The NIDA Methamphetamine Clinical Trials Group - Wiley Online Library

REPORT

The NIDA Methamphetamine Clinical Trials Group: a strategy to increase clinical trials research capacity Ahmed Elkashef1, Richard A. Rawson2, Edwina Smith1, Valerie Pearce2, Frank Flammino3, Jan Campbell4, Roger Donovick5, Charles Gorodetzky6, William Haning7, Joseph Mawhinney8, Michael McCann9, Dennis Weis10, Lorie Williams11, Walter Ling2 & Frank Vocci1 Division of Treatment Research and Development, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA,1 UCLA Integrated Substance Abuse Programs, Neuropsychiatric Institute and Hospital, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA,2 New York University School of Medicine, Department of Psychiatry, New York, NY, USA,3 University of Missouri–Kansas City, Department Psychiatry, Kansas City, MO, USA,4 Matrix Institute on Addictions, Costa Mesa, CA, USA,5 Quintiles, Inc., Kansas City, MO, USA,6 John A. Burns School of Medicine, Psychiatry Department, Honolulu, HI, USA,7 South Bay Treatment Center, San Diego, CA, USA,8 Matrix Institute on Addictions, West Los Angeles, CA, USA,9 Lutheran Hospital, Office of Research, Des Moines, IA, USA10 and SW Kidney Institute, PLC, Mesa, AZ, USA11

ABSTRACT Aims In order to increase the number of investigative teams and sites conducting research on pharmacological treatments for methamphetamine use disorders, the National Institute on Drug Abuse (NIDA) established an infrastructure of clinical sites in areas where methamphetamine addiction is prevalent. This multi-site infrastructure would serve to run multiple Phases II and III protocols effectively and expeditiously. Methods NIDA collaborated with investigators from the University of California at Los Angeles (UCLA) to set up the Methamphetamine Clinical Trials Group (MCTG). This paper describes the development process, as well as data from a test trial to assess the capability of research-naive sites to recruit research participants and conduct study procedures according to research protocol. Subsequent trials are also described. Results A total of 151 candidates signed consent; 65 individuals were enrolled and 35 (53.8%) completed the 12 weeks’ behavioral trial. Self-reported substance use report (SUR) showed comparable use of methamphetamine across sites with the individual site means ranging from 59% (site 5) to 80% (site 3). Drug use as measured by urinalysis was greatly reduced at week 13 compared to the baseline measure; the average rate of methamphetamine-free urine samples across all participants in sites at week 13 was 53%. The highest percentage of methamphetamine-free samples was 85% at site 5; the lowest was at site 1 (40%). Addiction severity index (ASI) composite scores at baseline and protocol completion for all participants demonstrated improvement in all categories over time, except for the medical composite score. The largest composite score reduction in baseline-protocol completion was in the drug domain (0.23 versus 0.15). The changes in the ASI scores from baseline to week 13 were consistent across all five sites. Conclusions Outcomes of the behavioral trial indicated that the MCTG recruited well; collected study data accurately and reliably; and created a vehicle that can assess promising pharmacotherapies for methamphetamine addiction treatment medications. The MCTG strategy appears to be a feasible approach to increase NIDA’s capacity to conduct clinical trials to evaluate potential pharmacotherapies for methamphetamine addiction. Keywords

Medication, methamphetamine, multi-site, pharmacotherapy.

Correspondence to: Ahmed Elkashef MD, Clinical Medical Branch, Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 6001 Executive Boulevard, Room 4151, Bethesda, MD 20892, USA. E-mail: [email protected]

INTRODUCTION Methamphetamine abuse is a serious public health problem in the Western and Midwestern United States and in various areas of the world [1]. Following a period

All authors declare no conflict of interests.

of chronic use, addiction could develop that could result in withdrawal syndrome upon discontinuation of methamphetamine [2]. Methamphetamine has been a major drug of abuse in the United States for nearly a decade [3]. Much of the methamphetamine in the United States is home-made in clandestine sites known as ‘mom and pop’ laboratories.

© 2007 Society for the Study of Addiction. No claim to original US government works

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The April 2002 issue of Pulse Check from the Federal Office of National Drug Control Policy indicated that eight of 20 cities surveyed consider methamphetamine as the drug associated with the ‘most serious consequences [4]. According to the Treatment Episode Data Set (TEDS) 1993–2003 report, primary methamphetamine treatment admissions increased from 20 776 in 1993 (1.3% of all admissions) to 116 604 in 2003 (6.3% of all admissions) [5]. The National Association of Counties (NACo) report, which surveyed 500 counties, demonstrates clearly that in many communities in the United States, methamphetamine is considered a serious public health and criminal justice problem [6].

NATIONAL INSTITUTE ON DRUG ABUSE (NIDA) INITIATIVE FOR METHAMPHETAMINE TREATMENT Treatment for methamphetamine users has far-reaching health ramifications, both in terms of reducing the consequences of drug use and in potentially reducing methamphetamine-driven sexual behaviors that spread disease. As a result, the development of effective treatments for methamphetamine addiction has become a pressing concern for the national and global drug abuse treatment community. In December 1996 Dr Alan Leshner, former director of NIDA, launched a Methamphetamine Initiative in San Francisco with a regional symposium on methamphetamine abuse, prevention and treatment [7]. NIDA launched this comprehensive Initiative with the intent of stimulating research to fill gaps in the scientific knowledge about the pharmacology, toxicity, epidemiology, prevention and treatment of methamphetamine abuse. In conjunction with NIDA’s development of behavioral therapies that focus on treatment and prevention, one of the Initiative’s goals was to develop medications to reduce methamphetamine use. The medications development effort culminated in the meeting of the Methamphetamine Addiction Treatment Think Tank (MATTT) on 12 January 2000 in Washington, DC, to discuss options for developing medications and behavioral treatments for methamphetamine addiction. The meeting was a consensus meeting that included researchers, substance abuse experts, scientists, psychologists and neurologists from across the country. The main purpose of the meeting was to determine how to set up a medications development program to combat methamphetamine addiction. At the conclusion of the meeting, the recommended goals agreed upon by participants focused on three major concepts: (1) primary targets for medication trials; (2) pre-clinical animal models; and (3) medications recommended for clinical studies and/or pre-clinical screening.

The participants were asked to advise NIDA on the initial group of medications to test by drawing on experiences from the development of medications for cocaine addiction, while recognizing the differences and similarities between methamphetamine and cocaine. In addition, the expert group was asked to help NIDA identify methods for increasing the rate at which medication testing could be performed, to hasten the process of pharmacotherapy development.

EVOLUTION OF THE METHAMPHETAMINE CLINICAL TRIALS GROUP (MCTG) At the time of the 2000 MATTT group, progress in the development of pharmacotherapies for methamphetamine-related disorders was at an early stage. A review of NIDA investigative groups suggested that there was an insufficient number of experienced clinical research groups with expertise in pharmacotherapy research in geographic areas with substantial methamphetamine use problems. It was concluded that this absence of an adequate number of investigative teams to evaluate promising pharmacological agents would be a serious limitation to NIDA’s methamphetamine medication program. There needed to be a way of expanding the capacity of clinical trials researchers in those geographic areas where it was possible to recruit sufficient numbers of individuals to meet the study participation goals adequately. Because methamphetamine use has been prevalent in California for many years, following the MATTT meeting the NIDA team, in collaboration with investigators from UCLA who have extensive experience in treating methamphetamine users, initiated the set-up of the MCTG. The structure of the MCTG evolved as a result of this meeting and was guided by NIDA’s and the Division of Treatment Research and Development’s, now the Division of Pharmacotherapies and Medical Consequences of Drug Abuse’s, interest in medications approved by the Food and Drug Administration (FDA) for treatment of methamphetamine addiction. In June 2000 five testing sites were chosen for the MCTG, and UCLA Integrated Substance Abuse Programs was designated as the coordinating center. The five sites were: the Matrix Institute on Addictions in Costa Mesa, CA; the Lutheran Hospital, Central Iowa Health Corporation in Des Moines, IA; Queens Hospital, University of Hawaii in Honolulu, HI; South Bay Treatment Center, San Diego, CA; and the University of Missouri–Kansas City in Kansas City, MO. The sites for the studies were selected based on the degree of the prevalence of methamphetamine use in the area as well as the clinical expertise of the principal investigators at the sites.



Strategy to increase clinical trials efficacy

Progress report NIDA and the MCTG have initiated and completed several clinical trials since the inception of the MCTG in 2000. Completed clinical trials include a ‘dry run’ pilot study and two Phase II studies; that is, a 50-subject pilot behavioral trial for the treatment of methamphetamine, a 120subject double-blind, placebo-controlled, dose–response trial of ondansetron for the treatment of methamphetamine addiction and a 150-subject double-blind, placebo-controlled trial of bupropion for the treatment of methamphetamine addiction. Pilot behavioral study The behavioral pilot study that was conducted from 2001 to 2002, prior to the initiation of actual pharmacotherapy trials at the MCTG sites, was conducted to provide information on the capability of the five sites to recruit successfully, and to carry out effectively all the clinical, safety and data collection tasks involved with a Phase II trial. In addition, this trial allowed NIDA to assess the cross-site comparability of treatment response to the cognitive–behavioral therapy (CBT) psychosocial treatment ‘platform’ to be used in subsequent medication trials.

METHOD Study design The study was designed as a 12-week open trial in which each of the five sites was scheduled to recruit a minimum of 12 randomized participants during a 6-month recruitment window. Study participants were involved in identical clinical interventions and data collection procedures. The goal of the study was not to test a null hypothesis, however, the study data were examined by treatment site. The data of primary interest were the recruitment data and the treatment response to the psychosocial platform (defined by study retention and urinalysis results during the trial and at study completion). Other measures of interest included the ability of each site to perform safety and data collection activities in a standardized manner consistent with the requirements of the FDA. Study sites MCTG study sites were located in five communities with substantial methamphetamine problems. The sites were all housed in either hospital settings (sites 2, 3 and 5) or out-patient clinics (sites 1 and 4). The sites had established clinical expertise in the treatment of individuals with methamphetamine-related disorders. Each site had an identified physician investigator who had interest and experience in working with methamphetamine users and

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a desire to participate in pharmacotherapy research trials. The coordinating center was located at the UCLA Integrated Substance Abuse Programs (ISAP) within the Department of Psychiatry and Biobehavioral Sciences at the David Geffen School of Medicine at UCLA. Participants Sixty-five methamphetamine participants were enrolled in the study. Study inclusion criteria were: (a) current diagnosis of methamphetamine addiction as determined by the Structured Clinical Interview for the Diagnostic and Statistical Manual version IV (DSM-IV) (SCID; [8]) and (b) evidence of methamphetamine use (at least one methamphetamine-positive urine sample) during the 2–4-week screening period. Individuals were ineligible if they were also dependent upon alcohol or benzodiazepines to the point of requiring medically supervised withdrawal, or if they were court-mandated to treatment. Following informed consent procedures, a 2–4week baseline data collection period was initiated. During this period, all candidates for study enrollment had a physical examination, a 12-lead electrocardiogram (ECG) and clinical laboratory studies (blood chemistry, hematology and urinalysis). Women were given a urine pregnancy test. In addition, candidates were scheduled to attend two group sessions per week to learn basic skills in discontinuing methamphetamine use. Candidates received $10 grocery vouchers for attendance at each scheduled session during the screening period. If candidates were able to attend a minimum of two ‘lead-in’ groups and complete all baseline screening data collection activities (including a methamphetamine-positive urine sample) within a 2-week period, they were enrolled into the study at the end of the 2-week period. If they did not attend at least two sessions, provide a methamphetamine-positive urine sample and complete all necessary data collection activities, the screening period was extended to a maximum of 4 weeks. If, at the end of 4 weeks, they were unable to comply with attendance requirements, did not complete all data collection activities or did not provide a positive urine sample, their study candidacy was terminated and they were referred to other community treatment providers. All study activities were conducted under the approval of the Institutional Review Board (IRB) of the University of California, Los Angeles and the IRBs of the local sites. Study measures In addition to study recruitment capability, a measure of importance in this trial was retention in the protocol. Since protocol drop-out is a substantial problem in pharmacotherapy studies, it was of interest to document the extent of retention in the protocol and the comparability



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of this retention across sites. A participant was considered active in the protocol until one of three events occurred: (1) participants missed a period of 14 consecutive days; (2) participants stated a desire to withdraw from the protocol; or (3) participants completed the protocol. Baseline data consisted of the Addiction Severity Index (ASI)–Lite score [9], the Hamilton Depression Rating scale (HAM-D) score [10] and several other scales not reported here. ASI–Lite was performed at baseline and at protocol discharge. The HAM-D was performed at baseline and at weeks 4, 8 and 12 during the protocol. The Substance Use Report (SUR), a measure of drug, alcohol and nicotine use in the days prior to the study visit day, was collected during each research visit. Vital signs, serious adverse events (SAEs) and concomitant medication use were assessed once per week during the protocol. Participants received a $10 coupon for groceries for attendance at each weekly data session. Urine testing Urine samples were scheduled to be collected at each of the 36 clinic visits. All samples were analyzed for metabolites of amphetamine and methamphetamine. A 300-ng cut-off was used to designate a positive test result. Treatment intervention (psychosocial platform) All participants were scheduled to attend a CBT group thrice-weekly during the 12 weeks of the protocol. The CBT procedure consisted of 36 group sessions (three per week for 12 weeks). The 90-minute sessions had four to eight participants and were guided by worksheets from a manual [11]. Each session’s worksheet presented a concept or a brief exercise that explained or illustrated an aspect of CBT. While there was no quantitative measure of therapist adherence, the session taping and supervision sessions appeared to produce a standardized experience.

12 participants, one site enrolled 14 and one site 15 (a total of 65). The ‘conversion rate’ was 43% for those candidates who signed consent to enroll in the study and those who became study participants. The conversion rate across sites was roughly equivalent. Each site recruited their cohort of participants within a 5–7month window. Participant characteristics The majority of the participants were male (62%); the mean age was 35.8. Non-Hispanic whites accounted for 78% of the sample, Asian/Pacific Islanders: 6%, Hispanics: 11%, and ‘others’: 5% (African Americans 3%, American Indian 2%). Almost all the participants had a high school degree or its equivalent, and only 9% reported that they had usually been unemployed over the previous 3 years. There were some apparent gender and ethnic differences across sites, but due to the small sample in this study statistical comparisons were not meaningful. Methamphetamine use The characteristics of the 65 participants’ drug use are provided in Table 1. The average number of years of methamphetamine use among this population was 8.8 years. The longest period of use for an individual subject was 22 years. The average number of days of methamphetamine use in the 30 days prior to screening was 14.3. Smoking was the most common route of administration at all sites (61%), with 92% of the site 3 participants reporting smoking as their route of administration. Twenty-three per cent of the total participants injected the drug intravenously, with 42% at site 4 being injectors. With the exception of one who took methamphetamine orally, the remainder took the drug intranasally. Methamphetamine use was reduced by 30% by urinalyses and 70% by self report compared to baseline for all sites (fig. 2 and 3).

Safety assessments Once per week during the active study phase, and at week 13 (or at the time of study discharge), participants were evaluated with an SAE assessment and vital signs. Serious adverse events were reported to the coordinating center and NIDA according to established FDA procedures.

RESULTS

Protocol retention Of the 65 participants at all of the sites, 35 (53.8%) remained active in the protocol for the entire 12 weeks of the intervention. The average length of stay in the protocol was 9.3 weeks [standard deviation (SD = 3.7]. Figure 1 shows the average weeks of retention across all sites. Participants from site 3 remained in the protocol for the longest period (10.1 weeks) and from site 1, the shortest period (8.1 weeks).

Site enrollment data A total of 151 candidates signed consent; 65 individuals completed the 2–4-week data collection process and were enrolled into the study. Three sites enrolled the target of

Safety reporting During the course of the trial there were seven serious adverse events (SAEs) that required reporting according




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Table 1 Drug use by site and across all sites. Sites

Site 1

Site 2

Site 3

Site 4

Site 5

All sites

Methamphetamine use: year Methamphetamine use: past 30 days Route of administration (%) Oral Nasal Smoke Intravenous THC use: past 30 days Alcohol use: past 30 days

7.5 (4,8)

7.1 (5,9)

7.2 (2,4)

9.7 (6,8)

12.6 (2,8)

8.8 (2,6)

13.2 (9,9)

15.7 (7,11)

9.5 (5,10)

15.6 (1,11)

18.1 (8,9)

14.3 (5,10)

0 25.0 56.3 18.7 3.9 (2,8) 4.6 (4,6)

0 8.3 58.4 33.3 6.7 (1,10) 5.9 (7,7)

0 0 92.3 7.7 1.7 (2,8) 3.1 (4.0)

8.3 0 50.0 41.7 1.5 (3,4) 0.9 (1,6)

0 33.3 50.0 16.7 4.6 (8,8) 5.1 (5,7)

1.5 13.9 61.5 23.1 3.7 (4,7) 4.0 (5,7)

12

Weeks in Treatment

10

8

6

4

2

Figure 1 Average weeks of retention across sites

0 All Sites

Site 1

Site 2

Site 3

Site 4

Site 5

Sites

Figure 2 Self-report of methamphetamine-free days by site during protocol participation

Percentage of Patient-Days of No Use (MA) during Treatment

90% 80% 70% 60% 50% 40% 30%

20% 10% 0% All Sites

to study protocol. These SAEs included three medical hospitalizations due to a recurrence of a previous injury/symptom, two overnight hospitalizations due to reports of suicidal ideation and two overnight hospitalizations due to episodes of increased methamphetamine use resulting in temporary psychosis. The SAEs occurred at sites 2, 3, 4 and 5. None of the SAEs were considered to be treatment-related; all SAEs were reported appropriately within the protocol’s required study timetable.

CM

DM

HNL

KC

SD

Sites

DISCUSSION Pilot trial The purpose of this study was to demonstrate that newly established clinical research sites relatively inexperienced in the conduct of pharmacotherapy research trials could recruit and engage effectively a heterogeneous group of methamphetamine users into such a trial for a substantial period of time and collect the prescribed study data.



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90% 80%

% Clean UA (Meth)

70% 60% 50%

Baseline Follow-up

40% 30% 20% 10% 0%

ALL

CM

DM

HNL

KC

SD

Sites

Outcomes of the behavioral trial indicated that the MCTG: (a) recruited well; (b) established procedures for expeditious screening and administration of consent and enrollment; (c) collected study data accurately and reliably; (d) created a vehicle that can assess promising pharmacotherapies for methamphetamine addiction treatment medications; (e) produced a cadre of trained study counselors, research assistants, study coordinators and nurses; (f) demonstrated ability to deliver the cognitive behavioral interventions in a consistent manner; and (g) produced a model that may be useful in transporting research skills from clinical practice to research. Ondansetron clinical trial The ondansetron study, 2002–03, was a four-arm dose-ranging study comparing three dose levels of ondansetron (0.25, 1.0, and 4.0 mg b.i.d.) to placebo in 120 randomized subjects. Ondansetron is a 5HT3 receptor antagonist, and data from various studies suggest that ondansetron may play a role in reducing cocainemediated reward and ameliorate post-cessation anxiety symptoms following cocaine cessation [12–16]. Ondansetron has been shown to reduce the development of behavioral tolerance sensitization to cocaine following a period of acute and chronic withdrawal. To date, the bulk of the research in the field is oriented towards treatment of cocaine addiction, and many of the suggestions on pharmacotherapies for methamphetamine abuse are based upon clinicians’ experiences with treating cocaine abuse. This medication was chosen because of its effects on cocaine abusers. The idea of applicability of cocaine treatment strategies for pharmacotherapy of methamphetamine addiction is based on the similarity of their pharmacological actions. The ondansetron study was completed (n = 120). For the ondansetron trial only, the University of Texas, San Antonio, was added as an additional site. No unexpected serious adverse events were reported, and the data for safety and efficacy of this trial are being submitted for publication.

Figure 3 Urinalyses results: baseline versus week 13 for participants providing both baseline and study termination samples

Bupropion clinical trial The bupropion study (2003–05) is a double-blind, placebo-controlled, parallel-group design study in which, after screening and a 2-week baseline period, 150 subjects were assigned randomly to either placebo or bupropion for 12 weeks with a follow-up assessment 4 weeks after treatment completion. Adaptive randomization was used to balance treatment groups based on gender and severity of methamphetamine use at baseline [heavy use (> three methamphetamine-positive urines) versus mild– moderate use (three methamphetamine-positive urines) during a 2-week baseline period]. As the list of potential candidates is extensive, bupropion was selected for study based on the following criteria: (a) the investigational compound should display a dopaminergic mechanism combined with ability to alleviate the dysphoria seen in early abstinence to reduce craving and to prevent the possibility of relapse, and (b) the investigational compound should be a well-tolerated marketed drug with a good safety record. The bupropion study is completed and results are being finalized.

CONCLUSION The challenge of building research capacity is an ongoing challenge in many areas of medical research. The need to increase research efforts on methamphetamine-related issues is still a priority at NIDA. According to the NIDA Computer Retrieval of Information on Scientific Projects (CRISP) research tracking system, as of 1 May 2006 there were only 25 funded NIDA projects addressing the problem of methamphetamine. For comparison, at the same time-point, there were 121 funded projects on cocaine. In addition, the completed MCTG behavioral study has shown that the sites established procedures for expeditious screening, administration of consent and enrollment; collected data accurately; and developed a




model that will be useful in translating research skills to clinical practice. As a result of the MCTG, the capability of NIDA to conduct standardized pharmacotherapy research to discover effective medications for the treatment of methamphetamine addiction has been expanded greatly. The MCTG model proved very useful and efficient in transferring research methodology to community sites. The MCTG concept can be exported to other clinical research areas where there is a need to increase research capacity using research inexperienced community sites. References 1. National Institute on Drug Abuse (NIDA) Community Epidemiology Work Group (CEWG). Epidemiologic Trends in Drug Abuse, 1, Highlights and Executive Summary. Publication no. 01 4916A. Bethesda, MD: NIDA; 2001. 2. American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: APA; 1994. 3. National Evaluation Data and Technical Assistance Center (NEDTAC). Epidemiology and Treatment of Methamphetamine Abuse in California: A Regional Report. Contract no. 270-94001. Rockville, MD: Center for Substance Abuse Treatment; 1998. 4. Office of National Drug Control Policy (ONDCP). Pulse Check. Washington, DC: Executive Office of the President; 2002. Available at: http://www.whitehousedrugpolicy. gov/publications/drugfact/pulsechk/apr02/index.html (accessed 18 March 2005). 5. Substance Abuse and Mental Health Services Administration (SAMHSA), Office of Applied Studies. Treatment Episode Data Set (TEDS). Highlights—2002. National Admissions to Substance Abuse Treatment Services, DASIS Series: S-22, DHHS Publication no. (SMA) 04–3946. Rockville, MD: SAMHSA; 2004. 6. National Association of Counties (NACo). The Meth Epidemic in America: Two Surveys of U.S. Counties: the Criminal Effect of Meth on Communities, the Impact of Meth on Children.

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