EXPERIENCE FROM RESEARCH AND PRACTICE Treating methamphetamine abuse disorder As prevalence of methamphetamine abuse mushrooms, practitioners face the challenge of treating the disorder, its withdrawal symptoms, and stimulant-induced psychosis

Walter Ling, MD Professor of Psychiatry and Founding Director ethamphetamine and other amphetamine-type stimulants are Integrated Substance Abuse Programs the world’s second most widely used group of illicit substances Larissa Mooney, MD (after Cannabis), with prevalence of abuse varying by region Assistant Clinical Professor of Psychiatry Director of Addiction Medicine Clinic and by locales within nations. As prescription use of stimulants has Margaret Haglund, MD grown dramatically in recent years, so has abuse of these substances. Deutsch Foundation Mood Disorders Fellow Given the widespread and growing misuse of amphetamine-type Staff Associate Physician stimulants (Box,1-3 page 38), clinicians are faced with the need to learn Department of Psychiatry and Biobehavioral how to recognize and manage methamphetamine abuse. Both pre- Sciences scribed and non-prescribed uses of stimulants present complex chal- David Geffen School of Medicine at UCLA Los Angeles, California lenges; in this article, we examine effects, manifestations, and current evidence-based behavioral and medical treatments of methamphet- Disclosures The authors report no financial relationships with any amine misuse and abuse, and look ahead to investigational therapies company whose products are mentioned in this article that hold promise for improving the limited existing approaches to or with manufacturers of competing products. 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 min- utes 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 inhibi- tion of dopamine storage and release of intracellular dopamine. Methamphetamine stimulates the CNS and the cardiovascular sys- PHOTO ILLUSTRATION BY JOHN J. DENAPOLI FOR CURRENT PSYCHIATRY

Current Psychiatry Vol. 13, No. 9 37 Box Worldwide, abuse of amphetamine-type stimulants rises; need for treatment grows

he highest prevalence of amphetamine- Cambodia, the Philippines, and Saudi Arabia Ttype stimulant (ATS) abuse is in North and other regions of the Near and Middle East.2 America, Western and Central Europe, and An increase in ATS use has been reported Methamphetamine South-East and East Asia. The United Nations recently in West Africa, Central Asia, and the estimates that up to 52.5 million people age 15 South Caucasus region.1 abuse to 64 had used an ATS in the past year.1 As in the rest of the world, methamphetamine Over the past decade, growing abuse has been the primary ATS used in the United of ATS has meant a rise in the incidence of States, although the rate of methamphetamine related disorders requiring treatment. The use disorder varies by state, with resulting percentage of people who need treatment for variations in the levels of treatment need ATS use disorder (among all those who require and treatment participation. Relatively few treatment for substance abuse) is now 10% methamphetamine treatment admissions in Europe; 12% in North America; 20% in are found in the Northeast, whereas Australia and New Zealand; 21% in Asia; and methamphetamine use is rampant in the 36% in East Asia and Southeast Asia. Abuse of Southwest. In California, 46.6% of young adults Clinical Point ATS accounts for more than 50% of treatment (age 18 to 25) in drug treatment had abused demand in Japan, South Korea, Thailand, methamphetamine.3 In severe cases of intoxication, a benzodiazepine, an antipsychotic, or both, tem through release of dopamine and ners may face several acute consequences might be indicated norepinephrine, which increases blood requiring attention. Prominent among pre- pressure, body temperature, and heart rate, senting conditions, especially during acute beyond calming and, occasionally, induces arrhythmia that intoxication, are agitation, anxiety, and psy- reassurance can contribute to heart attack and stroke. chotic symptoms, which may improve by Users experience euphoria, hypervigilance, providing the patient with calming reassur- suppressed appetite, and increased libido. ance in a quiet space. In more severe cases, Binge use is common to sustain eupho- a benzodiazepine, antipsychotic, or both ria and other reinforcing effects, which might be indicated4,5 (Table 1, page 40). subside with rapidly developing tolerance. Methamphetamine withdrawal is char- After days of repeated dosing, elevated acterized by anxiety, depression, and insom- methamphetamine blood levels can lead nia. These symptoms generally resolve in a to mood disturbances, repetitive motor matter of days after the start of withdrawal activities, and psychotic symptoms such without pharmacotherapy. In some cases, as hallucinations, delusions, and paranoia. depression or psychosis becomes chronic, Acute psychosis can bring on violence as a result of methamphetamine use itself6 and other injurious behaviors that involve or as an emergent concomitant psychiatric law enforcement and emergency medical condition. services. A sedative-hypnotic medication or an When methamphetamine is used over anxiolytic can be used as necessary to ame- months or years, health consequences liorate insomnia or anxiety, respectively. include anorexia, tremor, so-called meth Prolonged depression can be treated with mouth (broken teeth, infections, cavities, an antidepressant. An antipsychotic might burns), insomnia, panic attacks, confusion, be indicated for long-term management of Discuss this article at depression, irritability, and impaired mem- patients who have persistent psychosis. www.facebook.com/ ory and other cognitive processes. CurrentPsychiatry Therapy for methamphetamine Treating methamphetamine abuse intoxication and withdrawal Treatment of methamphetamine abuse— At initial clinical contact with a person with the goal of stopping drug use—is a Current Psychiatry 38 September 2014 who abuses methamphetamine, practitio- complicated matter on 2 counts: continued on page 40 continued from page 38

Table 1 Standard practices for treating acute methamphetamine intoxication and withdrawal Symptom Acute intoxication Acute withdrawal Agitation Supportive care Supportive care Benzodiazepines Benzodiazepines Methamphetamine Anxiety Supportive care Supportive care abuse Benzodiazepines Benzodiazepines Insomnia Sedating antipsychotics, antidepressants Sedating antipsychotics, antidepressants Psychosis Antipsychotics Antipsychotics Depression Not applicable Antidepressants

• No medications are FDA-approved for clinic attendance, as in the Miles trial) vs Clinical Point treating methamphetamine addiction. placebo for methamphetamine abuse was Psychostimulants • There are no accepted substitution recently published, with promising results medications (ie, stimulants that can be used that require confirmation in further study.11 can counter the in place of methamphetamine, as is avail- • Mirtazapine, an antidepressant, has cravings, dysphoria, able for opioid addiction). demonstrated efficacy in reducing metham- and fatigue phetamine use compared with placebo.12 produced by Pharmacotherapeutic possibilities. The • Modafinil, another medication with rationale for considering replacement phar- stimulant properties, reduced metham- methamphetamine macotherapy is that psychostimulants can phetamine use in a subgroup analysis of withdrawal counter the cravings, dysphoria, and fatigue heavy users, compared with placebo.13 produced by methamphetamine withdrawal • Dextroamphetamine, 60 mg/d, showed and can alleviate methamphetamine-related no difference in reducing methamphet- cognitive impairment. Although dextro- amine compared with placebo, but amphetamine and other psychostimu- did diminish cravings and withdrawal lants have been evaluated in small trials as symptoms.14 replacement medication, most countries are A trial of the phosphodiesterase inhibitor reluctant to consider their use, because of ibudilast (not available in the United States) the potential for abuse and accompanying for methamphetamine abuse is underway. liability. Ibudilast has anti-inflammatory activity in After decades of medication research, the peripheral immune system and the cen- several drugs have shown promise for tral nervous system, including modulating reducing methamphetamine abuse, the activity of glial cells.15 although results have not been robust Many medications have yielded negligi- (Table 2): ble results in studies: selegiline, baclofen, ser- • Bupropion has shown benefit in reduc- traline, topiramate, gabapentin, rivastigmine, ing methamphetamine use among users risperidone, and ondansetron.16 Recent eval- with less severe addiction.7,8 uation of disulfiram, vigabatrin, and lobeline • Methylphenidate, a psychostimulant also has yielded inconsistent findings.17 FDA-approved for attention-deficit/hyper- No drug has proved effective for pre- activity disorder, was found to reduce venting relapse; research continues, focus- methamphetamine use compared with pla- ing on several types of compounds that cebo in a European sample of amphetamine target various mechanisms: the dopamine injectors who had attained abstinence in a system, the opioid system (by way of the residential program.9 Those results were not γ-aminobutyric acid inhibitory system), and replicated in a recent study by Miles et al, cortico-limbic reward circuitry. however.10 A study with a more clinically Once-monthly injectable naltrexone Current Psychiatry 40 September 2014 realistic approach (ie, not requiring daily has potential for ameliorating craving and relapse by modulating the opioid receptor Table 2 system. However, the drug has not been adequately explored in generalizable set- Pharmacotherapeutic landscape tings of methamphetamine users. of methamphetamine abuse Trials of oral naltrexone in Sweden FDA-approved agents have shown encouraging results, includ- None ing reduced subjective effects and amphet- Drugs with evidence of effectiveness amine use in open-label trials18,19; results Bupropion were replicated in a subsequent placebo- Methylphenidate 20 Mirtazapine controlled trial. In an unpublished study, Modafinil however, no differences in amphetamine Naltrexone (oral) use were found among users randomized Drugs under investigation 21 to depot naltrexone or placebo. Dextroamphetamine Depot naltrexone with assured dos- Methylphenidate ing might have a role in treating metham- N-acetylcysteine Naltrexone (depot) phetamine abuse, however; a combination Other investigational compounds of depot naltrexone and oral bupropion is Clinical Point D-cycloserine being examined in a National Institute on Ibudilast Cognitive-behavioral Drug Abuse Clinical Trials Networks study Sigma-receptor antagonists (the ligand that commenced in 2013. Pairing medica- AZ66) therapy for meth Vaccines (various; containing tions that have different mechanistic targets abuse involves methamphetamine-binding antibodies might work toward promoting cessation individual or group of methamphetamine abuse and reducing counseling that relapse once patients are abstinent. Table 3 focuses on relapse In an early phase of research, but show- Non-drug management of prevention skills ing promise based on their ability to target methamphetamine abuse different systems, are: Evidence-based • N-acetylcysteine, modulator of the glutamate system Cognitive-behavioral therapy • D3 antagonists and partial agonists22 Contingency management • varenicline.23 Under investigation Potential “vaccines” against metham- Mindfulness meditation phetamine are in preclinical development, Combined pharmacotherapy−psychotherapy including use of a protein carrier or other immune-stimulating molecule to create antibodies that bind methamphetamine in the bloodstream and block its psychoactive management (CM) have been most widely effects.24,25 studied and applied in treatment settings. Sigma receptor effects are being studied CBT involves individual or group coun- in rodents as potential targets to mitigate seling that focuses on relapse prevention effects of methamphetamine. The ligand skills, including identification of relapse AZ66, a sigma receptor antagonist, has triggers, strategies to diminish cravings, demonstrated efficacy in reducing meth- and engagement in alternative non-drug amphetamine-induced cognitive impair- activities27,28 (Table 3). ment—suggesting that the sigma receptor CM, which is based on positive rein- has a potential role in ameliorating meth- forcement, offers tangible reinforcers, or amphetamine-related neurotoxicity.26 rewards, for behaviors (eg, clinic atten- dance, providing a drug-free urine sam- Psychosocial and behavioral interven- ple) according to guidelines set by the tions. Among the non-drug treatments practitioner. CM-based interventions are that have demonstrated efficacy for treat- the most reliably documented approaches ing methamphetamine abuse, cognitive- for treating methamphetamine abuse,29,30 Current Psychiatry behavioral therapy (CBT) and contingency but their utility might prove to be most Vol. 13, No. 9 41 tances combined with group and individ- Related Resources ual counseling reaches an inevitable end: • Karch SB, Drummer O. Karch’s pathology of drug abuse, fifth discharge into the community. Then the ed. Boca Raton, FL: CRC Press/Taylor & David; 2013. patient’s battle to avoid relapse begins. • Roll J, Rawson RA, Ling W, eds. Methamphetamine addic- tion: from basic science to treatment. New York, NY: Guilford Because cognitive impairment is com- Press; 2009. mon among patients who abuse metham- • Sheff D. Beautiful boy: a father’s journey through his phetamine, even after they stop using,35 son’s addiction. New York, NY: Houghton Mifflin Harcourt Methamphetamine Publishing Company; 2008. researchers have examined the potential abuse • Sheff N. Tweak: growing up on methamphetamines. New for increasing participation in psychosocial York, NY: Antheneum Books for Young Readers; 2007. interventions such as CBT by using medica- • National Institute on Drug Abuse. Drugs of abuse. www. tions that might have potential to increase drugabuse.gov/drugs-abuse/methamphetamine. cognitive function, such as modafinil.36 Drug Brand Names Increased attention and concentration Baclofen • Lioresal Naltrexone (depot) • Vivitrol afforded by medication could enhance effi- Bupropion • Wellbutrin Naltrexone (oral) • ReVia D-cycloserine • Seromycin Ondansetron • Zofran cacy of CBT. Results of trials and new drug Dextroamphetamine Risperidone • Risperdal development have been mixed37; no clear • Adderall Rivastigmine • Exelon Clinical Point Disulfiram • Antabuse Selegiline • EMSAM candidate for preventing relapse through Gabapentin • Neurontin Sertraline • Zoloft any of the putative mechanisms of action Patients who abuse Methylphenidate • Ritalin Topiramate • Topamax Mirtazapine • Remeron Varenicline • Chantix has emerged. methamphetamine Modafinil • Provigil Vigabatrin • Sabril can benefit from N-acetylcysteine • Mucomyst residential treatment Relapse is a problematic target in a drug-free for treatment Ending methamphetamine abuse and sus- settings for 30 days efficient in combination with medication— taining abstinence from stimulants require or longer once suitable pharmacotherapeutic options a change in the cognitive associations emerge. that have been laid down in a drug user’s Although CBT and CM remain accepted memory. Relapse occurs because of recalled standard treatments for methamphetamine memories that can be cued, or triggered, abuse, outcomes are suboptimal.27 Both by internal or external stimuli. Eliminating interventions have a high rate of dropout drug memories, perhaps assisted by medi- during the first month of treatment and a cations such as d-cycloserine (an antago- >50% relapse rate 6 to 19 months after treat- nist of the N-methyl-d-aspartate receptor), ment ends.31-33 could be useful for suppressing the inclina- As with treatment of other substance use tion to relapse. disorders, patients who abuse methamphet- Last, alternative, non-drug forms of cog- amine can benefit from residential treatment nitive amendment have shown efficacy in in a drug-free setting for ≥30 days.34 In the preventing relapse: for example, incorpo- residential approach, removing access to rating mindfulness meditation, which has drugs, drug cues, and drug-using acquain- shown promise in managing craving for continued on page 44 Bottom Line Practitioners who work in emergency, inpatient, and outpatient settings will be called on more and more to treat acute stimulant intoxication and withdrawal, stimulant- induced psychosis, and methamphetamine abuse. 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