“Oh no, I would never do cocaine– I’m much smarter than that. But I have a close friend who isn’t.

He took it through the nose, which left a drip in the back of his throat that tasted like pulverized clam shells and made his tongue numb…

Otherwise, he wasn’t impressed, and he did not want to do it again, which surprised him when he learned how addictive cocaine is. He doesn’t know why he got lucky. Maybe it was because he has ADHD? Maybe because he took Ritalin as a child? But Ritalin doesn’t work on the same part of the brain as cocaine, does it?”

You are smart never to do cocaine. 🙂 I would sure as heck never do that stuff. Chocolate will always be my personal drug of choice. Though now I’m really curious as to what exactly pulverised clam shells tastes like…

But as information for the masses (because I has it), cocaine and Ritalin actually work in a very similar way. I’m going to try very hard to explain this without excessive use of science-speak, partially because I don’t want people to give up reading halfway through with a headache, and partially because I would like to improve my science writing. And finally, because I think this stuff is INSANELY COOL. And I can’t deny that it would be great if everyone else thought it was cool, too. But it will involve some background.

So to begin with, I’m sure everyone knows that your brain is made up of cells. And I’m sure you all know that these cells communicate with each other all the time. They communicate with each other by releasing chemicals called neurotransmitters. These neurotransmitters pass into the space between cells, hitting receptors on the other side, and allowed cellular communication to take place. Three of these chemicals are important here: Dopamine (DA), Serotonin (5-HT), and Norepinephrine (NE). They are very important to me, because they are what I study. 🙂

These three chemicals have been getting a lot of press lately. Norepinephrine, which is related to epinephrine (adrenaline), has tons of different uses in the body. Where it is important in drugs is where it speeds up your heart rate and initiates your “fight or flight” reflex.

Serotonin, which I’m sure you have heard of, is mostly known because of its effects on mood. Most of the antidepressants out on the market right now directly increase the levels of serotonin in your brain. We’ve known for a long time that low levels of serotonin increase aggressive behavior, irritability, and of course can contribute to depression (though the actual explanation is a LOT more complex than that, that’s not what I’m talking about right now, and this post will be plenty long anyway). Another thing serotonin is important in right now is in migraine treatments. A lot of the new migraine drugs out there target serotonin receptors (the best known one for this is Topamax. Only slightly less well known is this: BIG increases in serotonin in your brain can cause hallucinations. LSD is almost exclusively a serotonin drug. This is also why many people who get migraines get aura, which is a kind of hallucination.

Dopamine (which is the biggest one when dealing with cocaine and Ritalin), sounds like ‘Dope’ for a very good reason.  It is often called the “feel good” molecule. But dopamine was FIRST known because it is one of the very key things in Parkinson’s Disease. Dopamine not only makes you feel good, it is very important in initiating movements and generally in locomotor activity. But where dopamine is important in addictive drugs is where it makes you feel good. Scientists believe that you can classify a drug as potentially addictive if it increases dopamine in your brain, specifically in an area called the Nucleus Accumbens, which is considered to be the reward center of the brain. Dopamine increases there happen when you eat food you like, have sex, and actually also occur in response to rock and roll (or other kinds of music if you don’t like rock and roll).

So you know that these are all neurotransmitters that send chemical messages from cell to cell. But once the chemicals have been released into the synapse, where do they go? If they stayed around, they would just keep stimulating the receptors on the other cell, over and over again, causing the messages to keep going. Which is not a good idea. So cell have transporters in their membranes. When dopamine, serotonin, or norepiphrine is released, they get sucked back up into the cell by the transporters, so that the signal to the other cell is terminated very quickly (we’re talking microseconds). This also helps your brain recycle the transmitters so they can be used over again, so you don’t have to make new neurotransmitters each time, which saves a LOT of energy (people estimate that if you had to make all of your chemicals instead of recycling them, our minimum calorie requirement would be 5,000 per day!). These transporters are very important when we’re talking about cocaine.

So, we’ve got dopamine, serotonin, and norepinephrine. We’ve got transporters that help recycle. On to the drugs.

Cocaine: cocaine is what we call a “psychostimulant“, and I’m sure you have heard it referred to as a stimulant before. And obviously this is because it stimulates you. Cocaine increases dopamine, serotonin, and norepinephrine in the brain, basically highjacking your natural reward and mood centers. Cocaine works by blocking the transporters that usually recycle dopamine, serotonin, and norepinephrine. This means that the neurotransmitters have no where to go, and build up outside the cells, stimulating the receptors over and over and over again. This makes you feel GREAT (my advisor jokes that cocaine is the best anti-depressant there ever was), and is what is responsible for the ‘high’ that coke users experience. Because it increases dopamine, it also make you move around a lot and stimulates your pleasure centers, hence the stimluant. The increases in serotonin are why you feel great. The increases in norepinephrine are why coke users also often feel paranoid (fight or flight, anyone?).

Obviously, there are problems with this. Your brain was never built to feel that kind of rush. The three systems are completely overwhelmed. I’ll add here that other systems get overwhelmed. Cocaine is not only an addictive drug, it is a topical anesthetic (which is why snorting cocaine makes your nose go numb, a fellow grad student actually had an 8th grader ask her that once), and it also causes rapid increases in blood pressure. One of the major side effects of high doses of cocaine is a heart attack.

So you feel this huge rush, your systems are totally flooded, you feel GREAT. And then, 20 minutes later, it’s gone. And, to some people, there is nothing that feels quite like it. Nothing is ever as good, because nothing natural can ever get your neurotransmitters that high. So they want to do it again, and again, and again.

But of course your brain can’t handle this very well. In fact, it handles it very badly. These neurotransmitters normally hit receptors to transmit messages. If coke is around a lot, the neurotransmitters are really high, and the receptors get overwhelmed. They stress, they freakout, they have nervous breakdowns, and they desensitize. So then, when the cocaine is gone, and your neurotransmitter levels are normal again, the receptors can’t FEEL normal levels of neurotransmitter anymore, because they’re too used to being whacked over the head with the high levels of neurotransmitter you get from coke. And then you don’t feel normal, you feel awful. Not only does this mean you feel awful, it means that when you take coke again, the receptors can’t feel the rush as much, and you DON’T GET AS HIGH. We call this tolerance. And with tolerance, comes more coke, and more tolerance, and more coke, and then you’re living out on the streets and selling yourself for your next hit.

As a kind of side note, there are many other psychostimulants out there. Most of them work in slightly different ways, but all of them cause extreme increases in dopamine in the nucleus accumbens (except for caffeine, but that’s a very different animal). Others that you might know are things like amphetamine, Meth, ecstasy, etc.

So, cocaine = bad. On to Ritalin.

Ritalin is actually a drug called methylphenidate (but I’ll call it Ritalin anyway, it’s easier). Methylphenidate is a chemical that is very closely related to amphetamine. But it works in a very similar way to cocaine. Methylphenidate increases dopamine and norepinephrine in the brain by blocking the dopamine and norepinephrine transporters. Unlike cocaine, it does NOT block the serotonin transporter, and so has no direct effects on serotonin (which is the topic of my thesis and is TOTALLY CRAZY). Lots of studies in animals have shown that animals will self-administer (which means shoot themselves up) with Ritalin without a problem, and they will use it as a substitute for cocaine if they can’t get cocaine.

So Ritalin is a psychostimulant, like cocaine. Why aren’t people with ADHD addicted to it? And why do people with ADHD take it in the first place?

I’m going to try and start with why people with ADHD take it in the first place. ADHD (attention-deficit hyperactivity disorder) is a disorder that’s usually noticed first in children, though 60% of children who have it will keep having the symptoms even as adults. The symptoms include decreased academic performance, social isolation and difficulties with social skills, inability to concentrate, inability to sit still, etc, etc. Right now, we think that maybe about 5% of the US population may show signs of ADHD. (I could go into why I think some of this is bogus and why I think we’re overtreating a LOT of kids, but that’s not the purpose of this post.)

So they’re hyper, they can’t sit still, why the heck would we give them a STIMULANT? And the weird thing is, stimulants in children with ADHD calm them down! At first, nobody knew why, and we’re still bickering about it. Most people write a lot of articles about the “paradoxical” effects of Ritalin on children with ADHD.

But pretty recently, some work came out that may help to clear things up.  The paper is Gainetdinov et al, published in Science in 1999. They were working with mice that were genetically altered to have really HIGH levels of dopamine (called dopamine-transporter knockout mice, or DAT-KO). These mice were really hyperactive, couldn’t learn, and couldn’t pay attention (sound familiar?). When they gave these mice Ritalin, they calmed down! They stopped moving around and got pretty slow. It turned out that mice with no dopamine transporter have dopamine signalling mediated through SEROTONIN.  This is totally wild, and there’s a lot of new work coming out on this.

So anyway. There are still lots of ideas as to why Ritalin works for ADHD, and I have my own pet theory that I might explain some other time. So Ritalin works for kids with ADHD. Why aren’t they addicted to it? It IS addictive, and you can abuse it just fine (and people DO abuse it, mostly to stay up all night either drinking or studying).

Most of the reason people aren’t addicted to Ritalin when we give it to them is because of the WAY we give it to them. When we give Ritalin as a pill, it goes to the stomach to get digested and then goes in to the bloodstream. The net result of this is that it takes a LONG time to get to your brain. Ritalin also lasts a good long while (about 5 hours between doses), and we give it in VERY small doses. So, because it takes a long time, and because it lasts so long, you don’t get the fast rush that you would get with something like cocaine (or that you would get if you snorted, smoked, or injected Ritalin).  Most of this is from work done by Nora Volkow, who’s currently the head of the National Institute on Drug Abuse.  She published this stuff in the Journal of Neuroscience in 2001.

Ok, so we give people Ritalin, and we give it to them for a long time. Increasing dopamine everywhere in your brain for a long time is going to cause some changes. Right now the big changes that we’re looking at are to a certain kind of dopamine receptor, called D2 (you remember that neurotransmitters hit receptors to send messages). We have found that if you have really low levels of D2 receptors, you are much more likely to abuse cocaine and other drugs. However, if you have really HIGH levels of D2, you are much LESS likely to abuse drugs (Nora Volkow found all this in humans in 2002 and published it in Synapse). Apparently high levels of D2 make getting high far less enjoyable than it would be otherwise.

And now we tie it all in together. People who have taken Ritalin for a really long time have changes in their brains by the time they are adults. We think (right now we only know for sure by looking in rats, Dr. Thanos out of Nora Volkow’s lab at The National Institute on Drug Abuse published this study in Pharmacology, Biochemistry, and Behavior in 2007) that long-term Ritalin makes you have really high levels of D2 receptors as an adult. This means that, if you take Ritalin throughout your childhood, and then try cocaine as an adult, you will like it LESS, or not like it at all.

So there’s your answer. Sorry it took so long…

Take home message #1: if you took Ritalin for a long time as a child, you won’t like cocaine much as an adult.

Take home message #2: Don’t abuse cocaine, or Ritalin for that matter.

6 Responses

  1. […] I’m taking a whack at it, for the edification of anyone who wants to read it (I did a previous post on the modern pharmacology of cocaine, how it works, and the addiction process).  And besides, who […]

  2. […] now I'm taking a whack at it, for the edification of anyone who wants to read it (I did a previous post on the modern pharmacology of cocaine, how it works, and the addiction process). And besides, who […]

  3. […] Cocaine is what's known as a psychomotor stimulant, which increases extracellular concentrations of neurotransmitters by blocking their reuptake from the synapse back in to the cell. Cocaine is known to act at the dopamine (DA), norepinephrine (NE), and serotonin transporters, and for a while, there was a lot of debate as which neurotransmitters was responsible for the whole "high" thing. Some experiments said DA, some said NE. So this experiment decided to look at both. What they did was to chemically lesion (basically inactivate) the NE and DA areas of the brain that had been narrowed down as possibly being involved in cocaine reinforcement. The trick? They did this in rats that had been self-administering cocaine. An aside on cocaine self-administration: Self-administration is a big deal in the drug abuse field. It's thought to be the closest mimic we have to an addict on the street. Except without the street, and the crack dealer, and the money changing hands, and the whole ruining your life and you can't feed your family bit. Ok, so it's not all that close. Still, it's better than just picking a rat up and injecting it over and over again, because in this case, the rat has to make a choice, and has to 'work' to get its hit. […]

  4. […] Today is the day. Today, one year ago, the very first post went up at Sci's old place. […]

  5. […] I’m taking a whack at it, for the edification of anyone who wants to read it (I did a previous post on the modern pharmacology of cocaine, how it works, and the addiction process). And besides, who […]

  6. I stumbled upon this post and was surprised in a good way at how well you explained the pharmaceutical nature of stimulants.

    I have ADHD I am also in my fifties and agree with most of what you are saying here.
    A couple of things to add
    I suffered from “had to go to Hospital” type migraine, but within 2 weeks of starting the stimulent my headaches disappeared and I have in 15 years only 1 attack but I had run out of meds. I also have a identical twin and to this day he still gets the head aches.
    I don’t a high or euphoric feeling when taking opoiod pain meds they work well but I get no buzz, the same for cosine, the only other thing is I cannot take paracetamol and stimulents as it makes me violently ill.
    In regards to people using stimulents to achieve an all night study test, this I find is not as pronounced in myself, but if I am interested in something or I have an immovable deadline I can hyper focus the a very long time, it won’t put a time here as people reading simply won’t believe that is possible. I have been able to hyper focus all my life and thought it was normal, but I would get frustrated when other couldn’t do it.
    Without the stimulents yes you can operate at normal levels but because your brain is going at million kilometres an hour the fatigue is crippling.
    So I will finish by saying that when the world is looking at banning drugs because they might cause addiction, they need the medical community to stand up and point out that there are a large group for which addiction doesn’t occur.
    Thank you for a fantastic post

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