Dr. Marilyn Huestis, chief of the Chemistry and Drug Metabolism Section of NIDA’s Intramural Research Program, talks about conducting research on drug effects with human subjects, developing tests to help law enforcement identify drugged drivers, and an assay to help identify children whose prenatal exposure to anti-HIV drugs may put them at risk for adverse developmental outcomes.
NN: How would you summarize your current work?
MH: In my lab, we study the pharmacology and toxicology of drugs of abuse—primarily cannabis, but also heroin, cocaine, methamphetamine, Ecstasy, and tobacco—as well as medications like buprenorphine and methadone that are used to treat addiction. We look at everything the drugs do to the body, as well as everything the body does to the drugs.
The participants in many of our studies are confirmed drug users. They have no interest in quitting drug use, and have declined the treatment opportunities we offer, but they are motivated to help us learn about the drugs they take. We carefully screen each individual for potential health and safety issues before allowing them to participate in a study.
In a study, the participant receives a drug that they normally use, at a dose equal to or lower than the one they normally take. We monitor for subjective, cognitive, and physiological effects of the drug, assess the participant’s performance on a wide variety of tasks, and collect samples of everything from blood and urine to hair and saliva. We may collect up to 25,000 biological samples in a single study. We analyze the samples with our gas and liquid chromatography mass spectrometer. Each one tells us something about how the drug moves through the body, and the changes that it may produce.
The insights we gain when we put all of this information together help us understand drug abuse and its dangers. They give us clues to successful prevention and treatment strategies, and provide the scientific data for evidence-based drug policy and legislation.
NN: What are some examples of practical applications of your work?
MH: When we know how the body metabolizes and excretes a drug, we can create tools and set windows for drug detection. We can design programs to suit the drug testing requirements of clinicians, employers, police, and other users.
For example, we have created models that clinicians can use to tell when the drug use occurred that has caused a patient’s blood or urine test to be positive. This information can be crucial for choosing the right clinical response, because it may distinguish whether the patient has had a brand new relapse or has residual drug in his system from an earlier relapse. It also enables the clinician to better help the patient pinpoint the triggers: Where were you at that time? Who were you with? What caused your craving?
Drugged driving is a major public safety problem in our country. We are conducting controlled drug studies to evaluate devices to identify drugged drivers—their validity and windows for drug detection. We anticipate that in the near future, police will pull someone over who is driving dangerously and give him a Breathalyzer test for alcohol and a saliva test for opiates, amphetamines, cocaine, and marijuana.
To give a sense of the time requirements of some of this work, we started studying drug disposition in oral fluid 1994. We expect that oral fluid will be approved for federally mandated drug testing later this year or next year.
NN: Tell us about a project that has you excited right now.
MH: As you know, drug abuse is a major risk factor for HIV infection, and the populations of drug abusers and HIV-infected individuals largely overlap. For that reason, NIDA conducts a great deal of research on HIV and AIDS. Right now, my lab is collaborating with researchers from the Pediatric HIV/AIDS Cohort Study (PHACS) to address problems that affect some children whose mothers take antiretroviral medications for HIV while they are pregnant.
The use of antiretrovirals during pregnancy is one of the greatest medical advances of our time. In Western countries, it has reduced the rate of mother-to-child HIV transmission during delivery to less than 2 percent. However, we are now seeing that some children whose mothers who took these medications have developmental abnormalities. Some have mitochondrial dysfunction, bone resorption—which can lead to bone fractures—growth restriction, or language delay.
The goal of our collaboration with PHACS is to understand the relationships between antiretroviral exposure and these adverse outcomes. A prerequisite for reaching this goal is to be able to precisely measure fetal exposure to the medications.
The PHACS researchers asked us to develop an assay for a wide spectrum of antiretrovirals in meconium. Meconium is the first stool an infant expels after birth. It is a good matrix for measuring fetal drug exposures, because to be in meconium, a drug has to have passed through the fetus. In contrast, a mother’s drug intake is not a very exact indicator of fetal exposure, because only a limited amount reaches the fetus.
We developed a meconium assay that accurately measures levels of 99.2 percent of all the antiretrovirals taken by women in the PHACS study. With the assay now in hand, we are starting a study of one antiretroviral, tenofovir, which has been linked to bone restriction and growth delay. We will measure levels of tenofovir in infants’ meconium, and see if they predict which infants go on to develop those problems. We are also planning a study of atazanavir, which has been associated with language delays.
These studies hopefully will enable physicians to identify and provide early interventions to children whose fetal exposure to antiretrovirals has put them at risk for developmental delays. Ultimately, we hope our results will enable physicians to adjust antiretroviral regimens to best protect both mother and child.
NN: Do outside groups often contact you, as PHACS did, for technical assistance?
MH: Yes, they do. We have about 40 ongoing research collaborations, some of them with NIH intramural groups, but most with extramural scientists from around the world. We’re working with groups in South Africa to study women who use methamphetamine, cannabis, and tobacco; a group in Uruguay that studies tobacco use in pregnant women; and a group in Scotland that is looking at fetal alcohol exposure. We also have cooperative research and development agreements with pharmaceutical companies to test new drugs.
NN: What are some of the biggest challenges you’re facing now?
MH: I believe our laboratory is the best in the world for training toxicologists. However, I’m worried that people who may be interested in coming into this research field will be discouraged when they see how long it takes to go from an idea to dosing the first participant.
Research with human subjects is highly regulated, and we follow guidelines from our institutional review board, the Food and Drug Administration, the Drug Enforcement Administration, and other specific Federal regulations. Because of this complex regulatory environment, the lag from conception to first dosing typically takes up to 4 years.
The truth is that you have to be passionate about doing this work, or else you’ll give up. However, if you do have that passion, it will be rewarded, because we have an incredible opportunity to save lives through discovery and education.