Anyone who has ever tried to kick a habit like cigarettes, alcohol, or cocaine has probably wondered why it is possible to clone a sheep but not develop more effective ways to treat addiction. Dependence on legal drugs such as nicotine and alcohol, and illegal ones like cocaine, methamphetamines, and heroin spans every demographic group. Study after study shows that addiction treatment is cost-effective, yet relatively few substance abusers seek treatment on their own, and those that do frequently relapse. Until a few years ago, overcoming substance dependence meant using willpower, psychotherapy, and only a few pharmacologic compounds that substitute for the drug in question, such as methadone for heroin or nicotine patches for cigarettes. Sometimes treatment has meant aversive therapies, like ingesting Antabuse to make alcohol intolerable. Some believe that pharmacologic treatments for addiction, like methadone, merely substitute one dependency for another without dealing with the devil of addiction itself. However, advances in both neuroscience and pharmacology are yielding new hope for treating addiction at the source, the brain.

It's all in your head

Over the past decade neuroscience research has begun to yield pivotal clues about the mechanisms of addiction. The results are being used to develop more effective medical methods of treating addiction. In the past few years, live imaging techniques such as PET scans, genetics, and pharmacogenomics have contributed greatly to scientists' understanding of the chemical and genetic bases of addiction, and are therefore yielding new targets. Specifically, a great deal of research is being done on the key role of neurotransmitters.

In 1999, French scientists showed that one new compound eased rats' cravings for cocaine by modulating dopamine levels, a key neurotransmitter implicated in many normal brain functions, as well as in Parkinson's disease and addiction. The study, published in Nature on July 22, 1999, demonstrated that the compound, BP-897, inhibited rats' craving of cocaine associated with environmental cues. Craving is one of the most serious and stubborn challenges of treating drug addiction.

Sokoloff discovered the third receptor for the neurotransmitter dopamine 10 years ago, known as D3, which is found in the nucleus accumbens, a part of the brain scientists now know to govern drug dependence. BP-897 modulates D3 receptor activity, binding to it and partially activating the receptor. BP-897 is the first partial D3 receptor agonist to be developed which does not act like a drug itself or induce new dependence, in contrast to other substances, such as methadone.

Researchers at Oregon Health Sciences University in Portland found that mice bred without the D2 receptor gene, which is associated with the brain's reward system, had a lower preference for, and sensitivity to alcohol than mice with the gene. The D2 receptor is one of five dopamine receptors identified which is thought to regulate feelings of reward/pleasure, which may be one "sensor" that helps fuel drug craving.

"Taking the D2 receptor away cut alcohol consumption in half," said Tamara Phillips, lead author of research. "It changed alcohol consumption to aversion," she added. More recent addiction research is pointing to a common mechanism linking many types of addictive drugs to the orbitofrontal cortex, the location of the brain that controls compulsive behavior and decision-making, and where D2 receptors are depleted in substance abusers. Prolonged abstinence restores levels of dopamine transporters, however it does not significantly ameliorate cognitive and motor function.

Searching for clues

On March 11, 2002, the National Institute on Alcohol and Alcoholism announced a five-year multidisciplinary initiative with $50 million of funding to define the brain circuits and mechanisms that underlie behavioral responses to chronic and excessive alcohol consumption. The new initiative, called the "Integrative Neuroscience Initiative on Alcoholism" or INIA, will integrate research from animal and human studies to understand the behavioral neuroadaptive process, changes in the brain that occur with chronic alcohol exposure that contribute to excessive drinking.

A few years ago, Scripps Research Institute (La Jolla, CA) scientist George Koob reported that heavy drinking depletes the brain's supplies of dopamine, serotonin, GABA, and opioid peptides, all elements responsible for feelings of well being and pleasure, and promotes the release of the stress chemical, corticoreleasing factor (CRF). The release of CRF causes tension and depression. Hoping to suppress those feelings, alcoholics drink more, but produce more CRF, leading to a vicious cycle and raising the "set point" for the amount of alcohol it takes to produce a "normal" feeling. Koob said that identifying individuals with high levels of CRF and low levels of dopamine could serve as warning signals to those at risk.

Koob will lead the first of three consortia for the new NIAAA study, in which his team will attempt to identify neuroadaptive changes that occur in the amydala, the region that comprises part of the brain's reward circuitry. They will test the hypothesis that genetic differences and other changes in the neurobiological processes within the amydala are responsible for variation in vulnerability to alcohol consumption. Like most chronic diseases, addiction involves a complex interplay between genetic makeup and environment.

Dr. Michael Kuhar and a team of neuroscientists at the Yerkes Regional Primate Research Center of Emory University found that a naturally occurring neurotransmitter produces behaviors associated with cocaine and methamphetamine. The finding suggests a role for the brain chemical, called CART (Cocaine- and Amphetamine-Regulated Transcript) peptide, in modulating or mediating the actions of drugs and a perhaps potential new avenue for treating addiction. Dr. Kuhar and collaborators published a paper in June 2001 titled, "Intracerebroventricular CART peptide reduces rat ingestive behavior and alters licking microstructure," which appeared in the American Journal of Physiology-Regulatory Integrative and Comparative Physiology (Vol. 280, Issue 6, R1613-R1619; see http://ajpregu.physiology.org/cgi/content/full/280/6/R1613).

The next big thing

When it comes to pharmacologically treating addiction, only a handful of companies, nearly all are biotechnology companies,are working in this area. At the top of the list are Nabi Biopharmaceuticals, Addiction Therapies, Inc., DrugAbuse Sciences, Addex Pharmaceuticals SA, Xenova Group PLC, NeuroSearch, and Forest Laboratories. Their approaches to treating addiction include developing monoclonal antibodies to "mop up" drugs from the bloodstream before they can travel to the brain, or block receptors in the brain, to active and passive immunization.

Nabi Biopharmaceuticals, a vertically integrated biopharmaceutical company in Boca Raton, Fla., is developing a vaccine called NicVAX to prevent and treat nicotine addiction. Nabi believes their vaccine creates highly specific antibodies that bind to nicotine and thereby prevent tobacco addiction in humans by blocking nicotine from reaching drug receptors in the brain.

"We have used an exotoxin from the cholera bacterium attached to a nicotine-related compound which, by themselves are too small to raise antibodies," explains Dr. Ali Fattom, senior director of research and developer of the vaccine. In humans, Dr. Fattom postulates that "the vaccine will work by first creating a physical barrier, preventing the drug from entering the brain and reaching nicotine receptors, and thereby de-condition the patient as a secondary effect from wanting the drug by removing the possibility of 'reward.'" Such a vaccine would be given periodically. The company also believes that NicVAX may be an effective product for those attempting to give up tobacco by helping to prevent relapse. Nabi has received a U.S. patent on NicVAX to prevent and treat nicotine addiction. It is currently in Phase I safety testing.

In late February 2002, Wayland, Mass.-based Addiction Therapies, Inc. (ATI) announced positive Phase I/II clinical trial results in a double-blind placebo-controlled study for The Straw Nicotine Oral Delivery System for tobacco dependence. The results show that delivery of nicotine with The Straw was well tolerated at dose levels of 4, 8, and 12 mg, and achieved systemic nicotine levels comparable to currently marketed nicotine replacement therapies. President and Chief Scientific Officer of ATI Barbara S. Fox, PhD, comments, "Exposure to cues previously associated with drug use triggers memories that drive unhealthy behavior. Addiction Therapies, Inc. is developing therapeutics that will, for the first time, help patients overwrite those memories and move down the path to recovery."

Take a sip

The Straw is a single-use plastic straw containing small beads of nicotine. An individual sips any beverage through The Straw and swallows the nicotine beads. The entire dose of nicotine is delivered in the first sip. The empty straw can then be thrown away or retained to occupy the individual's hand and mouth, replacing the stimuli associated with smoking. Early in the attempt to quit smoking, patients may use The Straw every time they crave a cigarette, up to 10-12 times per day. Doses are lowered over a 12-week period. This is the company's first product in a portfolio of active cognitive pharmacotherapy products. "Addiction, like many other behavioral disorders, is a memory-driven disease," said Dr. Fox.

In addition to its lead product, ATI has two products currently in preclinical development (studies in animals that precede human testing). The company's other smoking cession drug is ATI-823, an anti-craving drug is entering clinical trials this year. ATI expects it will be more potent and effective than Zyban. Another product in development is ATI-615, touted as a short-term substitution therapy for easing people off cocaine. The drug has a slower onset than cocaine and remains in the brain longer. Phase I testing of ATI-615 in tablet form is expected to begin in the first quarter of 2003. The company is hoping for fast-track Food and Drug Administration approval.

Oh Canada!

Taking a different approach to treat nicotine addiction, researchers at the University of Toronto in Canada have found a medication that partially blocks the body's ability to break down nicotine, which they say significantly improves the effectiveness of oral nicotine replacement in reducing a smoker's urge for nicotine. Methoxsalen is a drug used to treat skin disorders, and it also reduces the activity of an enzyme, CYP2A6, that metabolizes nicotine. "This renders more nicotine, whether from a cigarette or nicotine replacement, available in the blood, and keeps it there longer. When smokers who receive the drug light up a cigarette, they take fewer and shorter puffs, thereby reducing their exposure to tobacco smoke's carcinogenic components," said Dr. Edward Sellers at the University of Toronto.

Previous studies the group conducted found that individuals with a genetic deficiency in CYP2A6 metabolism are less likely to start smoking, and if they do start, smoke less than their counterparts with normal enzyme activity. With this understanding, the group tested over 200 compounds to find one that decreased activity of this enzyme. While methoxsalen is approved in the U.S., it has not proven safe for long-term use in humans, according to Dr. Sellers.

The granddaddy

Hayward, Calif.-based DrugAbuse Sciences (DAS) was founded in 1994 and is the oldest company entirely dedicated to anti-addiction therapy. The company has several drugs in development and one, Zeeblok (naltrexone tablet which DAS acquired the marketing rights from EON Laboratories Manufacturing Inc. for alcohol and opiate dependence), on the market. Research and development programs focus on both the prevention of relapse as well as the treatment of overdose. The company's drugs target the nucleus accumbens, believed to be responsible for craving, and the prefrontal cortex, which is responsible for rational thinking. DAS produces drugs that are D1 agonists, which have been shown to reduce craving in humans, and improve working learning memory in animals. D1 and D2 receptor subtypes in the brain are thought to hold complementary roles in mediating cocaine abuse, with the D1 receptor acting to reduce cocaine craving. Its lead drug, DAS-431, a dopamine agonist for cocaine dependence, is soon to enter Phase III testing.

DAS uses a novel, long-term drug delivery technology that enables the release of an injected drug for 30 days, which the company believes will help with patient compliance. Its third technology relies on immunologic barriers, antibodies and vaccines. Naltraxone Depot for alcohol dependence, which uses an extended-release system for once monthly dosing by injection, has completed Phase III testing and the company expects to file its New Drug Application (NDA) sometime this year. Naltrel, the same extended-release formulation with a different brand name, binds at the opiate receptor sites in the brain and blocks euphoria and other effects of heroin. Naltrel has begun Phase III trials.

Buprenorphine Depot for heroin dependence is currently in preclinical testing and will probably deliver a four-to-six week dose of the drug. In France, buprenorphine has been used since 1996 and has had tremendous popularity over methadone.

The company is also developing two more vaccines. COC-AB, an antidote for cocaine overdose, is designed to bind to free cocaine in the blood and remove it from the brain and heart. It is in preclinical development in Paris. Currently, there is no specific antidote for cocaine overdose, only fragmented approaches that deal with various organ systems separately. ITAC, a cocaine vaccine, is being developed in conjunction with The Scripps Research Institute to prevent relapse to cocaine dependence following treatment.

What's cooking across the pond?

In 2001, the former head of GlaxoSmithKline's experimental pathology unit, Francois Conquet, formed Addex Pharmaceuticals SA in Geneva, Switzerland. Dr. Conquet and his colleagues are searching for a drug that treats cocaine addiction by interrupting the neurochemistry of glutamate, the main excitatory neurotransmitter associated with learning and memory. While doing research for his former employer, Conquet discovered that glutamate is often overlooked, yet it's more essential to cocaine addiction than dopamine. Whereas dopamine tickles the reward portion of the brain with a much-sought-after high, glutamate governs long-term dependence. If Conquet finds a suitable glutamate antagonist, therapeutic possibilities abound, glutamate has been indicated in several psychiatric disorders, resulting in possible benefits for co-occuring disorders.

Cantab Pharmaceuticals (Cambridge, UK) was developing two vaccines when Xenova (Cambridge, UK) acquired the company. Although Xenova does not specialize in addiction treatments (they prefer to concentrate on the oncology market), the company is continuing their development. Their cocaine vaccine, TA-CD has been tested in Phase I and II trials. In the Phase II challenge trial, the vaccine was well tolerated by patients after repeated injections. It is now being tested in a Phase IIa trial with the National Institute of Drug Abuse (NIDA) in patients who have relapsed. Unofficial reports from the company state people from around the world are clamoring to participate in their TA-CD clinical trials. TA-CD is composed of a cocaine derivative coupled with a carrier protein, and generates drug-specific antibodies, which bind to cocaine, interfere with its transport from blood to brain, and neutralizes its psychoactivity. Xenova views the vaccine as complementary to behavioral therapy.

NeuroSearch is a Danish biopharmaceutical company focused on discovering new drugs for the treatment of diseases of the central nervous system. By enhancing dopaminergic activity for a prolonged period NeuroSearch believes that their drug, tentatively named NS2359, may be used as an effective therapy for the treatment of cocaine addiction. The drug is being developed in collaboration with the National Institute on Drug Abuse, which is also funding most of the development costs. NeuroSearch has retained all commercial rights to NS2359.

An aid for alcoholics

The powerhouse of the group mentioned in this article is Forest Laboratories. The company develops, manufacturers, and sells both branded and generic forms of ethical products, as well as non-prescription pharmaceutical products sold over-the-counter. In late February 2002, the Food and Drug Administration granted a priority review to the new drug application for acamprosate, the company's prescription medication under development in the U.S. to treat alcohol dependence. This central nervous system-acting medication is believed to help restore balance to the brain's neurotransmitter systems that have been adversely affected by the chronic exposure to alcohol. Forest licensed the U.S. marketing and distribution rights for acamprosate from Lipha, a French subsidiary of Merck KGaA in October 2001. Outside the U.S., the drug has been the subject of numerous clinical studies and is available by prescription in 24 countries. In nine European clinical studies, the drug "typically" increased non-drinking days by 30 to 50 percent, according to the company.

But what's the hold up?

If you build it, they will come. If only this were true in the field of dreams known as addiction treatment. While research in addiction moves forward, there are still only a handful of biotech companies, and even fewer pharmaceutical companies actively working in this area. The phenomena may be explained, at least in part, by the stigma against drug abuse and partly by economics, according to Frank Vocci, Director, Division of Treatment, Research & Development at NIDA. While the number of people with one or more addiction is at an all-time high, "most companies feel that it's an untested market, one with reimbursement issues looming very large," Vocci said.

Not to mention the difficult patients. Substance abusers have a very poor compliance rate in clinical trials. A 30 to 50 percent dropout rate in clinical trials for substance abusers is commonplace, while heart disease or diabetes groups may only have three percent. Those numbers are not terribly appetizing for big pharmaceutical companies.

The perception also exists, which may be only in part true, that individuals hooked on cigarettes, alcohol or "harder" drugs like cocaine don't want to quit. So why spend time and money developing treatments for them when there are other, surer markets? Vocci explains why mostly small biotech companies are working in addiction, in contrast to large pharmaceuticals by the "law of inverse size," large drug companies believe they need a huge financial base to develop a product. "If a product doesn't earn two billion in the first couple of years on the market, corporate decision-makers believe it's not worth their while," he said. Smaller companies can better afford to develop drugs with mid-sized markets. However, the 1997 estimate used by DrugAbuse Sciences Inc. states that there are approximately 22 million alcoholics, 6 million cocaine addicts, and 2 million heroin users in Europe and America, numbers large enough to make any big pharma company sit up and take notice.

But Vocci points out smaller companies are more likely to use NIDA's assistance in developing a drug, and are generally more willing to discuss their work in this area. NIDA also offers free preclinical testing and assistance with clinical trials. Vocci said he would like to see companies with possible leads come to NIDA sooner, rather than waiting to see if they test well for other CNS indications. "We'd like to parallel process such drug candidates for companies rather than waiting years for the outcome of other clinical trials," Vocci said. Companies could then have two possible uses for their drug, and sooner, he added. "There's a certain holding pattern for drugs at the corporate level that we'd like to see stop," Vocci said. "It may take us years to get our hands on a compound unless a company comes to us to develop it with them at the same time they are testing it for another indication," he added.

Ria Romano is the editor of Counselor, The Magazine for Addiction Professionals, and Vicki Brower is a New York City-based freelance writer who specializes in biotechnology and bioethics.

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