Amphetamines are a group of central nervous system (CNS)-stimulating drugs that include dextroamphetamine (Dexedrine), 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, anorexigenic, 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 [2]. Methamphetamine rapidly and efficiently crosses the blood-brain barrier because it is highly lipid-soluble [3].

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 [1,4]. 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 and hunger [4]. 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 and pharmaceutical industry made its surplus methamphetamine widely available, flooding the civilian market and resulting in the first methamphetamine epidemic (1945–1957). By 1954, an estimated 2 million Japanese were addicted to intravenously administered methamphetamine, with roughly 10% exhibiting symptoms of methamphetamine-induced psychosis [1,5]. 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 [5]. Widespread methamphetamine use persists in Japan, with methamphetamine-related crime accounting for 86% of all drug arrests in 2011 [6]. However, methamphetamine abuse in Japan is modest compared to Western countries [7].

In the United States, 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 [1,5]. Amphetamines were available over-the-counter in the United States 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 [5]. Until this period, the illicit market was comprised mainly of drugs diverted from pharmaceutical companies, distributors, and physicians. In 1962, amid growing concern over the abuse of amphetamine/methamphetamine, the U.S. Food and Drug Administration (FDA) launched an education campaign [1].

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 (dextromethamphetamine). By the mid-1990s, domestic and Mexican "superlabs," producing 10-plus pounds of high-purity methamphetamine within a 24-hour period, began competing with the more numerous small-scale labs [3]. Many of the precursor substances for these operations, such as pseudoephedrine, originate from Southeast Asia and Central Europe and are supplied through international trafficking organizations. The massive amount of money generated from such distribution and sales leaves the United States and is laundered by criminal organizations [1].

Data from the 2021 National Survey of Drug Use and Health indicate that approximately 2.5 million individuals (0.6% of the population) 12 years of age or older had used the drug in the past year, 1.6 million were current users, and 101,000 were new users [15]. According to data from the 2016 Monitoring the Future (MTF) survey, which examines adolescent drug use and attitudes, approximately 0.5% of 8th, 10th, and 12th graders had used methamphetamine in the past year [16]. This indicates that high school-age students are using methamphetamine less than they did five years ago. Overall, use of methamphetamine by adolescents has declined significantly since 1999, when the drug was first added to the MTF survey [16]. However, illicit use of other amphetamines is significantly higher among 8th, 10th, and 12th graders, with 3.5%, 6.1%, and 6.7% annual prevalence, respectively.

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; or reduce weight [27].

Inhibitors of the 2D6 isoenzyme can decrease the rate of methamphetamine elimination, while potential inducers could increase the rate of elimination [30]. 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 [10]. 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) and p-OH-amphetamine and norephedrine (both inactive) [30].

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 [38]. Methamphetamine is primarily available as [2]:

"Meth mouth" is widespread among certain populations of methamphetamine users, particularly those incarcerated for methamphetamine-related offenses [47]. "Meth mouth" (dental deterioration) is a constellation of signs and symptoms associated with chronic use of methamphetamine and is caused by methamphetamine-induced vasoconstriction and reduced salivary flow, methamphetamine-induced vomiting, jaw clenching, the high intake of sugary beverages often seen with methamphetamine users, and abandonment of oral hygiene. This condition is characterized by widespread tooth decay and tooth loss, advanced tooth wear and fracture, and oral soft tissue inflammation and breakdown [47].

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 [80]. 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 [80].

The fifth edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) does not distinguish symptoms of methamphetamine withdrawal from that of cocaine or other stimulant drug withdrawal [85]. 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 [4]. The associated withdrawal syndrome consists of several symptom clusters [76,86]:

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 [91,92]. 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 [90,92]. 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 [88,93].

The substantial cognitive dysfunction in many methamphetamine-dependent patients early in recovery makes engagement and participation in psychosocial-based treatment difficult. Effective pharmacotherapy has the potential to substantially improve patient comprehension and engagement in treatment, as well as improve treatment retention and reduce relapse to methamphetamine use [4]. 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 [119].

Although the number of female methamphetamine users seeking treatment is nearly comparable in number to men, women often display special needs, including high frequencies of personal and social disadvantage, psychiatric illness, sexual risk behavior, and history of sexual and/or physical abuse [24,84,153]. It is imperative that these special needs be assessed and addressed by treatment providers. Failure to address physical and sexual abuse issues and associated psychiatric disorders, such as post-traumatic stress disorder, may contribute to resumption of chemical use [84]. Gender differences in the motivation to use methamphetamine have also been found, with women more likely to use methamphetamine for weight loss and energy enhancement and men more likely to use methamphetamine for increased work productivity and sexual enhancement [40].

In the United States, methamphetamine abuse by gay and bisexual men is endemic in urban settings, where its use is profoundly intertwined with sexual and social behavior. Rates of use in this population are 5 to 10 times that of the general population [154]. It has been hypothesized that methamphetamine's effects of stimulating energy, confidence, and libido may be particularly effective in counteracting depression or fatigue [155]. This, coupled with the drug's relative inexpensiveness, may make methamphetamine particularly attractive to gay and bisexual men and/or persons with HIV [155]. Methamphetamine use can also increase the frequency and duration of sexual encounters and result in the abandonment of safe sex practices [156]. Consequently, methamphetamine-dependent gay and bisexual men are at heightened risk of STIs, in particular HIV transmission [20]. The issues surrounding concurrent methamphetamine use and hypersexuality among gay and bisexual men does not lend itself to discussion in a mixed group setting with heterosexual men, which could increase the likelihood of poor treatment engagement and early dropout [93].

Treatment of gay or bisexual methamphetamine users can be complicated by the presence of HIV infection. In these patients, the onset and severity of the medical, neurologic, and neurocognitive consequences of methamphetamine use can be accelerated. In addition, increased viral load and decreased compliance with antiretroviral therapy, possibly resulting in rebound of viral replication and the development of resistance to antiretroviral drugs, is common [160,161]. However, abstinent methamphetamine abusers who adhere to antiretroviral therapy can suppress HIV replication, underscoring the need to properly engage HIV-positive methamphetamine abusers in treatment [162]. Many methamphetamine abusers are also afflicted with hepatitis C virus, and the negative effects of hepatitis, HIV, and methamphetamine abuse on neurocognitive functioning are synergistic [163].

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 [166]. Patients with either severe psychiatric comorbidity or severe methamphetamine-induced psychiatric symptoms are unable to safely and effectively function as outpatients and should 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 [93,167].

Many patients who use methamphetamine 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 about these issues [77]. Management strategies for aggressive and violent patients include [168]:

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 [169].

Twelve-step programs for stimulant and other drug abuse and dependence include Narcotics Anonymous (NA) and Crystal Meth Anonymous (CMA) and are modeled after AA, an abstinence-based support and self-improvement program that is based on the 12-step model of recovery. AA has helped hundreds of thousands of alcoholics achieve sobriety [170]. 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 [170].

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 [171]. 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 [172]. 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.

For patients being treated for methamphetamine abuse 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 [57,177].