Methamphetamine Use Disorder (MUD)
MUD is known to be associated with abnormalities in the PFC. Here, the subject of focus on this and other mechanisms thought to be responsible for behaviors that reflect impulsivity, drug salience and prioritization.
MUD Diagnosis
According to the DSM-5-TR, diagnosis of MUD requires meeting at least two of eleven criteria, indicating a problematic pattern of use resulting in significant impairment or distress.
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Some of these criteria are categorized and summarized here.
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Methamphetamine is rarely prescribed in the US due to its high risk for adverse effects and misuse, but it may be prescribed for conditions, such as narcolepsy. For this reason, pharmacological criteria are not to be solely considered for diagnosis of MUD if the medication is used appropriately under medical supervision.
Social Impairment
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Stimulant use continues despite social or interpersonal problems caused or exacerbated by stimulants
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Giving up or reducing social, occupational, or recreational activities because of stimulant use
Risky Use
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Continuing stimulant use despite knowledge of having physical or psychological consequences of stimulants
Impaired Control Over Use
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Using more, or over a longer period, than intended
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Craving/strong desire to use stimulants
Pharmacological Criteria
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Tolerance (more of the stimulant is needed to achieve intoxication or desired effects)
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Withdrawal syndrome (may include dysphoria, sleep disturbances, cognitive deficits, increased anxiety, and craving)
Pharmacological Effects of Methamphetamine (METH)
METH, a potent synthetic psychomotor stimulant belonging to the amphetamine class, exerts profound sympathomimetic effects on the nervous system. It can be ingested orally, smoked, snorted, or injected. Intravenous injection or smoking, in particular, leads to immediate and intense euphoria.
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The acute effects of METH include heightened alertness, increased heart rate, elevated blood pressure and body temperature, and decreased appetite. Chronic use, however, can result in many severe health issues, such as tooth decay, infection, weight loss, malnutrition, kidney damage, respiratory problems, paranoia, depression, anxiety, violent behavior, and psychosis (Meyer et al., 2023). Some of these symptoms may persist for years following cessation of METH use (Prakash et al., 2017).
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METH acts as an indirect agonist of the catecholaminergic systems (norepinephrine, dopamine, and serotonin) by inducing the release of catecholamines from nerve terminals (Meyer et al., 2023). This excess of catecholamines has the potential to cause damage to axon terminals (Prakash et al., 2017).
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The mechanism of METH's action involves its entry into nerve terminals, partially facilitated by the dopamine transporter (DAT). Once inside, METH blocks DAT and the vesicular monoamine transporter 2 (VMAT2), preventing dopamine reuptake and causing dopamine release into the synaptic cleft (Volkow et al., 2024). High doses of METH are neurotoxic to dopamine- and serotonin-producing neurons in rodent studies (Prakash et al., 2017). Imaging studies have shown significant reductions in dopaminergic and serotonergic reuptake transporters in abstinent METH users for up to 3 years post-cessation (Prakash et al., 2017).
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METH can penetrate and damage the blood-brain barrier (BBB) directly by altering the stability of protein structures and indirectly by increasing body temperature, oxidative stress, and inflammation (Prakash et al., 2017). In vivo and in vitro experiments have linked chronic METH use to damage in oligodendrocytes (Zeng et al., 2023). Transcriptome profiling studies in mice exposed to METH revealed significant alterations in gene transcription, particularly the downregulation of genes related to mitochondrial structure and function in the prefrontal cortex (Zeng et al., 2023).
The neurotoxic effects mentioned here are thought to play a role in the structural and functional changes seen in the brains of individuals with MUD. The precise mechanisms underlying these changes and whether they are region-specific are not fully understood (Kauer & Malenka, 2007). Nevertheless, chronic METH use has been consistently linked to significant damage in the Prefrontal Cortex (PFC) (Meyer et al., 2023). These changes in structure and function are believed to impair the brain's ability to inhibit maladaptive behaviors and prepotent responses.
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Moreover, while individuals with MUD may exhibit complex problem-solving abilities in contexts related to obtaining drugs, this underscores simultaneous changes associated with heightened salience, potentially leading to interpersonal or social difficulties. This phenomenon is not unique to METH but extends to all addictive substances involving the reward pathway, particularly the Ventral Tegmental Area (VTA). Substantial evidence suggests that disruptions in the NMDA/AMPA receptor activity balance contribute to synaptic plasticity alterations within the reward circuitry (Volkow et al., 2023; Kauer & Malenka, 2007).
Future Directions
Further exploration into the mechanisms of METH on the neural circuits is needed, as well as the immune and gastrointestinal effects, that may provide insight into the neuropsychiatric symptoms of MUD. Currently, there are no pharmacotherapies available as an effective treatment option. As METH use is known to affect the immune system, immunotherapies (vaccines) have been developed and shown promise, but none have reached phase III clinical trials. According to some researchers, combating MUD with mindfulness may be an effective treatment option, as it has been shown to promote neuroplasticity in adults (Chmiel et al., 2024).