II. NIDA's Current Methamphetamine Treatment Development Efforts

Overview

NIDA recognizes the multi-faceted problems posed by methamphetamine abuse and addiction and has increased its research efforts accordingly, but much remains to be accomplished.

Research has confirmed that addiction is a treatable, though chronic and relapsing, disease of the brain. NIDA research shows that comprehensive treatments that focus on the whole individual, and not just on drug abuse, have the highest success rates. These programs typically include a combination of behavioral treatments, medications (if available), and other services (e.g., job training and referral to medical, psychological, and social services) that are tailored to the needs of the individual patient. Science-based treatments benefit not only the patient, but can also be cost effective for society, by saving money that would have been spent on the public health and safety consequences of drug abuse and addiction.

Methamphetamine Addiction Treatment Think Tank

In early 2000, NIDA's Division of Treatment Research and Development (DTR&D), now known as NIDA's Division of Pharmacotherapies and Medical Consequences of Drug Abuse (DPMCDA), convened a Methamphetamine Addiction Treatment Think Tank that brought together preclinical and clinical experts to provide NIDA with expert guidance on the establishment and research focus of NIDA's program for the development of medications for treating methamphetamine addiction and related problems. This panel of experts made several recommendations that NIDA is using to guide research on treatments for methamphetamine addiction.

Recommendation 1: The establishment of a Methamphetamine Clinical Trials Group (MCTG) that would conduct clinical trials of medications for methamphetamine.

NIDA Action: Sites in which methamphetamine abuse is prevalent were selected to conduct clinical pharmacology and outpatient studies of medications proposed to treat different aspects of methamphetamine abuse.

Recommendation 2: The primary focus of NIDA's program should be on the development of medications for treating methamphetamine addiction.

NIDA Action: This is the major focus of the MCTG described above. More details on medications development for methamphetamine addiction are discussed below.

Recommendation 3: NIDA should consider focusing on treatments for methamphetamine overdose.

NIDA Action: At present there are no specific pharmacological treatments available for treating methamphetamine overdose. NIDA is currently funding projects for the development of monoclonal antibody-based medications for treating methamphetamine overdose. These medications bind to the drug in the bloodstream thereby preventing its action to provide a rapid reversal of drug effects in an emergency room setting.

Recommendation 4: Several additional areas of research are needed; including treatments for other problems caused by methamphetamine abuse, such as possible neurodegeneration, cognitive impairment, and psychoses.

A first step in treating drug addiction is the treatment of the addiction itself. But many abused drugs can cause a multitude of other problems related to their profound effects in the brain. The panel of experts emphasized that the treatment of these other problems is necessary if a person is to recover and return to a normal and productive life. Thus, the panel agreed that medications development efforts should be broadened. For example, medications to improve cognitive skills or reverse the impairments produced by methamphetamine could facilitate treatment success, while at the same time allowing a recovering addict to function normally in work and home settings. Likewise, medications that address the resultant psychosis should also dramatically improve the success rate of treatment of methamphetamine addiction.

NIDA Action: Establish the Methamphetamine Treatment Discovery Program.

Methamphetamine Treatment Discovery Program (MTDP)

Continuing to capitalize on the input of its experts, NIDA's DPMCDA Medications Discovery and Toxicology Branch established the MTDP. Its mission is to identify, evaluate, and recommend potential treatments for the medical management of methamphetamine addiction and its effects using a preclinical (animal/cellular) approach. The program focuses on discovering medications to reduce or eliminate drug-seeking behaviors. In addition, the MTDP is developing the capability to evaluate, in animals, medications to reverse methamphetamine neurotoxicity and cognitive impairment.

The MTDP solicits and tests compounds submitted to the program by scientists funded through NIDA grants and contracts, by domestic and foreign pharmaceutical companies and by MTDP team members. The tests are conducted under blinded conditions; that is, the testers do not know the identity of the compound they are testing. In this manner, proprietary information is protected and potential experimental bias is eliminated.

The MTDP uses a number of approaches to choose specific compounds or classes of compounds to test. A "bottom-up" approach focuses on compounds with a compelling rationale based on findings in animals. A "top-down" approach identifies and tests approved therapeutic drugs already available to clinicians for treating indications other than drug abuse (e.g., anxiety, depression, or Parkinson's disease) for their potential as methamphetamine abuse therapeutics. In addition, since methamphetamine shares some of the same properties as cocaine, the MTDP is also testing compounds with preliminary data that suggest usefulness in treating cocaine addiction.

Once potential compounds are identified, they are first screened using a series of tests performed using tissues and cells. Next, they are tested in experimental animal models. As test results are returned to the MTDP, the members of the MTDP team analyze the data and, based on the test results, determine which compounds look most promising for further evaluation. Promising compounds can undergo further laboratory tests and computer modeling studies designed to predict whether they will be safe in humans. These tests search for side effects, determine if the drugs are toxic or carcinogenic, and evaluate whether there are interactions with other drugs (including drugs of abuse). In addition, duration of therapeutic effects and how long the compound remains in the body are determined.

After these tests, if a compound still looks promising, all the data are consolidated and presented to an independent group of outside consultants from the pharmaceutical industry and academia for review. This expert group is tasked with recommending whether a compound should be advanced to clinical trials in humans or if additional animal tests are required.

Animal Models Relevant to Medications Development

Animal models of drug abuse and addiction as well as models for the different consequences of drug abuse, including overdose, neurotoxicity and damage to the developing fetus of pregnant drug abusers, can be useful tools for understanding mechanisms of drug action. They not only provide valuable information on the specific sites in the brain where drugs act and the changes in neuronal function that they cause, but they provide a means of developing medications that target specific brain changes caused by drug abuse and testing possible pharmacotherapies for safety and efficacy before these therapies are tested in humans.

For example, animals can be trained to self-administer a drug, that is, they learn to press a lever to receive a dose of a particular drug. Because these drugs activate reward centers of the brain, these animals will continue to press the lever to obtain more of the drug. Potential pharmacotherapies can be tested to see if they interfere with this behavior. For example, the compound baclofen, which acts on the GABA neurotransmitter system of the brain, which is known to modulate dopamine neurotransmission, has been shown to decrease both methamphetamine and amphetamine self-administration in rats. This compound, as well as others initially tested using this model (e.g., lobeline) are now being tested in clinical trials (as discussed below).

Once an animal has been trained to self-administer a drug, this behavior can also be diminished by not providing the drug in response to the lever press. However, similar to what has been observed in human addicts, rats will resume lever pressing when re-exposed to the drug or after encountering a stressful event. Potential therapies can be tested in these models to see if they can prevent such reinstatement or relapse. For example, medications which block activity at a specific brain receptor (known as alpha-2 adrenoceptor) have been shown to induce relapse in an animal model of reinstatement, similar to when these animals are exposed to a stressful stimulus. For this reason, medications that may act to enhance activity at this receptor may prevent reinstatement due to stress. Clonidine is an already approved medication that acts at this site, and is currently being tested in clinical trials (as discussed below).

Another characteristic of repeated exposure to stimulants, which can be studied using animal models, is "sensitization", that is when some of the drug effects actually increase over time. For example, repeated administration of methamphetamine in rodents leads to an enhanced locomotor response (running or circling), which gradually can become stereotypic (repetitive and fixed) in nature depending upon the drug dosage, number of drug exposures, and individual vulnerability factors. It is thought that the sensitization model may be related to a number of characteristics of addiction in humans, including the intensification of craving that accompanies drug addiction, especially when one is presented with cues or reminders of their previous drug experiences; and the development of psychotic behaviors, including paranoid thinking, hallucinations and delusions. The neural circuitry underlying this behavior has been elucidated and important roles for the neurotransmitters glutamate and dopamine, among others, have been revealed. This information is being used in the development of novel approaches to counter some of the various aspects of addiction. For example, the medication valproate used to treat epilepsy has been shown to prevent behavioral sensitization when co-administered with methamphetamine and to affect the expression of sensitization when administered after its development. Similar medications such as topiramate are currently being tested in clinical trials (as discussed below).

Animal models are also currently being used to identify possible treatment approaches for repairing the damage to the brain following methamphetamine abuse. For example, these animal models are being used to assess the influence of neurotrophic factors, chemicals that are involved in cell survival and growth, which may someday be useful in reversing methamphetamine's harmful effects on the brain and the associated functional deficits (such as cognitive and motor deficits). In one study, nonhuman primates were injected with a substance known as glial cell-line derived neurotrophic factor (GDNF) in brain areas that are susceptible to the damaging

effects of methamphetamine. In this study, monkeys who were given GDNF showed less neurotoxicity from methamphetamine than animals that did not receive GDNF. These results suggest that GDNF might be useful for mitigating some of the harmful effects of methamphetamine.

Animal models are providing valuable information that can be used to understand all aspects of methamphetamine abuse and addiction, which in turn forms a foundation for the development of pharmacotherapies that can treat addiction to methamphetamine as well as the harmful consequences of its use.

In addition to NIDA's preclinical efforts and following recommendations from the Methamphetamine Treatment Think Tank, NIDA established the MCTG to conduct clinical (human) trials of medications for methamphetamine addiction. This group is capable of conducting both phase I (safety) and phase II (efficacy) clinical studies. It has sites in geographic areas in which methamphetamine abuse is particularly high: San Diego, Kansas City, Des Moines, Costa Mesa, San Antonio, Los Angeles, and Honolulu.

• Bupropion -- an antidepressant that inhibits the uptake of the neurotransmitter dopamine in the brain. This property may make bupropion useful for treating methamphetamine addiction as well as the depression that is exhibited by many drug abusers.
• Sertraline -- an antidepressant that blocks uptake of the neurotransmitter serotonin, which is also affected by methamphetamine. This property may make sertraline potentially useful for treating methamphetamine addiction as well as the depression that is exhibited by many drug abusers.
• Lobeline -- a compound that affects the dopamine and nicotine systems in brain neurons and reduces methamphetamine self-administration in rats.
• Aripiprazole -- a medication recently approved by the Food and Drug Administration (FDA) for treating schizophrenia, which acts on dopamine receptors and may help reducing the stimulant effects of methamphetamine as well as being useful for relapse prevention. Aripiprazole has also been shown to improve cognition in patients with schizophrenia, suggesting another potential benefit of the drug.
• Carvediol, Clonidine, Atomoxetine, and Prazosin -- medications that affect the neurotransmitters epinephrine and norepinephrine, which also have a role in the euphoric, motor activating, and rewarding effects of stimulants. These medications are already approved for clinical use, have generally well-understood mechanisms or action, are safe, and have been the subject of animal or clinical studies that suggest their potential for use in treating addiction to amphetamine/methamphetamine.
• Modafinil -- a novel non-amphetamine stimulant medication approved by the FDA for treating narcolepsy and currently under study for treating attention deficit hyperactivity disorder (ADHD), cognitive deficits in Alzheimer's disease and negative symptoms in schizophrenia. Modafinil is being considered for treating methamphetamine addiction and its consequences because: 1) its actions as a stimulant may decrease craving and methamphetamine seeking; 2) it has low abuse potential and does not seem to produce addiction; 3) it may improve concentration, daytime alertness and cognitive functions; 4) it may have antidepressant properties; and 5) the effects of modafinil are long-lasting and persist for as long as 4 months after treatment.
• Perindopril -- a medication currently used to treat hypertension. In animals, perindopril has been shown to increase dopamine levels in the brain and reduce neurotoxicity to the dopamine system. NIDA is conducting a human laboratory study to determine whether oral perindopril can be safely administered to patients taking methamphetamine to prepare for an outpatient-based clinical trial that would assess the ability of perindopril to prevent relapse to drug use in treatment- seeking methamphetamine addicted individuals.
• Rivastigmine -- a medication approved by the FDA to treat Alzheimer's dementia due to its cognitive enhancing properties. Amphetamine and methamphetamine addiction have been associated with neurocognitive deficits, both immediately after withdrawal and after long-term abstinence. A medication that is effective at reducing these neurocognitive deficits may assist individuals in recovery to obtain more benefit from counseling strategies and facilitate behavioral change.
• Topiramate -- a medication that acts on the neurotransmitter systems GABA and glutamate and is currently used to treat epilepsy. It has been hypothesized that topiramate will be associated with decreased dopamine release via its actions on the GABA and glutamate systems.
• Baclofen -- a compound that reduces the release of a variety of neurotransmitters in the central nervous system through its actions on the GABA neurotransmitter system and has been shown to decrease self-administration of cocaine and methamphetamine in animals.

Medications Development Working Group

In May 2004, the Director of NIDA convened a Medications Development Program (MDP) Subcommittee, composed of members from the National Advisory Council on Drug Abuse and distinguished leaders from the drug abuse and addiction field. The Subcommittee's objectives were to comprehensively review NIDA's current medications development programs and provide recommendations for ongoing and future research objectives on pharmacotherapies for treating drugs of addiction. As a result of this review, an external Medications Development Work Group was established to define and review decisions regarding the identification, advancement and discontinuation of addiction treatment compounds under development, including those to treat methamphetamine abuse. This Work Group met for the first time in March 2005 and plans to meet biannually to review NIDA's ongoing and proposed medications development efforts.

Clinical Behavioral Therapies Program

Research has clearly shown that behavioral therapies are an integral part of effective treatment programs. Consequently, and following the advice of the Methamphetamine Treatment Think Tank, NIDA is also conducting research on behavioral therapies that might be effective for treating methamphetamine addiction.

Studies have now shown that a program known as the Matrix Model can be used successfully for the treatment of methamphetamine addiction. The Matrix Model was developed in the 1980s for treating cocaine addiction. It consists of a 16-week program that includes group and individual therapy and components that address relapse prevention, behavioral changes needed to remain off drugs, communication among family members, establishment of new environments unrelated to drugs, and other relevant topics. When applied to methamphetamine abusers, the Matrix Model has been found to be an effective treatment approach.

Another promising behavioral therapy, Motivational Incentives for Enhanced Drug Abuse Recovery (MIEDAR), is a cost-effective, incentive method for cocaine and methamphetamine abstinence. A recent study showed that the incentive condition had approximately twice as many participants with at least 8 weeks of documented sustained abstinence compared to treatment as usual.

Because no single behavioral treatment will be effective for everyone, research into behavioral approaches for treating methamphetamine addiction is ongoing. It is expected that, as with other types of addiction, combining pharmacotherapies with behavioral therapies will be the most effective way to treat methamphetamine addiction.

Other Research Gaps to be Addressed

Although research has provided considerable insight into the mechanisms by which methamphetamine exerts its effects, gaps continue to exist in the scientific knowledge about the basic pharmacology, toxicity, and treatment of methamphetamine abuse. Some of these knowledge gaps include:

Identification of biomarkers. NIDA will also be conducting research aimed at identifying biomarkers or indicators that can be used to predict how individuals will respond to medications and behavioral therapies. These can include physiological, genetic, or hormonal markers as well as those that can be detected using neuroimaging techniques. This knowledge should increase dramatically the success rate of treatment for methamphetamine and other addictions.

Relapse prevention. Two of the major causes of relapse to drug abuse are craving and exposure to stressful situations. NIDA will be conducting human laboratory studies to screen medications that are effective in suppressing craving. These studies will target systems known to be involved in drug craving (glutamate and a specific brain dopamine receptor). Similarly, stress reduction using a combination of behavioral and pharmacological approaches, will be studied as an approach for preventing relapse. Novel medications are in development that act on brain chemicals involved in the stress response.

Cognitive impairment. Research has clearly established that methamphetamine causes impairments in certain cognitive functions, such as memory. An important area of research that NIDA will continue to pursue is the development of medications that can improve cognitive functions that have been altered by methamphetamine. These medications should not only improve treatment outcomes but also facilitate the return of methamphetamine abusers as functional members of society.

Associated psychoses. Finally, NIDA plans to conduct research to better characterize antipsychotic medications that may be useful for treating symptoms often found in methamphetamine abusers. This research will involve studies of the natural history of methamphetamine abuse and associated psychoses and the neurobiology and pharmacology of psychosis in methamphetamine patients.