Treating ADHD with Amphetamine

Doctor Randy Blakely describes an intriguing hypothesis for why amphetamine may be effective in treating some individuals with ADHD.

We recently found two young boys who, one had a combined form of ADHD, which means that he showed motor and impulsivity, as well as other attentional deficits, and the other child was more of a hyperactive, predominant ADHD. These two boys carry a small change in their dopamine transporter that makes the dopamine transporter act anomalously. It causes it to run backwards under conditions when it should be running forward. It should be pumping dopamine into the neuron, and we believe it’s now pumping dopamine out. Obviously that’s kind of a short circuit, as it were, of a chemical signal. What’s most interesting about that study, for us, was that we knew that that kind of activity of moving dopamine out into the synapse could also be triggered by a specific drug, and that drug is amphetamine. So, after we had found this change in the dopamine transporter in these two boys, we went back to our clinical records and asked, “What are these children being treated with?” It turned out that they were being treated with amphetamine. Now this didn’t make any sense. So, why are we giving amphetamine to children who have a problem with their dopamine transporter that looks like they are on amphetamine? In fact, behaviorally it looks like they are on amphetamine. We realized that we had not expressed the mutant dopamine transporter in the lab and exposed it to amphetamine. We had never done that combination. So we did it, and what we found was that amphetamine doesn’t act the way it does on the normal dopamine transporter on this mutated form. It actually stops the protein from running backwards. So in wild-type dopamine transporter, the one that probably you and I have, if we take amphetamine it would make our dopamine transporter run backwards. But in these kids, it’s already running backwards, and amphetamine shuts that backward leak off. So we had a little eureka moment about this, because understanding why amphetamines are therapeutically beneficial in the treatment of ADHD has aroused much interest over many decades, and it’s led to a number of ideas, some of which are probably pretty good in some people. But this is a new idea, and that is that there is a propensity of dopamine transporters to run backwards under certain conditions. In these kids, we think it’s because of their genes. But for others, it might be because of something else in the environment, it could be an intersection with other pathways in the brain and other chemicals. But however it happens, once it does happen, our prediction is amphetamine will be beneficial, and that opens us up to a new hypothesis that the reversal, the movement, the running backward of the dopamine transporter could be a convergent point for our thinking as we move forward in looking further into what causes ADHD in the first place.