Walter Ling, MD

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

 

Many medications have yielded negligi­ble results in studies: selegiline, baclofen, ser­traline, topiramate, gabapentin, rivastigmine, risperidone, and ondansetron.¹⁶ Recent eval­uation of disulfiram, vigabatrin, and lobeline also has yielded inconsistent findings.¹⁷

No drug has proved effective for pre­venting relapse; research continues, focus­ing on several types of compounds that target various mechanisms: the dopamine system, the opioid system (by way of the γ-aminobutyric acid inhibitory system), and cortico-limbic reward circuitry.

Once-monthly injectable naltrexone has potential for ameliorating craving and relapse by modulating the opioid receptor system. However, the drug has not been adequately explored in generalizable set­tings of methamphetamine users.

Trials of oral naltrexone in Sweden have shown encouraging results, includ­ing reduced subjective effects and amphet­amine use in open-label trials^18,19; results were replicated in a subsequent placebo-controlled trial.²⁰ In an unpublished study, however, no differences in amphetamine use were found among users randomized to depot naltrexone or placebo.²¹

Depot naltrexone with assured dos­ing might have a role in treating metham­phetamine abuse, however; a combination of depot naltrexone and oral bupropion is being examined in a National Institute on Drug Abuse Clinical Trials Networks study that commenced in 2013. Pairing medica­tions that have different mechanistic targets might work toward promoting cessation of methamphetamine abuse and reducing relapse once patients are abstinent.

In an early phase of research, but show­ing promise based on their ability to target different systems, are:  
   • N-acetylcysteine, modulator of the glutamate system  
   • D3 antagonists and partial agonists²²  
   • varenicline.²³

Potential “vaccines” against metham­phetamine are in preclinical development, including use of a protein carrier or other immune-stimulating molecule to create antibodies that bind methamphetamine in the bloodstream and block its psychoactive effects.^24,25

Sigma receptor effects are being studied in rodents as potential targets to mitigate effects of methamphetamine. The ligand AZ66, a sigma receptor antagonist, has demonstrated efficacy in reducing meth­amphetamine-induced cognitive impair­ment—suggesting that the sigma receptor has a potential role in ameliorating meth­amphetamine-related neurotoxicity.²⁶

Psychosocial and behavioral interven­tions. Among the non-drug treatments that have demonstrated efficacy for treat­ing methamphetamine abuse, cognitive-behavioral therapy (CBT) and contingency management (CM) have been most widely studied and applied in treatment settings.

CBT involves individual or group coun­seling that focuses on relapse prevention skills, including identification of relapse triggers, strategies to diminish cravings, and engagement in alternative non-drug activities^27,28 (Table 3).

CM, which is based on positive rein­forcement, offers tangible reinforcers, or rewards, for behaviors (eg, clinic atten­dance, providing a drug-free urine sam­ple) according to guidelines set by the practitioner. CM-based interventions are the most reliably documented approaches for treating methamphetamine abuse,^29,30 but their utility might prove to be most efficient in combination with medication— once suitable pharmacotherapeutic options emerge.

Although CBT and CM remain accepted standard treatments for methamphetamine abuse, outcomes are suboptimal.²⁷ Both interventions have a high rate of dropout during the first month of treatment and a >50% relapse rate 6 to 19 months after treat­ment ends.^31-33

As with treatment of other substance use disorders, patients who abuse methamphet­amine can benefit from residential treatment in a drug-free setting for ≥30 days.³⁴ In the residential approach, removing access to drugs, drug cues, and drug-using acquain­tances combined with group and individ­ual counseling reaches an inevitable end: discharge into the community. Then the patient’s battle to avoid relapse begins.

Because cognitive impairment is com­mon among patients who abuse metham­phetamine, even after they stop using,³⁵ researchers have examined the potential for increasing participation in psychosocial interventions such as CBT by using medica­tions that might have potential to increase cognitive function, such as modafinil.³⁶ Increased attention and concentration afforded by medication could enhance effi­cacy of CBT. Results of trials and new drug development have been mixed³⁷; no clear candidate for preventing relapse through any of the putative mechanisms of action has emerged.

Relapse is a problematic target for treatment
Ending methamphetamine abuse and sus­taining abstinence from stimulants require a change in the cognitive associations that have been laid down in a drug user’s memory. Relapse occurs because of recalled memories that can be cued, or triggered, by internal or external stimuli. Eliminating drug memories, perhaps assisted by medi­cations such as d-cycloserine (an antago­nist of the N-methyl-d-aspartate receptor), could be useful for suppressing the inclina­tion to relapse.

Last, alternative, non-drug forms of cog­nitive amendment have shown efficacy in preventing relapse: for example, incorpo­rating mindfulness meditation, which has shown promise in managing craving for methamphetamine and decreasing reactiv­ity to environmental cues for drug use.³⁸

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. Few evidence-based treatments and no FDA-approved medications are available to treat this addiction; many drugs and a few psychotherapeutic techniques have shown promise. Ongoing research promises to deliver medical and behavioral interventions to help patients quit using methamphetamine.

 

Related Resources
• Karch SB, Drummer O. Karch’s pathology of drug abuse, fifth ed. Boca Raton, FL: CRC Press/Taylor & David; 2013.
• Roll J, Rawson RA, Ling W, eds. Methamphetamine addic­tion: from basic science to treatment. New York, NY: Guilford Press; 2009.
• Sheff D. Beautiful boy: a father’s journey through his son’s addiction. New York, NY: Houghton Mifflin Harcourt Publishing Company; 2008.
• Sheff N. Tweak: growing up on methamphetamines. New York, NY: Antheneum Books for Young Readers; 2007.
• National Institute on Drug Abuse. Drugs of abuse. www. drugabuse.gov/drugs-abuse/methamphetamine.

Drug Brand Names
Baclofen • Lioresal                                Naltrexone (depot) • Vivitrol
Bupropion • Wellbutrin                          Naltrexone (oral) • ReVia
D-cycloserine • Seromycin                     Ondansetron • Zofran
Dexreoamphetaime • Adderall                Risperidone • Risperadal
Disulfiram • Antabuse                            Rivastigimine • Exelon
Gabapentin • Neurontin                          Selegiline• EMSAM
Methylphenidate  •  Ritalin                      Sertraline • Zoloft
Mirtazapine •  Remeron                          Topiramate • Topamax
Modafinil • Provigil                                 Varenicline • Chantix
 N-acetylcysteine • Mucomyst                 Vigabatrin • Sabril

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

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

 

Many medications have yielded negligi­ble results in studies: selegiline, baclofen, ser­traline, topiramate, gabapentin, rivastigmine, risperidone, and ondansetron.¹⁶ Recent eval­uation of disulfiram, vigabatrin, and lobeline also has yielded inconsistent findings.¹⁷

No drug has proved effective for pre­venting relapse; research continues, focus­ing on several types of compounds that target various mechanisms: the dopamine system, the opioid system (by way of the γ-aminobutyric acid inhibitory system), and cortico-limbic reward circuitry.

Once-monthly injectable naltrexone has potential for ameliorating craving and relapse by modulating the opioid receptor system. However, the drug has not been adequately explored in generalizable set­tings of methamphetamine users.

Trials of oral naltrexone in Sweden have shown encouraging results, includ­ing reduced subjective effects and amphet­amine use in open-label trials^18,19; results were replicated in a subsequent placebo-controlled trial.²⁰ In an unpublished study, however, no differences in amphetamine use were found among users randomized to depot naltrexone or placebo.²¹

Depot naltrexone with assured dos­ing might have a role in treating metham­phetamine abuse, however; a combination of depot naltrexone and oral bupropion is being examined in a National Institute on Drug Abuse Clinical Trials Networks study that commenced in 2013. Pairing medica­tions that have different mechanistic targets might work toward promoting cessation of methamphetamine abuse and reducing relapse once patients are abstinent.

In an early phase of research, but show­ing promise based on their ability to target different systems, are:  
   • N-acetylcysteine, modulator of the glutamate system  
   • D3 antagonists and partial agonists²²  
   • varenicline.²³

Potential “vaccines” against metham­phetamine are in preclinical development, including use of a protein carrier or other immune-stimulating molecule to create antibodies that bind methamphetamine in the bloodstream and block its psychoactive effects.^24,25

Sigma receptor effects are being studied in rodents as potential targets to mitigate effects of methamphetamine. The ligand AZ66, a sigma receptor antagonist, has demonstrated efficacy in reducing meth­amphetamine-induced cognitive impair­ment—suggesting that the sigma receptor has a potential role in ameliorating meth­amphetamine-related neurotoxicity.²⁶

Psychosocial and behavioral interven­tions. Among the non-drug treatments that have demonstrated efficacy for treat­ing methamphetamine abuse, cognitive-behavioral therapy (CBT) and contingency management (CM) have been most widely studied and applied in treatment settings.

CBT involves individual or group coun­seling that focuses on relapse prevention skills, including identification of relapse triggers, strategies to diminish cravings, and engagement in alternative non-drug activities^27,28 (Table 3).

CM, which is based on positive rein­forcement, offers tangible reinforcers, or rewards, for behaviors (eg, clinic atten­dance, providing a drug-free urine sam­ple) according to guidelines set by the practitioner. CM-based interventions are the most reliably documented approaches for treating methamphetamine abuse,^29,30 but their utility might prove to be most efficient in combination with medication— once suitable pharmacotherapeutic options emerge.

Although CBT and CM remain accepted standard treatments for methamphetamine abuse, outcomes are suboptimal.²⁷ Both interventions have a high rate of dropout during the first month of treatment and a >50% relapse rate 6 to 19 months after treat­ment ends.^31-33

As with treatment of other substance use disorders, patients who abuse methamphet­amine can benefit from residential treatment in a drug-free setting for ≥30 days.³⁴ In the residential approach, removing access to drugs, drug cues, and drug-using acquain­tances combined with group and individ­ual counseling reaches an inevitable end: discharge into the community. Then the patient’s battle to avoid relapse begins.

Because cognitive impairment is com­mon among patients who abuse metham­phetamine, even after they stop using,³⁵ researchers have examined the potential for increasing participation in psychosocial interventions such as CBT by using medica­tions that might have potential to increase cognitive function, such as modafinil.³⁶ Increased attention and concentration afforded by medication could enhance effi­cacy of CBT. Results of trials and new drug development have been mixed³⁷; no clear candidate for preventing relapse through any of the putative mechanisms of action has emerged.

Relapse is a problematic target for treatment
Ending methamphetamine abuse and sus­taining abstinence from stimulants require a change in the cognitive associations that have been laid down in a drug user’s memory. Relapse occurs because of recalled memories that can be cued, or triggered, by internal or external stimuli. Eliminating drug memories, perhaps assisted by medi­cations such as d-cycloserine (an antago­nist of the N-methyl-d-aspartate receptor), could be useful for suppressing the inclina­tion to relapse.

Last, alternative, non-drug forms of cog­nitive amendment have shown efficacy in preventing relapse: for example, incorpo­rating mindfulness meditation, which has shown promise in managing craving for methamphetamine and decreasing reactiv­ity to environmental cues for drug use.³⁸

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. Few evidence-based treatments and no FDA-approved medications are available to treat this addiction; many drugs and a few psychotherapeutic techniques have shown promise. Ongoing research promises to deliver medical and behavioral interventions to help patients quit using methamphetamine.

 

Related Resources
• Karch SB, Drummer O. Karch’s pathology of drug abuse, fifth ed. Boca Raton, FL: CRC Press/Taylor & David; 2013.
• Roll J, Rawson RA, Ling W, eds. Methamphetamine addic­tion: from basic science to treatment. New York, NY: Guilford Press; 2009.
• Sheff D. Beautiful boy: a father’s journey through his son’s addiction. New York, NY: Houghton Mifflin Harcourt Publishing Company; 2008.
• Sheff N. Tweak: growing up on methamphetamines. New York, NY: Antheneum Books for Young Readers; 2007.
• National Institute on Drug Abuse. Drugs of abuse. www. drugabuse.gov/drugs-abuse/methamphetamine.

Drug Brand Names
Baclofen • Lioresal                                Naltrexone (depot) • Vivitrol
Bupropion • Wellbutrin                          Naltrexone (oral) • ReVia
D-cycloserine • Seromycin                     Ondansetron • Zofran
Dexreoamphetaime • Adderall                Risperidone • Risperadal
Disulfiram • Antabuse                            Rivastigimine • Exelon
Gabapentin • Neurontin                          Selegiline• EMSAM
Methylphenidate  •  Ritalin                      Sertraline • Zoloft
Mirtazapine •  Remeron                          Topiramate • Topamax
Modafinil • Provigil                                 Varenicline • Chantix
 N-acetylcysteine • Mucomyst                 Vigabatrin • Sabril

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

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

 

Many medications have yielded negligi­ble results in studies: selegiline, baclofen, ser­traline, topiramate, gabapentin, rivastigmine, risperidone, and ondansetron.¹⁶ Recent eval­uation of disulfiram, vigabatrin, and lobeline also has yielded inconsistent findings.¹⁷

No drug has proved effective for pre­venting relapse; research continues, focus­ing on several types of compounds that target various mechanisms: the dopamine system, the opioid system (by way of the γ-aminobutyric acid inhibitory system), and cortico-limbic reward circuitry.

Once-monthly injectable naltrexone has potential for ameliorating craving and relapse by modulating the opioid receptor system. However, the drug has not been adequately explored in generalizable set­tings of methamphetamine users.

Trials of oral naltrexone in Sweden have shown encouraging results, includ­ing reduced subjective effects and amphet­amine use in open-label trials^18,19; results were replicated in a subsequent placebo-controlled trial.²⁰ In an unpublished study, however, no differences in amphetamine use were found among users randomized to depot naltrexone or placebo.²¹

Depot naltrexone with assured dos­ing might have a role in treating metham­phetamine abuse, however; a combination of depot naltrexone and oral bupropion is being examined in a National Institute on Drug Abuse Clinical Trials Networks study that commenced in 2013. Pairing medica­tions that have different mechanistic targets might work toward promoting cessation of methamphetamine abuse and reducing relapse once patients are abstinent.

In an early phase of research, but show­ing promise based on their ability to target different systems, are:  
   • N-acetylcysteine, modulator of the glutamate system  
   • D3 antagonists and partial agonists²²  
   • varenicline.²³

Potential “vaccines” against metham­phetamine are in preclinical development, including use of a protein carrier or other immune-stimulating molecule to create antibodies that bind methamphetamine in the bloodstream and block its psychoactive effects.^24,25

Sigma receptor effects are being studied in rodents as potential targets to mitigate effects of methamphetamine. The ligand AZ66, a sigma receptor antagonist, has demonstrated efficacy in reducing meth­amphetamine-induced cognitive impair­ment—suggesting that the sigma receptor has a potential role in ameliorating meth­amphetamine-related neurotoxicity.²⁶

Psychosocial and behavioral interven­tions. Among the non-drug treatments that have demonstrated efficacy for treat­ing methamphetamine abuse, cognitive-behavioral therapy (CBT) and contingency management (CM) have been most widely studied and applied in treatment settings.

CBT involves individual or group coun­seling that focuses on relapse prevention skills, including identification of relapse triggers, strategies to diminish cravings, and engagement in alternative non-drug activities^27,28 (Table 3).

CM, which is based on positive rein­forcement, offers tangible reinforcers, or rewards, for behaviors (eg, clinic atten­dance, providing a drug-free urine sam­ple) according to guidelines set by the practitioner. CM-based interventions are the most reliably documented approaches for treating methamphetamine abuse,^29,30 but their utility might prove to be most efficient in combination with medication— once suitable pharmacotherapeutic options emerge.

Although CBT and CM remain accepted standard treatments for methamphetamine abuse, outcomes are suboptimal.²⁷ Both interventions have a high rate of dropout during the first month of treatment and a >50% relapse rate 6 to 19 months after treat­ment ends.^31-33

As with treatment of other substance use disorders, patients who abuse methamphet­amine can benefit from residential treatment in a drug-free setting for ≥30 days.³⁴ In the residential approach, removing access to drugs, drug cues, and drug-using acquain­tances combined with group and individ­ual counseling reaches an inevitable end: discharge into the community. Then the patient’s battle to avoid relapse begins.

Because cognitive impairment is com­mon among patients who abuse metham­phetamine, even after they stop using,³⁵ researchers have examined the potential for increasing participation in psychosocial interventions such as CBT by using medica­tions that might have potential to increase cognitive function, such as modafinil.³⁶ Increased attention and concentration afforded by medication could enhance effi­cacy of CBT. Results of trials and new drug development have been mixed³⁷; no clear candidate for preventing relapse through any of the putative mechanisms of action has emerged.

Relapse is a problematic target for treatment
Ending methamphetamine abuse and sus­taining abstinence from stimulants require a change in the cognitive associations that have been laid down in a drug user’s memory. Relapse occurs because of recalled memories that can be cued, or triggered, by internal or external stimuli. Eliminating drug memories, perhaps assisted by medi­cations such as d-cycloserine (an antago­nist of the N-methyl-d-aspartate receptor), could be useful for suppressing the inclina­tion to relapse.

Last, alternative, non-drug forms of cog­nitive amendment have shown efficacy in preventing relapse: for example, incorpo­rating mindfulness meditation, which has shown promise in managing craving for methamphetamine and decreasing reactiv­ity to environmental cues for drug use.³⁸

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. Few evidence-based treatments and no FDA-approved medications are available to treat this addiction; many drugs and a few psychotherapeutic techniques have shown promise. Ongoing research promises to deliver medical and behavioral interventions to help patients quit using methamphetamine.

 

Related Resources
• Karch SB, Drummer O. Karch’s pathology of drug abuse, fifth ed. Boca Raton, FL: CRC Press/Taylor & David; 2013.
• Roll J, Rawson RA, Ling W, eds. Methamphetamine addic­tion: from basic science to treatment. New York, NY: Guilford Press; 2009.
• Sheff D. Beautiful boy: a father’s journey through his son’s addiction. New York, NY: Houghton Mifflin Harcourt Publishing Company; 2008.
• Sheff N. Tweak: growing up on methamphetamines. New York, NY: Antheneum Books for Young Readers; 2007.
• National Institute on Drug Abuse. Drugs of abuse. www. drugabuse.gov/drugs-abuse/methamphetamine.

Drug Brand Names
Baclofen • Lioresal                                Naltrexone (depot) • Vivitrol
Bupropion • Wellbutrin                          Naltrexone (oral) • ReVia
D-cycloserine • Seromycin                     Ondansetron • Zofran
Dexreoamphetaime • Adderall                Risperidone • Risperadal
Disulfiram • Antabuse                            Rivastigimine • Exelon
Gabapentin • Neurontin                          Selegiline• EMSAM
Methylphenidate  •  Ritalin                      Sertraline • Zoloft
Mirtazapine •  Remeron                          Topiramate • Topamax
Modafinil • Provigil                                 Varenicline • Chantix
 N-acetylcysteine • Mucomyst                 Vigabatrin • Sabril

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.