New Approaches to Drug Addiction Therapy

Drug and alcohol addiction costs the United States more than $100 billion a year. Neither law enforcement nor therapy has been able to adequately combat this problem, so it continues to grow. Some researchers are taking a new approach: Instead of looking at addiction as lack of self-control or escape, why not see it as a chronic, reoccurring disease? Research substantiates that there are fundamental biological processes at work in the brain of a drug user. Long-term changes occur there, predisposing the addict to drug cravings and relapses. Medications may offer the means for drug addicts to not only kick the habit, but also stay clean.1 Adaptedfrom figure by K. Janda Monoclonal antibodies prevent cocaine from crossing the blood-brain barrier, thereby blocking the stimulant effects induced by the drug. This may prove useful in treating long-term addicts who are prone to relapse. This type of vaccination may be effective for several months in humans. If necessary a booster can be given at the end of this time. Michael Owens, a professor of pharmacology and toxicology at the University of Arkansas for Medical Sciences, Little Rock, suggests, "Making a designer antibody for a designer drug may be the most efficient way [to treat addiction]." Most drugs are too small for the body to recognize as foreign, so there is no immune response. However, Owens has coupled phencyclidine compounds (PCP) to a foreign protein. The fused molecule, called a hapten, is used to immunize a mouse, which will produce monoclonal antibodies against the drug. These monoclonal antibodies can then be harvested and used to recognize PCP in the body. They function by binding the drug so it cannot reach the brain and drug receptors. Then the drug bound to the antibody is eliminated as waste. Owens explains, "The monoclonals will recognize virtually all the phencyclidine-like drugs [that] have been used ..., so one antibody could be universal for the whole drug class. Our approach is to use the antibody [as a new type of medication]."2 Owens has developed treatments for PCP overdose and long-term addiction using monoclonal antibodies. For an overdose the goal is to use a therapy that reverses an ongoing process quickly. "We envision giving antibody treatment in unit doses until the [overdose danger passes]," says Owens. The overdose treatment uses the antigen binding fragment (Fab) molecule of the intact immunoglobulin G (IgG) antibody. An immunoglobulin is a large protein capable of combining specifically with an antigen, which in this case is the PCP. In the rat overdose model the fragment has a shorter half-life, eight hours compared to eight days for the intact IgG. Currently, clinical trials are being planned for the Fab overdose treatment. The full IgG antibody would be useful for long-term addicts in behavioral therapy, because the half-life in humans is predicted to be 20-25 days. If a person slips and uses some PCP, there would be enough antibody in the body to block the effects of the drug. This may give the patient enough time to get over a relapse. Owens points out that this treatment will be most helpful to addicts truly wanting to recover. There are no small-molecule medications for PCP and other stimulants, so this offers an alternative to traditional drug discovery. The protein therapy does not go into the central nervous system; it stays in the blood and produces fewer side effects. This also means the therapy will not be addictive. Currently, the disadvantage is the cost of making large quantities of the antibody. Also, monoclonal antibodies produced in animal cells have to be humanized so the body does not form an allergic reaction against the antibody medication. Owens emphasizes that this is a prototype system. "We are trying to understand the pharmacological rules about how these antibodies are used." The valuable information gained from such studies may allow protein therapies to be developed for other drugs, such as nicotine. Kim Janda, a professor of chemistry and molecular biology at the Scripps Research Institute, La Jolla, Calif., is working on an antibody approach for cocaine addiction. His lab is looking at a vaccine that uses a hapten made of a cocainelike molecule attached to a large protein. As in any other vaccination, small amounts of the hapten trigger an immune response in the form of antibodies. "We are training the [human] immune system to recognize cocaine as a foreign invader and remove it," says Janda. The vaccine has been ready for three years, but there was a problem finding a company to take it forward. Drug Abuse Sciences in Menlo Park, Calif., has licensed the research recently, and Janda hopes the vaccine will now go into clinical trials. Janda is also creating humanized monoclonal antibodies in animal and plant systems. These can be isolated and then injected into the body in large doses to mop up cocaine. "This is useful for overdose, but it can also be used in conjunction with the vaccine," says Janda. The combination of the two approaches provides a stronger treatment because there is more antibody in the system. One monoclonal antibody can bind one cocaine molecule and hang on to it until it is eliminated, so it is important to have enough antibody in the system to counteract the amount of cocaine being used. There is some skepticism about whether a high enough titer of antibody can be achieved in the blood to completely prevent cocaine from affecting the brain. Barak Caine, instructor of psychiatry at Harvard Medical School, says, "Catalytic antibodies are an incredible step forward from the development of monoclonal antibodies." A catalytic antibody can bind cocaine and cleave the drug so it is no longer active. The catalytic antibody is then free to bind another molecule of cocaine, making it potentially a more efficient therapy. Caine is testing a catalytic antibody developed by Donald Landry, associate professor of medicine at Columbia University, in mice that self-administer cocaine. Animal and human studies suggest that cocaine itself can trigger craving. Thus, the antibody approaches may block relapse-produced craving. However, craving is also triggered by environmental stimuli such as sight, sound, and smell. Caine notes, "Antibodies presumably would not affect craving or withdrawal in the same way methadone produces beneficial effects in heroin treatment." Methadone is a small-molecule medication that crosses the blood-brain barrier and binds to the mu opiate (heroin) receptor. Though methadone has some properties of heroin, it does not produce the same "rush" experienced after injecting or smoking the drug. Methadone uptake into the brain is slower and its activity lasts longer. It is rarely abused, since the dosing is controlled as an oral medication in outpatient clinics. Used as a pharmacotherapy treatment, it allows the addicted individual to progress toward functioning in society without heroin and eventually without methadone. Dopamine, a neurotransmitter critical for a variety of normal motor and cognitive functions, appears to be involved in cocaine's abuse-related effects. Neurons release neurotransmitters, which other neurons and cells receive so the brain can signal the body. After the transmission of a signal, excess dopamine is transported back into the neuron or degraded. Cocaine binds to a receptor on the dopamine transporter and blocks the reuptake of the neurotransmitter. Elevated levels of dopamine result in the brain and presumably, the pleasurable effects of the drug are mediated by the interaction of dopamine with its receptors. Caine favors exploring multiple approaches to medication development, including dopamine partial agonists. These medications target the dopamine receptor or transporter to increase dopamine levels in the brain with limited stimulant effects.3 "If you could develop a medication [that] has few toxic effects and is orally active, then you may provide a substitute for cocaine's [stimulation] and facilitate abstinence in users," says Caine. But the problem with developing drugs that mimic or modify dopamine activity is the likelihood of side effects. There is also no proof that a dopamine agonist would facilitate abstinence in the same way methadone seems to do in heroin abusers. Despite possible shortcomings of such medications, many labs are targeting the cocaine receptor on the dopamine transporter. Ivy Carroll, vice president of chemistry and life science at the Research Triangle Institute, Research Triangle Park, N.C., is heading such a project. Two compounds from a family of 500 3-phenyltropane analogs his lab has synthesized are entering advanced toxicological and animal behavioral studies. Carroll describes this type of compound as "a medication that will block enough of the cocaine receptors to prevent patients from craving the next use of cocaine, and at the same time the medication has been designed with little or no abuse potential." Behavioral studies of these two compounds have shown slower rate of entry into the brain and longer-lasting biological activity. This is important for a medication that interacts at the cocaine receptor, because abused drugs enter the brain extremely fast to produce a short-lived high. Scott Lukas, director of the behavioral psychopharmacology research lab at McLean Hospital, Belmont, Mass., and associate professor of psychiatry and pharmacology at Harvard Medical School, stumbled across a completely different approach to cocaine addiction. While doing a single photon emission computed tomography (SPECT) study, his colleagues, Jonathan Levine and Perry Renshaw of McLean Hospital, noticed an interesting phenomenon in the brains of cocaine addicts. The SPECT study looked at brain perfusion, the blood flow getting to different areas of the brain. "We noticed tiny microperfusion deficits, a fancy term for miniature strokes, throughout the brains of the drug users," says Lukas. He and his colleagues decided to treat the damage from the miniature strokes with citicoline. Though small quantities of citicoline are found naturally in the brain, researchers in Europe have used large amounts of synthesized citicoline to repair brain membranes after head injury or stroke. In a double-blind, placebo-controlled clinical trial on crack smokers, the treatment showed promise.4 "We think citicoline is speeding up the repair process dramatically. We saw improvements in only two weeks of treatment in people who were actively using cocaine," says Lukas. He believes citicoline may be improving cognitive function so addicts may better handle psychotherapy. The citicoline also appeared to blunt the impact of environmental cues and take the edge off the cravings of participating addicts. This may indicate that citicoline is slightly increasing the release of dopamine and norepinephrine as has been shown in a previous rodent study. "We think the combination of improving cognitive function and reducing damage as well as elevating dopamine levels may offer a treatment for cocaine addiction," comments Lukas. Without funding from the National Institute on Drug Abuse (NIDA), most of the research in substance abuse would not be possible. Frank Vocci, director of the medications development division at NIDA, says, "Based on economic grounds, large pharmaceutical companies do not want to develop treatments for substance abuse with us." The potential market for addiction therapy is not large enough. Smaller companies in the biotechnology industry are far more interested in collaborating with the government and cofunding addiction therapies. Because a complex mechanism is involved, it is unlikely that one cure for drug addiction will be found. NIDA supports research in behavioral therapies as well as medications development. "Small-molecule and immune-response drugs may be complementary to behavioral therapies in treating drug addiction. We want to have an array of different tools that the clinician will be able to use in combination," comments Vocci. Nadia S. Halim can be contacted at nhalim@the-scientist.com. F.I. Carroll et al., "Pharmacotherapies for treatment of cocaine abuse: preclinical aspects," Journal of Medicinal Chemistry, 42:2721-36, July 29, 1999. J.S. Hardin et al., "Pharmacodynamics of a monoclonal antiphencyclidine Fab with broad selectivity for phencyclidine-like drugs," Journal of Pharmacology and Experimental Therapeutics, 285:1113-22, 1998. G.F. Koob and S.B. Caine, "Cocaine addiction therapy--are we partially there?" Nature Medicine, 5:993-5, September 1999. P.F. Renshaw et al., "Short-term treatment with citicoline (CDP-choline) attenuates some measures of craving in cocaine-dependent subjects: a preliminary report," Psychopharmacology, 142:132-8, February 1999.

New Approaches to Drug Addiction Therapy

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