California Pacific Currents 2005
Breaking the Chains, One Link at a Time: Studying Addiction with an Appreciation for Small Victories
Clinical investigators John Mendelson, MD, and Gantt Galloway PharmD, co-founders of the Addiction Pharmacology Research Laboratory (APRL), have received several million dollars in grants from the National Institutes of Health (NlH) to find better ways to evaluate substance abuse and treat addiction. The two researchers have complementary skills. Mendelson's expertise is primarily in clinical pharmacology, inpatient treatments, and laboratory. Galloway, by contrast, has experience in outpatient treatments and research.
"The Research Institute is just about the right size to comfortably support researchers, and there arc opportunities for collaboration," Galloway says. "It's been great that the NIH Center Gram and others have allowed us to start off with a bang," Galloway comments.
At California Pacific, the team is searching for new solutions to an old problem. As far back as the Bronze Age, a thriving drug trade supplied the middle East with opium and hashish for a variety of ailments-and possibly for recreation as well. Although people have long used drugs such as opium, heroin, and cocaine, these "traditional" substances have been joined by newer chemical concoctions including MDMA ("ecstasy") and methamphetamine ("meth," "crystal," "crank," or "ice"). The use of methamphetamine has surged in the past 15 years, particularly in rural areas and suburbs, where it is sending increasing numbers of users to emergency departments and generally wrecking lives on a scale with that of crack cocaine in the inner cities during the 1980s and 1990s.
Fortunately, new methods of defining and treating addiction are being developed. For example, it is relatively easy, with existing technology, to determine whether someone has recently used a drug like methamphetamine, because it will appear in the urine or blood. However, a more sophisticated approach for treating real-world addiction would enable the clinician to infer the amount of the drug that was taken and when.
Mendelson and Galloway believe that current methods of measuring addiction are not as helpful as they could be for addicted patients and the physicians who want to help them. They think that long-term assessments of drug dependency should include recognition of partial successes along the way, rather than the all-or-nothing benchmark of total abstinence. The California Pacific researchers assert that addiction isn't best described as an either/or proposition-either you're using the drug or you are not-but requires a more nuanced evaluation. In their view, total abstinence may not be the best gauge of therapeutic progress.
“The accepted criterion for deciding whether a medication treats addiction successfully has been if the person stops using the drug entirely," Mendelson explains. "The problem with that logic is that a combination of therapies may be needed to treat patients effectively. But if researchers or clinicians can't detect an incremental benefit from treatment, they have no way to develop such a combination."
At the APRL, Mendelson and his colleagues are testing methods that will account for the impact of each patient's physiology on the effects of methamphetamine. "We're developing a way to administer a marker, that is, a drug that has similar pharmacokinetic properties (absorption, metabolism, and elimination) as the methamphetamine used by the patients," he explains. The strongest candidate is L-methamphetamine, a chemical cousin of D-methamphetamine, the more typically abused version of the drug. "We'll give a small, non-psychoactive dose of L-methamphetamine along with the treatment drug, and the patient will give us a urine specimen every other day. This should provide us a good idea of the amount of illicit drug the person took and how much effect any given therapy has had. The goal is to understand the dynamics of addictive drug usage better."
Researchers at the APRL are aiming to find a medication that is safe, well-tolerated, and-in conjunction with counseling-effective at helping people stop using methamphetamine. "Methamphetamine appears to be associated with high-risk sexual and needle sharing behavior, and a lot of HIV transmission," Galloway says. "Research suggests that paranoia, increased violence, hypersexuality, and child abuse may result. So there are a lot of societal benefits that would accrue if we had a more effective treatment."
More than a hundred candidate compounds have failed so far, Galloway adds, partly because researchers may have pursued the misguided path of trying to treat the addiction by interfering with the pleasure of the stimulant. Although blocking the relevant physiological system is a successful approach to opiate addiction, the strategy doesn't work as well for stimulants. In fact, blocking physiological systems in stimulant addiction may even pose risks to the patient. "Drugs used to treat addiction to stimulants, such as Thorazine and Haldol, are unpleasant and can be dangerous," Galloway remarks. As a result, he and his colleagues are looking at other therapies. They are also searching for drugs that reduce the possibility of stress-related relapse.
Galloway thinks it's critical to develop such pharmacologic approaches partly because drug addicts (and our broader culture) tend to favor quick solutions to problems. "I think people perceive medications as an easy way to get better. If a program offered medication as well as counseling, more people would come in. The drug might not even be the most effective component of the package, but it would help get the word out on the street, and then we could say, 'Oh, by the way, you have to do the counseling too.' " Galloway also notes that better ways of evaluating degrees of addiction and treatment outcomes are critical to progress in the field. "People ask me, 'How successful is that treatment?' It's a tricky question. It's easy to say, 'Well, if a patient doesn't get altogether clean, what does it matter?' But long-term outcomes are what count."
Matching Craving and Behavior
Galloway and Mendelson are exploring not only how the drugs work but also the consequences of drug abuse. For example, addicted patients often stop using the drug but relapse due to withdrawal symptoms, stress, or cue exposures (environmental factors that trigger desire for the abused substance). Galloway explains that although medications are available to reduce craving, patients' responses vary. Additionally, craving has traditionally been measured, not during treatment, but only at its conclusion.
Measuring craving throughout treatment is an integral part of the work taking place at the APRL. Galloway explains, "If I ask a large sample of people how much they want chocolate cake at this moment, then measure the amount of cake they eat over the next three months, there would be a relationship between those two measurements. But that's not a very helpful approach to understanding an individual's craving, because most people's desire for chocolate cake goes up and down. How full are they? Did they just walk by a bakery? Are they stressed? Do they have an exam coming up? Ideally, it would be appropriate to measure levels of craving more frequently."
To find an answer to this question, researchers will loan enrolled addicts cell phones, then call them three times a day to assess their overall stress levels, their craving, and their drug use. To maintain confidentiality, the researchers will ask questions answerable on a 1-10 scale, so participants won't be put in awkward positions if they are with others when the researchers call. "This will give us a better understanding of how strong those relationships are and how much they predict drug use," Galloway explains.
Mendelson and his colleagues will also be studying several other aspects of addiction, including how abused drugs alter behavior and cognition, and how these compounds affect organs other than the brain. In a study of MDMA and its metabolites, for example, the team hopes to learn more about the physiological impacts of the drug and discover whether it is addictive. Another researcher at the lab, Matthew Baggott, a PhD candidate at DC Berkeley, will administer electroencephalograms and a series of cognitive tests to measure the mental and physical effects of MDMA and methamphetamine.
Success Outside the Laboratory
Expertise in matters of drug addiction, it turns out, has rewards beyond helping substance abusers recover. For some time now, Mendelson has served as a technical consultant to the television crime drama CSI. "The researchers call me when they need to know what tests a doctor might order in a certain situation, or what they'd say if a patient was brought into the ER with a particular injury or condition," he explains. "You may not feel as if you're having quite as profound an impact on people's lives, but it's a lot of fun."
As for their influence in the broader community, Mendelson, Galloway, and their colleagues hope that their research leads to therapeutic advances that enhance or even save lives. "When I was at the Haight-Ashbury clinic, I learned to appreciate small increments of progress," Galloway says. "I had the privilege of watching people struggle and move forward, and it changed my definition of success."