The use of methamphetamine, a highly addictive psychostimulant, continues to grow with devastating effects throughout the United States and worldwide. The use of the drug soared in the 1990s, mainly in the midwestern and western parts of the USA, eventually reaching epidemic status in the early 2000s [9]. In an attempt to temper the use and production of methamphetamine, many state governments began limiting over-the-counter access to methamphetamine precursor products such as pseudoephedrine in 2004 [10]. The federal government followed closely behind with federal legislation to impose the same limits in 2006 [10]. These regulations did cause methamphetamine use and laboratory incidents to trend downward for a few years; unfortunately, the 12-month prevalence of methamphetamine use by persons 12 years and older increased by 195% from 2010 to 2018 in the USA [11]. The prevalence of methamphetamine use, in 2019, was 0.7% which showed no significant increase from 2018. Recent data from the National Survey on Drug Use and Health (NSDUH) regarding methamphetamine use in the USA concluded that the number of people with stimulant use disorder methamphetamine type was 1,048,000 in 2019 [12]. This is a significant increase as compared with the data from 2016, which showed 684,000 people with stimulant use disorder methamphetamine type [12]. Two million people 12 years or older reported using the drug in the past year [12]. Overall, methamphetamine has a strong presence throughout the United States, which indicates that this psychostimulant will continue to be a significant component of the drug epidemic for years to come.

Methamphetamine works through various mechanisms to increase the availability of catecholamine neurotransmitters, including dopamine and norepinephrine, in nerve terminals in the central nervous system (CNS) and peripheral nervous system (PNS) [13]. Amphetamines, including methamphetamine, act as substrates for the plasmalemma dopamine transporter (DAT), allowing admittance into dopaminergic pre-synaptic terminals [14,15]. After amphetamines are in the presynaptic terminal, they interact with vesicular monoamine transporter 2 (VMAT2) to trigger dopamine release into the cytosol, disrupting the pH balance [16]. Following the release, cytosolic dopamine concentrations remain high because amphetamines also interfere with the vesicular reuptake of the catecholamine via VMAT2 [17]. Catecholamines are metabolized by the mitochondrial enzyme monoamine oxidase (MAO); methamphetamine interferes with MAO function to inhibit the metabolism of catecholamines [18]. The result of increased availability and decreased metabolism is a massive abundance of catecholamines released in synaptic clefts, which can produce a variety of physiologic consequences including addiction, psychiatric changes, neurologic damage, cardiovascular damage, and gastrointestinal damage [19].

Multiple studies have linked long-term methamphetamine use to alterations of brain structure and biochemistry [20]. The common consequences of these changes have included impairments of memory, learning, language skills, motor skills, and visuo-constructional abilities; high rates of psychiatric manifestations including psychosis, anxiety, and depression have also been observed [21,22,23]. Methamphetamine also has been shown to deplete dopamine, serotonin, and their metabolites in several brain regions [24]. The possible mechanisms of methamphetamine-induced brain changes are neurotoxicity and inflammation [25]. Excess dopamine auto-oxidizes in the cytoplasm of neurons, enabling significant production of reactive oxygen species [26]. Subsequent oxidative stress leads to significant dysfunction of neurons, terminal degeneration, and apoptosis [27]. Psychostimulants also cause excitotoxic damage by stimulating glutamate release [26,28].

Methamphetamine is proposed to upregulate inflammatory processes, in part, by activating toll-like receptor 4 (TLR4) [29]. The TLR4 signaling pathway is a well-studied component of the innate immune system’s proinflammatory cytokines and chemokines [30]. Methamphetamine-induced TLR4 signaling increases NF-κB activation of microglia and mRNA expression for the proinflammatory cytokine IL-6 in the ventral tegmental area (VTA) [29]. The downstream effect of this TLR4-IL-6 signaling in the VTA is neuroinflammation and an elevation of dopamine in the NAc shell [29]. These mechanisms of dopamine-induced neurotoxicity and inflammation cause disruption of endogenous dopamine signaling by destroying post-synaptic neurons and dopamine terminals [26].

Long-term methamphetamine abusers have been found to have reduced striatal dopamine levels [31]. A further study concluded that the dopamine levels in the putamen were as severely diminished as liken to people with Parkinson’s disease [32]. Morphological changes visible on MRI also provide evidence for neurotoxicity from methamphetamine use. Prominent changes include decreased hippocampal sizes, enlarged striatum, and loss of grey matter in cingulate and limbic cortices [33,34].