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.
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:
- “Modafinil has potential for abuse, study says” – The LA Times
- “Study: Modafinil increases dopamine, could be addictive” – SmartBrief
- “Study: ‘Smart drug’ Provigil may be habit-forming” – The Associated Press
- “Study says Provigil may be addictive” – The Philidelphia Enquirer
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.