MA inhibits the reuptake of released dopamine(Drug information on dopamine); the drug is taken into the dopaminergic neurons and exerts its action intracellularly. MA causes the docking of dopamine-containing vesicles to the cell membrane, and the leakage of dopamine into the synaptic cleft increases its concentration. MA thus increases the cytoplasmic concentration of dopamine, which undergoes oxidation and produces oxidation products such as free radicals, peroxides, and hydroxyquinones, which are toxic to nerve terminals.14-16 This neurotoxicity is compounded by MA's prolonged half-life and duration (8 to 12 hours).Effects on neuronal circuits
Findings from neuroimaging studies show that in persons who use MA, changes occur in the limbic and in the frontal and prefrontal cortical areas, further implicating chronic MA use in the failure of the frontal and prefrontal cortex to inhibit the limbic areas. Imaging research involving persons who are newly abstinent from MA17,18 has documented deficits in inhibitory control mechanisms, which can affect decision making and perhaps increase inhibitory control of the frontal lobe over the limbic reward circuitry.TREATMENT
Treatment for acute intoxication does not always require medication. Instead, patients can be reassured of the imminent passage of symptoms and placed in a dark, quiet environment. When symptoms are severe, medications such as the benzodiazepines and/or a high-potency antipsychotic can be administered. Haloperidol(Drug information on haloperidol) (5 mg) administered orally or parenterally in repeated doses can be used, often in combination with 1 to 2 mg of lorazepam(Drug information on lorazepam) and 1 mg of the antidyski- netic benztropine. Droperidol(Drug information on droperidol) has been shown to achieve more rapid and better sedation scores than lorazepam, requiring fewer repeated doses.19Withdrawal
Withdrawal symptoms within 2 weeks after a person's last MA use includes unique psychiatric and physical symptoms (eg, anhedonia is a key symptom of acute withdrawal20). To help patients combat these symptoms, rest, exercise, and a healthy diet may be appropriate.21 No medications are available yet to address severe craving and the attendant risk of relapse.Psychosis
Strategies used for the treatment of acute intoxication are also applicable to treatment of acute MA-induced psychosis. In US patients, psychosis is generally reported to be transient.
The appropriate duration of antipsychotic medication administration for the treatment of acute psychosis remains an issue. Administering low-dose antipsychotics between psychotic episodes may have some merit, but this is still open to question.22
Because the numbers of young users and the appearance of psychosis from MA use in adolescents are increasing (greater than 500% increase from 1993 to 200223), it is important to note that exposure to antipsychotics may have consequences in the maturing brain. Empiric support for the use of antipsychotics for the treatment of acute or chronic MA- induced psychosis is lacking.Behavioral treatment
Several behavioral therapies have been evaluated for the treatment of persons who are dependent on MA in multisite controlled randomized clinical trials and have shown evidence of efficacy.
The Matrix Model is a manualized behavioral therapy for MA dependence that proved effective in a large randomized clinical trial.24 The Matrix Model is a synthetic treatment approach that incorporates principles of social learning, cognitive-behavioral therapy (CBT), family education, motivational interviewing, and behavioral therapy. The Matrix Model has been modified and used to evaluate subgroups of MA abusers (gay and bisexual men)10 and was used as the behavioral treatment platform in pharmacotherapy trials for MA dependence.25
Contingency management (CM) entails the provision of reinforcements/ rewards for desired behaviors/performance (eg, drug-free urine test). Roll and associates26 recently conducted a multisite clinical trial in which a CM protocol was evaluated when added to an outpatient MA treatment program. Participants receiving treatment with the CM protocol demonstrated superior clinical performance on multiple outcome measures (number of MA-negative urine samples, number of consecutive weeks of abstinence, percentage of participants who completed the trial with continued abstinence).
In addition to the controlled evaluations of behavioral treatments in persons dependent on MA, there have been trials conducted in which CM and CBT27 and the Matrix Model28 have been evaluated with samples of persons who use MA and cocaine. In all cases, the treatment response of the 2 groups of stimulant users was indistinguishable. Similarly, in 2 data sets in which persons who used MA and cocaine were treated side-by-side in standard community treatment programs, the response of the 2 groups was comparable on all measures.29,30
It appears highly likely that persons who use MA and those who use cocaine respond quite similarly to psychosocial interventions, and treatments that produce positive outcomes for persons who use cocaine are likely to be equally effective for those who use MA. This conclusion would support the use of approaches such as the community reinforcement approach, 12-step facilitation therapy, and CBT. In addition, although there have been no controlled trial data to assess motivational interviewing/motivational enhancement therapy to date, this approach is recommended in the treatment of persons who use MA.Medications
Efforts to develop and evaluate medications that may be useful in the treatment of MA dependence address the postulated mechanisms of action of MA at the cellular-molecular level and at the neuronal circuit level in order to amend dysregulation and inhibit relapse. Bupropion and modafinil have exhibited some potential as adjuncts to behavioral therapy in treating MA dependence. Other medications (gabapentin, lobeline, vigabatrin, ondansetron(Drug information on ondansetron)) are under consideration, but evidence of their efficacy is lacking. Also under consideration is agonist therapy (ie, with "replacement/substitution" medication).31
Bupropion. In a recent trial, treatment with bupropion was associated with a reduction in MA use; bupropion produced significant reductions in MA use compared with placebo treatment (P = .03) in subjects who reported using MA fewer than 18 days in the past month.25 Seventy-two participants were randomized to placebo and 79 were randomized to sustained-release bupropion 150 mg bid. Bupropion in combination with behavioral group therapy proved effective for the treatment of participants with low to moderate MA dependence (defined as using fewer than 18 days in the month before intake). Bupropion reduced the subjective effects of MA and cue-induced cravings.20
Modafinil. Modafinil(Drug information on modafinil) is a non-amphetamine stimulant that is approved for managing symptoms of narcolepsy. The effects of modafinil may relieve acute depression accompanying recent abstinence,32 inhibiting relapse. As an adjunct to a behavioral therapy such as CBT, modafinil has been shown to significantly improve performance on cognitive tasks and executive system functioning33 in persons with schizophrenia34 and in persons with HIV.35 Modafinil also improves impulse control.36Conclusions
MA use in the United States has created significant public health and safety concerns. Women, men who have sex with men, rural residents, and adolescents are at elevated risk for becoming addicted to this drug. Use of MA causes significant damage to the body and the brain. Treatment for persons who use MA is available, has been proved empirically effective, and works in real-world clinical settings. Notably, the Matrix Model and CM have demonstrated efficacy.
Other psychosocial approaches with empiric support for persons who abuse cocaine are likely to be similarly effective with persons who are dependent on MA. Several studies have provided support for the use of bupropion, and there is great interest in modafinil as pharmacotherapy for persons who use MA.