Mission Statement
The disease of addiction is produced by interactions between individual biological organisms (people), specific pharmacological agents (drugs) and the social, economic, cultural, biologic and geographic milieu (environment).
The Addiction Pharmacology Research Laboratory is dedicated to understanding how specific pharmacologic compounds (drugs) contribute to developing or treating addictive disease. We believe that deciphering the biological effects of drugs is essential for developing effective therapies to treat addiction.
We exist to conduct human research on the effects of addictive and abused drugs and to develop new medications and treatments for drug addiction. We use the tools of clinical pharmacology – pharmacokinetics, pharmacodynamics, clinical trials – to assess the effects of addictive and abused drugs and to develop new treatments for addiction. We are dedicated to the safe and ethical human study of addictive and abused drugs, both in controlled laboratory settings and in people living and functioning in the community. 
Funding
The Addiction Pharmacology Research Laboratory is primarily funded by the NIH-NIDA. Various NIH initial review groups competitively review our projects with funding from program project grants (P50), RO1’s and contracts.
Under our NIDA funded P50 (starting October 1, 2004) we will be studying new pharmacotherapies for methamphetamine addiction. The principle investigators of the Methamphetamine Pharmacotherapy Development program are Dr John Mendelson and Dr Gantt Galloway.
Project Abstract
This project will test the safety and efficacy of medications that modulate adrenergic function as treatments for methamphetamine dependence. Methamphetamine abuse is a widespread problem that has killed a substantial number of Americans. In a coordinated series of laboratory and treatment studies we perform a systematic investigation of the utility of the adrenergic compounds clonidine, carvedilol, prazosin and atomoxetine for the treatment of methamphetamine addiction. Population pharmacokinetics is a powerful tool for measuring drug effect. We use population PK/PD modeling to provide an estimate of the amounts of illicit methamphetamine consumed during our trials. We postulate that quantifying the effects of candidate pharmacotherapies on illicit drug intake will substantially improve our ability to assess therapeutic outcomes. Relapse to drug use is a function of several complex alterations in mood, craving, stress and withdrawal symptoms. Surrogate markers can be essential in determining drug response. In our studies we assess the utility of using measures of the cytokines IL-6, CRP and TNF-alpha as surrogate makers of stress, a known predictor of relapse, to measure drug effect and predict outcome. Specific experiments are coordinated to so that results from one experiment informs the design of subsequent studies. In our laboratory component we assess interactions between our candidate drugs and methamphetamine, develop and validate under controlled conditions our method to quantify illicit drug intake and evaluate methamphetamine-cytokine interactions. Results from these studies are used to advance drugs to placebo controlled outpatient treatment trials. In our outpatient placebo-controlled trials we assess the efficacy of two of our candidate drugs, validate the quantitative methamphetamine ingestion method under real world conditions and assess the utility of our immune markers to predict relapse. Our studies are focused, mechanistically based and collaborative and present opportunities for methods development and efficacy evaluations that could not be practically achieved without a center.
We have obtained an excellent score on two RO1s for studies of the pharmacology of MDMA and related phenethylamines. NIDA Council will review these projects in October with funding anticipated in January or February of 2005.
Project Abstract
MDMA is an emerging drug of abuse with up to 11.3% of young adults in the US having tried this potentially addictive and toxic drug. Because of the increasing popularity of MDMA and its relatives we propose human studies to characterize pharmacologic effects. We will test the dose-, enantiomer-, and gender- dependent pharmacokinetic (PK) and pharmacodynamic (PD) response to MDMA (“Ecstasy”) and one active metabolite, MDA. Our data show that MDMA has non-linear and enantiomer selective kinetics with disproportional increases in drug exposure with increasing doses. We will determine the contributions of increasing bioavailability and/or inhibition of metabolism on the kinetics and effects of S(+)- and R(-)-MDMA. Using chiral capillary GC-MS and LC-tandem MS we have developed and validated sensitive and specific analytic methods to measure the isomers of MDMA and metabolites in plasma, urine and sweat (using patches and a ventilated capsule method, useful in biomonitoring of MDMA abuse). Synthesis and administration of deuterium labelled enantiomers of MDMA and MDA will be used to characterize bioavailability and clearance of drug and metabolite. Psychopharmacologic effects are evaluated under well-controlled laboratory conditions with subjects housed on the UCSF GCRC. Cardiovascular PD effects are measured non-invasively with trans-thoracic 2-dimensional echocardiography and impedance cardiography. We have an active IND for the human study of MDMA and are well experienced with administration of safe and tolerable doses that produce minimal physiological response. Experiment 1 will determine possible isotope effects of deuterium-labelled MDMA and the pharmacodynamic effects of intravenous MDMA. The bioavailability and effects of gender and dose on the pharmacology of optically pure S(+)- and R(-)-MDMA will be assessed in Experiment 2. Experiment 3 will investigate the PK and PD of a single modest oral dose of MDA, an MDMA metabolite that is also a drug of abuse. This experiment will help define the mechanism of action of MDA and also provide a useful data on metabolic pathways of MDMA. Experiment 4 will investigate the mechanisms underlying MDMA-induced hyponatremia, a significant complication of MDMA abuse seen in primarily female "rave" party participants. Case reports suggest that water retention and loss of sodium may play a role in the development of hyponatremia, possibly due to MDMA-induced antidiuretic hormone (vasopressin) secretion. The effect of exercise and water loading on sodium and water homeostasis will be tested in subjects receiving a low oral dose of MDMA. In Experiment 5 we will investigate the effect of the alpha-blocker prazosin on the response to MDMA. Alpha-blockers may attenuate MDMA actions in humans. This experiment will investigate the role of alpha-1 adrenergic receptors in the action of MDMA and will provide preliminary data on the possible use of prazosin in the treatment of acute MDMA toxicity.
APRL Scientists
John Mendelson MD
John Mendelson is a board certified Internist who has performed human pharmacologic studies with methamphetamine, MDMA, cocaine and buprenorphine. His clinical research involves the pharmacology, physiology and psych-ology of commonly abused drugs and development of treatments for drug abuse and associated medical and psychiatric complications. In his laboratory, pharmacologically active doses of abusable drugs are studied under controlled conditions. All studies are performed at or above FDA GLP standards and his clinical research unit is equipped to ethically and safely conduct studies in licit and illicit drug users.
He has successfully conducted NIH funded studies with methamphetamine, MDMA, cocaine, methamphetamine enantiomers, marijuana, opioids, and other addictive drugs in populations that are often difficult to deal with (including untreated cocaine and heroin addicts). He has studied the cardiovascular effects of MDMA, cocaine and methamphetamine. He has performed studies on interactions between ethanol and the stimulant drugs cocaine and methamphetamine and has developed novel cocaine self-administration paradigms. He has used stable isotope methods to define the pharmacokinetics of cocaethylene formation and elimination and measure the bioavailability of intranasal methamphetamine. Dr. Mendelson performed many of the basic pharmacokinetic and abuse liability studies used to support FDA approval of Suboxone (a combination of buprenorphine and naloxone), the first new primary pharmacotherapy for opiate addiction introduced in more than 30 years. Currently, he is conducting phase 1 safety interaction studies with potential new pharmacotherapies for methamphetamine addiction. Dr. Mendelson has extensive experience working with the many regulatory bodies that oversee research with addictive drugs, including the CPMC and UCSF Institutional Review Boards, the FDA, the UCSF General Clinical Research Center, and the California Research Advisory Panel.
Gantt Galloway, Pharm.D.
Dr. Gantt Galloway brings 16 years of research and clinical experience with alcoholics and other addicts to the group. He has worked in a number of treatment settings, such as the Haight-Ashbury Free Clinic. Together with Dr. Mendelson, he founded the Addiction Pharmacology Research Laboratory at California Pacific Medical Center. He has succeeded in designing and conducting clinical research with NIH funding in challenging clinical settings. Naltrexone and nalmefene are among the agents that he has tested for alcohol dependence. He has tested naltrexone as a treatment for methamphetamine dependence and for cocaine dependence. His research interests also include genetic contributions to the development of paranoia in methamphetamine users.
Matthew Baggott PhD candidate