Treatment for MA users has far-reaching health ramifications, both in terms of reducing the consequences of abusing this potent psychostimulant and in potentially reducing MA-driven behaviors that spread disease such as HIV. As a result, the development of effective treatments for MA dependence has become a pressing concern for the national and global drug abuse treatment community. The development of pharmacotherapies for the treatment of MA-related disorders is viewed as a critically important element in broadening the range of treatment options and improving therapeutic outcomes. The development of such pharmacotherapies is at an early stage.
Two approaches have been taken to achieve this goal: (1) evaluate medications that have been tested and demonstrated potential for cocaine addiction in small size, proof-of-concept trials; and (2) employ the industry model of medications development, with the goal of obtaining regulatory approval. The second strategy employs three major concepts: (1) rational targets; (2) preclinical animal models; and (3) systematic phase I–VI clinical trials.
In addition to the medications listed in , other medications currently being studied for treatment of MA dependence are bupropion, gabapentin, mirtazapine, atomoxetine, carvedilol, clonidine, peridopril, prazosin, rivastigmine, and topiramate.
Summary of Data on Published Medication Trials for Methamphetamine Dependence
NIDA’s pharmacotherapy division is leading the field in using the industry medication development model, with the main goal of seeking FDA approval. Starting with preclinical studies, several approaches that decrease appetitive drives for other drugs of abuse are applicable to MA. Thus, modulation of conditioned cues, priming, and stress-induced reinstatement appear to be rational approaches to the discovery and evaluation of medications for the treatment of MA dependence. Putative medications that affect one or more of these mechanisms could be tested.
New molecular entities and targets that fit the above profiles include CRF-1, dopamine D3, cannabinoid CB1 antagonists, and glutamate site modulators, which all show promising preclinical animal data.
The role of corticotropin-releasing factor (CRF) in drug addiction and the rationale for development of CRF-1 receptor antagonists as treatments for drug dependence have been extensively reviewed (34
). Interestingly, in rat models of stress-induced relapse or reinstatement of drug use, CRF-1 antagonists have been shown to block footshock-induced reinstatement of responding for cocaine (37
), heroin (38
), and alcohol (40
). These data suggest possible efficacy of CRF-1 antagonists in counteracting the widely acknowledged ability of stress to trigger relapse to multiple drugs that have addicting properties. Such efficacy in multiple drug addiction disorders would be beneficial because abuse and addiction to a single compound are less common than polydrug abuse and addiction. Multiple pharmaceutical companies have been working toward the development of CRF-1 antagonists for the treatment of depression and/or anxiety.
Dopamine D3 receptor ligands as potential treatments for drug abuse also have been the subject of several recent reviews (41
). These receptors were cloned in 1990 (45
) and have been of particular interest to drug abuse researchers, in part because they are selectively located in brain regions that are affected by drug abuse, and they are up-regulated in the brains of cocaine overdose fatalities (46
). Agonists of these receptors produce behavioral effects in rodents that do not resemble effects of stimulants (47
) but are perceived as cocaine-like by rodents and primates in that they will substitute for cocaine in self-administration paradigms (48
). The potency of compounds to activate D3 receptors is related to their ability to decrease cocaine self-administration in rats, suggesting the involvement of these receptor types in cocaine drug-taking (50
). In addition, dopamine D3 partial agonists have been shown to block the behaviorally activating effects of cues that have been paired with cocaine in rats, suggesting potential usefulness in blocking relapse following contact with environmental cues associated with drug use (51
Dopamine D3 antagonists also have been reported to block nicotine-primed reinstatement of nicotine self-administration in rats (52
) as well as cocaine-primed cocaine seeking in rats (53
). A D3 antagonist has been reported to dose-dependently block footshock-induced reinstatement of cocaine self-administration in rats (55
), overall suggesting a potential role for D3 antagonists in preventing the three triggers of relapse. A D3 antagonist has been shown to block enhancement of electrical brain stimulation reward by cocaine (56
), and D3 antagonists have been reported to block both the acquisition and expression of nicotine (57
), cocaine, and heroin (58
) conditioned place preference in rats. Taken together, results from different laboratories using different behavioral endpoints and different compounds suggest that both dopamine D3 partial agonists and D3 antagonists may be useful treatments and may be effective for polysubstance addiction.
Evidence that cannabinoid-1 (CB-1) receptor antagonists may prove useful in treating drug addiction disorders has been the subject of 2 recent reviews (59
). Particularly notable in these reviews is the ability of CB-1 receptor antagonists to modulate the pharmacology of THC, nicotine, cocaine, MA, opiates, and ethanol. These observations have generated a high level of interest in this class of compounds. Unlike compounds that block the ability of stress to trigger drug-seeking behavior in animal models of relapse, CB-1 antagonists act either by blocking the subjective/rewarding effects of drugs like THC or by blocking the ability of conditioned cues to promote reinstatement of drug-seeking behavior in animals extinguished from drug self-administration. Taken together, results suggest a role for the cannabinoid system for polysubstance addiction.
Reported interactions of virtually all drugs of abuse with glutamatergic systems in brain provide strong rationale for the pursuit of several related biochemical targets. Tzchentke and Schmidt (61
) have reviewed glutamatergic mechanisms in addiction, emphasizing a role for glutamate in stimulating dopamine systems related to reward and a dopamine-independent role for glutamate in altering the effects of conditioned stimuli on behavior. It has been proposed that the hallmark of addiction, an unmanageable motivation to take drugs, results from pathological changes in prefrontal accumbens glutamate transmission (62
There are data supporting a role for both group I and group II metabotropic glutamate receptors in addiction, which have been reviewed by Kenny and Markou (63
). A rationale for pursuing mGluR5 antagonists as addiction treatments is supported by the results of mGluR5 knockout studies (64
) and by reported effects of the mGluR5 antagonist MPEP on self-administration of cocaine, nicotine, and alcohol (65
). Additionally, a rationale for pursuing mGluR2/3 agonists is suggested by the efficacy of LY379268 in rat models of cue-induced relapse to cocaine (67
) and heroin (68
). Two other potentially promising mechanisms of glutamate modulation for addiction treatment are AMPA receptor antagonism (69
) and NAALADASE inhibition (71
Other pharmacological targets for stimulants addiction, for which a rationale is in earlier stages of development, include Orexin-A receptor antagonists (72
), Opioid receptor-like 1 agonists (74
), and muscarinic M5 receptor ligands (76
). It is anticipated that as research tools and potential medications are developed, additional data evaluating these targets will become available to guide decisions for further development.
Vigabatrin is a GABA transaminase inhibitor, which leads to a marked elevation of GABA levels. It has been shown to be very effective in animal models of cocaine and MA self-administration and in primate PET imaging studies to block dopamine release (78
). Early open-label pilot data in cocaine and MA actively using addicted patients showed promising results in facilitating abstinence (79
). Vigabatrin has been reported to cause visual field defects following prolonged use, which may or may not be an issue in its development for addiction treatment. Safety and proof-of-concept trials are planned to further clarify this issue.
The unique effect of MA on the VMAT2 makes lobeline a candidate for testing. Indeed preclinical studies showed that lobeline blocks methamphetamine self-administration (80
Methamphetamine has been shown to affect a number of cognitive processes. Attempting to get individuals with cognitive deficits to learn new cognitive skills can be time consuming and difficult. Thus, an alternate approach would be to develop medications for the treatment or normalization of cognitive processes affected by MA abuse, in order to enhance the therapeutic process. For example, amphetamine abusers have problems with extra-dimensional set shifting on neuropsychology tests. Drugs affecting the frontal cortex dopaminergic system, D-1 agonists, and 5-HT 6 antagonists can reverse this deficit. Another viable approach that involves learning could be to facilitate the extinction of conditioned cues. D-Cycloserine and other medications may facilitate this process. A third approach would be to pharmacologically modulate strategic thinking. Nootropic agents to improve cognitive functions may have such a capability. Modafinil has multiple effects on cognition, including an ability to increase strategic thinking.
Atypical antipsychotics, especially aripiprazole, may have a role in reducing craving, as has been shown for cocaine in comorbid schizophrenics, and for the treatment of MA-induced psychosis. Preliminary results from a Finnish randomized 3-arm study (n = 53) showed that methylphenidate treatment (54 mg/day) was associated with significantly decreased use of amphetamine, while aripiprazole treatment (15 mg/day) showed significantly increased use of amphetamine, when compared with placebo. This effect could be dose dependent—lower doses of aripiprazole in a relapse prevention study may not have the same effect; however, these preliminary data suggest that caution should be used in prescribing atypicals to methamphetamine- and amphetamine-dependent patients.
The increase in amphetamine use and dependence (81
) has resulted in greater demands on health services (83
), but few effective therapies have been identified and there is an urgent need for evidence-based treatments (85
). Maintenance treatment approaches have proven very effective for opioid dependence, with methadone (86
) and buprenorphine (87
) the major therapeutic agents. The model of opioid maintenance treatment has been adopted for amphetamine users in the U.K. using dexamphetamine (88
) and it has also been tried in Australia (94
Dexamphetamine acts by increasing synaptic concentrations of the monoamines dopamine, noradrenaline, and serotonin. In low oral doses it is used therapeutically in the treatment of narcolepsy and attention deficit/hyperactivity disorder (ADHD) without evidence of long-term harm (96
). Dexamphetamine also has a less pronounced central effect than MA (98
Maintenance programs using dexamphetamine have reported many positive outcomes, such as reductions in illicit amphetamine use and injecting and improvements in general health. In addition, the availability of such programs has increased the number of users presenting to services as well as increasing retention in treatment. Importantly, studies have found that the incidence of side effects, including psychotic symptoms, is low. However, the validity of most of these studies has been limited by factors such as small sample sizes, no control groups, and self-reported measures of illicit amphetamine use (99
In contrast, the present study is a randomized, double-blind, placebo-controlled trial that involves supervised daily dosing of the medication. The formulation of dexamphetamine being used is sustained-release, enabling efficient once-daily dosing. Moreover, the use of hair analysis in addition to self-report methods provides an objective and quantifiable means of assessing changes in illicit amphetamine use.