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P&S Journal

P&S Journal: Winter 1998, Vol.18, No.1
Drugs--Some Legal,--Some Not--Under the Microscope

Using unconventional research tools--crack pipes, video monitors, and scanners that record the bar codes on packages of food--researchers in the Division on Substance Abuse seek to explain cravings for cocaine and carbohydrates or show links between productivity and drug use in the work place.

By Devera Pine

8:00 a.m. Though much of CPMC is still quiet, the day has already begun in a small office in the Irving Center for Clinical Research. There, in the cocaine laboratory, a nurse prepares to insert two intravenous lines in the arms of a volunteer. One line will carry either a medication being tested for its ability to inhibit the effects of cocaine or a placebo. The other line will be used to draw blood for various assays or administer emergency medications if needed.

As the volunteer settles back into his reclining chair, the experimental medication flows through the IV line and into his body. A blood pressure cuff and EKG electrodes automatically monitor his heart and blood pressure.

Using a computer directly in front of him, the man responds to a series of statements--such as "I want cocaine" and "I feel stimulated"--by moving a cursor along a horizontal line labeled "not at all" on one end and "extremely" on the other. When he finishes, he must pick one of two choices displayed on the computer screen. One choice is a dose of cocaine (although some volunteers will get a placebo when they request cocaine). The other choice is a non-drug alternative, such as a $5 voucher to spend in a local store. Today, the volunteer chooses the first option, the cocaine (or placebo), by tapping the computer's space bar 200 times. Shortly afterward, a nurse brings in a crack pipe with a pellet of cocaine, which the volunteer smokes. He then completes another series of questions about how he feels.

9:00 a.m. In a residential lab on the fourth floor of the New York State Psychiatric Institute, four women sit at computers, ready to start their"jobs² for the day. One of their first projects is an incredibly boring task in which they push a button on a computer keyboard hundreds of times. The task is designed to test how hard the volunteers--all of whom are obese--are willing to work in order to earn a variety of reinforcers, in this case snack foods such as ice cream and chocolate. It is just one of the many measures of their eating behavior the volunteers will undergo as participants in a study at the Substance Use Research Center. This study--to determine whether Prozac affects the motivational aspects of eating in obese individuals--will help researchers better understand the role of neurotransmitters in eating behavior. The volunteers will spend three weeks living and working in the labıs four small bedrooms and one large communal living room.

These studies in the cocaine lab and Substance Use Research Center are two examples of ongoing work in the Division on Substance Abuse, a collaboration between P&S and New York State Psychiatric Institute. The division looks at both substance use and abuse, and its research encompasses everything from testing new treatments for cocaine and heroin abuse to understanding the mechanisms behind carbohydrate cravings. "Research in the department focuses on the antecedents and consequences of substance use and abuse, with particular emphasis on the development and testing of novel approaches to the treatment of substance abuse," says Dr. Herbert Kleber, professor of psychiatry and director of the division. The division studies various controlling substances--drugs, alcohol, food--on the assumption that common physiological and behavioral mechanisms are involved in substance misuse, regardless of the substance. For instance, understanding cocaine abuse involves more than simply blocking all or some of the drugıs effects. Cocaine abuse also is a behavioral problem, in that it is the uncontrolled use of a substance to the detriment of both the individual and society. Therefore, studies of the variables that control persistent and uncontrolled use of substances such as food, nicotine, or benzodiazepines may offer insights into the treatment and prevention of cocaine abuse.

9:30 a.m.
It is now 60 minutes after the volunteer in the cocaine lab was first offered a choice of active (or placebo) cocaine or a non-drug alternative. Every 14 minutes since then, he has been offered the same choice, followed by answering the questions on the computer. Traditionally, drug studies measure the subjective effects of the substance under investigation. But the cocaine labıs studies also measure cocaine-taking, which, ultimately, is the behavior that interests researchers."After all, cocaine abusers seek treatment because they cannot control their cocaine-taking, and any test of a new medication should include measuring cocaine-taking behavior," says Dr. Marian Fischman, co-director of the division, professor of behavioral biology, and director of all human research laboratories in the division. This study allows researchers to measure the extent to which a pharmacological intervention makes non-drug alternatives more appealing than cocaine. "We want to find medications that either disrupt cocaine-taking behavior or interfere with the other subjective effects of cocaine--the cravings, the high."

The cocaine lab recruits volunteers for its studies through ads in local newspapers. The volunteer for todayıs study is a man in his mid-30s, who, like all participants in the cocaine lab research, is a heavy user of cocaine and is not seeking treatment for drug abuse.

For every 100 telephone calls the program receives in response to advertising, about 10 individuals report for an initial screening interview. Of those 10, one or two are ultimately accepted for participation. The volunteers live in the hospital, taking part in studies for the two to four weeks. The labıs staff carefully screens volunteers to ensure that--except for substance abuse--they are physically and psychologically healthy.

This volunteer was offered treatment for his addiction but, like all the participants for studies in the cocaine lab, turned it down. The lab staff follows up after a study to again offer volunteers treatment. The rate of acceptance of the offer depends on the study and the drug. For example, many more heroin abusers than cocaine abusers express interest in being referred for treatment after completion of a study.

As much as possible, studies in the cocaine lab attempt to mimic the way the drug is used on the street. "Most IV or smoked-cocaine abusers use it in binges, taking a hit or injection of cocaine every 10 or 15 minutes for hours, as long as the drug is available," says Dr. Eric Collins, medical director of the cocaine laboratory and Herbert Irving assistant professor of psychiatry. Thus the cocaine lab studies offer volunteers the choice of a drug or a non-drug reward every 14 minutes. This choice also is a model of the real world: "Individuals are always choosing between taking drugs or buying some food, for example," says Dr. Collins.

The study design allows researchers to move quickly from the lab to clinical interventions. For instance, once lab tests show that a medication has promise for reducing the appeal of or craving for the drug, researchers can begin clinical trials in the divisionıs clinical service, Substance Abuse Treatment and Research Service; Dr. David McDowell, assistant professor of psychiatry, is medical director of the service.

So far, the researchers have not identified any drug that has a major effect on cocaine addiction. However, several drugs tested in the lab may be helpful in some aspects of the treatment of drug abuse.

The divisionıs research on drug abuse is not limited to cocaine addiction. Scientists also study the effects of heroin, using procedures adapted from the cocaine lab. Current studies include development of a model to evaluate medications for treating heroin abusers and antagonist detoxification of heroin abusers. These studies are part of a major medication development center grant from the National Institute on Drug Abuse. The center, headed by Drs. Fisch-man and Kleber, is studying ways to improve cocaine and heroin abuse treatment. The focus is on identifying and testing medications that will be useful in treating subsets of drug addicts, such as those with attention deficit hyperactivity disorder, depression, or schizophrenia.

Though drug abuse is a politically charged issue, the motto of the cocaine lab--and, indeed, the entire division--is that substance use and dependence are issues that can be studied scientifically, says Dr. Kleber."Through research we can learn how drugs affect the brain and thus develop better treatment methods," he says.

11:00 a.m. With a slide of a coca plant projected onto a screen behind him, Dr. Kleber is teaching first-year medical students about cocaine.The coca leaf was used for centuries by Andean Indians as a mild stimulant before the Spanish conquest of South America," he says. "But the active ingredient, cocaine, was not isolated until the late 1800s in Europe. Initially used in patent medicines, wines, and soft drinks, it eventually became a major drug of abuse both in Europe and the United States." Among the psychological effects of cocaine: intense euphoria, increased energy, decreased appetite, and sexual arousal. After heavy use, however, these effects are followed by their opposites: depression, fatigue, lack of pleasure, decreased interest in sex, irritability, and paranoia. The smoked form of cocaine--crack--is the most addicting drug Dr. Kleber has encountered in his 30 years in the field, increasing the importance of developing a medication to treat it. As part of his lecture, Dr. Kleber also projects a slide of PET scans of the brain, showing that the damage cocaine causes can last months after the last dose.

For several reasons, physicians traditionally have not asked patients about problems with substance abuse, says Dr. Kleber. First, they're not optimistic that they would know how to treat a problem if the patient reveals one. They may be concerned that patients will be offended by such questions or they may feel uncomfortable broaching the topic. In fact, many doctors do not have adequate training in how to evaluate and treat substance abuse,

notes Dr. Kleber. With lectures such as the ones Dr. Kleber gives, medical schools are taking steps to change that situation: Since 1992, the amount of time that medical students at P&S spend on the topic of substance abuse has increased four-fold. "We're now trying to develop innovative methods to train more doctors," he says. "First, we have to convince the students that it's important--and the best way to get medical students, interns, and residents to pay attention is if they know they're going to be tested. We're working with specialty boards to increase the number of questions that relate to substance abuse."

1:00 p.m. In a room on the fourth floor of the Psychiatric Institute, Drs. Adam Bisaga, substance abuse training fellow; Sandra Comer, assistant professor of psychiatry; Richard Foltin, associate professor of psychiatry and co-director of the Substance Use Research Center; Suzette Evans, assistant professor of clinical psychiatry; and Crawford Clark, research scientist, discuss the design of a study that will monitor the response of women to the pain of cold water during various phases of their menstrual cycles. The study, which Dr. Comer will lead, is in response to a request for applications by the National Institute of Dental Research for work on gender differences in response to painful stimuli and response to medications targeting that pain. The study marks the beginning of the division's interest in evaluating brain mechanisms involved in pain and the alleviation of pain.

The women will put their arms in a warm water bath first," says one of the researchers.

It's important to equalize the temperature before beginning the cold pressor test, interrupts Dr. Foltin.And we need to be sure that we include information about the superiority of this test in differentiating the response of men and women." The group then goes on to discuss alternative tests and their strengths and weaknesses for this study, concluding that this will be one of two tests proposed for the study to ensure that both the sensory and emotional aspects of pain are addressed. The study is one of many outpatient trials conducted at the center.

The substance abuse division is one of three in the country that have fellowship programs to train physicians for careers in substance abuse research. Fellows are involved in basic lab inpatient and outpatient studies and treatment research protocols.

Today, the hallway of the Substance Use Research Center is filled with volunteers filling out questionnaires that will help determine their eligibility for an outpatient study. Research volunteers in outpatient studies are typically required to return to the lab as often as every day for two to three weeks, so they are carefully screened with a phone interview, questionnaires, in-person interview (including a psychological and psychiatric evaluation), and, depending on the nature of the study, a physical exam. "The staff has to interact with the research participants a lot," says Dr. Foltin. "It's important for the staff to have a good rapport with the participants."

2:00 p.m. Back in the residential lab of the center, the four women volunteers are cleaning up from lunch and getting ready to resume their jobs. The lab's staff stocks the refrigerators and the women each carefully scan in the bar codes on the packages of the food they eat. During the three weeks of the study, the women may have no contact with the outside world--no phones, no televisions, no newspapers. From 9 to 5 they work at computer tasks specifically designed for the study; at night they can watch video tapes from the lab's ample supply, use the lab's video games, or read books and magazines from the shelves. A washer and dryer allow them to do their laundry whenever they wish. All of their activities in the lab are monitored through cameras and microphones.

The outside world is screened out to keep the variables of every study the same, says Dr. Fischman. "We're interested in the flow of behavior in the absence of artificial constraints, unless we design those constraints into the study.

Other residential lab research has studied the workplace effects of alcohol, amphetamines, marijuana, and benzodiazepines, but not heroin or cocaine use, which requires closer monitoring.Our studies have found that if participants are paid for their work output, then during working hours they will not take any drug that interferes with their work output," says Dr. Fischman. "In contrast, workplaces in which individuals are paid hourly wages with no contingencies placed on output are ideal environments for fostering drug use.

An upcoming residential lab study will examine the physical dependence and withdrawal effects of marijuana. "These type of studies are important for teaching adolescents about drugs," she says. "There's far too much teaching based on scare tactics and not enough based on empirical data. It's likely that marijuana does have physical-dependence-producing effects, and youngsters need to know that."

4:00 p.m. As the work day draws to a close for the participants in the residential lab, it's just beginning for the lab's 4 p.m. to midnight shift. One full-time person and one part-time person work the shift each day to monitor the study and to offer help to the resident participants during their hours awake. (Participants and staff are allowed to meet in the vestibule of the residential lab--the only place where participants are allowed a limited interaction with the "outside" world.) From midnight to 8 a.m., one staff person monitors the lab. The night staff person remains there, sitting just outside in a control room--surrounded by a bank of computer screens and monitors--until the next morning when the volunteers wake up, ready to begin another day in the lab.


A Research Sampler

The Division on Substance Abuse has the unique ability to examine substance abuse issues at three levels: in non-human primates, in controlled laboratory research with human subjects, and in clinical treatment of cocaine and heroin-abusing patients, says Dr. Herbert Kleber, professor of psychiatry and director of the division. Faculty conduct their own research and foster collaborative research at the New York State Psychiatric Institute and throughout CPMC. A sampling of research projects under way in the division:

Cocaine lab studies
  •   Testing new medications for the treatment of cocaine abusers (Drs. Marian Fischman, Eric Collins, Amie Ward, and Margaret Haney)
  •   Evaluation of the cocaine abstinence syndrome (Drs. Richard Foltin, Suzette Evans, and Margaret Haney)
  •   NMDA influences on cocaine use (Drs. Marian Fischman, Eric Collins, and Amie Ward)
  •   Neuroimaging of cocaineıs effects (Drs. Ronald Van Heertum and Eric Rubin)
Heroin lab studies
  •   Development of a model to evaluate medications for treating heroin abusers (Drs. Marian Fischman, Sandra Comer, and Eric Collins)
  •   Antagonist detoxification of heroin abusers (Dr. Eric Collins)
Substance Use Research Center

  •   Drug use by the workforce (Drs. Marian Fischman, Sandra Comer, Margaret Haney, Richard Foltin, and Amie Ward)
  •   Brain mechanisms involved in eating behavior (Drs. Richard Foltin, Sandra Comer, Margaret Haney, and Amie Ward)
  •   Relationship between aggression and eating behavior (Dr. Margaret Haney)
  •   Physical dependence and withdrawal from THC (Drs. Margaret Haney and Amie Ward)
  •   Evaluation of medications that might be useful for alcoholics. (Dr. Maria Sullivan)
Womenıs studies

  •   Factors affecting vulnerability to drug abuse in women (Dr. Suzette Evans)

Cocaine treatment studies

  •   Treating cocaine abusers diagnosed with attention deficit hyperactivity disorder (Dr. Frances Levin)
  •   Treating cocaine abusers with an NMDA antagonist (Drs. Marian Fischman and David McDowell)
  •   Treating depressed cocaine abusers with desipramine (Dr. Edward Nunes)
  •   Treating cocaine abusers with risperidone (Dr. Edward Nunes)

Heroin treatment studies
  •   Improving treatment retention in naltrexone-based treatment by use of network therapy involving a significant other and community reinforcement (Drs. Herbert Kleber and Angela Seracini)
Other

  •   Nicotine use by schizophrenics (Dr. Maria Sullivan)
 The Ethical Issues
Research in the Division on Substance Abuse--especially studies that provide drugs to drug abusers who show no interest in treatment--can be controversial. Dr. Herbert Kleber, director, and Dr. Marian Fischman, co-director, deal with critical questions head on.

The motto of the cocaine lab--and the entire division--is that substance use and dependence are issues that can be studied scientifically, says Dr. Kleber. "Through research we can learn how drugs affect the brain and thus develop better treatment methods." "This research is badly needed," says Dr. Fisch-man, "and we believe that to refrain from doing it would be unethical. Drug abuse and dependence remain a staggering public health problem. There continues to be high morbidity and mortality associated with the abuse of such drugs as cocaine and heroin, underscoring the need for research to develop better drug abuse prevention and treatment methods. In addition to the personal suffering associated with drug abuse, its contribution to other social problems such as AIDS, crime, and family disintegration makes necessary continued research in this area."

The division's research focuses on several aspects of the problem of drug abuse. One of these is the continued testing of medications that might be useful in treating drug abusers. First, researchers test medications in a laboratory. "We are able, with relatively few individuals and in a relatively short period of time, to provide answers to questions related to the safety of the medication being tested when it is combined with cocaine or heroin." Addicts in treatment generally combine the medication with the illicit drug, since there is no such thing as a "silver bullet" for treating drug abusers. "Secondly, we can provide information about the likelihood that the medications in question will block or change the effects of cocaine or heroin so that addicts will be less likely to abuse them and more likely to stay in treatment." Once medications look promising in the lab, researchers can proceed to treatment in the clinic with the assurance that the effects of the medication are understood.

"Our research is not undertaken lightly,² says Dr. Fischman. "Because there are questions that can only be answered through research with human participants, we believe that the work we are doing is important, necessary, and carried out in a safe and ethical fashion."The research includes these safeguards and benefits:

  •  The Institutional Review Board at the local level and the NIH at the federal level approve the research, addressing such issues as adequacy of the informed consent process and the risk-benefit ratio of the research.

  •  Benefits include free medical and psychological screening, free HIV counseling and testing, and contact with the medical establishment. For most of the volunteers, contact with the medical establishment has been non-existent for many years.

  •  Volunteers are given sufficient information to make an informed assessment of the risks and benefits of study participation.

  •  Volunteers, who are experienced users of the drug being studied, are well-informed about that drug. "We do not introduce drugs of abuse to those who are not users nor do we administer drugs of abuse to any individuals we are able to refer to treatment," notes Dr. Fischman.

  •  Volunteers are screened before study participation to eliminate individuals likely to be harmed by drug administration. All volunteers are appropriately monitored throughout the study.

  •  Participation is unlikely to worsen drug dependence because the amount of drug administered is limited (generally less than what they use outside of the lab) and because the setting in which drugs are administered is not at all similar to the places drugs are taken outside of the lab. "For most of our research volunteers," says Dr. Fischman, "participation involves considerably less drug than they are accustomed to taking and drug administration is scheduled during periods of the day when they find it less enjoyable (daytime vs. nighttime hours)."

  •  Volunteers are routinely encouraged to enter drug abuse treatment‹before being screened for the study and after completion of the study.
 
Dr. Marian Fischman: "This research is badly needed, and we believe that to refrain from doing it would be unethical."   Dr. Herbert Kleber: "Through research we can learn how drugs affect the brain and thus develop better treatment methods."


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