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.
- Jatlow P, Toll B, Leary V, Krishnan-Sarin S,S. O’Malley SS. Comparison of expired carbon monoxide and plasma cotinine as markers of cigarette abstinence. Drug and Alcohol Dependence 2008:98: 203-209.
A placebo-controlled trial of bupropion combined with nicotine patch for smoking cessation in schizophrenia.
George TP, Vessicchio JC, Sacco KA Weinberger AH, Dudas MM, Allen TM, Creeden CL, Potenza MN, and Jatlow PI. Biol Psychiatry. 2008 Jun 1;63(11):1092-6. Epub 2007 Dec 21.
- Baker J, Jatlow P, Pade P, Ramakrishnan V, McCance-Katz EF. Acute Cocaine Responses Following Cocaethylene Infusion. 2007: J Drug and Alc Abuse, 33:619-625.
- Baker JR, Jatlow P, and McCance-Katz EF. Disulfiram Effects on Responses to Intravenous Cocaine Administration. Drug and Alcohol Dependence 2007: 87:202-2009.
- Bradberry CW, Lee T, Jatlow P, Rapid induction of behavioral and neurochemical tolerance to cocaethylene, a model compound for agonist therapy of cocaine dependence., Psychopharmacology 1999; 146: 87-92.
- Jatlow P, Elsworth JD, Bradberry CW, Winger G, Taylor JR, Russell R, Roth R.Cocaethylene: a neuropharmacologically active metabolite associated with concurrent cocaine-ethanol ingestion. LifeSciences 1991; 48:1787-1794.
Full List of PubMed Publications
- Schick SF, Blount BC, Jacob P 3rd, Saliba NA, Bernert JT, El Hellani A, Jatlow P, Pappas RS, Wang L, Foulds J, Ghosh A, Hecht SS, Gomez JC, Martin JR, Mesaros C, Srivastava S, St Helen G, Tarran R, Lorkiewicz PK, Blair IA, Kimmel HL, Doerschuk CM, Benowitz NL, Bhatnagar A: Biomarkers of Exposure to New and Emerging Tobacco and Nicotine Delivery Products. Am J Physiol Lung Cell Mol Physiol. 2017 May 18; 2017 May 18. PMID: 28522563
- Baldassarri SR, Hillmer AT, Anderson JM, Jatlow P, Nabulsi N, Labaree D, Cosgrove KP, O'Malley SS, Eissenberg T, Krishnan-Sarin S, Esterlis I: Use of Electronic Cigarettes Leads to Significant Beta2-Nicotinic Acetylcholine Receptor Occupancy: Evidence From a PET Imaging Study. Nicotine Tob Res. 2017 Apr 29; 2017 Apr 29. PMID: 28460123
- MacLean RR, Valentine GW, Jatlow PI, Sofuoglu M: Inhalation of Alcohol Vapor: Measurement and Implications. Alcohol Clin Exp Res. 2017 Feb; 2017 Jan 5. PMID: 28054395
- Valentine GW, Jatlow PI, Coffman M, Nadim H, Gueorguieva R, Sofuoglu M: The effects of alcohol-containing e-cigarettes on young adult smokers. Drug Alcohol Depend. 2016 Feb 1; 2015 Dec 24. PMID: 26778759
- Tanner JA, Novalen M, Jatlow P, Huestis MA, Murphy SE, Kaprio J, Kankaanpää A, Galanti L, Stefan C, George TP, Benowitz NL, Lerman C, Tyndale RF: Nicotine metabolite ratio (3-hydroxycotinine/cotinine) in plasma and urine by different analytical methods and laboratories: implications for clinical implementation. Cancer Epidemiol Biomarkers Prev. 2015 Aug; 2015 May 26. PMID: 26014804
- O'Malley SS, Gueorguieva R, Wu R, Jatlow PI: Acute alcohol consumption elevates serum bilirubin: an endogenous antioxidant. Drug Alcohol Depend. 2015 Apr 1; 2015 Jan 28. PMID: 25707709
- O'Malley SS, Wu R, Mayne ST, Jatlow PI: Smoking cessation is followed by increases in serum bilirubin, an endogenous antioxidant associated with lower risk of lung cancer and cardiovascular disease. Nicotine Tob Res. 2014 Aug; 2014 May 8. PMID: 24812024
- Jatlow PI, Agro A, Wu R, Nadim H, Toll BA, Ralevski E, Nogueira C, Shi J, Dziura JD, Petrakis IL, O'Malley SS: Ethyl glucuronide and ethyl sulfate assays in clinical trials, interpretation, and limitations: results of a dose ranging alcohol challenge study and 2 clinical trials. Alcohol Clin Exp Res. 2014 Jul; 2014 Apr 28. PMID: 24773137
- D'Souza DC, Ahn K, Bhakta S, Elander J, Singh N, Nadim H, Jatlow P, Suckow RF, Pittman B, Ranganathan M: Nicotine fails to attenuate ketamine-induced cognitive deficits and negative and positive symptoms in humans: implications for schizophrenia. Biol Psychiatry. 2012 Nov 1; 2012 Jun 19. PMID: 22717030
- Sofuoglu M, Herman AI, Nadim H, Jatlow P: Rapid nicotine clearance is associated with greater reward and heart rate increases from intravenous nicotine. Neuropsychopharmacology. 2012 May; 2012 Feb 15. PMID: 22334123
- Toll BA, White M, Wu R, Meandzija B, Jatlow P, Makuch R, O'Malley SS: Low-dose naltrexone augmentation of nicotine replacement for smoking cessation with reduced weight gain: a randomized trial. Drug Alcohol Depend. 2010 Oct 1; 2010 Jun 12. PMID: 20542391
- Jatlow P, O'Malley SS: Clinical (nonforensic) application of ethyl glucuronide measurement: are we ready? Alcohol Clin Exp Res. 2010 Jun; 2010 Apr 5. PMID: 20374218
- Weinberger AH, Reutenauer EL, Jatlow PI, O'Malley SS, Potenza MN, George TP: A double-blind, placebo-controlled, randomized clinical trial of oral selegiline hydrochloride for smoking cessation in nicotine-dependent cigarette smokers. Drug Alcohol Depend. 2010 Mar 1; 2009 Nov 24. PMID: 19939587
- Jatlow P, Toll BA, Leary V, Krishnan-Sarin S, O'Malley SS: Comparison of expired carbon monoxide and plasma cotinine as markers of cigarette abstinence. Drug Alcohol Depend. 2008 Dec 1; 2008 Jul 22. PMID: 18650033
- Schepis TS, Duhig AM, Liss T, McFetridge A, Wu R, Cavallo DA, Dahl T, Jatlow P, Krishnan-Sarin S: Contingency management for smoking cessation: enhancing feasibility through use of immunoassay test strips measuring cotinine. Nicotine Tob Res. 2008 Sep. PMID: 19023841
- Toll BA, O'Malley SS, Katulak NA, Wu R, Dubin JA, Latimer A, Meandzija B, George TP, Jatlow P, Cooney JL, Salovey P: Comparing gain- and loss-framed messages for smoking cessation with sustained-release bupropion: a randomized controlled trial. Psychol Addict Behav. 2007 Dec. PMID: 18072836
- Toll BA, McKee SA, Martin DJ, Jatlow P, O'Malley SS: Factor structure and validity of the Medication Adherence Questionnaire (MAQ) with cigarette smokers trying to quit. Nicotine Tob Res. 2007 May. PMID: 17454716
- Weinberger AH, Sacco KA, Creeden CL, Vessicchio JC, Jatlow PI, George TP: Effects of acute abstinence, reinstatement, and mecamylamine on biochemical and behavioral measures of cigarette smoking in schizophrenia. Schizophr Res. 2007 Mar; 2007 Feb 9. PMID: 17293085
- Staley JK, Krishnan-Sarin S, Cosgrove KP, Krantzler E, Frohlich E, Perry E, Dubin JA, Estok K, Brenner E, Baldwin RM, Tamagnan GD, Seibyl JP, Jatlow P, Picciotto MR, London ED, O'Malley S, van Dyck CH: Human tobacco smokers in early abstinence have higher levels of beta2* nicotinic acetylcholine receptors than nonsmokers. J Neurosci. 2006 Aug 23. PMID: 16928859
- O'Malley SS, Cooney JL, Krishnan-Sarin S, Dubin JA, McKee SA, Cooney NL, Blakeslee A, Meandzija B, Romano-Dahlgard D, Wu R, Makuch R, Jatlow P: A controlled trial of naltrexone augmentation of nicotine replacement therapy for smoking cessation. Arch Intern Med. 2006 Mar 27. PMID: 16567607
- Kosten TA, Sanchez H, Jatlow PI, Kehoe P: Neonatal isolation alters the estrous cycle interactions on the acute behavioral effects of cocaine. Psychoneuroendocrinology. 2005 Sep; 2005 Apr 12. PMID: 15919581
- Staley JK, Gottschalk C, Petrakis IL, Gueorguieva R, O'Malley S, Baldwin R, Jatlow P, Verhoeff NP, Perry E, Weinzimmer D, Frohlich E, Ruff E, van Dyck CH, Seibyl JP, Innis RB, Krystal JH: Cortical gamma-aminobutyric acid type A-benzodiazepine receptors in recovery from alcohol dependence: relationship to features of alcohol dependence and cigarette smoking. Arch Gen Psychiatry. 2005 Aug. PMID: 16061765
- Sughondhabirom A, Jain D, Gueorguieva R, Coric V, Berman R, Lynch WJ, Self D, Jatlow P, Malison RT: A paradigm to investigate the self-regulation of cocaine administration in humans. Psychopharmacology (Berl). 2005 Jul; 2005 Feb 22. PMID: 15726333
- Sacco KA, Termine A, Seyal A, Dudas MM, Vessicchio JC, Krishnan-Sarin S, Jatlow PI, Wexler BE, George TP: Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Arch Gen Psychiatry. 2005 Jun. PMID: 15939842
- Epperson CN, O'Malley S, Czarkowski KA, Gueorguieva R, Jatlow P, Sanacora G, Rothman DL, Krystal JH, Mason GF: Sex, GABA, and nicotine: the impact of smoking on cortical GABA levels across the menstrual cycle as measured with proton magnetic resonance spectroscopy. Biol Psychiatry. 2005 Jan 1. PMID: 15607299
- Petrakis IL, Limoncelli D, Gueorguieva R, Jatlow P, Boutros NN, Trevisan L, Gelernter J, Krystal JH: Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism. Am J Psychiatry. 2004 Oct. PMID: 15465973
- Jatlow P, McKee S, O'Malley SS: Correction of urine cotinine concentrations for creatinine excretion: is it useful? Clin Chem. 2003 Nov. PMID: 14578327
- Epperson CN, Jatlow PI, Czarkowski K, Anderson GM: Maternal fluoxetine treatment in the postpartum period: effects on platelet serotonin and plasma drug levels in breastfeeding mother-infant pairs. Pediatrics. 2003 Nov. PMID: 14595087
- Jacobsen LK, Gore JC, Skudlarski P, Lacadie CM, Jatlow P, Krystal JH: Impact of intravenous nicotine on BOLD signal response to photic stimulation. Magn Reson Imaging. 2002 Feb. PMID: 12034334
- Rainey PM, Friedland GH, Snidow JW, McCance-Katz EF, Mitchell SM, Andrews L, Lane B, Jatlow P: The pharmacokinetics of methadone following co-administration with a lamivudine/zidovudine combination tablet in opiate-dependent subjects. Am J Addict. 2002 Winter. PMID: 11876585