|Overview of Rare Diseases Research Activities
The National Institute on Drug Abuse (NIDA) provides national leadership and conducts and supports biomedical and behavioral research, health services research, research training, and health information dissemination addressing the prevention of drug abuse and treatment of drug addiction. NIDA plans, conducts, fosters, and supports a comprehensive program of research and research training relating to the causes, prevention, treatment, patterns, and consequences of drug abuse and addiction. Research is performed in NIDA's own laboratories and through contracts and grants made to scientific institutions and individuals. Training relevant to fundamental sciences and clinical disciplines of drug addiction is performed via institutional and individual research training awards and collaborations with other research institutes and Federal health agencies. NIDA conducts and fosters health information dissemination activities, including the collection and dissemination of research findings and related educational materials for health professionals, educators, and the public. In addition, NIDA coordinates with institutions, professional associations, and agencies both domestic and abroad that specialize in the treatment and research of drug addiction, specifically with the Substance Abuse and Mental Health Services Administration on services research issues as well as on other programmatic issues.
Size of Drug-addicted Population
The abuse of opiates such as heroin and other narcotics exceeds 1 million persons and stimulants such as cocaine and “crack cocaine” exceeds 2 million; they are endemic in the United States (U.S. Office of National Drug Control Policy). However, even the lowest estimates from any source put addiction levels of these substances at figures well above the 200,000 threshold generally used for defining orphan products. Incidence and prevalence figures for addiction on controlled substances are difficult to estimate, as they vary from type of drug, community, and supply availability (generally a function of supply interdiction/law enforcement). There may be various drug addiction indications that affect less than 200,000 persons in the United States. The total cost to society of drug abuse and addiction in the United States has been estimated to exceed $484 billion per year.
Drug Addiction as an Orphan Disease
Although drug addiction is a serious public health concern, it is a historical fact that drug addiction is treated as an orphan disease because the pharmaceutical industry rarely profits from marketing drugs for the treatment of drug addiction and there exists little or no incentive for pharmaceutical companies to pursue research and development of new treatment medications for this population. Although total numbers of persons afflicted may seem sufficient in the aggregate, unlike other disease states, many of these persons are not seeking treatment upon diagnosis. Therefore, the actual patient population is less than the total number of persons afflicted.
Additionally, many of these persons will be treated in publicly funded clinics where companies perceive reimbursement as modest or inadequate and perhaps subject to artificial cost controls.
Finally, much of the U.S. treatment system is based on nonpharmacological treatment modalities.
A further complication is that some treatment agents may themselves be abusable and will be strictly controlled (witness methadone, classified as a Schedule II controlled substance for use in opiate maintenance therapy—some 900 U.S. clinics are licensed to dispense methadone and serve approximately 190,000 persons per year with a pharmaceutical market value of approximately $40 million per year). This is simply not an attractive market to most manufacturers based on projected return on investment when compared to nearly any other indication. Each of these points is well documented in the Institute of Medicine Report on the Development of Medications for the Treatment of Opiate and Cocaine Addiction, 1995, and all are well known to the pharmaceutical and market research industries. Therefore, while de jure opiate and cocaine addiction do not fit the definition of orphan products, de facto they certainly are treated as such. As an instructive example, consider the development and approval of levomethadyl acetate hydrochloride (trade name ORLAAM), an alternative to methadone for the treatment of opiate addiction. Despite the facts that human data on 6,000 subjects from government-sponsored studies were available for levomethadyl acetate hydrochloride and the government had a large supply of the compound available for anyone interested in obtaining a New Drug Application (NDA), no private sector entity attempted to finish the development of this compound until NIDA paid a contractor to do so. Similarly, the development of naltrexone was largely a NIDA-funded effort. Therefore, these products should be viewed as entirely “orphan-like” insofar as their ability to attract private sector sponsors.
History of NIDA Rare Diseases Research
Currently, there are four medications for the treatment of opiate addiction that have received orphan product designation. Each of these products was developed with substantial involvement by NIDA. These drugs are ORLAAM, naltrexone, buprenorphine, and buprenorphine combined with naloxone. ORLAAM received NDA approval in 1993. Naltrexone, an opiate antagonist for use in detoxified patients, was approved in 1985. Currently, orphan exclusivity for ORLAAM and naltrexone has expired. Additionally, ORLAAM’s distributor notified physicians that distribution of the product would be discontinued in 2004, due to poor sales in the United States and its withdrawal from European markets. ORLAAM’s orphan product designation expired in 2000 and thus there is no legal requirement for a manufacturer to maintain the product in the U.S. market.
The opiate partial agonist buprenorphine and a combination of buprenorphine plus naloxone have also received orphan designation (see details below) and were approved for marketing in the United States on October 8, 2003. These products represent a major success as the FDA designated them both as orphan products. Buprenorphine became the first product to receive an orphan designation based on an economic rather than a population-based rationale, i.e., the product would not recoup their developmental expenses in 7 years of exclusivity in the U.S. market.
Recent Scientific Advances in Rare Diseases Research
The discovery of opiate receptors by NIDA-funded scientists in the 1970s opened a new era of neurobiological research that is ongoing today. Scientists continue to map brain receptor system types and subtypes, continuously gaining understanding of their structure and function. This information will allow the design of interventions (behavioral, chemical, and genetic) that may be useful in the treatment of a huge number of disorders of mankind, all of which are mediated in the brain.
A generation of research has shown that drug addiction is a complex biomedical and behavioral disease that affects those parts of the brain that underlie and mediate human emotions. Evolution in scientific research has demonstrated that both depression, an illness commonly observed in drug-addicted individuals, and drug addiction are brain diseases that can and often should be treated with medicine.
The role of a medication is to reestablish normality to brain function and behavior so that the addicted patient has the opportunity for rehabilitation through counseling, psychotherapy, vocational training, and other therapeutic services. While the mechanisms of many central nervous system disorders are still to be elucidated, scientists working in the field of drug abuse have now identified and cloned the putative site of action in the brain for every major drug of abuse. In addition, recent application of microarray technology to characterize drug effects on gene expression has identified intracellular proteins that are altered by drugs of abuse after their initial receptor interactions. Thus, the potential to develop new treatments is enormous.
Rare Diseases Research Initiatives
As described in the history section above, NIDA considers medications for the treatment of addiction on controlled substances to be de facto orphans. Thus, the development of medications for the treatment of addiction could be considered rare diseases research within the context of an urgent public health need with a wholly inadequate private sector response. Therefore, NIDA’s Medications Development Program effort may (until facts prove otherwise) be considered as part of a rare diseases research initiative.
The Functions of the Division of Pharmacotherapies and Medical Consequences of Drug Abuse
In 1990, the Medications Development Division (MDD) was established in NIDA. In 1999, the MDD become the Division of Treatment Research and Development (DTR&D). In 2004, DTR&D became part of the Division of Pharmacotherapies and Medical Consequences of Drug Abuse (DPMC). The functions of MDD within the new division remained the same; namely, DPMC conducts studies necessary to identify, develop, and obtain FDA marketing approval for new medications for the treatment of drug addiction and other brain and behavior disorders; develops and administers a national program of basic and clinical pharmacological research designed to develop innovative biological and pharmacological treatment approaches; supports training in fundamental sciences and clinical disciplines related to the pharmacotherapeutic treatment of drug addiction; collaborates with (a) the pharmaceutical and chemical industry in the United States and other nations, and (b) the Federal medications development programs of other institutes and entities; and works closely with the FDA in assuring that research designed to show the clinical efficacy of new compounds is evaluated and approved in the most expeditious manner possible.
The DPMC operates within the larger context of a NIDA-wide Medications Development Program that incorporates basic research discoveries from both the intramural and extramural communities in the quest to develop new pharmacological treatments. Application of research results from the intramural and extramural community allows DPMC to have access to the latest theoretical bases and an opportunity to test new hypotheses in controlled clinical settings. As physicians now have a choice of several different FDA-approved products for treating opiate addiction (methadone, buprenorphine, buprenorphine/naloxone, and naltrexone) and no FDA-approved products for treating addiction to stimulants (e.g., cocaine or methamphetamine), NIDA’s efforts are currently shifting toward a greater emphasis on discovery and development of medications for treating stimulant addiction (cocaine, methamphetamine, nicotine) and, as of 2003, cannabis addiction. Clinical trials in this area have focused on medications that are already marketed for other indications, and substantial efforts are also being devoted to the discovery and development of novel compounds that may specifically address the problem of stimulant addiction through attempts to collaborate with the pharmaceutical industry. Efforts are also directed toward supporting, through grants and contracts, synthesis of novel compounds for screening and pharmacological testing.
Significant areas of research and development are summarized below:
1. Opiate Addiction Treatment
Buprenorphine/Buprenorphine-Naloxone Combination: A major milestone and achievement for NIDA’s Medications Development Program and for Reckitt Benckiser Pharmaceuticals, Inc., (NIDA’s collaborator in a Cooperative Research and Development Agreement) was the
October 8, 2002, FDA approval for the marketing of two new products for the treatment of opiate addiction. These two new products, known under the trade names Subutex and Suboxone, represent new tools in the arsenal of anti-addiction medications. Both have been designated as orphans, based on the expectation that these products will not recoup their developmental expense during their period of U.S. marketing exclusivity. Marketing of these products began in January 2003 but is subject to certain restrictions imposed by U.S. law and regulations. Nevertheless, these products may, under the conditions specified in law and regulations, be prescribed in a variety of settings, including physician’s offices.
Subutex and Suboxone now join methadone as medications that will be available for the treatment of heroin and other opiate addiction. They offer a broader array of options to physicians and patients and should expand treatment availability.
These products represent the culmination of several years of research and development between NIDA and Reckitt Benckiser Pharmaceuticals, Incorporated. The unique pharmacology of Subutex (buprenorphine) and Suboxone (buprenorphine combined with naloxone) and the statutory changes enacted by the Drug Addiction Treatment Act of 2000, as contained in P.L. 107-273, “The Children’s Health Act of 2000,” permits these products to be prescribed by appropriately trained physicians in settings other than the existing, but limited, Opiate Treatment Programs (OTPs). It is hoped that this will translate into an increase in treatment availability across the United States. A wider dispersal of new treatment settings should follow the introduction of these products to the market. Additionally, patients who either have no OTP programs available or who cannot avail themselves of these programs will have another option for treatment. As of the date of this report, the Substance Abuse and Mental Health Services Administration (SAMHSA), U.S. Department of Health and Human Services, reports that 6,202 physicians have taken the training required by law to prescribe these two medications and 3,905 have registered as potential providers.
Depot Naltrexone: Naltrexone, a marketed long-acting, orally effective opioid antagonist, was approved in 1983 for the indication of blocking the pharmacological effects of exogenously administered opiates. It is an adjunct to the maintenance of the opioid-free state in detoxified, formerly opioid-addicted individuals.
One of the major obstacles to the success of naltrexone has been patient compliance with therapy. Naltrexone must be taken at least three times per week and has no effect other than to block the effects of heroin, a drug that the patient is not supposed to use. Because of this, many patients forget to take or stop taking their medication. Therefore, the greatest success with naltrexone has been in the limited population of highly motivated formerly opiate-addicted patients.
During 1999, NIDA completed, via a Small Business Innovative Research (SBIR) grant to Biotek, Inc., the production and preclinical testing of a batch of 120 doses of depot naltrexone. These doses are designed to last 30 days when administered subcutaneously in humans and to produce a blood level of about 2–3 ng/ml (which will be relatively constant over this period). This product has been shown, in an inpatient clinical study, to block subjective responses to heroin challenges at 12–25 mg. This study was completed in 2000 and showed that it was possible to block 25 mg heroin challenges up to 5 weeks after depot injection. A two-site outpatient double-blind study was designed to test the product in a real-world setting. This outpatient study began in November 2000 and was completed in 2003. The results were reported at a scientific meeting in June 2004 and are pending publication. The results indicate a significant effect of the depot preparation to limit relapse to heroin in the trial.
Additionally, another investigational formulation of a sustained release formulation of naltrexone supplied by Alkermes, Inc., has undergone clinical trials at NIDA’s Intramural Research Program. This study provided information on the safety and duration of effect of this potential treatment product. The oral form of naltrexone was approved in 1994 for the treatment of alcohol abuse; the depot preparation may also be of value for the treatment of that disease.
Alkermes has reported that their dosage form of depot naltrexone reduces heavy drinking behavior in males (but not females) and that the company intends to pursue further development of their dosage form. They plan a submission to FDA for approval within the next 2 years.
Thus, the feasibility of a sustained release formulation of naltrexone for the treatment of opiate and alcohol addiction is moving rapidly from concept and clinical testing toward potential regulatory approval and marketing.
2. Cocaine Addiction Treatment
Several small studies of potential cocaine addiction treatment agents have been completed and are in various stages of data analysis. Clinically significant findings will be followed up in larger controlled trials as warranted. In addition, NIDA continues to work toward the discovery and development of new molecular entities, such as kappa opioid antagonists, for cocaine addiction treatment.
Ondansetron: A 5HT3 antagonist that can block dopamine release and increase GABA tone has been shown to be efficacious in reducing cocaine use at dose of 8 mg/day in a recently completed NIDA study. The consensus from the data analysis and safety data review was to proceed forward with a follow-up phase IIb study to explore and confirm the results of the phase IIa study with two doses of ondansetron—8 mg and 16 mg—and placebo. This study will be conducted in roughly 200 patients.
Quetiapine: An atypical neuroleptic has been shown to decrease cocaine use and craving in co-morbid bipolar patients. A phase I safety trial is under way. A phase II proof-of-concept study with two doses of Quetiapine and placebo is planned.
Cabergoline: A long acting dopamine agonist that showed a trend for efficacy in reducing cocaine use in a small pilot study is being studied for confirmation in a large phase II study. This study is completed and data are being analyzed.
Modafinil: A nondopaminergic stimulant has been shown to reduce cocaine use in a pilot study (Dackis 2004). It is currently being studied in a multisite trial for confirmation of efficacy. Recruitment for this study is about to begin.
RPR: A CCK-B antagonist that modulates dopamine release and is currently in phase I safety trials.
Tiagabine: A GABA uptake inhibitor has been shown to decrease cocaine use in two pilot studies. A multisite trial has been recently completed. Data analysis is under way.
Atomoxetine: A norepinephreine uptake inhibitor approved for ADHD is currently in phase I trials for safety in cocaine-abusing subjects. Pending safety data, a phase II study will be planned for study in co-morbid cocaine subjects with ADHD.
Baclofen: A GABA-B agonist has been shown in a pilot trial to reduce cocaine use in heavy users. It is being studied in a multisite trial to confirm earlier findings.
Disulfiram: There is a growing body of evidence generated by NIDA grantees concerning the potential use of disulfiram in the treatment of cocaine addiction. Disulfiram (Antabuse), marketed as aversive therapy for treating alcoholism, is also showing promise in the treatment of cocaine addiction. Several NIDA-sponsored studies conducted at Yale University documented interaction of disulfiram with cocaine in humans. Pharmacokinetics studies showed that disulfiram increases plasma concentrations of cocaine and potentiates physiological-cardiovascular responses to cocaine. Three efficacy trials conducted with different populations of cocaine-addicted individuals suggest that disulfiram in combination with each of three different therapeutic interventions (cognitive behavioral treatment, 12-step facilitation, or clinical management) might be effective in treating cocaine addiction. In cocaine-alcohol abusers disulfiram treatment showed sustained effect on reduced cocaine and alcohol use 1 year after cessation of the therapy. Disulfiram treatment of cocaine-abusing opioid-addicted patients maintained on methadone resulted in significant decrease of the amount and frequency of cocaine use. A preliminary study showed that disulfiram also decreases cocaine use in cocaine-opioid addicts maintained on buprenorphine.
NIDA is currently sponsoring three large outpatient clinical trials with disulfiram as the treatment for cocaine addiction: (1) study on 160 opioid-cocaine-addicted patients maintained on methadone, conducted at Yale University; (2) study on 180 opioid-cocaine-addicted patients maintained on buprenorphine, conducted at Yale University; (3) study evaluating disulfiram and naltrexone alone and in combination in the treatment of 208 alcohol-cocaine-addicted individuals, conducted at the University of Pennsylvania. All these studies include some form of behavioral or cognitive therapy and drug counseling. They are monitoring not only use of cocaine but also opiates or alcohol. Finally, NIDA is planning a clinical pharmacology/safety study of the interactions between disulfiram and iv-administered cocaine, prior to launching large-scale phase III multi-center trial with this medication.
GBR 12909 (Vanoxerine): Major neurochemical effects of cocaine include release of dopamine (DA), serotonin, and noradrenaline via a transporter-mediated exchange mechanism. There is considerable evidence that the initiation and continuation of cocaine use is associated with the effects of the drug on the dopaminergic, serotonergic, and noradrenergic modulation of the central nervous system (CNS) function. Animal studies suggest that the mesocorticolimbic dopaminergic pathways are important mediators of cocaine’s reinforcing and addictive properties. Cocaine binds to these transporters and blocks the removal of these neurotransmitters from the synaptic gap. The neurobiological mechanisms underlying the effects of cocaine are not well understood. Preclinical studies indicate that cocaine’s blockade of the DA transporter plays a key role in producing cocaine’s addictive and reinforcing effects. Primate and nonprimate studies have shown that GBR 12909 has a strong affinity for the DA transporter. GBR 12909 is a high-affinity, selective, and long-acting inhibitor of DA uptake that produces a persistent and noncompetitive blockade of DA transporters and substantially reduces cocaine-induced increases in extracellular mesolimbic DA. In addition, GBR 12909 has a higher affinity than cocaine for the DA transporter. Ongoing research is searching for a dopamine-sparing cocaine antagonist that might be developed as a pharmacological treatment to block cocaine from acting at the transporter level to produce its reinforcing effects. GBR has been postulated to act by binding only to precise sites on the dopamine transporter that are required for cocaine binding and making available the sites where DA binds to the transporter.
A phase I clinical study was conducted in support of an Investigational New Drug (IND) application filed by NIDA. The main objectives of this study were to determine the safety, tolerance, and pharmacokinetics of multiple escalating dosages of oral GBR 12909 in healthy volunteers. In addition, PET scans measuring the occupancy of the DA transporter by GBR 12909 were obtained. The occupancy scan results are being correlated with the safety data to determine an optimal oral dose of GBR 12909.
The study report from the Phase I (healthy volunteer) study showed 30–40-percent dopamine transporter occupancy at the 100 mg dose level. Based on primate data showing equivalent levels of occupancy at doses reducing cocaine self-administration, this may be clinically meaningful in cocaine treatment. Consultants reviewed the study in October 2001. The consultants recommended a follow-up study in cocaine-addicted patients to address the safety and other metabolic issues that were raised in the first study in planning for a cocaine interaction study. Phase I studies in cocaine-addicted subjects have begun.
Dopamine Agonists: The activation of the dopaminergic reward system in the brain appears to be the principal neurochemical mechanism involved in the addiction to stimulants such as cocaine and amphetamine. Chronic abuse of these drugs results in dopamine deficiency in the brain, which has been hypothesized to lead to craving for stimulants, depression, anhedonia, and dysphoria.
Most recently, studies in rodents, and to a lesser extent in monkeys, have differentiated the roles of D1 and D3 receptors with regard to cocaine. The D1 system may inhibit the effects of cocaine, while the D3 system may block conditioned cues. Compounds that affect both systems are under study.
Kappa Opioid Antagonists: While the discovery of a selective kappa opioid antagonist for potential use in preventing relapse to opiates has been a goal of NIDA for several years, the recent discovery and evaluation of JDTic—a highly selective kappa antagonist synthesized by a NIDA chemist—has provided a rationale for effectiveness in preventing relapse to cocaine. Interestingly, JDTic was shown to prevent stress-induced reinstatement of responding to cocaine in a rat model of cocaine relapse. The compound is currently undergoing initial preclinical safety testing to determine its developability as a medication.
Glucocorticoid and Corticotropin Releasing Factor (CRF) Antagonists: Studies have shown that cocaine causes the release of stress hormones known as glucocorticoids in both rats and humans. There is some evidence from rat studies that glucocorticoid antagonists and CRF antagonists reduce cocaine self-administration in a dose-related manner. NIDA will follow up on these basic research findings with additional studies aimed at developing a potential treatment for cocaine addiction. DPMC is attempting to obtain CRF antagonist compounds from pharmaceutical company sources.
Immunology: During 1998, NIDA sponsored a meeting on the potential of utilizing peripheral blockers for prevention and treatment of cocaine addiction. The ability to block cocaine's entry into the brain or decrease its rate of entry (and thus attenuate the "high" produced) was discussed. Several approaches (active and passive immunization, catalytic antibodies) were actively explored. One of these theoretical constructs has now been translated into actual therapeutic entities that are currently at various stages of research and development as listed below.
Researchers funded by NIDA’s DPMC reported that they have successfully immunized rats against many of the stimulant effects of cocaine. Cocaine was prevented from entering the brain when rats were “vaccinated” with a substance that triggers the body to produce antibodies to cocaine. These antibodies then acted as biological “sponges” to which cocaine binds, thereby reducing the amount available in the blood to reach the brain. The results of this
research are presented in “Suppression of Psychoactive Effects of Cocaine by Active Immunization” in the December 14, 1995, issue of Nature.
Researchers Kim Janda, Ph.D.; Rocio Carrera, M.A.; George Koob, Ph.D.; and colleagues at The Scripps Research Institute demonstrated a greater than 70-percent reduction in cocaine uptake in the brains of rats inoculated with the antibody-producing compound as compared to a group that
was not inoculated. Researchers designed the compound so that the antibodies produced would respond specifically to the cocaine molecule yet not affect normal brain chemistry.
In the study, Dr. Janda and colleagues used an “active immunization” approach by developing a substance that when administered to rats would trigger the immune system to produce antibodies that are specific for the cocaine molecule. The researchers inoculated the rats over a 35-day period and then tested their responses to cocaine. The immunized animals showed significantly lower responses to the stimulant effects of cocaine than control animals because the immunization prevented much of the cocaine from getting to the brain. Cocaine concentrations in the brain tissue of the immunized animals were found to be dramatically less than the concentrations of cocaine in brain tissue of controls.
Other immunotherapy research for drug abuse treatment has explored the use of catalytic antibodies and other external agents that can be used to treat cocaine addiction. The research reported in Nature differs by inducing the production of antibodies that remain in the bloodstream for an extended period of time and block cocaine’s effects after it is used.
Another vaccine, currently owned by Xenova, a United Kingdom company, links a carrier protein to cocaine, resulting in an antigen that induces antibody formulation. This vaccine generates antibodies that can retain cocaine in the bloodstream and allow naturally occurring cholinesterases to convert cocaine into inactive metabolites. NIDA has supported the initial research via a SPIRCAP grant. Thirty-four subjects, all former cocaine abusers, completed the initial phase I study in the United States, and the vaccine was found to be clinically safe and to produce substantial levels of anti-cocaine antibodies that persist for at least 3 months following the final vaccination. An additional study examining the extent to which the antibody can block the effects of administered cocaine was also funded under the SPIRCAP award.
A phase II safety and immunogenicity study funded through a NIDA grant to Dr. Thomas Kosten at Yale University started in 2002. The company plans to continue development of the vaccine.
Dr. Michael Owens, at the University of Arkansas for Medical Sciences in Little Rock, presently receives NIDA funding to develop a new generation of monoclonal antibody-based medications for treating drug abuse (“Immunotherapy for Drug Abuse,” R01 DA07610, “Antibody-Based Therapy for Methamphetamine Abuse,” R01 DA11560, and “Preclinical Testing of Antibody Therapy for Methamphetamine Abuse”, P01DA14361). This research is focused on treatments for methamphetamine, ecstasy (MDMA), and phencyclidine (PCP) abuse. Additionally, NIDA awarded an STTR grant in FY04 to Inflexion Therapeutics for the advanced development of the anti-PCP monoclonal antibody invented by Dr. Owens. This project focuses on the production of anti-PCP monoclonal antibodies in tobacco plants and clinical development of the antibody. These medications function as pharmacokinetic antagonists and are designed to reverse the effects of drug overdose and/or help blunt the reinforcing effects of drugs of abuse. Because of the unique pharmacological profile of these new medications, they would be well suited for use with other more conventional chemically based medications and treatments, such as behavioral modification, to aid in the long-term recovery from drug addiction.
Cocaine "Receptor" Imaging Studies: In addition to the categories of compounds being tested as described above, a new and potentially useful technology is being investigated as to its value for predicting efficacy of potential cocaine treatment medications. Research in the field of structure-activity relationships has revealed highly selective and potent binding ligands for the dopamine transporter. NIDA intramural researchers have identified three “generations” of such compounds, with each succeeding generation being more selective and potent than the previous one. RTI-55, the first potent compound, was shown to be an effective in vivo labeling agent in animal studies and was subsequently examined in human imaging studies by SPECT. A second compound, RTI-121, was found to be more selective for the dopamine transporter but had a higher apparent lipid solubility and exhibited lower specific to nonspecific binding in vivo. NIDA researchers are testing new compounds and are also utilizing some older compounds (e.g., WIN-35,428) in brain imaging studies. Procedures have been developed for estimating the occupancy of transporter sites in vivo. Dopamine transporter imaging studies of cocaine abusers have been completed (see section on GBR 12909). This technology may make it possible to estimate the effectiveness of a potential treatment compound or regimen by correlating receptor occupancy (as shown in imaging studies) with actual clinical results. NIDA will continue to follow this line of research.
Additionally, NIDA is participating in an effort with NIMH, NINDS, and NIAAA to develop appropriate imaging ligands that will be essential to the study of many brain and CNS conditions as well as the effects of various treatments.
3. Methamphetamine Addiction Treatment
Methamphetamine is a potent psychomotor stimulant that has gone through episodic periods of widespread use and abuse in the United States. Cocaine abuse and addiction surpassed use of methamphetamine in the 1970s and 1980s, but methamphetamine abuse and addiction have been reappearing in some regions of the United States and are widespread in Western U.S. cities such as San Francisco, Denver, Phoenix, and Los Angeles. According to the 2003 National Survey on Drug Use and Health, approximately 12.3 million Americans ages 12 and older reported trying methamphetamine at least once during their lifetimes, representing 5.2 percent of the population ages 12 and older. Approximately 1.3 million (0.6 percent) reported past year methamphetamine use and 607,000 (0.3 percent) reported past month methamphetamine use.
There are no accepted treatment medications for methamphetamine addiction or abuse. As a result, NIDA has developed a Medication Discovery Program for methamphetamine and is funding a number of extramural and intramural studies to develop medications to treat methamphetamine abuse.
Ondansetron: There is evidence that selective serotonin 5-HT3 receptor antagonists attenuate behavioral responses to d-amphetamine and methamphetamine, suggesting that 5-HT3 receptors modulate brain dopamine in animals. This action of 5-HT3 receptor antagonists may reduce the rewarding effects of abused substances. Ondansetron is a selective 5-HT3-receptor antagonist. Ondansetron decreases stimulated dopamine release and has been shown to reduce the development of behavioral tolerance and sensitization to cocaine following a period of acute and chronic withdrawal. It has also been suggested that 5-HT3 antagonists may reduce discomfort or post-cessation anxiety following psychostimulant withdrawal. These data prompted us to test whether Ondansetron might reduce cocaine-mediated reward and ameliorate post-cessation anxiety symptoms following cocaine use cessation. NIDA and UCLA established a Methamphetamine Clinical Trials Group (MCTG). The MCTG conducted a phase II double-blind, placebo-controlled dose-response trial with Ondansetron. The study was completed in 2003. There were no significant effects for any Ondansetron dose compared to placebo.
Selegiline: A selective monoamine oxidase-B (MAO-B) inhibitor that is used to treat patients afflicted with Parkinson's disease. Parkinson's disease is a neurological disorder that results from brain dopamine depletion. Selegiline improves brain dopamine levels and helps restore and maintain functionality in patients with Parkinson's disease. Methamphetamine produces its behavioral and cognitive effects by affecting dopaminergic mechanisms in the midbrain. Specifically, methamphetamine causes dopamine release and blocks its reuptake in dopaminergic nerve endings. Excess dopamine in brain synapses stimulates the midbrain reward centers but eventually dopamine is depleted. NIDA decided to test selegiline for its potential to reduce methamphetamine craving by restoring the depleted dopamine. A phase I interaction trial to determine the safety of selegiline in the presence of methamphetamine was completed in November 2003. No safety concerns were identified. A phase II, double-blind, placebo-controlled clinical trial of selegiline for methamphetamine relapse prevention is scheduled to start January 2004.
Aripiprazole: An atypical neuroleptic drug that has been approved by the FDA to treat schizophrenia and bipolar mania. It is a functional antagonist at dopamine D2 receptors in a hyperdopaminergic environment, a functional agonist at dopamine D2 receptors in a hypodopaminergic environment, and a serotonin antagonist at serotonin 5-HT2A receptors and partial agonist at serotonin 5-HT1A receptors. It has moderate affinity for alpha1-adrenergic and histamine (H1) receptors. Long-term methamphetamine abuse results in schizophrenia-like symptoms. By extension aripiprazole may have potential as a methamphetamine abuse therapeutic. NIDA is currently conducting a Phase I safety interaction study with aripiprazole and methamphetamine at UCLA and NYU.
Lobeline: A derivative from Indian tobacco plants. It stimulates a subclass of nicotine receptors and thus was tested in the clinic for its potential as a smoking cessation therapeutic. Additionally lobeline redistributes dopamine in nerve terminals by preventing dopamine uptake into synaptic vesicles without inhibiting MAO-B. In contrast, methamphetamine enters synaptic vesicles and inhibits MAO-B. Studies in rats revealed that lobeline decreases methamphetamine self-administration without affecting the rats' ability to self-administer sugar water. These data suggest that lobeline may reduce acute rewarding effects of methamphetamine and corresponding abuse liability. NIDA is collaborating with a pharmaceutical company to conduct a phase I double-blind, placebo-controlled, ascending-dose pharmacokinetic, safety, and tolerability study of lobeline with an eye toward testing it as a methamphetamine abuse therapeutic.
Reserpine: An alkaloid extracted from the roots of the plant Rauwolfia serpentina. It's a monoamine depleter that works at the synaptic vesicle, the same site of action as lobeline. Reserpine has been used since the 1950s to treat mild to moderate hypertension. In addition, it was one of the first antipsychotic drugs. Its present use in psychiatry is almost obsolete, as other neuroleptic drugs are more effective. NIDA is completing a phase I single-dose study with reserpine at UCSF. The data are currently being analyzed. An earlier proof-of-concept study with reserpine for cocaine abuse did not show efficacy. Further studies of reserpine for methamphetamine abuse are a low priority at this time in view of this finding.
Bupropion: A medication that has been approved to treat depression and promote smoking cessation. It is a dopamine uptake inhibitor that is well tolerated and has a good safety record. NIDA is testing bupropion for its ability to alleviate the dysphoria seen in early abstinence and reduce methamphetamine craving and relapse to drug using. Currently we are conducting a phase II, double-blind, placebo-controlled study of Bupropion.
Modafinil: A nondopaminergic stimulant used to treat narcolepsy. It is hypothesized that this effect is accomplished by modulating the glutamate/GABA system. Recently it has been shown that modafinil blunts cocaine euphoria under controlled conditions and improves clinical outcome in cocaine-addicted patients receiving standardized psychosocial treatment. Methamphetamine, like cocaine, is a stimulant. Thus NIDA is endeavoring to evaluate the potential of modafinil as a methamphetamine abuse therapeutic. NIDA is planning a phase I safety trial, as requested by FDA, prior to conducting a phase II trial.
Topiramate: A fructopyranose derivative that is approved for treating seizure disorders. In a clinical trial it was found to be superior to placebo at improving drinking outcomes in alcohol-addicted individuals. Data from a pilot proof-of-concept study suggest that topiramate may be a useful medication for preventing relapse to cocaine use. As both cocaine and methamphetamine are stimulants it is not unreasonable to hypothesize that topiramate may be a useful medication for preventing relapse to methamphetamine use. To that end NIDA is providing grant support to conduct a phase I safety interaction study between topiramate and methamphetamine.
GBR 12909: A potent dopamine uptake inhibitor that has been shown in non-human primate positron emission tomography (PET) imaging studies to block amphetamine-induced dopamine release. Currently, GBR 12909 is being tested in phase I interaction studies for cocaine abuse. NIDA is planning a phase I safety interaction study with methamphetamine. Barring any safety concerns NIDA would test GBR 12909 in an outpatient proof-of-concept study for methamphetamine relapse to using prevention.
4. Medications Development for Cannabis-related Disorders
The treatment of cannabis-related disorders (CRDs) is an issue of great public health concern.
Currently, marijuana is the most commonly used illicit drug in the United States with recent estimates from the SAMHSA of 14.6 million users in the past month, with particularly heavy use occurring in adolescent populations (over 20 percent of all high school seniors). Approximately 2.4 million people use marijuana for the first time every year and two-thirds of them are between 12 and 17 years of age. In addition, of the 3.5 million people who met criteria for past-year cannabis abuse or addiction in 2001, more than two-thirds were between the ages of 12 and 25 years. An estimated 852,000 individuals reported marijuana as the specific substance for which they received their last or current treatment among persons who received treatments in the past year, and approximately one-half of those individuals were 25 years old or younger.
Sufficient research has been carried out to confirm that the use of cannabis can produce serious physical and psychological consequences. The consequences of cannabis use may be due to the acute effects of the drug or due to the chronic exposure that may ultimately produce addiction. The use of a large amount in a short period of time may induce hallucinations, delirium, and other perceptual manifestations similar to a psychotic episode. Chronic users of cannabis may experience difficulty in stopping or controlling drug use, develop tolerance to the subjective and cardiovascular effects, and eventually present withdrawal symptoms after sudden discontinuation of use.
Unfortunately, there is currently no effective pharmacological treatment for CRDs and there is very limited research focused on the identification and development of medications to treat these disorders. Drug abuse treatment research as a whole has rarely focused on the treatment of CRDs. One indicator is the fact that there are no published randomized controlled clinical trials to evaluate pharmacotherapies for CRD as the primary outcome.
There are multiple reasons why it is timely to develop medications to treat CRDs. First, there are newly marketed medications available whose mechanisms of action may have potential therapeutic effects on the clinical manifestations of CRD. Second, the recent discovery of an
endogenous cannabinoid system with specific receptors and endogenous ligands, the availability of genetically engineered knockout mice that lack functional cannabinoid receptors to study genetic predispositions to the effects of cannabinoids, and the subsequent development of reliable preclinical models to study the rewarding and addiction-producing effects of THC all provide understanding of the basic therapeutic mechanisms. Last, there is the discovery and development of new chemical entities, some of them already being investigated at the clinical level, that target the cannabinoid system and have the potential for therapeutic benefit. All these factors are setting the stage for the development of medications to treat CRDs.
5. New Research Projects for Medications Development for Cannabis-related Disorders
Based on the needs as described above, NIDA funded several new research grants through RFAs, the goal of which was the development of safe and effective medications for the treatment of CRDs. Preclinical and clinical studies are focusing on the treatment of marijuana, hashish, or other cannabis derivatives use disorders. Medications studied under this RFA are aiming to treat cannabis use disorders, such as abuse and addiction, or cannabis-induced disorders, such as intoxication, delirium, psychosis, and anxiety. They are also focusing on the specific symptoms of the disorder such as withdrawal, craving or relapse, complications such as cognitive impairment and sleep disorders/disruption of normal rhythms, or the clinical surrogates of their use such as depression and other mood disorders.
The rationale for choosing the medication(s) to be investigated have been based on a top-down approach, a bottom-up approach, or both approaches combined. The top-down approach is the testing of marketed medications that are available for other indications and may be promising candidates for the treatment of CRDs. For example, an FDA-approved antidepressant has been chosen as a target medication. The bottom-up approach involves the identification and testing of new chemical entities that because of their chemical characteristics and
mechanism of action are candidates being developed specifically for CRDs.
6. Consequences of Drug Addiction
Currently, the program of research on medical consequences of drug abuses and co-occurring infections resides within the DPMC. As a result of the reorganization that created DPMC, critical research in the area of medical consequences of drug abuse will become a focus for NIDA. As described below, these studies involve marketed medications but typically will not be performed by the public sector. Under this program, the supported studies may be categorized into four major programs of research that are in various stages of development and progress. These are: (1) Metabolic and Endocrine Disorders of HIV/AIDS and Drug Abuse; (2) Pharmacokinetic/pharmacodynamic Drug-Drug Interactions Between Medications Used in the Treatment of Drug Addiction (e.g., methadone, newly FDA-approved buprenorphine), Infections (HIV, HCV, TB), and Mental Disorders; (3) Medical and Health Consequences of Chronic (long-term) Use/abuse of Licit and Illicit Drugs of Abuse and Co-occurring Infections (HIV, HCV, TB, STDs, and others); and (4) Oro-Maxillary Complications (such as facial and dental injuries) associated with Drug Abuse and Co-occurring Infections. New avenues of research are planned that fit within these major themes: (1) metabolic and endocrine disorders of HIV/AIDS among drug abusers, (2) directly observed therapy for HIV infected drug abusers, (3) hepatitis C, (4) issues in the medical management of HIV/HCV co-infections among drug abusers, (5) mini-symposium on TB among drug abusers, and (6) role of hormones and nutrition in drug abusers co-infected with HIV and HCV.
Injection drug use and sexual contact among users is a highly correlated vector in the spread of HIV, hepatitis, and tuberculosis. This creates a public health problem of enormous magnitude. The medical consequences may range from effects on the brain leading to drug addiction causing brain disease to effects on almost every physiological/organ system, including the central and peripheral nervous systems, cardiovascular, endocrine/hormonal, pulmonary/respiratory, renal, hepatic/metabolic, reproductive, immune, and other systems. For example, stimulants such as cocaine and methamphetamine (met, speed, or ice) increase the heart rate while constricting the blood vessels; in susceptible individuals, these two actions together set the stage for cardiac arrhythmias and strokes. Cocaine use decreases the blood flow to the brain, increases the heart rate, and elevates the blood components that promote clotting—effects that can lead to stroke or heart attack even in those not otherwise at risk for these serious cardiovascular events. NIDA-funded research also shows that chronic cocaine use is associated with left ventricular dysfunction and increased calcium deposits in the coronaries of HIV-infected African Americans and that its use may also facilitate the entry of HIV into brain cells, leading to cognitive and memory impairment. The club drug methylene-dioxy-methamphetamine (MDMA), also known as ecstasy, which many users mistakenly believe to be safe, has caused malignant hyperthermia, permanent kidney damage, and death. MDMA also damages serotonin nerve fibers in the brain. Heroin can cause a life-threatening kidney condition called focal glomerulosclerosis. Opiate (heroin) use is associated with consequences ranging from nausea and constipation to renal, dental, and orofacial complications. PCP (phencyclidine, or angel dust) decreases heart rate and blood pressure, triggers violent aggression, and may trigger muscle contractions strong enough to break a bone. The use of the most-abused illicit drug in the world, marijuana, that is often perceived by many as innocuous, is also associated with consequences ranging from memory, cognitive, and motor problems in young as well as adult individuals to possible lung cancer in chronic marijuana smokers (see Clinical Consequences of Marijuana in a special supplement to the Journal of Clinical Pharmacology, Vol 42, no.11, Nov 2002).
Injecting drug use further promotes blood clots, severe skin infections, and blood-borne infections including life-threatening endocarditis, viral hepatitis, and HIV/AIDS. Abuse of some drugs is associated with impulsive sexual activity that elevates individuals’ risks for acquiring and transmitting HIV/AIDS and other STDs.
In a relatively new area of research at NIDA, data show that nutrition may play an important role in HIV disease progression. Preliminary research shows that drug abusers with inadequate nutrition, particularly with suboptimal levels of antioxidant micronutrients such as selenium and zinc, are at high risk of mortality if they are also co-infected with HIV/AIDS. Clinical trials are under way to determine if supplementation with selenium, zinc, and other antioxidant micronutrients would slow the progression of HIV/AIDS disease. This research would have worldwide implications, such that underdeveloped countries where poor people cannot afford expensive antiretroviral therapy would benefit from an inexpensive treatment modality to slow disease progression and improve the quality of life.
Research also shows that hepatitis C virus (HCV) is another blood-borne pathogen that is easily transmitted through contaminated drug injection paraphernalia. Further, both viruses, HCV and HIV, frequently coexist because of common routes of transmission. Hepatic injury seems to occur in HIV/HCV co-infection through the induction of a novel signaling pathway that is cooperatively activated by specialized protein molecules, known as HCV E2 and HIV gp120, thereby providing a rationale for therapeutic interventions. NIDA continues to support a wide spectrum of research on epidemiology, natural history, underlying pathogenesis, prevention, and treatment of HIV/HCV co-infections among drug abusers.
Research shows that some illicit drugs and drug abuse medications can interact with medications used for treating diseases, resulting in possible loss of efficacy and adverse effects. For example, an interaction can occur between methadone and the protease inhibiting drugs that are currently the most effective treatments for HIV infection. The result can be ineffectiveness and increased toxic side effects from one or both drugs. In some cases, the presence of a protease inhibitor has inhibited the metabolism (processing) of methadone sufficiently to cause patients to go into withdrawal. The identification of such interactions and development of alternative regimens is a high NIDA priority under a new program of Research on Drug-Drug Interactions.
Due to the lack of pharmaceutical industry interest in developing new medications to treat addiction to controlled substances, NIDA has been substantially involved in the development of nearly all such medications since the Institute’s inception in 1974.