The Diseases of Addiction: Methamphetamine Abuse
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
In the past decade, the manufacture and abuse of methamphetamine in the United States has gained increased attention. The admissions rates for treatment of methamphetamine-related disorders have ballooned alarmingly in some areas, particularly in rural or frontier areas, causing public health concerns. As a result, it is important that healthcare professionals have a solid knowledge of the effects and appropriate treatment of methamphetamine abuse and dependence. Research regarding effective treatment modalities for methamphetamine-dependent patients has generally been limited to those used in the treatment of dependence to other stimulants, such as cocaine. Because the use characteristics and demographics associated with methamphetamine use are unique, these special populations' needs should be taken into consideration in both the evaluation and treatment processes. More than 12 million Americans report having used methamphetamine at least once. The number of new users of methamphetamine increased by 250% between 1996 and 2002. Regional use of methamphetamine varies widely, with rural areas being the most severely impacted. Methamphetamine manufacturing and use affects a wide range of individuals, and all patients should be educated about the dangerous effects of the drug. It is important that healthcare professionals have a solid knowledge of the effects and appropriate treatment of methamphetamine abuse and dependence.
The purpose of this document is to review methamphetamine addiction, clinical symptomatology, treatment and prognosis. Various programs addressing substance abuse and methamphetamine abuse are also discussed. The Fellowship of Crystal Meth Anonymous works a Twelve Step program of recovery. Crystal Meth Anonymous is a fellowship of men and women who share their experience, strength and hope with each other, so they may solve their common problem and help others to recover from addiction to crystal meth. The only requirement for membership is a desire to stop using.
History and Background of Amphetamines and Methamphetamine
Amphetamines are a group of central nervous system (CNS)-stimulating drugs that include dextroamphetamine (Dexadrine), methamphetamine (Methedrine, Desoxyn), mixed amphetamine salts (Adderall), and amphetamine (Benzedrine) (1). Amphetamine and methamphetamine are structurally related and very similar; both act by stimulating the release of central and peripheral monoamines, such as dopamine, serotonin and norepinephrine, and both exhibit psychomotor, cardiovascular, anorexogenic, and hyperthermic properties. However, methamphetamine has greater CNS action than peripheral nervous system action and is more potent and longer lasting in its subjective effect. Methamphetamine rapidly and efficiently crosses the blood-brain barrier because it is highly lipid-soluble (2).
Amphetamine and methamphetamine were originally synthesized in Japan in 1893 for use as substitutes for the plant-derived ephedrine, which has been used for centuries in Asia to treat respiratory conditions (1)(3). Widespread use began in World War II (WWII), when American, German, and Japanese soldiers utilized the drugs to increase endurance and performance and to counter fatigue. In addition to its military use, methamphetamine was given to Japanese factory workers to increase productivity and diminish the need for sleep and was sold over-the-counter. Immediately following WWII, the Japanese army made their surplus methamphetamine widely available, flooding the civilian market and resulting in the first methamphetamine epidemic (1945-1957). By 1954, estimated 2 million Japanese were addicted to intravenously administered methamphetamine, with roughly 10% exhibiting symptoms of methamphetamine-induced psychosis. In response to the increase in crime and homicides linked to methamphetamine use, the Japanese government enacted the Stimulants Control Law and the Mental Health Act, enacting strict laws and permitting the involuntary treatment of methamphetamine abusers. During the second Japanese methamphetamine epidemic (1970-present), use spread to a wider cross-section of Japanese society, including blue-collar workers, students, housewives, and office workers. The demographics of Japanese methamphetamine abusers are somewhat different from those in other regions in that persons 35 years of age and older comprise the majority of users (1). Widespread methamphetamine use persists in Japan, with methamphetamine-related crime accounting for 90% of all drug arrests in 1998.
In the U.S., medical use of amphetamines began in 1932, when the American Medical Association approved amphetamine (marketed as Benzedrine) as a treatment for asthma and a variety of other medical and psychiatric conditions, including alcoholism, narcolepsy, attention deficit hyperactivity disorder (ADHD), appetite suppression, schizophrenia, morphine addiction, smoking cessation, low blood pressure, radiation sickness, and even intractable hiccups (1)(3). Amphetamines were available over-the-counter in the U.S. as tablets until 1951 and as inhaler ingredients until 1959. Prescriptions for amphetamines peaked in 1967, when 31 million prescriptions were written for amphetamines for indications such as obesity and depression. Until the 1960s, methamphetamine was widely available in the U.S. under the brand names Desoxyn and Methadrine. A liquid formulation became widely popular in the 1960s as a treatment for heroin addiction, leading to an emerging pattern of abuse among intravenous (IV) users. Before the current methamphetamine epidemic, which began in the late 1980s, the chemical phenyl-2-propanone (P2P) was the primary precursor for domestically produced methamphetamine (1). The subsequent use of ephedrine and pseudoephedrine was simpler, more efficient, and yielded a higher concentration of the psychoactive D-isomer (dextro-methamphetamine).
Risk Factors for Methamphetamine Abuse and Dependence
Data from a large community survey of drug abuse conducted from 1995 to 1998 found the factors most robustly associated with progression from stimulant use to stimulant dependence were early onset of stimulant use, multiple-substance abuse, and daily cigarette smoking between 13 and 17 years of age (4). Contributory and risk factors for methamphetamine abuse include the presence of depression, ADHD, a desire to enhance sexual pleasure, the manic phase of bipolar disorder, obesity, childhood Conduct Disorder and adult Antisocial Personality Disorder (4). Several motivational factors for methamphetamine use have been identified. In comparison to other stimulants (i.e., cocaine), methamphetamine carries the perception of producing a better, cheaper, and more satisfying drug effect. Users are also initially attracted to methamphetamine out of a desire to cope with mental illness, emotional trauma, and/or mental distress; stay awake longer; enhance sexual experience and performance; and/or reduce weight.
Methamphetamine stimulates the release and blocks the presynaptic reuptake of serotonin, dopamine, and norepinephrine (4). It is metabolized at a much slower rate than some other stimulants, such as cocaine. As a result of methamphetamine's 12-hour half-life, inexpensive synthesis, and abundant supply, abusers spend 25% to 30% as much as cocaine-dependent persons on their drug of choice (6). Purity of methamphetamine is now very high, at 60% to 90%. It is predominantly d-methamphetamine, which has greater CNS potency than the l-isomer. Common abused doses are 100 to 1000 mg/day, and chronic users on a binge may ingest up to 5000 mg/day (9). Single doses of amphetamines, including methamphetamine, improve performance across several dimensions of cognitive function in humans (4). Behaviorally, an acute dose of methamphetamine acts by stimulating the release of newly synthesized catecholamines, including serotonin, dopamine, and norepinephrine, brain chemicals that mediate pleasure and reward, mood, sleep, and appetite, and blocking their presynaptic re-uptake (9). Dopamine transmission levels in the synaptic cleft are primarily increased through inhibition of the dopamine transporter, essentially reversing the direction of these transporters (4). Methamphetamine also acts on other presynaptic sites, including storage vesicles and monoamine oxidase (MAO), the enzyme that breaks down dopamine and norepinephrine to inactive metabolites (9).
Methamphetamine is rapidly absorbed from the gastrointestinal tract. The primary site of metabolism is in the liver, by aromatic hydroxylation, N-dealkylation, and deamination. At least seven metabolites of the drug have been identified in the urine. Excretion occurs primarily in urine and is dependent on urine pH; alkaline urine will significantly increase the drug half-life. Approximately 62% of an oral dose is eliminated in the urine within the first 24 hours, with about one-third as intact drug and the remainder as metabolites (9). Inhibitors of the 2D6 isoenzyme can decrease the rate of methamphetamine elimination, while potential inducers could increase the rate of elimination (9). Approximately 10% of white individuals are deficient of this isoenzyme, making them ultrasensitive to the effects of methamphetamine because they lack the ability to metabolize and excrete the drug efficiently. Following oral administration, peak methamphetamine concentrations are seen in 2.6 to 3.6 hours and the mean elimination half-life is 10.1 hours (range: 6.4 to 15 hours). The amphetamine metabolite peaks at 12 hours, or slightly longer following IV injection. Methamphetamine is metabolized to amphetamine (active), p-OH-amphetamine, and norephedrine (both inactive) (4)(9).
Use Characteristics of Methamphetamine Abuse:
Illicit methamphetamine is also referred to as "speed," "meth," "ice," "crystal," and "crank" and can be ingested through several routes of administration, depending on the specific preparation. Methamphetamine is primarily available as (2): "Speed," a low-grade, locally manufactured powder that is snorted or injected. Pills that are often combined with other drugs, such as ketamine. "Base" or "paste," an often locally manufactured, glue-like substance. "Crystal meth" and "ice," which are highly pure, crystalline forms that are smoked or injected. Binge use of methamphetamine is a frequently reported pattern of use and is characterized by frequent ingestion of the drug, generally 8 to 10 times per day for 3 to 10 days. High doses (0.3 to 1 or more grams per day) are used because tolerance to the desired subjective drug effects develops quickly. Users who initially snorted or smoked methamphetamine often find they need to administer the drug intravenously to achieve the desired effects (15).
Compared to other stimulants, the progression to methamphetamine addiction is accelerated, particularly the time from initial use to regular use and regular use to first treatment. This is likely mediated by the synergistic interaction of the pharmacological properties with the behavioral, social, and psychological effects of the drug (6). Although treatments designed and validated for cocaine abusers have constituted the mainstay of treatment for methamphetamine, two important distinctions in patient characteristics may limit treatment generalizability: the long-term drug effects on cognitive and emotional functioning, and lifestyle and background differences associated with methamphetamine-addicted patients. Differences in neurotoxicity between methamphetamine and other stimulants have also been identified. Methamphetamine damages neurons that inhabit dopamine and serotonin brain pathways, while cocaine is not toxic to these neurons (6)(7). The anergia, dysphoria, and lack of mental energy seen in post-acute withdrawal from methamphetamine are much more severe and protracted than that observed among cocaine-dependent patients. Persistent paranoia is also unusual in abstinent cocaine addicts, whereas methamphetamine abuse can predispose the patient to paranoia several years into abstinence. Withdrawal from methamphetamine is likely the manifestation of both the short-term stimulant withdrawal syndrome (anergia and psychasthenia) experienced and the expression of long-term functional changes and/or neurotoxicity unique to this drug (7). Users of methamphetamine exhibit cognitive impairment distinct from that induced by other stimulant drugs, with impairment of perceptual speed, information manipulation, and tasks combining these skills with visuomotor scanning (4). Methamphetamine abusers continue to display deficiencies in these neuropsychological dimensions three years into abstinence (16).
Who are at risk?
Several motivational factors for methamphetamine use have been identified. In comparison to other stimulants (i.e., cocaine), methamphetamine carries the perception of producing a better, cheaper, and more satisfying drug effect. Users are also initially attracted to methamphetamine out of a desire to cope with mental illness, emotional trauma, and/or mental distress; stay awake longer; enhance sexual experience and performance; and/or reduce weight. Data from a large community survey of drug abuse found the factors most strongly associated with progression from stimulant use to stimulant dependence were early onset of stimulant use, multiple-substance abuse, and daily cigarette smoking between 13 and 17 years of age (7). Contributory and risk factors for methamphetamine abuse include the presence of depression, ADHD, a desire to enhance sexual pleasure, the manic phase of bipolar disorder, obesity, childhood conduct disorder, and adult antisocial personality disorder (4)(6).
What are the effects?
Acute effects of methamphetamine use include (2)(3)(6): euphoria; hyperactivity; restlessness and tremors; grandiosity; elevated body temperature and sweating; aggressive behavior; uncontrollable jaw clenching.
Chronic effects of methamphetamine use can include (2)(3)(6): paranoia; insomnia; psychosis; poor coping abilities; sexual dysfunction; dermatological conditions; "meth mouth" (widespread tooth decay and tooth loss, advanced tooth wear and fracture, and oral soft tissue inflammation and breakdown); burn injuries from lab accidents and explosions during production; chemical burns from contact with precursors or by-products of production.
Biologically-based causes of methamphetamine-induced mortality include stroke and cerebral hemorrhage, cardiovascular collapse, pulmonary edema, myocardial infarction, hyperpyrexia, and renal failure (4).
Cognitive and Neurobiological Effects
Prolonged use of methamphetamine is associated with changes to the brain and CNS through several general mechanisms: depletion of presynaptic monoamine reserves; down-regulation of neurotransmitter transporters and receptors; and neurotoxicity through reactive metabolic byproducts of dopamine and serotonin. Neurotoxicity can occur from as little as several days of methamphetamine exposure and may persist for months and even years (8). Even a sub-neurotoxic reduction of dopamine activity can produce the lingering motivational difficulties often encountered by patients in early-to-intermediate recovery (10). Another mechanism of methamphetamine-induced neurotoxicity is the substantial and prolonged release of the excitatory neurotransmitter glutamate triggered by acute ingestion (3).
Cognitive and Neurobiological Dysfunction in Abstinent Methamphetamine Users
During the first several weeks of abstinence, methamphetamine abusers have been found to display functional and structural changes to key brain regions that are associated with attention deficits, impaired visual pattern recognition, and impaired decision-making speed and accuracy (13). Abnormalities consistent with frontal lobe vascular damage are related to the amount and duration of methamphetamine use and may underlie the dysfunction in craving and compulsive behavior seen in methamphetamine addicts (14). Substantial impairment in attention/psychomotor speed, verbal learning and memory, and fluency-based measures of executive systems functioning has been reported (15). Metabolic brain abnormalities in the limbic and paralimbic regions observed in methamphetamine addicts may underlie the affective dysregulation often experienced in early recovery.
Methamphetamine is potentially neurotoxic to the developing fetus, and the lifestyle of methamphetamine-addicted mothers, who typically engage in poor prenatal care (i.e., consume cigarettes, alcohol and marijuana, or neglect proper nutrient intake), is a contributory factor. Infants born to methamphetamine-addicted mothers may exhibit methamphetamine withdrawal upon birth, with one study finding 49% of 134 methamphetamine-exposed infants exhibiting withdrawal symptoms (12). Neonates exposed to methamphetamine tend to exhibit lower birth weight, decreased head circumference, and overall decreased growth, as well as subsequent increased aggressive behavior, impaired social adjustment, deficits in the acquisition of mathematics and language skills, and poor visual recognition memory relative to non-methamphetamine-exposed infants (12). These infants also display reduced hippocampal and striatal nuclei volume associated with long-term emotional and behavioral dysfunction (4). Methamphetamine-exposed children often exhibit deficits in brain development, including significantly smaller subcortical brain volume corresponding with significantly worse scores on measures of visual motor integration, attention, verbal memory, and long-term spatial memory compared with healthy infants (13).
Any stimulant drug can induce psychotic symptoms if used in high doses over several days. However, methamphetamine use is associated with more severe and protracted delusions and paranoia than cocaine and other stimulants. Psychotic symptoms are associated with both methamphetamine use and methamphetamine withdrawal. Most users of methamphetamine develop psychoses, typically auditory hallucinations, persecutory delusions, and delusions of reference, within one week of continuous use (16). Continued use results in further loss of insight, increased psychoses, and possible violent behavior. Although psychotic symptoms resolve within 96 hours following cessation for many users, a sizeable percentage of patients remain psychotic for months or even years after they stop using the drug (18). Methamphetamine-induced psychoses are believed to be due, in part, to the level of methamphetamine metabolites in the bloodstream and excess synaptic dopamine. The condition is usually indistinguishable from paranoid schizophrenia. Compared with nonpsychotic methamphetamine addicts, patients with methamphetamine-induced psychoses are more likely to be diagnosed with major depression, alcohol dependence, and antisocial personality disorder, with earlier and heavier use of methamphetamine positively correlated with the development of psychoses. Neurological morbidity, such as traumatic brain injury, birth trauma, learning disabilities, and soft neurological signs (e.g., poor balance and coordination), is associated with treatment-resistant methamphetamine psychoses (4). Psychoses and paranoia can develop from stimulant abuse in persons without pre-existing psychotic symptoms. However, patients with a psychotic disorder are most vulnerable to stimulant-induced psychoses, with 50% to 70% of patients diagnosed with schizophrenia or psychoses exhibiting a psychotic response to a single dose of a stimulant drug, even with antipsychotic pretreatment (18).
Aggressive and Violent Behavior
The acute effects of methamphetamine can include irritability, agitation, hypervigilance, and possibly violent outbursts, and chronic use of methamphetamine has a greater association with violent behavior than any other psychoactive drug (8). Biological factors play a role in methamphetamine-induced violent behavior, with alteration in serotonin, dopamine, and norepinephrine levels being implicated. A study of more than 1,000 methamphetamine outpatients found that 11.7% experienced difficulty in controlling violent behavior in the past month, with no significant gender differences (17). Violence is also associated with methamphetamine-induced psychoses (17)(18). A community sample of 205 methamphetamine users in Los Angeles County found that 26.8% (30% male, 23% female) committed acts of violence under the influence of methamphetamine, including acts of domestic, drug-related, or gang-related violence or random acts of violence, such as road rage or stranger assault (18). Although methamphetamine use creates the clear potential for violent behavior, the authors of the study emphasize that violent behavior is not an inevitable outcome of even heavy, long-term methamphetamine use.
Withdrawal from Methamphetamine
The fourth edition of the American Psychiatric Association's Diagnostic and Statistical Manual (DSM-IV-TR) does not distinguish symptoms of methamphetamine withdrawal from that of cocaine or other stimulant drug withdrawal (25). Withdrawal from methamphetamine is generally characterized more by psychiatric symptoms than physical symptoms (4). Catecholamine depletion is believed to underlie the withdrawal/protracted abstinence syndrome, which may persist for more than 12 months beyond complete cessation of methamphetamine use. The associated withdrawal syndrome consists of several symptom clusters:
The prominence and duration of the anhedonia, irritability, and poor concentration associated with methamphetamine withdrawal has been characterized as an apathy syndrome rather than a depression-mediated syndrome. This symptom cluster is also observed in neuropsychiatric disorders associated with dysregulated brain dopamine systems, such as Parkinson's disease, Huntington's disease, and progressive supranuclear palsy. The treatment implications for this are compelling, as pharmacotherapy for apathy syndromes involves dopaminergic agents that are generally distinct from antidepressant agents.
Methamphetamine Addiction Management:
Compared to other stimulants, the progression to methamphetamine addiction is accelerated, particularly the time from initial use to regular use and regular use to first treatment. Effective treatment of methamphetamine-dependent patients poses many challenges. Referral to treatment is vital for all methamphetamine users, as effects can be devastating and long-term. Available treatment modalities include psychosocial therapy and pharmacotherapy. It is also important to consider the needs of special populations (women, gay/bisexual individuals, patients who are HIV positive, and those that live in rural areas), as these needs will affect adherence to and effectiveness of treatment. Most patients will benefit from involvement in a 12-step program, which can enhance the quality of social support and the social network of the member, a potentially highly reinforcing aspect that would be forfeited if drug use is resumed.
Although amphetamines and methamphetamine have been abused for over 60 years, effective treatment approaches have only recently emerged and are in the early stages of development and evaluation. Most have been borrowed from approaches effective in treating cocaine dependence, including cognitive-behavioral therapy (CBT), contingency management (CM), and the Matrix Model. Treatment of methamphetamine dependence is typified by the Matrix Model, which combines cognitive, behavioral, and psychological approaches and is delivered to the patient immediately following acute withdrawal. Effective treatment of methamphetamine-dependent patients poses many challenges, some of which are unique. For instance, poor treatment engagement and high treatment dropout rates, severe or ongoing paranoia or psychotic symptoms, high relapse rates, and intense protracted cravings, dysphoria, and anhedonia are among the commonly cited obstacles to success in this population (11). In addition to the medical, dental, relationship, occupational, child welfare, financial, and legal consequences associated with addiction to methamphetamine, this drug produces psychiatric and neurological consequences that are relatively unique, as well as a heightened risk of sexually transmitted infections (STIs), including HIV infection (2). Determining the most effective treatment components for methamphetamine addiction is complicated by the special needs of methamphetamine-using subgroups. Each special population has unique needs that should be addressed to optimize therapeutic outcome. This is illustrated by the culturally sensitive approach tailored for gay and bisexual men, termed gay-tailored cognitive-behavioral therapy (GCBT).
The Matrix Model
The Matrix Model was first conceptualized and developed during the 1980s in response to the overwhelming need for cocaine treatment programs, following evidence that the traditional private sector 28-day inpatient treatment programs for alcohol- and opioid-dependent patients were ineffective for patients with stimulant dependence (19). This model integrates several empirically validated interventions into a single treatment model, with pragmatics given priority and programs based on theory and ideology being avoided (18). The goals of the Matrix Model include stopping drug use, transmitting knowledge of issues critical to addiction and relapse to the patient, educating family members impacted by addiction and recovery, familiarizing patients with 12-step programs, and implementing drug and alcohol testing (19). Elements of the Matrix Model include:
These elements are incorporated into several treatment protocols, including individual sessions, early recovery groups, relapse prevention groups, family education sessions, 12-step meetings, social support groups, relapse analysis, and urine tests. In a multisite study across eight different communities, 978 methamphetamine-dependent outpatients were randomized to either the Matrix Model or conventional outpatient treatment (20). Conventional treatment was considered the best available option in the eight communities in which the study took place. Significant variation existed in the conventional outpatient conditions. Although subjects receiving the Matrix Model exhibited significantly better treatment retention, program completion, treatment engagement, more methamphetamine-free urine samples, and longer periods of abstinence during treatment than conventional treatment recipients, these differences did not persist into the post-treatment follow-up period. No differences were noted in methamphetamine-free urine at 6-months (69% of total urine samples methamphetamine-free in both groups). The authors state that although the Matrix Model resulted in a more rapid reduction in methamphetamine use and increased treatment utilization, comparing the Matrix Model to eight different types of comparison treatment conditions increased within-group variance and obscured differences among the groups.
Cognitive-Behavioral Therapy (CBT)
CBT is one of the most studied psychosocial approaches in the treatment of substance abuse disorders in general and non-methamphetamine stimulant abuse in particular. This approach integrates behavioral theory, cognitive social learning theory, and cognitive therapy. The rationale for CBT is the finding that craving for methamphetamine is triggered by exposure to conditioned cues and that the strength of cue response is a factor in relapse. CBT is delivered by a clinical psychologist or other licensed mental health professional in either an inpatient or outpatient setting. Most treatment programs for substance abuse in the U.S., and even 12-step programs such as Alcoholics Anonymous (AA), incorporate elements of CBT (19).
Gay-Tailored Cognitive-Behavioral Therapy (GCBT)
Developed and first evaluated in 2005 to address the dual concern of methamphetamine abuse and HIV-risk behavior, GCBT integrates the core features of CBT with an emphasis on behavioral and cultural aspects that are relevant to gay and bisexual men. Topics are gay-referent, and discussion of relapse triggers includes gay cultural events and environments. Group sessions cover topics such as sexual risk reduction, sexual behavior on and off of methamphetamine, and recognition of characteristics of sexual partners and significant others who do and do not use methamphetamine (21). Shoptaw et al. randomized 162 methamphetamine-dependent gay and bisexual men (52.2% of whom were HIV positive) to 16 weeks of CBT, CM, CBT plus CM, or GCBT to determine efficacy in reducing drug use and sexual risk behavior (19). Immediately post-treatment, GCBT group participants exhibited a significant reduction in unprotected receptive anal intercourse, and participants in the CM and CBT plus CM groups showed the greatest mean duration of methamphetamine-negative urine and the greatest total methamphetamine-negative urine samples. At one-year follow-up, all four groups displayed significant reductions in unprotected receptive anal intercourse relative to baseline, and there were no significant between group's differences for methamphetamine use, with all group's reporting significant reductions from baseline levels. Interestingly, employment and legal problems increased from baseline to end of treatment and follow-up. The data suggest that the culturally sensitive GCBT leads to the most rapid reduction in sexual risk behavior, while treatments containing CM result in the most rapid reduction in methamphetamine use, although reductions in sexual risk behavior and drug use were eventually achieved with all treatment approaches studied.
Contingency Management (CM)
CM is based on the behavioral theory that both desired and undesired behavior increase when they are reinforced. CM manipulates reinforcers to shape behavior in the desired direction. This type of therapy is used in outpatient settings and is provided by conventional chemical dependency treatment personnel. Patients are rewarded for submitting drug-free urine samples by receiving vouchers with progressively increasing value. The vouchers are ultimately exchanged for goods and services that promote a drug-free lifestyle, such as groceries, clothing, electronic equipment, or plane fare, but are not exchanged for cash (21). Studies comparing the effectiveness of different reinforcement schedules in promoting abstinence from methamphetamine found that an escalating schedule, whereby the reinforcement vouchers are progressively greater for each successive negative drug test with a reset contingency that reduces voucher value with evidence of drug use, is most effective. CM in the form of prize-based vouchers was added to usual care and compared with usual care only in a mixed sample of 415 cocaine- and methamphetamine-dependent outpatients (21). Subjects randomized to CM exhibited significantly greater treatment retention, increased counseling session attendance, and more frequent alcohol and drug-free urine tests. These individuals were also more likely to achieve 4, 8, and 12 weeks of continuous abstinence than control subjects. Although the authors state that CM increased treatment retention and improved drug-free outcomes, it remains unknown if these short-term benefits persisted when reinforcement was withdrawn (21).
The efficacy of conventional residential treatment with methamphetamine-dependent patients was studied (22). A sample of 199 methamphetamine abusers was admitted to an inpatient residential treatment setting for a mean stay of 86 days. Treatment consisted of group therapy, individual case management, and psychiatric assessment and referral in a semi-structured environment. The therapy was performed by trained chemical dependency counselors with knowledge of methamphetamine addiction. At 60 days following admission, significant reductions were observed on measures of anxiety (compulsions, obsessions, social phobia, generalized anxiety) and major depression. Approximately 25% of the sample was available for 6-month follow-up, with significant reductions in methamphetamine use noted through self-report. Conclusions of efficacy are severely limited by subject attrition and subjective, nonverifiable outcome measures.
Although many patients with methamphetamine addiction are coerced into treatment through criminal justice or child protection services pressure, little research has been completed about the outcome of such patients. A study evaluated the treatment outcomes of 350 outpatient methamphetamine abusers randomly selected from a large database of outpatient and residential treatment patients in Los Angeles County (22). Approximately 50% of the sample reported legal coercion as the motivation to enter treatment. Coerced clients remained in treatment longer but did not significantly differ from noncoerced clients in abstinence rates at 6-month follow-up (59% coerced versus 49% noncoerced). Although there were no significant differences between the groups in percentage of days of methamphetamine use or percentage of patients reporting complete abstinence at 24-month follow-up, the number of months in treatment was associated with a more positive outcome, suggesting a benefit of longer treatment programs for methamphetamine-dependent patients.
Pharmacotherapy and Biological therapy
There are currently no FDA-approved medications for the treatment of methamphetamine dependence. However, several potential strategies for pharmacotherapy of methamphetamine addiction have been identified. These strategies include targeting the depressed mood and drug craving associated with withdrawal, using drugs that elicit an aversive response when methamphetamine is ingested, using agents that block the positive effects of methamphetamine, treating the co-occurring conditions pharmacologically, and providing agonist therapy, in which a safer pharmaceutical amphetamine-type compound is substituted for methamphetamine.
Many methamphetamine withdrawal symptoms (fatigue, anhedonia, depressed mood, hypersomnia) simulate a major depressive episode, providing the rationale for the use of the selective serotonin reuptake inhibitor (SSRI) sertraline in methamphetamine patients. However, Shoptaw et al. found that outpatients receiving sertraline exhibited significantly worse outcomes in tested urine samples, group attendance, and ability to achieve three consecutive weeks of methamphetamine abstinence, with no reduction in depressive symptoms or cravings (23). These findings suggest that sertraline should not be given to methamphetamine users complaining of depression or depressive-like symptoms. It is possible that depressive symptoms in early methamphetamine abstinence may be a syndrome distinct from primary, non-methamphetamine-induced depression. Another randomized trial using the SSRI paroxetine to treat methamphetamine dependence was reported, 20 methamphetamine-dependent patients to either paroxetine 20 mg/day or placebo for 8 weeks (22). The substantial attrition rate (85%) prohibited any conclusions regarding efficacy to be drawn. However, the authors stated that the weight gain, sexual side effects, and sedation often induced by paroxetine and other SSRIs are opposite of the desired effects of methamphetamine, possibly heightening problems with patient acceptance and compliance with this class of medications. A randomized, placebo-controlled trial of mirtazepine, an antidepressant with presynaptic alpha2-adrenergic antagonist, serotonin 5-HT-1 agonist, serotonin 5-HT2 and 5-HT-3 antagonist, and histamine H1 antagonist properties, was performed to assess its impact on amphetamine withdrawal (6). Twenty amphetamine-dependent subjects detained in a short-term correctional facility received either mirtazepine (15-60 mg/day) or placebo for 14 days and were evaluated on days 3 and 14. Active treatment subjects exhibited significantly lower hyperarousal, anxiety, and total withdrawal scores compared with subjects receiving placebo, with no significant differences in depression between the groups. These results may indicate specificity for amphetamine withdrawal symptom reduction distinct from depression reduction with mirtazepine.
Norepinephrine and Dopamine Reuptake Blockers
As noted, chronic methamphetamine use can result in neuroadaptation in presynaptic dopamine neurons, manifesting as dysphoria, drug craving, and cognitive impairment in early abstinence. This indicates the possible utility of the dopamine and norepinephrine reuptake blocker bupropion. In a randomized, single-blind, placebo-controlled trial, 26 non-treatment-seeking subjects meeting the criteria for methamphetamine abuse or dependence received either a placebo two times per day or 150 mg extended-release bupropion two times per day for 6 days in addition to IV methamphetamine or placebo (22). Subjects were housed in a clinical research unit during the study. Compared with placebo, bupropion treatment was associated with reduced ratings of "drug effect," "high," and "desire to use," as well as reduced cue-elicited cravings. Although the sample was small and the results require replication, these findings suggest that bupropion may play a role in reducing craving for methamphetamine in early abstinence and may diminish relapse severity by limiting the reinforcing effects of methamphetamine.
Agonist Replacement Therapy
An approach consistent with the harm reduction model has been proposed by Shearer, Sherman, Wodak, and van Beek and involves prescribing dextroamphetamine to patients addicted to methamphetamine (11). The basis for this treatment is the success seen with agonist replacement therapy (methadone) treatment of heroin addiction and nicotine replacement therapy for smoking cessation. However, ideological and regulatory obstacles exist in the U.S. to the implementation of such a treatment regimen. Preliminary data from an investigation utilizing methylphenidate to treat withdrawal symptoms in non-ADHD, long-term prescription amphetamine abusers appears promising (22). Specifically, severe and protracted depression following amphetamine cessation was resolved with ongoing methylphenidate treatment at long-term (2- to 4-year) follow-up assessment.
GABA Receptor Agonists
GABA neurons decrease dopamine transmission in the nucleus accumbens and ventral tegmental mesolimbic regions, possibly decreasing the reinforcing effects of methamphetamine and providing the basis for trials of GABA agonists with methamphetamine-abusing patients. Heinzerling et al. reported the results of two GABA agonists, baclofen (20 mg three times per day) and gabapentin (800 mg three times per day), in a double-blind, randomized, placebo-controlled trial of 16 weeks duration (23). A total of 88 methamphetamine-dependent outpatients were randomized to either baclofen, gabapentin, or placebo, and all subjects attended clinic three times a week for assessment, counseling, and urine drug testing. There were no statistically significant differences in completion of the 16-week trial, reduction in depressive symptoms, craving of methamphetamine, or reduction in methamphetamine-positive urine samples between the groups. However, when patients with high protocol adherence were compared, baclofen recipients exhibited greater numbers of methamphetamine-negative urine samples relative to gabapentin and placebo subjects, suggesting a small but positive effect of baclofen in reducing methamphetamine use. Greater attendance of psychosocial therapy groups was also associated with decreased methamphetamine use across all three groups, underscoring the importance of psychosocial therapy augmentation of pharmacotherapy for methamphetamine addiction.
The safety and efficacy of another GABA agonist, gamma vinyl-GABA (GVG), was evaluated in a 9-week, open-label, pilot study involving 10 methamphetamine-dependent, 17 methamphetamine- and cocaine-dependent, and 3 cocaine-dependent subjects (23). Because GVG has not received FDA clearance in the U.S. due to concerns over concentric visual field defects associated with its use, the study was carried out in Mexico. A total of 18 subjects completed the trial. Of those 18, 16 subjects tested negative for methamphetamine and cocaine during the last 6 weeks, with a median of 42 days drug free for this group during the 63-day study period. Visual field defects were not observed during the study period. Although unblended and lacking a control group, these results are promising, especially in light of the absence of effective pharmacotherapy for methamphetamine addiction. However, more rigorous testing must be completed before any conclusions regarding efficacy and safety can be drawn.
The possible efficacy of the tricyclic antidepressant imipramine in improving treatment retention and drug use-related outcomes was tested in a randomized controlled trial of 32 methamphetamine-dependent outpatients (24). Participants received either 10 mg/day or 150 mg/day imipramine for 180 days in addition to counseling, medical care, and psychiatric support. Although patients receiving the 150 mg dose remained in treatment longer, no differences in craving, depression, percentage of methamphetamine-positive urine, days since last methamphetamine use, or study visit attendance were noted between the groups. These results suggest that imipramine may be ineffective as a treatment for methamphetamine dependence.
Mesolimbic dopamine pathways are believed to play a large role in the reinforcing properties of stimulant drugs, including methamphetamine, and serotonin (5-HT) may also contribute to the subjective effects of amphetamines. Based on the observation that dopamine-blocking agents attenuate the reinforcing properties of stimulant drugs in animal studies, the dopamine D2 blocker haloperidol and the D2 and 5-HT2 receptor antagonist risperidone were given to nonaddicted human subjects in a placebo-controlled trial to examine their possible efficacy in blocking the rewarding effects of methamphetamine (24). Neither drug was found to block the euphoric effects of methamphetamine, suggesting that the pleasurable and rewarding properties of methamphetamine are not mediated through dopamine D2 or 5-HT2 activation.
Treatment of Agitation Associated with Methamphetamine Abuse
Paranoid, psychotic, and depressive symptoms can be present during active methamphetamine use, persist into abstinence, and/or emerge during abstinence among methamphetamine patients. Therefore, it is important to frequently assess for and/or actively monitor these symptoms over the course of treatment (25). Patients with either severe psychiatric comorbidity or severe methamphetamine-induced psychiatric symptoms are unable to safely and effectively function as outpatients and must be admitted to an inpatient facility to undergo medical evaluation, treatment, and observation. Some patients require only 48 to 72 hours of observation for agitation, paranoia, anxiety, or psychotic symptoms to be properly evaluated and managed, while others exhibit symptoms that are not readily alleviated, even with optimal pharmacotherapy. Antipsychotic medications such as olanzapine may be necessary on a long-term basis.
Many methamphetamine patients have difficulty controlling angry and violent impulses, reflecting the importance in addressing these issues in treatment. The high rates of anger and violence in female methamphetamine abusers also underscore the importance of avoiding gender stereotypes and questioning female patients as thoroughly as male patients on these issues. Management strategies for aggressive and violent patients include:
Users in a state of methamphetamine-induced agitation or psychoses often present to the emergency department and require rapid sedation. In these cases, lorazepam IV or droperidol IV produce a similar magnitude of sedation within five minutes, with droperidol producing faster and more pronounced sedation and requiring fewer repeat dosings than lorazepam.
Alternative/Complementary Treatment of Methamphetamine Dependence
Self-Help and 12-Step Therapy
Twelve-step programs for stimulant and other drug abuse and dependence include Narcotics Anonymous (NA) and Crystal Meth Anonymous (CMA) and are modeled after Alcoholic Anonymous (AA), an abstinence-based support and self-improvement program that is based on the 12-step model of recovery. AA is widely considered the most successful treatment for alcoholism and has helped hundreds of thousands of alcoholics achieve sobriety (25)(26). The 12-step model emphasizes acceptance of addiction as a chronic progressive disease that can be arrested through abstinence but not cured. Additional elements of the AA model include spiritual growth, personal responsibility, and helping other addicted persons. By inducing a shift in the consciousness of the addict, 12-step programs offer a holistic solution and are a resource for emotional support. Part of the effectiveness of AA, NA, and CMA is rooted in their ability to provide a competing and alternative reinforcer to drug use. Involvement in a 12-step program can enhance the quality of social support and the social network of the member, a potentially highly reinforcing aspect that would be forfeited if drug use is resumed. Other reinforcing elements of 12-step involvement include recognition for increasingly durable periods of abstinence and frequent awareness of the consequences of drug and alcohol use through attendance of meetings. Research shows that establishing a pattern of 12-step program attendance early in treatment predicts the level of ongoing involvement. Thus, healthcare providers should emphasize and facilitate early engagement in a 12-step program (26). Twelve-step programs are not considered substitutes for treatment. Instead, they are organizations that provide ongoing support in maintenance of abstinence, personal growth, and character development.
Crystal Meth Anonymous (CMA)
Although a fairly new organization, CMA meetings can be found in over 114 metropolitan areas throughout the United States, Canada, New Zealand, and Australia. Only one study involving members of CMA has been published, not surprising considering it is a new organization. Lyons et al. primarily focused on the role of CMA on sexual behavior in a subpopulation of methamphetamine- and cocaine-abusing gay and bisexual men attempting to abstain from sex through 12-step program involvement. The qualitative study noted that many methamphetamine users have difficulty with sex in recovery because sex is so intimately associated with methamphetamine use. Although the reductions in stimulant use were not explicitly measured, data gathered from this study indicate that CMA involvement led to dramatic reductions in the number of sexual partners and the frequency of unprotected anal intercourse. The authors concluded that although the reductions in sexual risk behavior may not be entirely due to the teachings of CMA, the program appears to be a valuable forum to help methamphetamine- and cocaine-addicted persons work through issues, such as sex, that are intimately associated with their stimulant abuse. For additional information, please visit the CMA website at http://www.crystalmeth.org.
Unrelenting dysphoria and impaired motivation and cognition, common in methamphetamine patients, can complicate or derail the best available treatment. Poor prognosis and relapse are associated with (26):
For methamphetamine patients treated in outpatient settings, the abundant supply of illicit methamphetamine and the enticement of rapid relief from protracted withdrawal symptoms can result in resumption of methamphetamine use in the early stages of treatment. Treatment dropout often follows, before any benefit from psychotherapy or pharmacotherapy can be achieved. This is unfortunate because treatment retention is the single most robust predictor of positive treatment outcome in methamphetamine dependence (15)(26). Neurobiological factors associated with prognosis have been identified (26). Specifically, a significant correlation was found between vulnerability to methamphetamine relapse and the severity of degraded brain function in the region mediating decision-making capacity, autonomic arousal processes, guessing, selective attention, and distinguishing task-relevant from task-irrelevant events. Additionally, patients with more severe dopamine transporter depletion have been found to exhibit higher rates of relapse and treatment dropout.
Methamphetamine Use during Pregnancy
A remarkable increase in the incidence of methamphetamine-exposed pregnancies and related complications has been anecdotally reported. Recent U.S. study reported that in 1994, methamphetamine accounted for 8% of admitted pregnant women with substance abuse, rising to 24% by 2006. The majority of methamphetamine admissions occurred in the West (73%) among white (64%) unemployed (88%) women (27). Similar year-to-year increases have been noted internationally, particularly in Pacific-Rim countries such as New Zealand and Thailand. Methamphetamine use is associated with a risk of acute death, often as a result of hypertensive events such as cerebrovascular accident. Perinatal complications are not solely limited to clinical outcomes but also involved an apparent dramatic breakdown of expected mother-infant bonding as demonstrated by the exceeding high foster care and adoption rate. This study's (28) conclusion was the unusual demographic characteristics of the methamphetamine-using cohort. They are fairly distinct from the typical population, representing as noted an older, smoking, less educated, unemployed, white non-Hispanic woman with a probable history of domestic violence. This pattern of factors is so distinct that it may allow screening in a more directed manner those patients who may be methamphetamine users. Methamphetamine use in pregnancy is complicated by more morbid maternal and neonatal outcomes when compared with the general obstetric population. The incidence of methamphetamine use is rising; attempts to identify these patients early and intervene in an effort to improve pregnancy-related outcomes are warranted.
The epidemic of methamphetamine abuse has become more widespread than previous periods and has resulted in substantial medical, public health, social service, and criminal justice concerns. This wave of methamphetamine addiction has primarily afflicted persons who are white, and rural inhabitants of Western and Midwestern states. In addiction, urban-dwelling gay and bisexual males have experienced an alarming increase in methamphetamine abuse, resulting in rapid spread of HIV infection fueled by unsafe sexual practices. Thus, medical, mental health, and other healthcare professionals working in a variety of settings with a variety of patient populations are likely to encounter patients with a methamphetamine use disorder. However, devising and implementing effective treatments for patients addicted to these substances has posed a challenge, as the methamphetamine abuser generally differs from the typical patient for whom the 28-day inpatient model was designed in terms of demographics, disease characteristics, and resources. The knowledge gained from this review can greatly assist healthcare professionals in identifying, treating, and providing an appropriate referral to patients with methamphetamine use disorders.