A New Disease

What is addiction?

Let’s say we suddenly find a new disease. It's dangerous. It kills people. We’ve got to fix this fast. We have to find a cure, or if we can't find a cure, we have to find a way to control it. And in either case we want to find a way to prevent it. And we have to do it now. This sort of thing happens from time to time and epidemiologists have a procedure all worked out.

The first step is figuring out what causes it, and to do that, we have to figure out who has it and who doesn't. In epidemiology that's called case finding, and before you can do case finding you have to do case definition. After all it's a new disease, so no one really knows what it is yet.

So that's where everybody starts, defining the disease. Does it cause a fever? Is there a rash? Does it affect the old, the young? What subjective symptoms do people report? These things usually clarify themselves very quickly, so you would be forgiven for thinking that after 150 years of trying to fix something we wouldn't still be at the “defining the disease” stage, but with addiction that's exactly where we are.

Before the Civil War, the drug that caused the trouble was alcohol. Yes, there was food, and there was gambling, and there was sex, but those things all seemed within a normal range and they didn't stand out to society the way alcohol did. So addiction and alcoholism we're pretty much synonymous. Case definition was pretty easy: you drank too much.

After the Civil War, and its attendant increased demand for pain control from wounded soldiers of both sides, opiates became a bigger player in the American drug scene. There was some overlap of cases. There were “alcoholic inebriates” who were also “opiate inebriates.” But there were also cases in which they did not overlap, so the problems appeared to people to be different yet overlapping diseases.

As each new drug entered America, we saw it as a new scourge, a new disease, usually brought to our shores by some foreign people. We saw the disease of addiction like an infection with a clear-cut cause: drugs.

So our two-century American effort to fix addiction gave us case definitions, case finding procedures, and causes we could count on. Well, if we were right, we should've had the whole thing wrapped up in about 20 minutes. But it's been a great many years and the problem has only gotten worse. Maybe, it's time to start over looking at addiction as if it were a new disease. We could start the way every new disease starts, case definition. So what is addiction?

It isn’t drug use. There are millions of drug users in America without addiction. So how will we tell apart those people using drugs that have the illness and those that don’t? We could measure how much drug use a person does, but that doesn’t really work either. There are people who use a lot and don’t have addiction, and there are people who use a little and do. This case definition thing seems, on the surface, to be a hard task, and we can understand why those who came before us gave up and just used drug use criteria for their case definition. But that didn’t work, so we’ll have to try harder.

If it isn’t the drugs or how much drug, perhaps it’s what the drugs do. There are very old (from the 1930’s) findings on what drugs do to people with addiction. The first thing they do is fix something, and we can get more specific about that in a bit. The second thing the drugs do is create a craving for more drug. Let’s talk about that one first.

This phenomenon of craving after taking a dose of drug is not a normal response to any pharmaceutical. Let’s take alcohol for example. The average person takes a drink and feels a little more relaxed, a little looser. Perhaps their inhibitions are lowered. If they take another drink the sedation continues and they may start to slur their words or stumble. After about three they feel a tad bit out of control, and some start to feel a queasiness if they move too fast. They decide to stop for now. That’s not what someone with addiction experiences. One drink gives them energy, get up and go. And shortly after that comes the drive to get another drink to keep that energy up. It seems a physical compulsion, a craving, and it doesn’t happen in people who don’t have addiction. To be clear, people without addiction can drink more than 3 drinks given the right occasion or right decision, but they don’t feel a physical compulsion to do so. That’s the difference, not the behavior, but the reason for the behavior. You can see why our predecessors ignored it; it’s a harder nut to crack.

So let’s say that we agree that craving is a physical result of taking the drug and it’s different than the effect in people without addiction. We can solve this quickly. Don’t use, then you don’t get the craving. Simple, yes? Well, no. Remember I said that another thing the drug does is fix something? Well that something is what keeps people from staying quit once they stop. It’s a different sort of drive that occurs even without the substance being available. There’s a very old case definition for it to (also from the 1930’s) that fits to this day. That definition is that the person is feeling restless, irritable, and discontented.

Imagine walking around feeling restless, irritable, and discontented all the time, and the only thing that works to make you feel better is the thing you are trying not to use. The drive is constant. Your brain telling you that you could feel better in seconds if you’d just do the reasonable thing and go get it. After all, other people are doing it, and other people feel good. Why can’t you feel normal for a bit? It all seems perfectly reasonable when you step back from it.

So we have two parts to the definition: a base state of restlessness, irritability, and discontentedness that keeps the person from staying stopped and the phenomenon of craving that brings on uncontrolled use after restarting. Well if these are real there will be a biological correlate that we can find that makes sense of them, right? And there is, one for each.

Restless, irritable, and discontented (RID) maps very well to low stimulation of the Nucleus Accumbens (NA) in the midbrain. Another group of cells called the Ventral Tegmental Area (VTA) make and send dopamine to the NA, and it is this dopamine that creates the stimulation relieving RID. It should be no surprise that all drugs of abuse, and many other things, cause an increase in this NA tone. But what explains the compulsive use?

When the dopamine hits the NA it sends a reinforcing signal back to the VTA using endorphin, the brain’s endogenous opioid, which stimulates the release of even more dopamine. Of course, when that dopamine hits, the same thing happens, and this goes on in a positive reinforcing feedback loop until all the dopamine that is lined up ready to go is gone. That reinforcing feedback loop causes a large spike in dopamine level and leads to exhaustion of the dopamine stored for release. That exhaustion causes a crash. So the positive feedback loop causes a spike and crash of dopamine at the NA. Or rather, the feedback loop causes a spike and the spike causes a crash. The crash causes a physical craving for more drug.

So, we see that we have two criteria for the illness and each has a biological correlate. This is important because it does two things. First it makes clear who has the illness and who doesn’t regardless of the drug used. Second, by focusing on dopamine tone, and not the external agent that causes the dopamine release, it helps us find cases even when no “drug” is involved.

For instance, here’s an incomplete list of things that research has shown to increase dopamine tone at the NA:

Dangerous or risky behavior[1]

Staying up late or sleeping in[2]

Being the center of attention[3]

Being liked3

Making someone smile[4]

Completion of a hard task[5]

Sexual climax[6]

Taking in food[7]

So all of these things could be “drugs” used in addiction as well. This gives us much better case finding, because our previous drug based definitions could never give us good results when we tried to do the genetics of addiction. Here’s an example.

Let’s say we wanted to look at the genetics of alcohol use disorder. So we gather a bunch of men who meet criteria for it and a bunch who don’t, all of whom are the biological sons of alcoholic men. We do genetics on everyone and compare. We want to see who inherited “the gene” and who didn’t. But here’s the problem. There are people in the “don’t have it” group who have addiction, but because their father was an alcoholic have chosen never to touch alcohol. They’ve been using something else to raise dopamine, but we’ll never know it if we use a drug based case finding system. This is such a big problem that when I went to visit one of the early companies to offer genetic testing to individuals they told me they couldn’t replicate even a single genetic study of addiction.

So to summarize, addiction is a brain illness that is defined by having symptoms that exist before the reward use and reward use to counter those symptoms as well as a response to the reward that produces craving and compulsive use as opposed to a normal response. These factors have physical correlates and are the core of the illness. Of course we can complicate it with other factors and we will later, but for now, this is the core. Being aware of the core phenomenon of addiction will give us a clearer view of what it is, how to find it, and how to end it as a problem in our lifetime.

[1] Laviola G, et al. Risk-taking behavior in adolescent mice: psychobiological determinants and early epigenetic influence. NeuroSci and Biobehav Rev 27 (1-2): 19-31.

[2] Martinez D, et al. Dopamine Type 2/3 receptor availability in the Striatum and Social Status in Hjman Volunteers. Bio Psych 67 (3): 275-278.

[3] Hsu DT, et al. Response of the mu-opioid system to social rejection and acceptance. Mol Psych (20 August 2013) doi:10.1038/mp.2013.96

[4] Iwase M et al. Neural substrates of human facial expression of pleasant emotion induced by comic films: A PET study. NeuroImage, 17:758-768.

[5] Wassum KM, et al. Phasic mesolimbic dopamine signaling precedes and predicts performance of a self-initiated action sequence task. Bio Psych 71(10):846-54.

[6] Komisaruk BR and Whipple B. Functional MRI of the Brain During Orgasm in Women. Brain Research 1024.1 (2004): 77-88.

[7] Wang GJ, et al. Enhanced striatal dopamine release during food stimulation in binge eating disorder. Obesity 19(8):1601-8.