The mystery of addictions, Part 2: What we can learn from studying humans and animals

In an earlier post, I outlined some of the reasons that investing in research on addictions is crucial, as well as why it is reasonable to conceive of drug abuse as a disease of the brain. Simply put, the structure and function of the brain is different in people suffering from an addiction, compared to non-affected people, and those changes contribute directly to their profound difficulty with achieving and maintaining abstinence.

The brains of individuals who are addicted to drugs (or even food) differ dramatically from those who are not addicted.

But even if one accepts my assertions, the questions that arise logically are: well, why not just study the brains of addicts themselves!? Conversely, why is it necessary to also study animal models (rats, mice, monkeys), none of which naturally develop drug addictions, in the wild, in the way some people are prone to do?

Studying human brains

I received a voice mail from someone about a year ago. She said that she had “a friend” who was a chronically relapsing addict who was interested in participating in my research, in order so that animals could be spared. Surely, if her friend participated in our studies, in place of a rat, the results would be much more conclusive, right?

Wrong.

To illustrate why, let’s do a simple thought experiment. Two people show up in my lab: Tom is a heroin addict and Sally is not (she is a “control” subject – a person who has never used drugs). Why can’t I simply compare their two brains to each other and find the mystery of addiction?

The answers to this are simple, but multi-fold.

To start with, many differences between Tom’s and Sally’s brains are unrelated to addiction. Tom is male, and Sally is female, so gender alone is a factor. Perhaps Tom is a college student, and Sally is a teenager, so age also explains differences in their brains. Tom might have been raised by an abusive mother, a history that affected the development of his brain, while Sally was raised in a idyllic home. This could go on and on. For all these reasons, we have to study MANY addicts and MANY controls, who are matched in as many ways as possible (for sex, age, upbringing, etc.) except for experience with the drug in order to make the relevant comparisons… This is already a more complex study, but one certainly still worth doing.

Even if we do a study with hundreds of addicts and hundreds of controls, we still have serious problems. This is because addiction co-occurs with many other factors. Because their drug abuse disrupts their life plans, addicts are less likely to be as  educated as controls. Their lives are more likely to be stressful. They are often thinner (leaner) and often have poor diets; they are sometimes more sedentary. They are  at times more likely to catch contagious diseases because of their intravenous drug use. This could go on and on. If any of these factors affects the brain (anyone think education level, stress, food intake and disease can affect the brain?), the differences in the brains of addicts and controls could be to the drug or to any other factor that regularly co-occurs with drug use.

It is still worth doing this study, yet we have even more serious problems that remain. Which of the factors that differ between addicts and controls developed after their drug use started and which were there to begin with (possibly being factors that made them susceptible for addictions)? This alone is an essential issue, which I will take up in a subsequent blog post.

Which of the differences in their brains caused by the drug are related to the drug’s negative effects (the disease process) and which are related to the degree to which the brain tries to defend itself from the drug? This is a huge issue. If you counteract one of the drug’s negative effects, people may get better and stop using! If you counteract one of the changes the brain made in order to protect itself, you make the addict more vulnerable to the drug. One example relates to tolerance. As I mentioned in the previous post, one thing that happens as addiction develops is that people get less and less sensitive to the effects of the drug; consequently, they take more and more of it. Eventually, they are able to take quantities of the drug that would kill a non-affected person. If one counteracts the mechanisms that give them tolerance, the doses of the drug they are taking could suddenly kill them. Unfortunately, there is no way of knowing, in advance, which differences in the brain give the drug its power and which are the walls the brain has thrown up to protect itself from the drug.

And perhaps most importantly, a chief limitation of this approach is that the ability to detect differences in the brains of people depends upon the methods available to measure those differences. Studies of the human brain are limited (by ethics) to two types: brain imaging in living subjects and direct study of brain matter collected from people who have died. Despite the fact that brain scanning machines sometimes look incredibly high tech, what they are able to measure is extremely limited. They can not measures the structure and connection between brain cells. They can mostly not detect the communication between brain cells. They can not measure individual molecules that may be affected by the drug.

A magnetic resonance imaging device for brain scanning

An image of the brain captured by a magnetic resonance imager. You can see brain structure, but you cannot see the microstructure of brain or its molecular constitution.

The mysteries of addiction are in the cells, molecules and chemistry of the brain, and this can only be measured in brain tissue itself. But studying brains from persons that died is, itself, complicated. Without getting too graphic, the longer the brain is dead, the more it “decomposes” and that decomposition (which happens quite rapidly) degrades the very molecules in the brain that we need to study. Most human brains can only be obtained many hours after death, so this window has closed substantially.

Overall, there are serious limitations on what we can learn from studies of one, or even many, human brains. One of the reasons that progress in curing addictions has been as limited as it has is because of technological limitations on human research. Animal research covers some, but not all, of these gaps.

Animal Studies

Because animal studies are highly controlled and very specific, they can overcome almost all of the issues indicated in the previous paragraphs. We can directly assess the effects of the drug on the brain, in isolation from all other confounding factors, because the animal brain responds to addictive drugs in a manner nearly identical to the way the human brain does. In an earlier post on the SpeakingofResearch blog, I noted that:

…despite obvious differences in the brain, rats also very much enjoy the effects of these drugs. When offered an opportunity, they will take them voluntarily (e.g., press a button to trigger an injection of the drug). Even more impressively, even fish find addictive drugs rewarding. So, actually, despite the superficial differences, there is a huge amount going on in the brain that is similar across model organisms. This is because the anatomical differences between rat and human brains are actually much smaller than what is shared between them: common sets of circuits with similar functions.

Because of these animal models, we can directly ascertain the functional significance changes in brain caused by the drug, i.e., whether they are compensations (protective effects) or decompensations (drug-induced brain failures). And animal studies allow you to directly, effectively and humanely measure brain processes you can not easily monitor in humans, like the activity of single neurons, the release of neurotransmitters, the drug-induced changes in neuronal structure and function, etc. Only by studying animals can you really localize what changes in brain chemistry occur as a consequence of drug use and which are related to pathological aspects of drug use. But before neuroscience can be translated into a treatment, we have to have answers to all of these questions, and that takes time.

It is thanks to animal studies that we have made some progress and developed some treatments, including Depade/Revia/Vivitrol for alcoholism, Chantix for tobacco dependence, etc. The lack of more treatments isn’t an indication that either human- or animal-based research hasn’t worked. Rather, it’s an indication that profound progress requires massive amounts of knowledge about the functions of the brain that. themselves, require decades of basic and biomedical research to obtain. Rather than calling for less animal research, those who crave a future that comes along with the cures and treatments for disease should be calling for an increased pace, more discovery and greater progress. Scientists are committed to this future, and we are determined to achieve it.

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