Clinical Trials and Medication Development Projects


The National Drug Abuse
Clinical Trials Network

Walter Ling, M.D., Principal Investigator (lwalter@ucla.edu)
Richard A. Rawson, Ph.D., M. Douglas Anglin, Ph.D., & Steven Shoptaw, Ph.D., Co-Investigators
Albert L. Hasson, M.S.W., Project Director

In September 2005, the Pacific Region Node began its sixth year as a member of the NIDA Clinical Trials Network. As one of 17 Regional Research Training Centers, ISAP continues to collaborate with seven local community treatment programs in an effort to make substance abuse research more relevant to the treatment community. The Betty Ford Center, Bay Area Addiction Research and Treatment, Inc., Matrix Institute on Addictions, Hina Mauka Treatment  Programs, Phoenix House, Tarzana Treatment Center, and the Van Ness Recovery Center are participants within the Pacific Region Node helping to guide the CTN research portfolio.
The Pacific Region Node continues to take an active role in the Clinical Trials Network. In addition to leading a 9-site trial comparing the impact of Suboxone and methadone on liver function in treatment-seeking opioid-dependent individuals, “Starting Treatment with Agonist Replacement Therapy” (START), ISAP is the co-lead on a project evaluating Suboxone with and without enhanced medical management in the detoxification of prescription opioid users. “Prescription Opioid Addition Treatment” (POAT) is currently being piloted in two sites including ISAP, with eight more sites nationwide set to begin recruitment in 2007. (Additional information is available at www.uclaisap.org/ctn/index.html.)

The National Drug Abuse Clinical Trials Network was funded by the National Institute on Drug Abuse, Grant 2 U10 DA13045 (September 2005 through August 2010).

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Medication Development for
Stimulant Dependence (MDS)

Walter Ling, M.D., Principal Investigator (lwalter@ucla.edu)

Outstanding facilities and appropriately trained staff experienced in the conduct of clinical trials provides UCLA ISAP with a superior reputation in the area of medication development for stimulant dependence. UCLA ISAP serves as one of only a few medication development groups across the nation contracted with the National Institute on Drug Abuse to investigate the effectiveness of new medications for stimulant dependence in Phase I and Phase II research. Each umbrella contract includes a mechanism whereby proposed investigations are offered through a task order to a MDS group for clinical trial research. The specific study is funded according to the pertinent aims, scope, and design of the protocol, and includes a study team led by a principal investigator named by Dr. Ling. Individual studies are typically administered in conjunction with investigators affiliated with the UCLA Department of Family Medicine and the UCLA Department of Psychiatry and Biobehavioral Sciences.

The MDS contract focuses on medication development for stimulant abuse by evaluating medications in the context of carefully metered doses of specific behavioral therapies, by advancing measurement and analysis strategies, and by increasing the efficiency of the clinical trials processes. From extensive research experience conducting medication trials for pharmacological and behavioral treatments for drug dependence, the MDS project contributes to the knowledge base regarding treatments for stimulant abuse. Innovative work is also possible through collaborative efforts with the UCLA ISAP Center grant for research addressing pharmaceutical treatment for stimulant abuse (see “UCLA Medication Development Unit for Stimulant Abuse,” Page 34). Until recently, the MDS also served as the umbrella contract for the Methamphetamine Clinical Trials Group (MCTG), tasked with investigating medications specifically for methamphetamine-dependent individuals.

Medication Development for Stimulant Dependence (MDS) was funded by the National Institute on Drug Abuse, Grant N01DA-3-8824 (January 2003 through January 2008).

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Phase I Double-Blind, Placebo-Controlled Assessment of Potential Interactions between Intravenous Methamphetamine and Aripiprazole

Thomas Newton, M.D., Principal Investigator
(tnewton@ucla.edu)
Charles Glatt, M.D., Roger Donovick, M.D., Timothy Fong, M.D., Matt Torrington, M.D., & Arif Karim, M.D., Co-Investigators
Richard De La Garza, II, Ph.D., Project Director

This is a double-blind inpatient study in which subjects’ eligibility for participation, including cardiovascular responses to screening/baseline methamphetamine (MA) infusions of 15mg and 30mg IV administered over 5 days (sessions #1-3), will be established. Four days after infusion, a MA cue reactivity test will be conducted. Fivedays after infusion session #3 or when urine MA level is lower than 1,000ng/mL, subjects will be randomized into one of two treatment groups and on the same day will initiate treatment with 15mg aripiprazole (n = 8) or matched placebo (n = 8) for 20 days. Thirteen days after initiation of daily treatment with either 15mg aripiprazole or placebo, another MA cue reactivity test will be conducted. Fourteen days after initiation of daily treatment with either 15mg aripiprazole or placebo, subjects will receive treatment MA infusions of 15mg and 30mg IV over 6 days (sessions #4-6). For 2 days after infusion sessions #2, 3, 5, and 6, samples for PK analysis will be collected. Each series of repeated MA administrations (screening/baseline and treatment) will consist of 3 infusions; each infusion session will be conducted on a different day with a 1-day break between infusions except for a 2-day break between infusions #5 and #6. Subjects will be randomized with the order of administration of the saline, 15mg MA, and 30mg MA infusions; the 15mg MA infusions will always precede 30mg MA infusions. The subjects will be discharged from the hospital 4 days after the last dose of aripiprazole and treatment infusion. The subjects will be asked to return twice for safety follow-ups 1 and 4 weeks after clinic discharge. 

Phase I Double-Blind, Placebo-Controlled Assessment of Potential Interactions between Intravenous Methamphetamine and Aripiprazole was funded by the National Institute on Drug Abuse, Grant N01DA-3-8824 (July 2004 through October 2005).

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Phase I – Interaction Clinical Trial with Disulfiram, Cocaine, and Alcohol

Thomas Newton, M.D., Principal Investigator
(tnewton@ucla.edu)
Charles Glatt, M.D., Roger Donovick, M.D., Timothy Fong, M.D., Matt Torrington, M.D., Arif Karim, M.D., & Gilles Fleury, M.D., Co-Investigators
Richard De La Garza, II, Ph.D., Project Director

This 2-site, double-blind, placebo-controlled inpatient study determined the cardiovascular and psychiatric safety of alcohol use in cocaine-dependent subjects who had used cocaine after treatment with disulfiram. In this study, subjects were screened for eligibility including initial screening for clinical tolerance to a cocaine infusion of 30mg IV. Thereafter, baseline cardiovascular responses to IV cocaine and ethanol infusions (on Days 2 and 1, respectively) were established. One day after infusion #3, subjects were randomized into one of two treatment groups and on the same day initiated oral dosage treatment with 250mg disulfiram or placebo once a day for 7 days. Three days after initiation of daily treatment with either 250mg disulfiram (n = 8) or placebo (n = 4), all subjects received treatment infusions. On Day 4, subjects received only IV saline; on Day 5, 30mg IV cocaine; on Day 6, IV dose of ethanol; and on Day 7, 30mg IV cocaine followed by IV ethanol 5 minutes later. After the Day 7 dose of disulfiram/placebo, double-blind oral treatment ceased, but the subjects remained in the hospital until discharge 1 week later on Day 14. Subjects were requested to return for safety follow-ups approximately 1 and 2 weeks after the day of discharge. All infusions were single blind and “double-dummy”; i.e., the cocaine infusion was blinded by a parallel saline infusion and the alcohol infusion was blinded by a parallel glucose infusion. Study agent (disulfiram/placebo) was administered double-blind.

Phase I – Interaction Clinical Trial with Disulfiram, Cocaine, and Alcohol was funded by the National Institute on Drug Abuse, Grant N01DA-3-8824 (July 2004 through October 2005).

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Phase II Double-Blind, Placebo-Controlled Trial of Bupropion for the Treatment of Methamphetamine Dependence

Richard A. Rawson, Ph.D., Principal Investigator (rrawson@mednet.ucla.edu)
Valerie Pearce, B.A., Project Director

The National Institute on Drug Abuse - Methamphetamine Clinical Trials Group (MCTG) established 5 clinical research sites coordinated by UCLA researchers where medications with potential value for methamphetamine (MA) users were tested. The goal of this network was to speed the development of MA pharmacotherapy research by establishing multiple research clinics in geographic regions of the United States with substantial MA problems. The bupropion protocol was conducted from August 2003 through June 2005 by investigators associated with five organizations: University of Missouri-Kansas City; University of Hawaii (Queens Hospital) Honolulu; Matrix Institute on Addictions, Costa Mesa, California; South Bay Treatment Center, San Diego, California; and the Iowa Health Systems (Office of Research, Lutheran Hospital), Des Moines, Iowa. This study was a preliminary assessment of the efficacy and safety of bupropion in reducing MA use in subjects with MA dependence. It was hypothesized that bupropion treatment, compared to placebo, would be associated with fewer days of MA use as measured by quantitative urine analysis for MA. This was a double-blind, placebo-controlled, randomized, two-arm study comparing 150mg BID dose of bupropion to placebo administered to MA-dependent outpatients. All subjects received a base of standardized, manual-driven cognitive behavioral therapy (a 90-minute group session thrice weekly) over 12 weeks of treatment. A final follow-up assessment was conducted 4 weeks after completion of treatment.  Results are in review for publication. 

Phase II Double-Blind, Placebo-Controlled Trial of Bupropion for the Treatment of Methamphetamine Dependence was funded by the National Institute on Drug Abuse, Contracts  N01DA-0-8804 and N01DA-3-8824 (July 2004 through October 2005).

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UCLA Medication Development Unit
for Stimulant Abuse

Steven Shoptaw, Ph.D., Principal Investigator
(sshoptaw@mednet.ucla.edu)
Keith Heinzerling, M.D., M.P.H., & Thomas Newton, M.D., Co-Investigators
Erin Rotheram-Fuller, Ph.D., Project Director

ISAP’s P50-funded Center “Medication Development Unit for Stimulant Dependence” (MDU; DA 12755, Principal Investigator (PI) Walter Ling, M.D.) conducted medication development trials for stimulant abuse and dependence beginning in 1999. Continuation of the P50 funding replaces and extends that original effort with the “Medication Development Unit for Stimulant Abuse” (MDUSA; PI Steven Shoptaw). The MDUSA Center continues to involve the substantial expertise in clinical drug abuse research of ISAP faculty, and the scope of the Center is broadened by integrating P50 activities with research conducted by investigators of the UCLA Department of Psychiatry and Biobehavioral Sciences and Department of Family Medicine.

Like past P50 efforts, the continuation Center focuses on medication development for stimulant abuse by evaluating medications in the context of carefully metered doses of specific behavioral therapies, by advancing measurement and analysis strategies, and by increasing the efficiency of the clinical trials processes. The Center reflects significant strengths of proven multidisciplinary collaborations that have helped guide medication development through early safety experiences to single-site pilot studies to multisite clinical trials. The Center has outstanding facilities and  staff members who are trained and experienced in the conduct of clinical trials. Moreover, the local environment has diverse populations of stimulant abusers (particularly methamphetamine abusers) in sufficient numbers to enable successful conduct of the proposed research.

The thematic emphasis that unifies the Center research is the development of pharmacological treatments for stimulant abuse through comprehensive and efficient methodologies applied by a multidisciplinary team. The Center team’s decades of experience in conducting medication trials for pharmacological and behavioral treatments for drug dependence are the basis for the Center’s integrative approach. The Center will increase the knowledge base on treatments for stimulant abuse by means of an ever greater linkage of Phase I with Phase II work, a stronger effort to apply advanced biostatistical methods to isolate potential medication effects in subgroups, a more concerted effort to identify biomarkers that discriminate meaningful differences between subgroups of stimulant abusers, and a more focused approach to the evaluation of medications within the context of carefully specified and timed behavioral interventions, ultimately seeking to improve clinical practice and to address emerging problems in the field. 

UCLA Medication Development Unit for Stimulant Abuse was funded by the National Institute on Drug Abuse, Grant 5 P50 DA018185 (September 2004 through February 2010).

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Phase I Double-Blind, Randomized, Placebo-Controlled Trial of Rivastigmine as a Potential Medication for Methamphetamine Abuse

Thomas Newton, M.D., Principal Investigator
(tnewton@ucla.edu)
Roger Donovick, M.D., Timothy Fong, M.D., Matt Torrington, M.D., & Gilles Fleury, M.D.,
Co-Investigators
Richard De La Garza, II, Ph.D., Project Director

The purpose of this study is to assess the efficacy and safety of rivastigmine in the treatment of methamphetamine dependence. The study will evaluate rivastigmine at two dose levels. Methamphetamine-dependent non-treatment-seeking volunteers will receive rivastigmine or placebo. Participants will stay in an inpatient research nursing unit at UCLA for 16 days. On two different study days, participants will receive safety infusions to identify participants who do not tolerate the drug administration. On four other study days, participants will take part in choice sessions where they will have to choose between a dose of the drug and a range of increasing monetary amounts. During these procedures, the participant’s heart rate and blood pressure will be monitored. They will also be asked to answer questions regarding their response to cocaine and will undergo neurocognitive assessments.

Medication Development Unit for Stimulant Dependence was funded by the National Institute on Drug Abuse, Grant 1 P50 DA018185 (September 2004 through July 2009).

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Methamphetamine Dependence:
Treating Neurocognitive Impairment

Ari Kalechstein, Ph.D., Principal Investigator
(adk@ucla.edu)
Thomas Newton, M.D., & Richard De La Garza, Ph.D.,
Co-Investigators
Liza Harrison, B.A., Project Director

Over the past several years, UCLA ISAP investigators have built upon clinical experience gained from providing treatment for methamphetamine-dependent individuals to develop a human laboratory program aimed at assessing the neurobiological consequences of methamphetamine (MA) exposure. Current research designs at ISAP and other research groups focus on the evaluation of MA-dependent individuals following abstinence initiation. While these studies are important, they do not utilize neurocognitive impairment as a marker for determining the extent of MA-associated neurotoxicity. Because impaired neurocognitive functioning is associated with poorer functional outcomes (e.g., employment status, treatment outcome), reversal of these impairments could enhance the quality of treatments for MA dependence. We propose to explore whether a candidate medication, modafinil, can ameliorate MA-associated neurocognitive impairment in non-treatment seeking MA-dependent volunteers. The data generated from this study will eventually provide valuable insights into the neurobiological mechanisms that underlie MA-associated neurocognitive impairments. The specific aim of the current study is to determine the effects of modafinil on neurocognition in volunteers with MA dependence during the initial phases of abstinence. We hypothesize that modafinil treatment will enhance performance on neurocognitive measures relative to placebo in a sample of recently abstinent MA-dependent individuals.

Methamphetamine Dependence: Treating Neurocognitive Impairment was funded by the National Institute on Drug Abuse, Grant 1 R03 DA02059 (September 2005 through September 2006).

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Double-Blind, Placebo-Controlled Trial of Prometa Pharmacotherapy for the Treatment of Methamphetamine Abuse

Walter Ling, M.D., Principal Investigator (lwalter@ucla.edu)
Maureen Hillhouse, Ph.D., Project Director

This study assesses the efficacy of the PROMETAÔ pharmacotherapy compared to placebo for initiating abstinence and for preventing relapse to methamphetamine (MA) use in treatment-seeking individuals meeting criteria for MA abuse in multiple treatment locations. The study design includes random assignment to pharmacotherapy condition, and both participants and study personnel are blinded to assigned condition. Screening verifies participant eligibility and collects demographic, drug use, psychiatric, and neuropsychological information before participants are randomly assigned to either the PROMETAÔ pharmacotherapy condition (n = 45) or to the placebo condition (n = 45). Pharmacotherapy includes 2 infusion phases (starting at Day 0, and again at Day 21) in addition to 40 days of oral medications. Participants are also provided with weekly cognitive behavioral therapy for the duration of the study. Weekly assessments collect information to evaluate medical and psychological status throughout the study (12 weeks). Drug use outcomes are measured using self-report, verified by biological markers of abstinence (urine tested for metabolites of MA, cocaine, heroin, marijuana, and benzodiazepines). Individuals assigned to receive the PROMETAÔ pharmacotherapy, compared to placebo, are expected to demonstrate significantly fewer and less intense withdrawal symptoms, more days of abstinence from MA use, and fewer relapses to MA use. (Additional information is available at www.hythiam.com.)

Double-Blind, Placebo-Controlled Trial of Prometa Pharmacotherapy for the Treatment of Methamphetamine was funded by Hythiam, Inc., Clinical Trial 05072347 (March 2005 through January 2007).

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Hyperalgesia in Methadone-Maintained Patients: Can It be Treated?

Walter Ling, M.D., Principal Investigator (lwalter@ucla.edu)
Peggy Compton, Ph.D., Co-Investigator
Albert Hasson, M.S.W., Project Director

Addressing the undertreatment of clinical pain has sparked increasing efforts aimed at identifying effective interventions for subgroups of patients most at risk for suffering unrelieved pain. Novel data accumulated by our investigative group has shown that methadone-maintained (MM) patients for the treatment of addiction have significantly diminished tolerance for pain, or hyperalgesia. This, in addition to contextual prohibitions associated with providing opiate analgesics to known opioid addicts, makes this a population uniquely vulnerable to the undertreatment of their pain. Unfortunately, little is known about how best to manage pain suffered by over 120,000 methadone-maintained (MM) patients in this country, in part because hyperalgesia appears to be akin to opioid-induced and neuropathic pain.

In this study, we build upon our previous research to explore the underlying mechanism from a pharmacological perspective. Utilizing a double-blind, placebo-controlled design, we are evaluating the ability of several drugs typically used to treat pain (e.g., dextromethorphan and gabapentin) to diminish or reverse the opioid-induced hyperalgesia complicating the pain states in MM patients. As such, medication that may interfere with the development of opioid-induced hyperalgesia will be evaluated for its ability to ameliorate or diminish hyperalgesia in MM patients, as reflected by changes in pain threshold and tolerance to both cold-pressor and electrical pain. The results of this work will provide pharmacologic insight into the mechanisms underlying poor pain tolerance in this at-risk population, as well as direction for the medical management of pain complicated by opioid-induced hyperalgesia.

Hyperalgesia in Methadone-Maintained Patients: Can It be Treated? was funded by the National Institute on Drug Abuse, Grant 5 R01 DA015463 to UCLA School of Nursing, with collaboration by UCLA ISAP (September 2002 through May 2007).

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Clinical Research Education for
Drug Abuse Professionals

Thomas Newton, M.D., Principal Investigator
(tnewton@ucla.edu)
Richard De La Garza, II, Ph.D., Project Director

The Clinical Research Education for Drug Abuse Professionals (CREDAP) program seeks to increase and improve clinical research expertise among health care professionals addressing drug dependence. The overarching goal of the CREDAP program is to provide a coordinated, sustainable infrastructure of dedicated education and training that will produce independent healthcare professionals capable of conducting and disseminating clinical research pertaining to drug dependence and its treatment, issues of great importance for public health. Formal evaluation will be utilized to provide input on areas that can be improved. The curriculum includes a coordinated education program of clinical research training combining formal coursework and hands-on research and clinical experiences. By immersion in the uniquely integrated environment of research, education, and practice offered by the program and its setting at UCLA, post-residency psychiatrists and other drug abuse professionals receive comprehensive education and training in clinical research topics and methods pertinent to the study of drug dependence and its treatment.

Clinical Research Education for Drug Abuse Professionals was funded by the National Institute on Drug Abuse, Grant 2 R25 DA14593 (September 2002 through May 2007).

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Laboratory Models of
Cocaine Self-Administration

Thomas Newton, M.D., Principal Investigator
(tnewton@ucla.edu)
Todd Zorick, M.D., Stefan Rowney, M.D., Gilles Fleury, M.D., & James McCracken, M.D., Co-Investigators
Richard De La Garza, II, Ph.D., Project Director

The purpose of this study is to determine the effects of treatment with disulfiram on self-administration of cocaine on cocaine users. This study involves two 9-day inpatient stays on an inpatient research unit at UCLA. On study days 5 and 7, subjects will choose between a cocaine dose and a money alternative.  Participants make 10 choices at 15-minute intervals during each session. The amount of money available begins at $.05 and increases to $16. The dose of cocaine available is either 0mg or 20mg per choice, and one dose (either no cocaine or 20 mg cocaine) is randomly assigned each day. Throughout each session blood pressure and subjective effects will be assessed. On study days 1, 4, and 8, participants will complete neurocognitive testing. During these procedures, participants’ heart rate variability will also be assessed. Each participant will complete this experiment twice, once while receiving daily placebo and once while receiving daily disulfiram in a randomized order. 

Laboratory Models of Cocaine Self-Administration was funded by the National Institute on Drug Abuse, Grant 1 R01 DA017705 (September 2005 through June 2009).

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Double-Blind, Placebo-Controlled Trial of Topiramate for the Treatment of Methamphetamine Dependence

Richard A. Rawson, Ph.D., Principal Investigator (rrawson@mednet.ucla.edu)
Donnie Watson, Ph.D., & Mark Hrymoc, M.D.,
Co-Investigators
Valerie Pearce, B.A., Project Director

This is a double-blind, multicenter, placebo-controlled, randomized, parallel group design study on methamphetamine-dependent outpatients. This protocol is coordinated through the Department of Veterans Affairs and the Cooperative Studies Program Coordinating Center. Subjects (N = 140) with DSM-IV criteria for methamphetamine (MA) dependence will be randomized in a 1:1 ratio to daily dosing with the investigational products, topiramate or matched placebo. Once during baseline and once per week during the 12-week treatment phase, all subjects will receive Brief Behavioral Compliance Enhancement Treatment (BBCET), a manual-driven, low-intensity supportive program to foster, maintain, and promote compliance with investigational product use and to promote continuation in the study. A final follow-up assessment will be conducted approximately 28 days after completion of treatment.

The topiramate protocol will be conducted by investigators associated with eight organizations: UCLA/Friends Research Institute, Torrance, California; Matrix Institute on Addictions, Costa Mesa, California; South Bay Treatment Center, San Diego, California; Iowa Health Systems (Office of Research, Lutheran Hospital), Des Moines; University of Virginia Health System, Charlottesville; Salt Lake City Health Care System, Utah; START Research & Treatment, Kansas City, Missouri; and University of Hawaii (Queens Hospital) Honolulu. This study is a preliminary assessment of the efficacy and safety of topiramate in reducing MA use in subjects with MA dependence. It is hypothesized that topiramate treatment, compared to placebo, will be associated with fewer days of MA use as measured by quantitative urine analysis for MA.

Double-Blind, Placebo-Controlled Trial of Topiramate for the Treatment of Methamphetamine Dependence was funded by the National Institute on Drug Abuse, Contract NIDA-CSP-1025 (October 2005 through March 2007).

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Perindopril-Methamphetamine
Interaction Study

Thomas Newton, M.D., Principal Investigator
(tnewton@ucla.edu)
Charles Glatt, M.D., Roger Donovick, M.D., Timothy Fong, M.D., Matt Torrington, M.D., Arif Karim, M.D., & Gilles Fleury, M.D., Co-Investigators
Richard De La Garza, II, Ph.D., Project Director

The aim of this Phase I trial is to assess the safety of perindopril treatment in a population of methamphetamine (MA) users so that an outpatient trial can be conducted to assess whether perindopril will decrease craving and relapse and thus help with cessation of MA use. This is a double-blind inpatient study in which, after establishing eligibility by screening the responses to MA infusions of 15 and 30mg IV, subjects will be randomized to receive either perindopril (2, 4, 8, or 16mg) or matched placebo. On the third and fifth day of perindopril (or placebo) treatment, subjects will receive additional MA infusions of 15 and 30mg. Each MA infusion will either be preceded or followed at 1 hour by a control saline infusion in random order. Safety of MA administration in perindopril-dosed subjects will be evaluated using primarily cardiovascular assessments. Subjective effects of MA as well as ratings of craving will also be assessed.

Perindopril-Methamphetamine Interaction Study was funded by the National Institute on Drug Abuse, Grant 1 R21 DA017182 (September 2003 through December 2006).

Last Updated: 02/01/2007

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2016 ISAP Publications
2015 ISAP Publications