Research & Publications
My research is concerned with the clinical pharmacology of drugs of abuse.
Earlier research focused on the clinical pharmacology of cocaine. Most cocaine abusers concurrently use ethanol, and report that euphoria is prolonged, and the dysphoria of acute withdrawal is lessened. When the two are used concurrently, cocaine is converted to an active metabolite, cocaethylene (EC). We have shown that EC is equipotent to cocaine in its ability to block dopamine uptake, is equipotent to cocaine as a reinforcer in animals, and has similar effects to cocaine when administered to humans. With a longer half life than cocaine, EC might serve as a model or prototype drug for development of a pharmacological treatment for cocaine abuse.
Through participation in a transdisciplinary tobacco use research center, I have become interested in biochemical markers of tobacco/nicotine use. We have reported a study showing that plasma concentrations of cotinine (a nicotine metabolite) are far more sensitive than the commonly used expired carbon monoxide measurements for identifying recent smoking or, alternatively documenting abstinence. Thus, clinical trials concerned with smoking cessation that have relied on expired carbon monoxide measurements to document abstinence, may have significantly over estimated treatment success.
More recently, we have been begun an investigation of two minor ethanol metabolites, ethyl glucuronide and ethyl sulfate. We are characterizing the elimination of of these metabolites following consumption of various doses of ethanol and will study the application of their measurement to clinical trials of new treatments for alcohol use disorders.
Extensive Research Description
My research continues to be concerned with the clinical pharmacology of drugs of abuse. Earlier research focused on the clinical pharmacology of cocaine, and in particular cocaethylene (EC) an interesting metabolite, which arises through transesterification of cocaine when cocaine and ethanol are used concurrently. Our studies indicated that EC, like cocaine, blocks the reuptake of monoamines including dopamine, is reinforcing in animals, and cannot be discriminated from cocaine by humans. EC has a longer half life than cocaine, is somewhat less potent, and has greater selectivity for the dopamine transporter. We thus suggested that EC might serve as a prototype drug for agonist substitution therapy for cocaine abuse.
My laboratory has received support from an NIH funded Transdisciplinary Tobacco Use Research Center. We have been involved with several tobacco abuse treatment trials, and nicotine challenge studies on the assumption that the outcome of such studies cannot be optimally interpreted in the absence of objective data regarding nicotine exposure (as reflected by concentrations of nicotine and/or its major metabolite, cotinine, in plasma). Nicotine, with its short half life is a good marker of acute or very recent nicotine exposure, while its major proximal metabolite, cotinine, with its slower disposition is the superior marker of chronic nicotine exposure. One of our previous interesting findings was that schizophrenics demonstrate about twice the plasma cotinine levels per cigarette smoked when compared to non-schizophrenic smokers. This observation is consistent with the hypothesis that schizophrenics, many of whom are heavy smokers, are self-medicating their disorder with tobacco smoking.
We recently reported the results of a laboratory based study designed to quantify the relative reliability of various biochemical markers of smoking abstinence. Although, expired carbon monoxide (CO) is frequently used to confirm self reports, it has a relatively short half life, calling into question whether this measure might provide misleading information by exaggerating smoking cessation success rates. To examine this question, we analyzed expired CO, plasma cotinine and self report data collected in a clinical smoking abstinence clinical trial (N = 207). Measurements, which were made at 6 weeks, 3 and 6 months, showed that expired CO very significantly overestimated abstinence rates as compared with plasma cotinine. In fact self reports were more sensitive than expired CO. We conclude that outcomes of clinical trials for treatment of tobacco/nicotine abuse that rely on expired CO rather than cotinine measurements to verify sustained abstinence may significantly overestimate treatment success, and that cotinine measurements are much to be preferred.
Most recently, we have been interested in two minor metabolites of ethanol , ethyl glucuronide (EtG) and ethyl sulfate (EtS). Assays for the parent drug and/or major metabolite(s) that provide a detection window of three or more days are available for most drugs of abuse. Such assays are important for clinical trials that evaluate new therapies for substance abuse disorders, as well as for patient management in treatment programs. Alcohol (ethanol) is an exception. Blood alcohol concentrations become undetectable within hours after ethanol consumption, even following heavy drinking. EtG and EtS are minor ethanol metabolites, that, using very sensitive assays employing tandem mass spectrometry, can be measured in urine for several days following alcohol consumption. Although studied for more than decade, mostly in Europe, their application has largely been in forensic and/or emergency room contexts. Moreover, the elimination of these minor metabolites, over a range of ethanol doses, has not been systematically studied. Guidelines for the clinical use of these potentially important assays have not been validated nor even well established.
We plan to perform an inpatient experimental study during which EtG and EtS elimination will be quantified following administration of varying doses of ethanol to volunteers employing a highly specific and sensitive LC/MS/MS assay We will also correlate urinary EtG and EtS concentrations with self reports in two clinical trials with goals of achieving abstinence and drinking moderation respectively.
We will characterize ethyl glucuronide and ethyl sulfate elimination, including inter-subject and intra-subject variability and dose dependency following controlled ethanol doses ranging from light to high. This will be an in-patient study.
We will determine concentrations of EtG and EtS at defined intervals in subjects participating in ongoing clinical trial that have goals of abstinence or moderation respectively and correlate with more traditional outcome measures, including self reports and blood alcohol measurements.
We also plan to conduct a preliminary study to determine if genetic polymorphisms (differences) in glucuronyl transferases alter fractional elimination of ethyl glucuronide.