Neurobiology, Clinical Presentation, and Treatment of Methamphetamine Use Disorder: A Review

Abstract

Importance: The prevalence of and mortality associated with methamphetamine use has doubled during the past 10 years. There is evidence suggesting that methamphetamine use disorder could be the next substance use crisis in the United States and possibly worldwide.

Observation: The neurobiology of methamphetamine use disorder extends beyond the acute effect of the drug as a monoaminergic modulator and includes intracellular pathways focused on oxidative stress, neurotoxic and excitotoxic effects, and neuroinflammation. Similarly, the clinical picture extends beyond the acute psychostimulatory symptoms to include complex cardiovascular and cerebrovascular signs and symptoms that need to be identified by the clinician. Although there are no pharmacologic treatments for methamphetamine use disorder, cognitive behavioral therapy, behavioral activation, and contingency management show modest effectiveness.

Conclusions and relevance: There is a need to better understand the complex neurobiology of methamphetamine use disorder and to develop interventions aimed at novel biological targets. Parsing the disorder into different processes (eg, craving or mood-associated alterations) and targeting the neural systems and biological pathways underlying these processes may lead to greater success in identifying disease-modifying interventions. Finally, mental health professionals need to be trained in recognizing early cardiovascular and cerebrovascular warning signs to mitigate the mortality associated with methamphetamine use disorder.

Figure 1:

Summary statistics of articles published mentioning methamphetamine and past year methamphetamine use from 2009-2019

Figure 2:

Methamphetamine-induced changes in synaptic and intracellular pathways. Methamphetamine increases dopamine in the synaptic cleft and the cell via its effects on the cell surface dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT), respectively. Methamphetamine: (1) directly alters mitochondrial fusion and fission via sigma-1 receptor (σ_1R binding leading to an increase in reactive oxygen species (ROS); (2) increases glutamatergic (GLU) transmission, which via increased intracellular calcium (Ca²⁺) and nitric oxide synthase (nNOS) leads to endoplasmic reticulum (ER) stress; and (3) binds to the toll-like 4 (TLR4) receptor to activate inflammatory pathways via nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and tumor necrosis factor receptor associated factors (TRAF) to produce pro-inflammatory cytokines (IL6).