Report on the Rare Diseases and Conditions Research Activities of the National Institutes of Health 1999
National Institute on Drug Abuse (NIDA)
Overview of NIDA Rare Diseases Research Activities
NIDA provides national leadership and conducts and supports biomedical and behavioral research, health services research, research training, and health information dissemination with respect to the prevention of drug abuse and treatment of drug abusers. 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 through research performed in its own laboratories and through contracts and grants to scientific institutions and to individuals. NIDA supports training in fundamental sciences and clinical disciplines relating to drug abuse by individual and institutional research training awards and coordinates with other research institutes and other Federal health and other agencies on activities relevant to drug abuse and addiction. 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 lay public. In addition, NIDA coordinates with institutions and professional associations and with international, national, State, and voluntary agencies working in these areas, including collaboration with the Substance Abuse and Mental Health Services Administration (SAMHSA), on services research issues and other programmatic issues.
History of NIDA Rare Diseases Research
To date, four drug abuse treatment medications have received orphan product designation. These drugs are levomethadyl acetate hydrochloride, naltrexone, buprenorphine, and naloxone. Levomethadyl acetate hydrochloride (ORLAAM; Roxand Laboratories, Inc.), an alternative to methadone in opiate maintenance therapy, received New Drug Application (NDA) approval in 1993. Naltrexone, an opiate antagonist for use in detoxified patients, was approved in 1985 and no longer enjoys orphan exclusivity. The opiate partial agonist buprenorphine and a combination of buprenorphine plus naloxone have also received orphan designation (see details below) but do not currently have approved NDAs.
Incidence and prevalence figures for dependence on controlled substances (not alcohol or nicotine) are always difficult to estimate because they vary according to type of drug, community, and supply availability (generally a function of supply interdiction/law enforcement). Unlike other disease conditions, illicit marketers have a reason (profit) to introduce and infect the population with abusable and/or dependence-producing substances. Illicit drugs used in some communities are not always available or in vogue in other communities. Thus, various drug dependence indications, in and of themselves, may affect fewer than 200,000 individuals in the United States. Clearly, however, abuse of opiates (e.g., heroin and other narcotics) and stimulants (e.g., cocaine and "crack cocaine") are endemic in the United States. Even the lowest estimates put dependence levels of these substances at figures well above the 200,000 threshold generally used for defining orphan products. The total disease burden of drug abuse in the United States has been estimated to exceed $68 billion per year. Additionally, 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 that is being treated as an orphan disease by the pharmaceutical industry.
Despite the enormous public health burden of this disease state, little or no incentive exists for pharmaceutical companies to pursue research and development of new treatment medications for this population. Although total population afflicted may seem sufficient in the aggregate, unlike with other disease states, many of these individuals are not seeking treatment at the same time. Therefore, the actual population comprising a potential market for medications is only a fraction of those who could benefit. Additionally, many will be treated in publicly funded clinics, where reimbursement is perceived by companies as modest or inadequate and subject to artificial control. 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/year with a pharmaceutical market value of approximately $30 million/year). This is simply not an attractive market to most manufacturers based on projected return on investment compared with nearly any other indication they could pursue. Each of these points is well documented in the recent Institute of Medicine Report on the Development of Medications for the Treatment of Opiate and Cocaine Addiction (1995) and is well known to the pharmaceutical and market research industries.
Finally, pharmacological treatment of drug-dependent populations is not the dominant treatment modality in the United States. Most therapeutic regimens are nonpharmacologically based. Because no medications have demonstrated efficacy for the treatment of cocaine dependence, NIDA's orphan product experience to date has focused on medications to treat opiate dependence.
Therefore, although de jure opiate and cocaine dependence do not fit the definition of orphan products, de facto opiate and cocaine dependence do. As an instructive example, consider the development and approval of levomethadyl acetate hydrochloride, an alternative to methadone. Despite the fact that human data on 6,000 subjects from Government-sponsored studies were available for levomethadyl acetate hydrochloride, despite the fact that the compound was off-patent, and despite the fact that the Government had a large supply of the compound available for anyone interested in obtaining an 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 "orphanlike" insofar as their ability to attract private-sector sponsors, and, until recently, this was also persuasive to the FDA.
In the case of pharmacological treatment for opiate dependence, the treatment population cannot exceed 180,000 per year. Given these facts, historically orphan designation was permitted for two products substantially developed by NIDA (naltrexone, 1985; ORLAAM, 1993) as treatments for opiate dependence. ORLAAM received orphan designation because it could be used to transfer patients from methadone (and fewer than 200,000 were receiving methadone), and naltrexone received designation because fewer than 200,000 were detoxified addicts at any given time.
In the more recent (1994) designation of buprenorphine, the FDA appeared to be taking a more restrictive view via application of its more recently promulgated regulations. Although the issue was not definitively answered in the case of buprenorphine, the FDA expressed the view that orphan designation where the population in question exceeded 200,000 would be difficult unless there was a medical/biological reason why 200,000 people could not use the product. In other words, treatment capacity or the number of people seeking treatment might not suffice for orphan designation.
This did not prove to be an insurmountable burden in the case of buprenorphine because that product's sponsor could prove to the FDA that, based on historic, current, and projected expenditures, it would not recoup its investment during 7 years of exclusive marketing in the United States. Thus, a unique situation exists where the preclinical efforts are completed; NIDA is supporting clinical trials, and the sponsor has the expertise to manufacture new formulations. Buprenorphine became the first product to receive an orphan designation based on an economic rather than a population-based rationale. The sponsor selected this route because there was less certainty that the FDA would continue to allow orphan designation on the basis of the capacity of the treatment system as opposed to the actual incidence and prevalence of opiate dependence.
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. 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 innumerable disorders of humankind, all of which are mediated in the brain.
A generation of research has shown that drug addiction is a complex biomedical and behavioral disease with its roots in those parts of the brain that underlie, mediate, and allow people to have the emotions that make them human. Just as depression was found to be a brain disease that can be treated with medicine, drug addiction was found to be a brain disease that can and should be treated with medicine.
A critical distinction exists between drug abuse and drug addiction. Drug abuse is a voluntary behavior; the casual user makes a free and conscious decision to break the law and use an illicit, mind-altering substance. Drug addiction is a disease of the brain, resulting from repeated and prolonged self-administration of such a substance. Addiction is brought on by drug-taking behavior in much the same sense that lung cancer is brought on by cigarette smoking and heart disease is brought on by excessive fat intake. Once the disease is established, however, be it in the brain, lung, or heart, the physiological dysfunction must be corrected to restore health.
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. Although the mechanisms of many CNS 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. Thus, the potential to develop new treatments is enormous. For example, having cloned the dopamine (DA) transporter mechanism where cocaine exerts its action, NIDA scientists are now designing molecules that will block cocaine's effects at this site without disrupting essential neurotransmitter functions of DA.
Additionally, NIDA and other scientists have developed pharmacological agents for the treatment of opiate dependence in various functional categories. For example, methadone and LAAM are µ-agonist medications currently approved for opiate treatment. Naltrexone is an opiate antagonist approved for treatment, and naloxone is approved for use in the treatment of opiate overdose. NIDA is working on a partial µ-agonist (buprenorphine) that will further contribute to the arsenal of agents available for treatment.
Rare Diseases Research Initiatives
As described above, NIDA considers medications for the treatment of dependence on controlled substances to be de facto orphans. Development of medications for the treatment of these conditions may thus 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 be considered part of a rare diseases research initiative until facts prove otherwise.
In 1990, the Medications Development Division (MDD) was established in NIDA. In 1999, MDD became part of the Division of Treatment Research and Development (DTR&D). The functions of MDD within the new division remain the same; namely, DTR&D conducts studies necessary to identify, develop, and obtain FDA marketing approval for new medications for treatment of drug addiction and other brain and behavioral 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 abuse; collaborates with (1) the pharmaceutical and chemical industry in the United States and other nations and (2) the Federal medications development programs of other Institutes and entities; and works closely with the FDA to ensure that research designed to show the clinical efficacy of new compounds is evaluated and approved expeditiously.
The division operates within the larger context of a NIDA-wide medications development program that incorporates basic research discoveries from other divisions (intramural and extramural) in the quest to develop new pharmacological treatments. Application of research results from the intramural and extramural community enables the division to have access to the latest theoretical bases and an opportunity to test new hypotheses in controlled clinical settings.
Recognizing that physicians will soon have a choice of five different FDA-approved products for treating opiate addiction (i.e., methadone, ORLAAM, buprenorphine, buprenorphine/naloxone, and naltrexone) and no FDA-approved products for treating addictions to stimulants (e.g., cocaine or methamphetamine), NIDA's efforts are shifting toward a greater emphasis on discovery and development of medications for treating stimulant dependence. Whereas initial clinical trials have focused on medications that are already marketed for other indications, substantial efforts are being devoted to the discovery and development of novel compounds that may specifically address the problem of stimulant dependence. Note that within the pharmaceutical industry, approximately $75 million are devoted to biological screening and pharmacological testing for each successful new medication that reaches the market. NIDA is willing to make such an investment in medications discovery and is working to establish collaborations with pharmaceutical companies that will allow NIDA to screen chemical libraries at biochemical targets (e.g., dopamine D1 receptors) implicated as potential sites of action for effective medications. 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.
Opiate Addiction Treatment
A 16-week, 735-patient, 12-center trial of buprenorphine, an opiate partial agonist medication for the treatment of heroin dependence, has been completed. Data from this study and other previous and ongoing studies have been analyzed. These data demonstrate the effectiveness of buprenorphine in reducing illicit opiate abuse and in retaining patients in treatment (Ling et al., Addiction, 1998).
A combination dosage of buprenorphine plus naloxone, which would be useful as a potential nonnarcotic or "take-home" treatment medication is under development. Testing is under way to determine the abuse potential of buprenorphine-naloxone. Tablet forms of buprenorphine and buprenorphine-naloxone are also under development, and commercial sponsorship for these products has been negotiated. A 12-site, 52-week trial of the tablet products was completed in September 1998. An NDA for buprenorphine was submitted in 1997. The NDA for buprenorphine-naloxone was submitted and reviewed in 1999. The FDA has deemed both submissions approvable and hopes for actual approval in fall 2000.
Naltrexone, a marketed long-acting, orally effective opioid antagonist, was approved in 1985 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-dependent individuals.
One of the major obstacles to the success of naltrexone has been patient compliance with therapy. Naltrexone must be taken three times per week and has no action 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-dependent patients.
During 1999, via a Small Business Innovative Research (SBIR) contract, NIDA completed 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 2 to 3 ng/ml (which will be relatively constant over this period). The product blocked challenges in primates, and a similar preparation blocked some of the effects of morphine challenges in humans.
The preparation prepared under the SBIR contract will be tested first in an inpatient clinical study to assess its ability to block specific responses to heroin challenges between 12 and 25 mg. Based on the results of this study, an outpatient double-blind study was designed to test the product. The outpatient study began in the spring of 1999. Additionally, a small positron emission tomography (PET) study to assess the receptor occupancy of naltrexone during a challenge protocol is planned.
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.
A revolutionary advance in understanding one of the basic neurochemical mechanisms underlying opiate addiction has resulted from recent animal investigations of the role of N-methyl-d-asparate (NMDA) receptor antagonists in opiate addiction. Drugs that antagonize the NMDA receptor complex are capable of inhibiting opiate withdrawal and tolerance and, in some cases, of reversing tolerance.
First, NIDA plans to assess the toxicity of NMDA receptor antagonists and to evaluate their effects on conditioned cues and drug abuse. It is hypothesized that this class of drugs has a unique pharmacological effect in decreasing the conditioned cues that appear to perpetuate opiate-seeking behavior. Furthermore, these compounds should not have the abuse liability associated with other opiate treatments, such as methadone and buprenorphine.
NIDA and Algos Pharmaceutical Company are conducting clinical research under a Cooperative Research and Development Agreement to test whether an NMDA antagonist (dextromethorphan) can reverse opiate tolerance. The reversal of opiate tolerance is an important concept that could lead to lowering the doses needed for opiate medications currently used to treat pain and opiate addiction. These trials are in the clinical pharmacology stage, testing the dosing levels of dextromethorphan in methadone-maintained subjects.
Medication Systems for Neonatal Treatment
NIDA has expressed an interest in the development of medications and formulations to treat withdrawal symptoms in babies born to opiate-dependent mothers. Although many scientists are interested in novel drug-delivery systems, few have considered the treatment of neonates. NIDA plans to focus on narcotic skin patches for the treatment of neonates born to addicted mothers.
Infants born to mothers who abuse opiates or are on methadone maintenance can go through withdrawal periods lasting for 3 weeks or more . Currently, no FDA-approved medications exist for the treatment of these neonates, although paregoric (opium solution) has been used.
A transdermal delivery system (patches) for opiate agonists, such as fentanyl or buprenorphine, offers advantages over oral or injectable dosage forms because of its convenience for use in neonates. This technology is available, is in use, and could be readily adapted for use in neonates undergoing withdrawal. Clinical trials will require careful planning, and both FDA approval and regulations concerning use in treatment may present unique problems not anticipated by the Narcotic Addict Treatment Act.
Opioid Peptides as Medications
Three major types of opioid receptors are found in the brain: µ, , and . Morphine, heroin, methadone, and LAAM bind to the µ-receptor with high affinity. The naturally occurring ligand for the -opioid receptor is dynorphin A.
Animal studies indicate that dynorphin A alleviates opiate withdrawal and decreases tolerance to chronically administered µ-opioid receptor agonists (e.g., morphine). Indeed, -opioid abnormalities in the CNS may underlie the drug-seeking behavior of heroin addicts. The effects of dynorphin on opiate withdrawal in optiate-dependent subjects are being investigated by NIDA-funded scientists.
Cocaine Addiction Treatment
Compounds in Advanced Clinical Testing
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. The development of anticocaine medications has proven to be a daunting task; to date, only one potential medication has been identified that justifies a phase III trial. A retrospective analysis of a phase II trial of selegiline in cocaine addicts indicated a differential outcome in favor of selegiline versus placebo. However, this finding needs to be replicated in a larger and more statistically powerful clinical trial. NIDA's DTR&D will conduct a phase III multicenter trial of selegiline beginning in fall 2000.
Additionally, a conflicting body of evidence was generated by NIDA grantees concerning the potential use of amantadine and disulfiram in the treatment of cocaine dependence. Whereas several studies were negative, two studies involving coupling psychotherapy and pharmacotherapy have shown a positive effect. DTR&D will review these findings and followup with more definitive studies, if warranted.
Cooperative Research and Development Agreement with NeuroSearch, AG
In late 1997, NIDA entered a Cooperative Research and Development Agreement with NeuroSearch, AG, a small Danish company, to perform research on NeuroSearch's proprietary compound NS2359, which is targeted exclusively as a potential treatment for cocaine dependence. As part of this agreement, NeuroSearch has conducted the first human safety trials on this product. Assuming that analysis of the data generated from this trial is supportive of its safety, NIDA will undertake the necessary safety and efficacy trials required by the FDA to further development of this compound.
Major neurochemical effects of cocaine include release of DA, serotonin, and norepinephrine via a transporter-mediated exchange mechanism. Considerable evidence shows that the initiation and continuation of cocaine use is associated with the effects of the drug on the dopaminergic, serotonergic, and noradrenergic modulation of 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 seeking a DA-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 12909 has been postulated to act by binding only to precise sites on the DA 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 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 will be correlated with the safety data to determine an optimal oral dose of GBR 12909. The current study has completed all four dosage levels. Unexpected adverse events included insomnia, increased libido, and disinhibition of aggressive feelings. The data are being analyzed.
Activation of the dopaminergic reward system in the brain appears to be the principal neurochemical mechanism involved in addiction to stimulants such as cocaine and amphetamine. Chronic abuse of these drugs results in DA deficiency in the brain, which has been hypothesized to lead to craving for stimulants, depression, anhedonia, and dysphoria.
Several clinical reports, such as that reported for amantadine, suggest that DA agonists may decrease cocaine use. NIDA proposes to clinically test several approved medications that would increase dopaminergic tone in the brain and to study novel compounds. Examples of these agents are (1) direct DA agonists and partial agonists, (2) DA precursors, (3) reversible monoamine oxidase inhibitors, and (4) drugs that inhibit DA, serotonin, and norepinephrine neuronal reuptake (mimicking cocaine but with a slower onset of action and, presumably, less addictive).
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, whereas the D3 system may provide a cocaine substitute of lesser dependence potential. Compounds that affect both systems are under study.
Recent studies have shown that -opioid compounds exhibit effects opposite to that of cocaine in terms of DA release and neuron firing patterns. In animal studies, -opioids block drug discrimination and self-administration of cocaine and prevent context-independent sensitization to cocaine. NIDA and NIDA grantees are testing compounds of this class in clinical studies.
Studies have shown that cocaine causes the release of stress hormones known as glucocorticoids in both rats and humans. Evidence from rat studies suggests that glucocorticoid antagonists and corticotropin-releasing factor (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. DTR&D is pursuing CRF antagonist projects with a pharmaceutical company supplier.
Researchers funded by DTR&D 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 were published ("Suppression of Psychoactive Effects of Cocaine by Active Immunization," Nature (Lond), 1995).
Kim Janda, Rocio Carrera, George Koob, and colleagues at The Scripps Research Institute demonstrated a greater than 70% reduction in cocaine uptake in the brains of rats inoculated with the antibody-producing compound compared with 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, 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 specific for the cocaine molecule. Rats were inoculated over a 35-day period and then their responses to cocaine were tested. 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 lower than those in 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 dependence. The research reported in Nature differs by inducing the production of antibodies that remain in the bloodstream for an extended period and block cocaine's effects after it is used.
ImmuLogic Pharmaceutical Corporation (Waltham, MA), a biotechnology company, also recently announced having developed a cocaine vaccine. Barbara S. Fox of ImmuLogic discussed some of the company's findings in Chemistry and Engineering News (1995) and at a January 18, 1996, meeting of the Maryland Bioscience Alliance at the request of NIDA. ImmuLogic had previously received phase I SBIR funding from NIDA. In 1996, NIDA awarded $700,000 to ImmuLogic to complete preclinical development of a vaccine to treat cocaine dependence. Results of ImmuLogic's early vaccine work in animals have received attention in national and trade press, were presented at the College on Problems of Drug Dependence, and were published in Nature Medicine (1996, vol. 2, pp.1129-1132).
The vaccine links a protein to cocaine, resulting in a molecule that induces antibody formlation. Once titers reach a certain level, cocaine's ability to cross the blood-brain barrier is impeded. The award expedited completion of preclinical design and early testing of the vaccine. A phase I (dosing and tolerability) trial was successfully completed in 1999. ImmuLogic is no longer in business but sold the rights to the vaccine to Cantab, Ltd., a U.K. company specializing in vaccine development. Cantab is undertaking further phase I clinical trials with the vaccine during 2000.
Cocaine increases extracellular levels of serotonin, DA, and norepinephrine in the brain. Serotonin is an extremely versatile neurotransmitter that activates numerous subreceptors. Studies of two subtypes of receptors (5-HT2 and 5-HT3) suggest that these structures may be involved, directly and indirectly through an effect on DA, in the rewarding and, possibly, the mood-elevating effects of cocaine. Antagonists of these receptors, which decrease DA release, may reduce cocaine craving and use. Therefore, NIDA plans to test serotonin antagonists as potential medications for cocaine addiction.
Serotonin Reuptake Inhibitors
A major symptom of cocaine addiction is anhedonia, which is clinically similar to depression. In addition, it has been postulated that cocaine addiction is a form of self-medication for chronic depression. Initial results of studies of the potent serotonin reuptake blocker fluoxetine (an antidepressant) have yielded mixed results in regard to being efficacious in facilitating abstinence from cocaine use. Evaluation of serotonin reuptake inhibitors as potential medications will continue. One such compound, the currently marketed antidepressant Venlafaxine (a serotonin and noreprinephrine uptake inhibitor), is being studied by two NIDA grantees.
Nootropic Drugs and Cocaine Dependence
Abuse of stimulants, such as cocaine and amphetamines, is associated with some degree of neurological damage, resulting in cognitive impairments, brain perfusion deficits, strokes, intracranial hemorrhages, and development of early symptoms of movement disorders. NIDA-sponsored studies are under way to test several nootropic medications as potential treatments for cocaine-induced neurological deficits.
Cocaine "Receptor" Imaging Studies
In addition to the categories of compounds described above, new and potentially useful technology is being investigated for its value in 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 DA transporter. NIDA intramural researchers have identified three generations of such compounds, with each succeeding generation being more selective and potent. RTI-55, the first potent compound, was an effective in vivo labeling agent in animal studies and was subsequently examined in human imaging studies by single-photon emission computerized tomography (SPECT). A second compound, RTI-121, was found to be more selective for the DA transporter but had a higher apparent lipid solubility and exhibited lower specific to nonspecific binding in vivo. NIDA researchers are testing new compounds and using 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. DA transporter imaging studies of cocaine abusers have been completed (see section on GBR 12909). This technology may enable estimation of 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.
Methamphetamine Treatment Discovery Efforts and Program Activities
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 has been reappearing in some regions of the United States and is widespread in western U.S. cities such as Los Angeles and San Francisco, CA; Denver, CO; and Phoenix, AZ. According to the National Household Survey on Drug Abuse, in 1994, an estimated 3.8 million people had tried methamphetamine; by 1998, the total had increased to 4.7 million. The epidemic is spreading to rural areas, and more than 11,000 acute hospital admissions were related to amphetamine toxicity nationwide in 1998.
No accepted treatment medications exist for methamphetamine addiction or abuse. As a result, NIDA has developed a Medication Discovery Program for methamphetamine and is funding several extramural and intramural studies to develop such medications.
Preclinical Methamphetamine Program
Methamphetamine abuse has become a substantial drug problem in certain parts of the American Southwest, and data suggest that its use is increasing and spreading to other parts of the United States. Methamphetamine is a powerful stimulant that shares some characteristics with cocaine but differs from cocaine in others. A Methamphetamine Think Tank meeting was held on January 10, 2000, to gather a group of consultants to consider the direction of a methamphetamine treatment development program. Based on recommendations of these consultants, several types of methamphetamine-specific screening assays are being developed to evaluate and characterize compounds for their potential usefulness in the treatment of methamphetamine dependence. Some of the assays are similar to those used in the Cocaine Treatment Discovery Program, and substantial overlap will occur between the programs. Existing contract protocols will be used to test compounds for their interactions with DA transporters, but additional assays will be used to measure DA release in vitro, which is an effect of methamphetamine not shared by cocaine. In addition, behavioral assays are being set up to assess a compound's ability to block the locomotor stimulant effects of methamphetamine, block the discriminative stimulus effects of methamphetamine, and determine effects on methamphetamine self-administration. Also, assays to measure effects of potential treatment compounds on the cardiovascular system, both alone and in combination with methamphetamine, are being developed. Finally, methods for assessing the neurotoxic effects of methamphetamine are under development, and these assays may be useful in assessing potential treatment medications.
Clinical Methamphetamine Program
Since January 2000, NIDA has been working on choosing sites for a new methamphetamine clinical trials network and has identified four sites (Des Moines, IA; Los Angeles and San Diego, CA; and Honolulu, HI) with a high concentration of methamphetamine users. Plans are under way to visit these sites and begin developing a protocol for bupropion as the first medication trial for this network. NIDA hopes to start a multisite bupropion study by July/August 2000. Four clinical pharmacology studies are also being developed in Los Angeles and San Francisco to study safety interactions of methamphetamine and selegiline as a potential treatment. These studies are planned for May/June 2000.
Michael Owens, University of Arkansas for Medical Sciences in Little Rock, is receiving NIDA funding to develop a new generation of monoclonal antibody-based medications for treating drug abuse-Immunotherapy for Drug Abuse (R01-DA-07610) and Antibody-Based Therapy for Methamphetamine Abuse (R01-DA-11560). This research is focused on treatments for methamphetamine, ecstasy (MDMA), and phencyclidine (PCP) abuse, which function as pharmacokinetic antagonists and are designed to reverse the effects of drug overdose and 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.
If successful in humans, these treatments will not only provide a rapid reversal of drug effects in an emergency room setting but will also reduce or prevent the long-term medical problems associated with stimulant drugs of abuse (i.e., neurotoxicity and addiction). Owens' studies on treating PCP effects are the most advanced and are the model system for development of antibody-based therapies for other classes of drugs and toxins. To this end, Owens has successfully developed an anti-PCP monoclonal antibody that rapidly (in minutes) removes PCP from the CNS of rodents. Owens' group is currently focused on completing the preclinical animal studies necessary for filing an IND application and on refining previously developed scale-up methodology for the production of the monoclonal antibody fragments. In other studies, Owens has shown that a single administration of an anti-PCP monoclonal IgG antibody can significantly reduce PCP's behavioral effects and CNS concentrations for at least 2 weeks, even when PCP is repeatedly administered in large doses to the animals over the entire 2-week period. This is important because a 2-week period in animals is equivalent to 1 or 2 months of protection in humans. His preliminary studies of antibody-based treatments for methamphetamine are showing the same type of long-term neuroprotective effects.
In collaboration with Brooks Gentry, a clinician/scientist at the University of Arkansas (Mechanisms of Onset and Offset of Rapid Stimulant Effects; K08-DA-00339), Owens is studying the fundamental medical consequences of rapid input of drugs of abuse into the CNS. These experimental data from animal models of human drug abuse will help clarify why drug abusers usually prefer rapid routes of drug administration (intravenous and smoking) over slower modes of administration (oral). Finally, these pharmacokinetic and pharmacodynamic studies are being used to help develop of novel therapeutic approaches to the treatment of stimulant drugs of abuse.
Last Reviewed: January 27, 2005