Clinical Pharmacology and Therapeutics Research Branch
Chemistry and Drug Metabolism Section
Mission Statement
The Chemistry and Drug Metabolism Section designs and conducts original controlled clinical drug administration studies to improve our understanding of the physiological, cognitive, subjective, psychomotor and biochemical effects of nicotine and illicit drugs. The timecourse of drug effects are studied with simultaneous measurements of drug and metabolite plasma concentrations to better examine the relationship between the onset, peak and duration of effects and concurrent drug concentrations. The experiments are conducted via different routes of drug administration, an important variable in drug delivery to the brain and subsequently, a drugs’ abuse liability. Understanding a drug’s pharmacokinetics and its pharmacodynamic effects enables better prevention and treatment efforts. Many of our research protocols focus on the evaluation of new treatment medications including nicotine patches and gum, buprenorphine for opiate replacement therapy and SR141716, the first CB1-cannabinoid receptor antagonist, a potential cannabinoid dependence treatment. A second mission of the Section is the quantitative analysis of biological fluids and tissues for drugs and metabolites. These measurements are necessary for the determining drug pharmacokinetics, but also serve as objective biological outcome measures for determining the success of different treatment and prevention strategies. In addition, these data from controlled drug administration studies provide the scientific database for the interpretation of drug test results of both routine specimens, i.e., blood and urine, and newly developing alternate matrices including saliva, sweat and hair. A third mission of the Section involves the application of advanced analytical instrumentation to resolve complex biological problems. We collaborate with investigators within and outside the IRP to address neurotransmitter, peptide and protein identification, interaction and quantitation in animal and human models to better understand the neurobiology of drugs of abuse.
Program Areas
Cannabinoid research
The goals of the cannabinoid research program are a) to increase our understanding of the endogenous cannabinoid system through modulation by cannabinoid agonists, antagonists and reuptake inhibitors, b) To increase our understanding of marijuana’s physiological, biochemical and behavioral effects, as well as the time course of drug absorption, distribution, metabolism and excretion, and the relationship between these parameters.
Teen Tobacco and Nicotine Research Center
Three thousand young people in the United States take up smoking everyday and many of them try to quit and fail. One third of them will eventually die of tobacco-related illnesses. The Teen Tobacco Addiction Treatment Research Clinic (TTATRC) was established to address the need for high quality research and treatment of adolescent tobacco dependence. Our treatment program is assessing the safety and efficacy of the nicotine patch and gum for teens that want to quit smoking (in combination with group therapy). To date no medications are available for prescription in teens, contrary to adult smokers who can obtain nicotine patches and gum over the counter. The TTATRC team is composed of a multidisciplinary group of professionals including a pediatrician, a psychiatrist, psychologists, social workers and nurses. The clinic’s mission is to help adolescent smokers kick their tobacco addiction through a comprehensive 3-month treatment program.
Pharmacokinetics and Pharmacodynamics of Drugs of Abuse and Treatment Pharmacotherapies
The goals of our pharmacokinetic and pharmacodynamic research studies are: To determine how the processes of drug absorption, distribution, metabolism and excretion affect physiological, subjective, and performance responses in humans.
It is important in the diagnosis, treatment and prevention of drug abuse that we have an understanding of the information provided by drug tests on various body fluids and the relationship of these tests to drug-induced effects.
In Utero Drug Exposure/Disposition of Drugs and Metabolites in Alternative Biological Matrices
The goals of our in utero drug exposure and disposition of drugs and metabolites in alternative matrices research are: 1) To evaluate the effects of maternal use of abused drugs during gestation on neonatal outcomes; 2) To provide objective means of assessing the effectiveness of drug treatment pharmacotherapies during pregnancy; and 3) To improve the diagnosis, deterrence, severity assessment and treatment of drug abuse with measurement of drug and metabolite concentrations in diverse biological matrices.
Core Chemistry Laboratory
We develop sensitive and specific new analytical methods for the quantitation of drugs and metabolites in a wide variety of biological specimens, and have recently expanded our array of instrumentation to include GC/MS-CI, LC/MS, LC/MS/MS, MALDI-TOF and Q-TOF techniques. The application of these advanced analytical techniques to resolve biological problems has enabled us not only to address many of our research goals, including receptor-ligand interactions and neurotransmitter measurement, but also to offer expertise and resources to further the research goals of many other preclinical and clinical NIDA IRP investigators. Additional methods must be developed as new drugs appear in the therapeutic and illicit drug markets and, also, as new and important metabolites, possibly active drug species, are identified in metabolic studies.
Name: Marilyn A. Huestis, Ph.D.
Title: Acting Chief, Chemistry and Drug Metabolism Section
Telephone Number: (410) 550-2711
Email: mhuestis@intra.nida.nih.gov
Dr. Huestis’ research program is focused primarily on cannabinoids, the pharmacokinetics and pharmacodynamics of drugs of abuse and in utero drug exposure. Recent advances in the science of cannabinoid neuropharmacology offer exciting new opportunities to understand, prevent, and treat marijuana abuse and to understand the role of endogenous cannabinoid systems in human physiology. These advances include the identification of cannabinoid receptors, endogenous cannabinoid ligands, neurotransmitter hydrolytic enzymes and a synaptic reuptake system. In addition, the recent Institute on Medicine report encouraged research into the clinical efficacy and safety of medical marijuana. We have several different approaches to our cannabinoid research including the first phase I studies of the CB1-cannabinoid receptor antagonist, SR141716, in marijuana smokers, controlled drug administration studies of smoked marijuana and oral tetrahydrocannabinol (THC), and studies on the neurological consequences of long-term heavy marijuana use during abstinence.
Drug-abusing women have higher rates of pregnancy complications and an increased incidence of infants with lower birth weights and higher rates of congenital malformations and mortality. To better understand the role illicit and licit substances have on the developing fetus, it is necessary that we develop improved methods of detection and gain a better understanding of the transport process involved in the transfer of drug across the placental membrane. We are following women’s drug use during gestation and relating this information to neonatal abstinence syndrome, birth weight and length, and other outcome measures. Maternal saliva, urine, sweat and hair are collected during gestation, placenta, cord blood, and neonatal meconium and hair are obtained at birth to determine the best means of identifying maternal drug abuse and to evaluate the relationship between drug exposure and neonatal effects. Drug testing provides a means to ensure that the mother and child receive adequate medical, social and psychological care.
Information about human drug exposure can be obtained by chemical testing of biological specimens. Each type of specimen may impart different chemical and pharmacodynamic knowledge. Human drug exposure can occur through a variety of different means including self-administration, passive inhalation, external contamination, exchange of body fluids and in utero exposure. For drug testing in alternate matrices to be useful, an understanding must be developed of the fundamental chemical and pharmacological principles governing the appearance and disappearance of drugs and their metabolites in these matrices. Biological monitoring provides an objective outcome measure to evaluate alternative behavioral treatment strategies and new treatment medications, and to differentiate populations at risk.
Name: Stephen J. Heishman, Ph.D.
Title: Research Psychologist
Telephone Number: (410) 550-1547
Email: sheish@intra.nida.nih.gov
Dr. Heishman’s research program is primarily focused on the effects of the administration of tobacco and nicotine and the absence of tobacco (nicotine withdrawal) on cognitive processes, such as attention and memory, in human research volunteers. We are currently studying the effects of nicotine on specific aspects of attention and memory, the ability of cigarettes without nicotine to alleviate the mood and cognitive decline observed during nicotine withdrawal, and we are using brain-imaging techniques (PET, MRI) to investigate brain regions underlying the cognitive changes during withdrawal.
A secondary research interest is tobacco craving and how it may affect cognitive processes. Craving is experienced by nearly everyone who attempts to quit smoking and plays a critical role in a person's relapse to smoking after a few days of successful abstinence. We have developed a tobacco craving questionnaire and an imagery procedure that reliably induces craving in the laboratory. We are currently investigating the effect of increased tobacco craving on memory processes and the duration of imagery-induced craving. In future studies we will examine the effect of increased craving on tobacco self-administration.
Name: Eric T. Moolchan, M.D.,
Title: Director of the Teen Tobacco Addiction Treatment Research Clinic and Attending Physician, Clinical Research Unit
Telephone Number: (410) 550-1846
Email: emoolcha@intra.nida.nih.gov
Dr. Moolchan is a Clinical Research Fellow and Dr. Moolchan’s main area of research is the Teen Tobacco Addiction Treatment Research Clinic that was established in August 1999 as an outpatient research program for the study of adolescent tobacco dependence and its treatment. This unique treatment setting offers a rich opportunity for basic, clinical and translational research. Dr. Moolchan’s primary protocols are trials of the safety and efficacy of nicotine patch and gum in nicotine dependent adolescents. He is also studying the characteristics of teens seeking smoking cessation, and a retrospective study of tobacco dependence among adult poly-substance abusers.
Dr. Moolchan’s secondary interest is in treatment monitoring (especially pharmacokinetics) of opioids and cocaine dependence. He is assessing the elimination pharmacokinetics and metabolic disposition of cocaine in a population of chronic cocaine users during acute cessation. Comparisons are being made with historical controls that received single doses of cocaine under experimentally controlled conditions. The usefulness of saliva analysis as an alternative to blood and hair analysis as a measure of historical cocaine use in chronic cocaine users is being investigated. He is also comparing saliva and plasma concentrations of methadone as predictors of opioid treatment outcomes and how saliva measurement could be used to clinically monitor the adequacy of methadone dosage.
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Clinical Pharmacology and Therapeutics Research Branch
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