Researchers studying how ADHD meds enter brain

Individual genetics also play a large role in how children and adults with ADHD will react to certain medications and doses, with side effects ranging from stomach ache to adverse cardiovascular reactions.

The National Institutes of Health (NIH) has granted the Medical University of South Carolina (MUSC) $1.3 million to examine how medications used to treat ADHD (methylphenidate, amphetamine, atomoxetine and modafinil) work in the brain. Discoveries from this body of work could help in decreasing the amount of time patients spend finding the right medication, as well as significantly reducing the possibility of side effects and adverse drug events.

John S. Markowitz, PharmD., associate professor of pharmaceutical sciences and principal investigator of the study, said that a multidisciplinary approach to the work, as well as the potential benefits to patients, were likely deciding factors that enabled MUSC to obtain the highly competitive funding.

"Physicians have tried to monitor how much ADHD medication a patient is actually getting by looking at the amount in a person's blood level, similar to how they monitor the amount of immunosuppressant drugs in transplant patients, or lithium in patients with bipolar disorder," he said. "The problem is there is no guaranteed way to know how much of the medicine is actually making it into the brain to exert its intended effects without leading to untoward adverse effects. Presently, patients treated with one or more of these medications may be experiencing a lot of side effects, possibly even toxicity, yet that person's blood level of the medication may appear normal and within expected ranges for the particular medication."

For years the assumption has been that blood concentrations of medications reflect those typically attained within the brain. Additionally, there have been few practical means to determine concentrations of medications in the brain. It is becoming more apparent that blood concentrations can differ substantially from brain concentrations through use of a variety of research techniques.

From day to day, physicians try to help patients who respond differently to one medication versus another. Patients A and B might be of the same sex, weight and height, but while one medication will offer patient A relief from ADHD symptoms, patient B could experience serious side effects or, in rare cases, life-threatening reactions.

The key is learning more about how the body allows substances in and out of its most important and complex organ: the brain. The blood brain barrier (BBB) functions as a gatekeeper to keep potential toxins from entering the central nervous system, while allowing "cleared" substances in. Specific drug transporters (proteins found in the body and BBB) allow passage of various molecules required for normal function while also serving a protective role. In the case of the BBB, some drug transporters can determine the degree to which therapeutic medications gain access to the brain, and their function once inside. Some transporters allow the movement of medications in and out, while other transporters only work to bounce out substances that threaten the brain's delicate balance of what it needs and what can become toxic.

Depending on an individual's genetics, different levels of various transporters are found in the body. Preliminary studies at MUSC examined the potential role of transporters known as organic cation transporters (OCTs) which are abundant in many tissues, including the heart, brain and placenta. Results of these investigations provided strong evidence that OCTs may have some involvement in transporting ADHD medications to the brain, which could have consequences for the ultimate effectiveness, tolerability, and safety of these agents.

The current NIH study will examine the role of OCTs in the disposition and action of drugs used to treat ADHD by using a number of experimental methods. One interesting method includes a unique genetically engineered mouse that lacks OCT transporters to examine how ADHD medications make it into the brain, and how the pharmacological effects may differ from normal animals.