A co-worker, colleague, and fellow student of mine approached me a long time ago saying she had a story that I absolutely had to hear. While home for the Christmas holidays, she wound up talking with some in-laws and family friends. One of these people turned out to be some sort of naturopathic practitioner. There was some disagreement about the value of statins, as could be expected (apparently someone suggested that everyone on statins should just take high-dose vitamin E instead). But the part that interested me was the fact that my colleague wound up having to explain the dopamine hypothesis of ADHD.
In short, the naturopath didn't understand why hyperactivity was commonly treated with stimulants. This is a reasonable question if you don't understand how amphetamines work. Most ADHD drugs are prescription amphetamines, essentially "Speed" used for a legitimate medical purpose. The same drugs are also sometimes used for narcolepsy. On the surface, it really does seem like a massive contradiction. Why give children who are having trouble focusing because they can't sit still stimulants?
The current hypothesis supposes that ADHD is at least in part caused by an insufficient quantity of the neurotransmitter dopamine in the brain and central nervous system. Dopamine is associated with pleasure and reward; in fact, all addictive drugs, directly or indirectly, have some effect on dopamine pathways in the brain. In ADHD, insufficient dopamine results in "lack of satisfaction," resulting in children and adults with ADHD being unable to focus on tasks. In essence, their brains are not programmed to acknowledge task completion as worthwhile, making it difficult to concentrate; the brain is too busy trying to find something else to do that is worthwhile. Many stimulants, amphetamines included, increase the concentration of dopamine in the brain. Appropriate stimulation of the brain and central nervous system increases "satisfaction" in patients with ADHD and allows them to focus more effectively.
Unfortunately, amphetamines have other side-effects. They speed up the heart, increase blood pressure, and, if the dose is too high, may cause insomnia, jitteriness, and anxiety. So the naturopath's next question was reasonable. "If dopamine is low, why can't you just give kids with ADHD dopamine?"
I don't expect laymen to know the answer to that question. I do expect anyone with an understanding of pharmacology to know. Naturopaths claim they understand the workings of the human body. Clearly, drug bioavailability is beyond their expertise.
There are a whole slew of reasons why you can't just take dopamine tablets. Some of them are specific to dopamine; others are general drug issues. Bioavailability sounds like a tough word, but its meaning is actually fairly simple. Essentially, bioavailability is a measure of how much of a drug the body can use after the drug is given. In order for a drug to have an effect, it has to reach its site of action. An anaesthetic has to diffuse into nerves before it can produce a numbing effect. Drugs designed to lower blood pressure have to be able to access the heart, arteries, and veins.
When you swallow a tablet, it goes to the stomach and is broken down to release its contents. In order to get into the bloodstream, the active drug must cross body membranes; otherwise, it will proceed through the intestines and be expelled unchanged. Luckily, your intestines have a large surface area and are good at absorbing things--otherwise, eating would be rather pointless, because you wouldn't be able to get any of the nutritional value from your food. However, there are limits to what is allowed to cross the intestinal membrane. Some drugs or chemicals can't cross it at all. In fact, some drugs are designed not to cross the membrane; they stay in the intestine and do their work right there. Alli is a good example. It doesn't need to be absorbed into the body. It stays in the intestine and binds fat molecules, preventing them from being absorbed.
Once a drug is across the intestine and in the bloodstream, the first stop is the liver. The liver is responsible for removing poisons from the body; it would be irresponsible for your body to deliver absorbed substances directly to organs like the heart and brain without filtering the contents first!
The liver is responsible for breaking down many drugs introduced to the body, usually by adding or removing a chemical group to inactivate the drug or make it water-soluble so that it can be excreted more readily. The liver does this to substances your body makes naturally, too; when red blood cells die (they only live about 120 days), the liver modifies the remnants, recycles them, and converts the waste products to a form your body can easily get rid of.
There's an enzyme called COMT (or catechol-O-methyl transferase) that's responsible for breaking down neurotransmitters like epinephrine (also called adrenaline, depending on which side of the pond you're on), norepinephrine, and dopamine. If we gave dopamine by mouth, COMT in the liver would rapidly inactivate most of the dose, assuming it were absorbed across the intestinal membrane.
So give a higher dose, you say. Or give it by some other route. You can bypass the liver in a lot of different ways; inhalation, injection, tablets absorbed through the cheek or under the tongue, skin patches or creams...
Let's go for broke and say we inject ADHD patients with dopamine shots like we give insulin to diabetics. What's going to happen?
Increased heart rate, first of all. Dopamine acts directly on the heart. It has different functions in different parts of the body, though dopamine isn't the primary regulator of heart rate (that would be due to the combined efforts of epinephrine and acetylcholine, which is also the neurotransmitter that is responsible for muscle contractions). It will increase blood pressure, too. Same side-effects as amphetamines, more or less. In fact, dopamine is sometimes used in emergency situations to raise patient BP and heart rate (though a synthetic alternative, dobutamine, is actually better for the task). But isn't it a more natural way to deal with dopamine insufficiency in the brain?
Nope. Here's why.
The blood-brain barrier is essentially the brain's defensive perimeter. It is composed of tightly-jammed cells that are designed to keep out miscellaneous poisons and waste products to prevent damage to the central nervous system. In order for a drug to affect the brain, it has to cross the BBB. Lots of drugs do. But dopamine doesn't. The brain would like to keep the dopamine it has...in the brain. The BBB prevents dopamine from escaping or entering.
Let's summarize. Extensive metabolism will break down an oral dose of dopamine very quickly. And even if we bypass the liver, the dopamine will never enter the brain. We'd have to inject the dopamine directly into the brain with a long needle. Try to get your kid to hold still while you do that. Even if we could get dopamine directly into the brain, neurons are good at recycling or re-absorbing stray neurotransmitters. The best case scenario is that we'd get a very brief improvement. The worst case scenario is that we'd go overboard on the dopamine level and the kid would have hallucinations.
Dopamine, in short, is a crappy drug. The solution is to give other substances (amphetamines) that indirectly increase dopamine levels to push the brain in the right direction. And you know what? It works. Sometimes the chemical your body would use to naturally regulate a function isn't something we can easily replace or modify directly.
So that's why we give hyperactive kids uppers to chill them out. It seems counterintuitive at first, but there is a good explanation. And the theory behind the dopamine hypothesis holds up in clinical trials; kids (and adults) treated with amphetamine do get better.
Isn't pharmacology fascinating?