am super impressed.

  5. Is is Modafanil or Modafinil? I saw the title, laughed, thought it was a modafakking funny name for a chemical, then realized joke won’t work if it is modafinil, dammit!

  6. Whoops, Arvind, you’re right, it IS Modafinil…

  7. Decades ago, I was addicted to “speed” (amphetamines) for a few years. I remember only too well the desperate craving, and the trouble I had withdrawing. Ritalin affected me just like speed, BTW. Let’s not even mention cocaine.
    Recently, I was prescribed Provigil for fatigue and sleepiness (e.g. while driving), residual to an episode of depression that was otherwise in remittance. It woke me up and brightened my mood, but even though I took up to 400mg daily (it is somewhat tolerance-inducing) for a couple of years, I was able to stop without any physical or psychological withdrawal.
    In my experience, modafinil is more fun than caffeine, but much more benign than speed, Ritalin or coke. Your mileage may vary, of course. My only complaint is that it’s way expensive — that’s why I stopped taking it, my insurance wouldn’t pay for it anymore. I find I’m awake enough without it now, anyway.

  8. Abby –
    Just out of curiosity, when you were using Ritalin, were you ingesting it or snorting it? Because I have noted a hella big difference in the effects (not with Ritalin, but with meth).
    My first experience with meth scared the hell out of me, because it was extremely potent (came in crystals that looked like minimally flawed quartz – no color) and in spite of really wanting to try to sleep, I couldn’t stop. Though I didn’t have too much trouble when the party ended – but that is very much a DuWayne thing – abuse the shit out of highly addictive drugs and walk away when it runs out.
    It took a close friend quite a while to convince me to try meth again, only instead of snorting it, he suggested that I put a wee bit in my coffee on days I needed an extra boost. Even he was surprised at how long it took me to actually finish the teener, better than a month. I only used it when I really needed to focus. And while I did mention my lack of susceptibility to highly addictive substances, I want to be clear that I am very much a “if it’s in front of me, I will do it” kind of guy. That can now be amended to “if I try a little and it’s in front of me I’ll do it,” but at thirty-two I should hope to have gained that much self-control.
    I’m just curious, because I’ve run across few enough “recreational” speed users who actually ingest it, as apposed to snorting or smoking it. Most of the people I know who ingest it have ADHD and I’ve noticed that a lot of people with ADHD tend to have a similar experience to my own, when it comes to addictions.

  9. “The major way that pharmacologists decide whether or not a drug is addictive is NOT whether it increases dopamine in the nucleus accumbens. Rather, it is whether or not you can get an animal to hit a lever for it. Results with modafinil are mixed.”
    Right – as I’ve gone on about at length before, neuroscience can tell you how behaviours happen, but it doesn’t tell you anything about what the behaviour is. It can tell why a certain drug is “addictive”, but not whether it’s addictive.
    As for modafinil, I still can’t spell it after all these years. Maybe I need to take some.

  10. Like Danimal, I also have EDD. Modafinil doesn’t make me feel high, and that’s exactly why I like it. It is very effective at keeping me alert and focused, but it rarely makes me feel jittery or panicky. I’ve tried Adderall in the past, and I just couldn’t tolerate it. I have been taking Modafinil for a few years now (I don’t take it every day; just when I need it) and I have noticed that if I take it regularly for a few months, it will actually make me feel more drowsy, and I have to stop taking it for a few weeks until it is effective again.

  11. John
    There is a common genetic polymorphism that around 25% of european descended people have that seem to be associated with an almost complete lack of response to modafinil. you might be on of those people.
    I read the paper as well. 18 authors and 10 people and it got into JAMA was the first shock. The drug has been around since the 80s. What’s new here?
    Secondly I didn’t understand the bit about injecting cocaine. Does that mean they are studying the effects of modafinil on cocaine or the direct effects of modafinil? Sadly my neurosci skills are way below understanding the reason for doing it that way.

  12. I was prescribed Modafinil for sleep apnea and have one serious side effect – complete loss of appetite. This is a catastrophe, since I am underweight as it is, and I had to stop taking it. But I concur with most of the others – it does not make you high and I can’t ever see it as a recreational drug.

  13. The information about modafinil for cocaine addiction is helpful. Can you recommend a way to talk to a doctor about prescribing modafinil for this purpose? Are there any additional clinical trials/studies at present that may be using modafinil for cocaine addiction? Your response is very much appreciated.

  14. All these people saying they cant see Modafnil as a recreational drug really spins me out. I have taken it on 2 occasions when i went out only and i had the best time. Better than any amphetamine i have had and i have taken all of them apart from ice. It makes you more alert, much more talkative. Its actually quite dangerous because it takes away the feeling of giving a shit and you can get yourself in some dangerous situations. Best thing is you feel normal.. you don’t feel like you are under the influence of a drug but are confident and don’t stop talking.
    I guess people want to feel smashed when they take drugs. I dont like that feeling. Mods make you feel like you can do anything but you dont know why. The danger is a think im straight but im totally off my chops and do shit i would never do if i was not on mods.
    Dont take this stuff.. can easily get hooked i recon. Not that i am.

  15. Has anyone been prescribed Modafinil for bipolar depression? Antidepressants are not very useful in the long term for this. I read that trials have been done, with some evidence of mania trigger. But I would like to try it because of the lack of energy that goes along with depression.

  16. My lab recently went over this paper and another: Modafinil does not serve as a reinforcer in cocaine abusers Based in the new publication linked above, it seems likely that modafinil does have DAT effects in vivo, but isn’t really subjectively cocaine-like to cocaine users.

  17. I have taken modafinil and cocaine. And modafinil is NOT addictive at all.

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