Treating methamphetamine abuse disorder: Experience from research and practice

Methamphetamine and other amphetamine-type stimulants are the world’s second most widely used group of illicit substances (after Cannabis), with prevalence of abuse varying by region and by locales within nations. As prescription use of stimulants has grown dramatically in recent years, so has abuse of these substances.

Given the widespread and growing misuse of amphetamine-type stimulants (Box,^1-3), clinicians are faced with the need to learn how to recognize and manage methamphetamine abuse. Both pre­scribed and non-prescribed uses of stimulants present complex chal­lenges; in this article, we examine effects, manifestations, and current evidence-based behavioral and medical treatments of methamphet­amine misuse and abuse, and look ahead to investigational therapies that hold promise for improving the limited existing approaches to management.

Effects and manifestations of methamphetamine use
Different routes of administration produce different consequences, in terms of medical comorbidity and propensity to induce addiction. Smoked or injected, methamphetamine enters the brain in seconds; snorted or taken by mouth, the drug produces its effects in several min­utes and a half hour, respectively.

Rapid uptake and effects of methamphetamine result from its ability to cross the blood−brain barrier. Its primary effects are caused by inhibi­tion of dopamine storage and release of intracellular dopamine.

Methamphetamine stimulates the CNS and the cardiovascular sys­tem through release of dopamine and norepinephrine, which increases blood pressure, body temperature, and heart rate, and, occasionally, induces arrhythmia that can contribute to heart attack and stroke. Users experience euphoria, hypervigilance, suppressed appetite, and increased libido.

Binge use is common to sustain eupho­ria and other reinforcing effects, which subside with rapidly developing tolerance. After days of repeated dosing, elevated methamphetamine blood levels can lead to mood disturbances, repetitive motor activities, and psychotic symptoms such as hallucinations, delusions, and paranoia. Acute psychosis can bring on violence and other injurious behaviors that involve law enforcement and emergency medical services.

When methamphetamine is used over months or years, health consequences include anorexia, tremor, so-called meth mouth (broken teeth, infections, cavities, burns), insomnia, panic attacks, confusion, depression, irritability, and impaired mem­ory and other cognitive processes.

Treating methamphetamine intoxication and withdrawal
At initial clinical contact with a person who abuses methamphetamine, practitio­ners may face several acute consequences requiring attention. Prominent among pre­senting conditions, especially during acute intoxication, are agitation, anxiety, and psy­chotic symptoms, which may improve by providing the patient with calming reassur­ance in a quiet space. In more severe cases, a benzodiazepine, antipsychotic, or both might be indicated^4,5 (Table 1).

Methamphetamine withdrawal is char­acterized by anxiety, depression, and insom­nia. These symptoms generally resolve in a matter of days after the start of withdrawal without pharmacotherapy. In some cases, depression or psychosis becomes chronic, as a result of methamphetamine use itself6 or as an emergent concomitant psychiatric condition.

A sedative-hypnotic medication or an anxiolytic can be used as necessary to ame­liorate insomnia or anxiety, respectively. Prolonged depression can be treated with an antidepressant. An antipsychotic might be indicated for long-term management of patients who have persistent psychosis.

Therapy for methamphetamine abuse
Treatment of methamphetamine abuse— with the goal of stopping drug use—is a complicated matter on 2 counts:
• No medications are FDA-approved for treating methamphetamine addiction.
• There are no accepted substitution medications (ie, stimulants that can be used in place of methamphetamine, as is avail­able for opioid addiction).

Pharmacotherapeutic possibilities. The rationale for considering replacement phar­macotherapy is that psychostimulants can counter the cravings, dysphoria, and fatigue produced by methamphetamine withdrawal and can alleviate methamphetamine-related cognitive impairment. Although dextro­amphetamine and other psychostimu­lants have been evaluated in small trials as replacement medication, most countries are reluctant to consider their use, because of the potential for abuse and accompanying liability.

After decades of medication research, several drugs have shown promise for reducing methamphetamine abuse, although results have not been robust (Table 2):
• Bupropion has shown benefit in reduc­ing methamphetamine use among users with less severe addiction.^7,8
• Methylphenidate, a psychostimulant FDA-approved for attention-deficit/hyper­activity disorder, was found to reduce methamphetamine use compared with pla­cebo in a European sample of amphetamine injectors who had attained abstinence in a residential program.⁹ Those results were not replicated in a recent study by Miles et al, however.¹⁰ A study with a more clinically realistic approach (ie, not requiring daily clinic attendance, as in the Miles trial) vs placebo for methamphetamine abuse was recently published, with promising results that require confirmation in further study.¹¹
• Mirtazapine, an antidepressant, has demonstrated efficacy in reducing metham­phetamine use compared with placebo.¹²
• Modafinil, another medication with stimulant properties, reduced metham­phetamine use in a subgroup analysis of heavy users, compared with placebo.¹³
• Dextroamphetamine, 60 mg/d, showed no difference in reducing methamphet­amine compared with placebo, but did diminish cravings and withdrawal symptoms.¹⁴

A trial of the phosphodiesterase inhibitor ibudilast (not available in the United States) for methamphetamine abuse is underway. Ibudilast has anti-inflammatory activity in the peripheral immune system and the cen­tral nervous system, including modulating the activity of glial cells.¹⁵