Clinical Review & Education

JAMA Psychiatry | Review

Neurobiology, Clinical Presentation, and Treatment

of Methamphetamine Use Disorder
A Review
Martin P. Paulus, MD; Jennifer L. Stewart, PhD

Supplemental content
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 Author Affiliations: Laureate
Institute for Brain Research, Tulsa,
underlying these processes may lead to greater success in identifying disease-modifying Oklahoma (Paulus, Stewart);
interventions. Finally, mental health professionals need to be trained in recognizing early Department of Community Medicine,
cardiovascular and cerebrovascular warning signs to mitigate the mortality associated with The University of Tulsa, Tulsa,
Oklahoma (Paulus, Stewart).
methamphetamine use disorder.
Corresponding Author: Martin P.
Paulus, MD, Laureate Institute for
JAMA Psychiatry. doi:10.1001/jamapsychiatry.2020.0246 Brain Research, 6655 S Yale Ave,
Published online April 8, 2020. Tulsa, OK 74136 (mpaulus@
laureateinstitute.org).

I
n the wake of the opioid crisis, methamphetamine has re- methamphetamine use disorder (MUD). This review focuses on 3
emerged as a challenge to mental health clinicians and research- specific aspects of MUD. First, the neurobiology of methamphet-
ers alike. Methamphetamine is now available in different forms amine is more complex than the traditional view of it as a monoami-
such as ice, powder, and pills, with different pharmacokinetic char- nergic modulator. Second, the clinical presentation is not limited to
acteristics that make them popular among certain types of the symptoms associated with use disorder but extend to medical
individuals.1 Recent seizure data suggest that methamphetamine presentations, most notably the cardiovascular and cerebrovascu-
production and trafficking are spreading into new areas of the globe.2 lar systems. Third, pharmacologic interventions focused on modu-
According to the Automation of Reports and Consolidated Orders lating the monoaminergic pathways have largely failed, and new
System, methamphetamine consumption increased 4-fold be- pharmacologic approaches are necessary to focus on novel treat-
tween 2015 and 2016 and total stimulant use doubled in the last ment targets. In the final section, several suggestions will be pro-
decade.3 From 2011 through 2016, the age-adjusted rate of drug over- posed for both clinicians and researchers to advance the under-
dose deaths involving methamphetamine more than tripled.4 More- standing of MUD.
over, drug overdose deaths involving cocaine, amphetamines, or
both substances combined increased 42.4% from 12 122 in 2015 to Biological Pathways, Neural Basis, and Cognition
17 258 in 2016.5 Based on the most recent data from the National Methamphetamine has been conceptualized primarily as a
Survey on Drug Use and Health,6 the 12-month prevalence of indi- releaser of dopamine, serotonin, noradrenaline, and adrenaline
viduals aged 12 years or older reporting methamphetamine use has from nerve terminals in the central and peripheral nervous
increased by 195% from its low in 2010 to 2018 (Figure 1), and it is system,9 which occurs via several different mechanisms, including
estimated that 1.86 million Americans used methamphetamine in (1) redistributing catecholamines from synaptic vesicles to the cyto-
2018. These numbers underline the importance of paying atten- sol, (2) reversing the plasma membrane transport of neurotrans-
tion to the possibility of the next substance use crisis. However, mitters, (3) blocking the activity of monoamine transporters, (4)
whereas opioid use disorder can be treated pharmacologically7 and decreasing the expression of dopamine transporters at the cell sur-
behaviorally,8 there are significant challenges for the treatment of face, (5) inhibiting monoamine oxidase activity, and (6) increasing

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 Clinical Review & Education Review Neurobiology, Clinical Presentation, and Treatment of Methamphetamine Use Disorder

Figure 1. Summary Statistics of Articles Published Mentioning Methamphetamine and Past-Year Methamphetamine Use From 2009 to 2019

A Articles in PubMed B Individuals who used methamphetamine in past year

2000 2000

1600 1600

Individuals , No.
1200 1200
Articles, No.

800 800

400 400

0 0
2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Year Year

Figure 2. Methamphetamine-Induced Changes in Synaptic and Intracellular Pathways

Presynaptic terminal

Microglia

Meth
σ1R VMAT

DA

3 DAT
ROS Meth

TLR4 Methamphetamine (Meth) increases

dopamine in the synaptic cleft via its
effect on the cell surface dopamine
(DA) transporter (DAT) and increases
Meth
GLu 12
TRAF DA in the the cell via its effect on the
vesicular monoamine transporter
NFKB (VMAT). Methamphetamine (1)
1
Meth directly alters mitochondrial fusion
Ca2+ and fission via sigma-1 receptor (σ1R)
σ1R
IL6
IL6 binding, leading to an increase in
IL6
nNOS reactive oxygen species (ROS);
IL6
Meth
σ1R (2) increases glutamatergic (GLu)
ER stress
transmission, which via increased
ROS
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
κ–light-chain enhancer of activated B
cells (NFκB) and tumor necrosis
factor receptor–associated factors
Postsynaptic terminal (TRAF) to produce proinflammatory
cytokines (interleukin 6 [IL-6]).

the activity and expression of tyrosine hydroxylase, the critical described as oxidative stress, neurotoxic and excitotoxic effects,
enzyme for synthesizing dopamine.10 However, there has been a and neuroinflammation11 (Figure 2).
substantial expansion of methamphetamine-associated neurobio- For example, mitochondria are theprimary sites of oxidative
logical targets during the past decade. Methamphetamine modu- metabolism and are organized in a tubular, dynamic network that
lates at least 3 different molecular cascades, which have been undergoes continuous remodeling via fusion or fission.12 Metham-

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 Neurobiology, Clinical Presentation, and Treatment of Methamphetamine Use Disorder Review Clinical Review & Education

phetamine induces changes in morphologic characteristics of mi- identify modifiable drug targets to develop novel pharmacologic
tochondria in neurons and microglia, which disturbs the mitochon- interventions for MUD.
drial homeostasis, morphologic characteristics, and oxidative stress Others have proposed that compulsive drug taking is associ-
metabolism toward an increase in oxidative burden conducive to ated with an imbalance between an orbitofrontal cortex–
neurodegeneration. 13 Methamphetamine also causes single- dorsomedial striatal “go” circuit and an opposing dorsolateral frontal–
strand and double-strand breaks in DNA owing to reactive oxygen striatal “stop” circuit.24 Numerous studies have focused on examining
species, leading to persisting alterations at the chromosomal level evidence of structural and functional alterations within these cir-
at blood concentrations that are observed in individuals taking cuits. For example, individuals taking methamphetamine show wide-
methamphetamine.14 Methamphetamine-induced neuroinflamma- spread gray and white matter alterations, particularly affecting the
tion is partially mediated by direct binding to the toll-like receptor frontostriatal system,25 as well as prominent reductions in the left
4 transmembrane protein within the ventral tegmental area, which superior temporal gyrus and the right inferior parietal lobe that pro-
has the downstream effect of elevating dopamine levels in the nucleus vide contextual information to the dorsolateral frontal circuits.26
accumbensshell.15 Theinflammatorychangesinthebrainoccurlargely Moreover, abnormalities include deficits in markers of dopaminer-
in microglia (ie, the primary cells of active immune defense in the cen- gic and serotonergic neurotransmitter systems, differences in glu-
tral nervous system). The inflammasome is a molecular system that cose metabolism, and deficits in gray matter.27 Individuals taking
consists of the sensing molecule NLRP3, the adaptor apoptosis- methamphetamine on a long-term basis show aberrant patterns of
associated speck–like protein, and the executive enzyme cas- brain connectivity and function within both the orbitofrontal-
pase-1. Methamphetamine upregulates caspase-1 and apoptosis- striatal and dorsolateral frontal–striatal systems when engaged in
associated speck-like protein aggregation, which promotes cognitive tasks and at rest.28 Functional neuroimaging studies have
inflammasome-mediated interleukin 1β maturation and secretion, shown that individuals taking methamphetamine show changes in
mediating microglia-induced neurotoxic effects.16 This process also the orbitofrontal cortex during empathic processing,29 in salience
occurs in several conditions ranging from neurodevelopmental dis- and dorsolateral frontal functioning areas during decision
orders to neurodegenerative disorders.17 making,30,31 and in both the dorsolateral and inferior frontal areas
More important, the methamphetamine-induced cellular dys- during inhibitory processing.32 Lower corticostriatal connectivity as
regulation in neurons and microglia may be associated with neural measured by resting-state functional magnetic resonance imaging
processing,18 altered reward motivation due to sickness behavior,19 has been associated with a higher concentration of peripherally mea-
and reduced prefrontal control20 that, together, may be associ- sured cytokines,33 which may provide evidence for the link be-
ated with the development and maintenance of drug-taking tween neuroinflammation and brain processing changes in MUD. Al-
behavior.21 Methamphetamine-induced neurotoxic effects have though functional brain activation differences during various
been hypothesized to be the result of interdependent mecha- behavioral tasks among individuals with MUD have been used to as-
nisms, including (1) excessive dopamine, resulting in an increased sess relapse,34-36 none of these measures have thus far been clini-
production of reactive oxygen species, such as peroxides, that can cally useful37 (ie, none have been able to aid in the diagnosis, prog-
damage cell structures; (2) ubiquitin-proteasome system dysfunc- nosis, or treatment of the disorder.38)
tion, activating intracellular degradation systems leading to au- The association of methamphetamine with cognition has been
tophagy; (3) protein nitration, leading to an increase in radical nitric heavily debated,39 and a dearth of longitudinal studies makes it dif-
oxide with subsequent cytotoxic effects; (4) endoplasmic reticu- ficult to assess whether the observed cognitive dysfunctions are
lum stress, leading to increased apoptosis; (5) increased tumor pro- preexisting, a consequence of the exposure, or a consequence of
tein p53 expression in the striatum, altering DNA repair, arresting behaviors that are associated with substance use disorders in gen-
cell cycles, and dysregulating the expression of stress response eral. Nevertheless, several recent studies provide a more cohesive
genes; (6) inflammatory cytokines, leading to inflammatory activa- picture of the cognitive problems that exist both shortly after ces-
tion in the brain; (7) activation of the dopamine D3 receptor, result- sation of use and, to some extent, after longer periods of absti-
ing in hyperthermia; and (8) microtubule deacetylation, disrupting nence. For example, individuals with MUD in early abstinence but
the blood-brain barrier.22 after the acute withdrawal period show poorer performance on
Together, these neurobiological cascades of oxidative stress, tasks examining motor and processing speed, verbal fluency, and
neurotoxic and excitotoxic effects, and neuroinflammation are attention.40 Even after prolonged abstinence, individuals with
associated with a unique metabolic state of the brain that has MUD perform more poorly than matched comparison individuals
been termed the Warburg effect (ie, when cells favor metabolism on learning efficiency, visual-spatial processing, comprehension
via glycolysis rather than the much more efficient oxidative knowledge, retrieval fluency, processing speed, and psychomotor
phosphorylation).23 Thus, methamphetamine use acutely, and pos- speed.41 In addition, dysfunctions of impulsivity have been associ-
sibly chronically, places the brain in a different metabolic state char- ated with a greater severity of methamphetamine use42 and an
acterized by (1) a quicker but less efficient availability of energy, (2) earlier age at onset of methamphetamine use.43 Global assess-
an increased rate of biosynthesis, (3) acidification of the microen- ments of cognitive function support the idea that more than two-
vironment, and (4) altered cell signaling via reactive oxygen thirds of individuals with MUD show cognitive impairment,44 the
species, which promotes an oncogenic and degenerative cell envi- extent of which is associated with older age, longer duration of use,
ronment. In summary, MUD does not reflect just dopamine dys- and higher frequency of use. Aside from providing an objective
regulation but represents an altered brain state that is consistent with assessment of the outcomes of methamphetamine use, a neuro-
those observed in degenerative central nervous system diseases. psychological assessment can also be used as a prognostic indica-
These complex molecular dysregulations provide an opportunity to tor. For example, cognitive measures, such as problems with sus-

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 Clinical Review & Education Review Neurobiology, Clinical Presentation, and Treatment of Methamphetamine Use Disorder

tained attention, may be associated with reduced treatment consistent with the observation that the rate of methamphet-
motivation,45 and different forms of impulsivity may be associated amine use among women, who are much more likely than men to
with poorer 6-week outcomes in treatment.46 Taken together, report using methamphetamines for weight-related issues, is higher
methamphetamine use is associated with moderate dysfunction of among adolescents relative to adults.60 Second, there is emerging
several cognitive processes, limiting the degree to which individu- evidence of individuals using methamphetamine as an opioid sub-
als with MUD are able to focus attention on goal-directed activity stitute to obtain a synergistic high or to balance the effects of
away from methamphetamine use in early abstinence. Given that opioids.61 Recent longitudinal evidence suggests that the increase
neuropsychological function may be used to assess treatment of cannabis use among adolescents may increase the probability that
retention and success, more work needs to be done to determine they will initiate the use of other illicit drugs, such as methamphet-
whether any of these cognitive dysfunctions can be remediated by amine, via both biological and social processes,62 providing some
targeted interventions. evidence for the “gateway hypothesis.”63 Similar to many other sub-
stance use disorders, the course of MUD is often characterized by
repeated periods of intense use with intermittent periods of sobri-
ety and relapse.64,65 Those who do not undergo treatment show
Clinical Presentation
5-year remission rates of up to 30%,66 and of those who do un-
The acute behavioral outcomes of methamphetamine use include dergo treatment, 61% relapse within the first 12 months and an-
increased energy and alertness, decreased need for sleep, eupho- other 14% relapse during years 2 to 5.65 These findings underscore
ria, increased sexuality, excessive talking, weight loss, sweating, tight- the fact that MUD is a chronic, relapsing, and possibly degenera-
ened jaw muscles, grinding teeth, and loss of appetite.47 The symp- tive condition, which is consistent with the profound molecular
toms exacerbated by methamphetamine use can be divided into the changes induced by methamphetamine use.
following 3 factors: (1) positive psychotic symptoms such as suspi- The most severe medical problems and the leading causes of
ciousness, unusual thought content, hallucinations, and bizarre be- death associated with MUD are cardiovascular disease and cerebro-
havior; (2) affective symptoms including depression, suicidality, guilt, vascular disease.67 Methamphetamine-associated strokes68 have
hostility, somatic concern, and self-neglect; and (3) psychomotor been increasing, most often among young men, and are primarily
symptoms such as tension, excitement, distractibility, and motor hemorrhagic in nature. Methamphetamine use is associated with va-
hyperactivity.48 The clinical picture can be complex and mimics many soconstriction, pulmonary hypertension, atherosclerotic plaque for-
psychiatric disorders. The transition from casual to compulsive meth- mation, cardiac arrhythmia, and cardiomyopathy.69 Methamphet-
amphetamine use can be rapid, and some have reported that it takes amine-associated cardiomyopathy 70 is characterized by left
a mean of approximately 50 days from the onset of use to the first ventricular dilatation and impaired left ventricular ejection fraction
drug craving, 60 days to regular use, and 85 days to compulsive as well as elevated tissue markers of inflammation and fibrosis.71 On
use.49 Although most methamphetamine-associated psychoses are electrocardiograms, these individuals frequently show tachyarrhyth-
brief, lasting hours to days, in some cases, psychotic episodes may mia, right axis deviation, left ventricular hypertrophy, a P pulmon-
persist for longer than 6 months and can reoccur during periods of ale pattern, inferior Q waves, lateral T-wave inversion, and a longer
abstinence from the drug.50 A mean of 36.5% of individuals using QTc interval.72 The symptoms preceding death due to the toxic ef-
methamphetamine, regardless of age or sex, report psychotic symp- fects of methamphetamine include collapse, breathing difficulty, and
toms, but when lifetime symptoms are taken into account, this per- hyperthermia, which may be a consequence of acute abnormal en-
centage increases to 42.7%.51 Some have suggested that self- largement of the heart.73 Methamphetamine was also present in
reported psychotic illness is more prevalent among individuals using 63% of individuals who died of opioids.74 For individuals who pre-
crystal methamphetamine than among those using other forms of sent with acute intoxication with methamphetamine, symptoms of
methamphetamine,52 which may be associated with the purity of dyspnea, angina, palpitations, cough, and hemoptysis should prompt
crystal methamphetamine and the self-selection of individuals who the clinician to closely monitor the medical status to prevent
use this form of the drug. The psychiatric comorbidity of MUD is mortality.
complex53 because there is evidence for both preexisting factors that
increase the risk for psychiatric disorders (eg, a 44% prevalence of
moderate to severe childhood abuse or neglect).54 Moreover, early
Interventions
lifetime adversity, such as emotional or sexual trauma, may also in-
crease the likelihood of MUD owing to the fact that some individu- There are very limited pharmacologic options to treat MUD for which
als use methamphetamine as a coping method.55 In addition, other there are sufficient data.75 The Table summarizes all of the inter-
psychiatric disorders, such as mood disorders (16.0%), psychotic dis- vention trials registered at ClinicialTrials.gov that contained the term
orders (13.0%), and anxiety disorders (7.0%), coexist with MUD.56 methamphetamine. Of the 159 registered studies, 65 represented
Both early-life trauma and psychiatric comorbidity can be ad- randomized clinical trials; of those, 25 reported results, of which 14
versely associated with both age at first use of methamphetamine57 resulted in publications with identifiable PMIDs (PubMed refer-
and treatment success.58 ence numbers). Examining these publications, 8 reported no ef-
The path to methamphetamine use involves at least 2 trajec- fect, 3 reported some effect, and 3 reported effects that did not
tories. First, younger individuals use methamphetamines primarily speak to the efficacy of the intervention. Moreover, the studies sub-
for recreational and performance enhancement purposes, whereas mitted to ClinicalTrials.gov were mostly unclear with respect to ef-
those initiating at a later age may use methamphetamines to “self- ficacy or reported null results (eTable in the Supplement). This short
medicate” (eg, to cope with stressful life events).59 This finding is summary is consistent with the conclusions of systematic reviews

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 Neurobiology, Clinical Presentation, and Treatment of Methamphetamine Use Disorder Review Clinical Review & Education

methamphetamine use at weeks 4 and 12,83 findings consistent with

Table. Data on Intervention Trialsa
those in a systematic review that found weak evidence for an in-
Studies, No. (%) creased percentage of abstinent days (during a 90-day period) and
Trials All (n = 159) RCTs (n = 65) reduced MUD symptoms.84 Similarly, behavioral activation, which
Trials with a randomized intervention model aims to maximize activities that are not drug-related but are posi-
With some results reported 25 (15.7) 25 (38.5) tively valued by the individual, was associated with abstinence of
Published 14 (8.8) 14 (21.5) alcohol, tobacco, opioid, and methamphetamine use in 7 of the 8
Studies with PMIDs reviewed studies and with improved depression over time in 6
No effect 8 (5.0) 8 (12.3) studies.85 Finally, several studies demonstrated a beneficial asso-
Some effect 3 (1.9) 3 (4.6) ciation of exercise with reducing MUD symptoms. For example, an
Unclear 3 (1.9) 3 (4.6) aerobic exercise program was associated with reducing cravings for
Other studies methamphetamine and with improved inhibitory control in indi-
No effect 5 (3.1) 5 (7.7) viduals with MUD.86 Moreover, compared with a health education
Some effect 0 0 control group, exercise by individuals taking methamphetamine was
Unclear 6 (3.8) 6 (9.2) associated with reduced levels of depression and anxiety during an
8-week period.87 Taken together, there is some evidence that
Abbreviations: PMID, PubMed reference number; RCTs, randomized clinical
trials. contingency management, cognitive behavioral therapy, behav-
a
Registered at ClinicalTrials.gov that contained the term methamphetamine. ioral activation, and exercise help to maintain abstinence. There is
also encouraging evidence for computer-delivered interventions88
and app-based approaches.89 Nevertheless, there are 2 significant
and meta-analyses. Specifically, in a systematic review examining 49 shortcomings. First, intervention programs for methamphetamine
studies investigating 20 potential pharmacotherapies, 35 studies use have high discontinuation rates. For example, in 1 large pro-
were associated with 33 phase 2 randomized clinical trials (ie, effi- gram, 51% of individuals dropped out within the first 2 weeks, and
cacy studies).76 For the 5 medications that were included in mul- the mean number of days that individuals stayed in the program was
tiple randomized clinical trials, 4 of these—methylphenidate, bu- only 60 days.90 Second, there is little understanding as to how these
propion, modafinil, and naltrexone—demonstrated some limited behavioral interventions affect the underlying neurobiology of MUD
evidence of benefit for reducing methamphetamine use. The au- and whether these interventions improve neural processing and cog-
thors concluded that none of these drugs showed sufficient or con- nitive dysfunctions in these individuals.
sistent evidence of effectiveness to support its use in routine treat-
ment. This assessment is similar to that in 2 other studies, one of
which concluded that no agent demonstrated a broad or strong
enough effect of achieving methamphetamine abstinence in phase
Conclusions
2 trials77 and the other concluding that there was no sufficient evi- Methamphetamine use disorder is reemerging as a significant pub-
dence available for dopamine analogue treatment after the initial lic health burden, a challenge for clinicians, and a difficult problem
withdrawal period.78 Studies of anticonvulsants, antipsychotics, opi- to solve for researchers. First, MUD can develop rapidly, has a com-
oid antagonists, varenicline, and atomoxetine provided either low- plex course characterized by episodes of intense use and intermit-
strength evidence or insufficient evidence of no association with the tent abstinence, has profound medical consequences, is difficult to
outcomes of interest (ie, abstinence, defined as ⱖ3 consecutive treat, and is associated with significant long-term cognitive and neu-
weeks with negative urine drug test results).79 Immunotherapy has rologic deficits. Second, clinicians faced with the presentation of an
been suggested as an alternative form of treatment for drug abuse; individual with acute methamphetamine intoxication should exam-
however, none of the antidrug immunotherapies have reached phase ine the patient for evidence of cardiovascular and cerebrovascular
3 clinical trials so far, to our knowledge.80 Although some have re- signs and symptoms, which are the primary causes of death due to
ported that the combination of pharmacologic treatments aimed at methamphetamine use. Third, there are several steps to consider
treating psychiatric target symptoms and brief cognitive behav- for a pragmatically focused program of research. Modifiable bio-
ioral treatments in a research setting outperformed control logical targets should be examined in individuals with MUD that fo-
conditions,81 there is no sufficient evidence that pharmacologic in- cus on dysregulation of oxidative stress, neurotoxic and excito-
terventions by themselves are useful for the treatment of MUD. toxic effects, and neuroinflammation. Neuromodulatory approaches
Results from studies using behavioral interventions to treat MUD appear promising in ameliorating impairments associated with MUD.
are more encouraging. In a recent network meta-analysis, com- For example, electroencephalography neurofeedback targeting the
pared with treatment as usual, only contingency management (ie, beta frequency band has increased, among other outcomes, peri-
a procedure that aims to alter drug use by systematically arranging ods of abstinence in individuals taking methamphetamine.91 More-
consequences that are designed to weaken drug use and strengthen over, repetitive transcranial magnetic stimulation targeting the fron-
abstinence) plus community reinforcement (ie, adjusting an indi- tal regions has resulted in decreased methamphetamine craving
vidual’s environment such that abstinence is more rewarding than and/or increased cognitive-emotional function.92 Real-time func-
using the drug) increased the number of abstinent patients with MUD tional magnetic resonance imaging neurofeedback, which demon-
at the end of treatment.82 Others reported that brief cognitive be- strates the beneficial effect of reducing depressive symptoms,93 may
havioral therapy resulted in significant reductions in the frequency also be helpful in reducing dysphoria present in individuals taking
of methamphetamine use, MUD severity, and number of days of methamphetamine. Understanding the neurobiology of exercise-

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 Clinical Review & Education Review Neurobiology, Clinical Presentation, and Treatment of Methamphetamine Use Disorder

induced reduction in craving methamphetamine94 may help to assessments of brain-associated changes are necessary to deter-
delineate novel disease-relevant targets. Fourth, preventive mine what brain-based treatment targets are modifiable and
behavioral interventions focused on factors such as childhood what brain processes put individuals at high risk for relapse.
trauma and dysregulated negative affect processing that increase Taken together and given the limited evidence-based interven-
the likelihood of initiating or continuing methamphetamine use tion options, it will be critically important to develop an imple-
may help to reduce future use.95 Fifth, the neurobiology of this mentation framework such that behavioral interventions can be
disorder is derived almost entirely from cross-sectional studies, delivered with high fidelity to maximize treatment effects and
which provide very little mechanistic insights. Thus, longitudinal help individuals overcome MUD.

ARTICLE INFORMATION 4. Hedegaard H, Bastian BA, Trinidad JP, Spencer ACS Chem Neurosci. 2019;10(8):3622-3634. doi:10.
Accepted for Publication: January 29, 2020. M, Warner M. Drugs most frequently involved in 1021/acschemneuro.9b00225
drug overdose deaths: United States, 2011-2016. 16. Xu E, Liu J, Liu H, Wang X, Xiong H.
Published Online: April 8, 2020. Natl Vital Stat Rep. 2018;67(9):1-14.
doi:10.1001/jamapsychiatry.2020.0246 Inflammasome activation by methamphetamine
5. Kariisa M, Scholl L, Wilson N, Seth P, Hoots B. potentiates lipopolysaccharide stimulation of IL-1β
Author Contributions: Drs Paulus and Stewart had Drug overdose deaths involving cocaine and production in microglia. J Neuroimmune Pharmacol.
full access to all of the data in the study and take psychostimulants with abuse potential—United 2018;13(2):237-253. doi:10.1007/s11481-018-9780-y
responsibility for the integrity of the data and the States, 2003-2017. MMWR Morb Mortal Wkly Rep.
accuracy of the data analysis. 17. Salter MW, Stevens B. Microglia emerge as
2019;68(17):388-395. doi:10.15585/mmwr. central players in brain disease. Nat Med. 2017;23
Concept and design: Both authors. mm6817a3
Acquisition, analysis, or interpretation of data: (9):1018-1027. doi:10.1038/nm.4397
Stewart. 6. Substance Abuse and Mental Health Services 18. Weinhard L, di Bartolomei G, Bolasco G, et al.
Drafting of the manuscript: Both authors. Administration. 2018 National Survey of Drug Use Microglia remodel synapses by presynaptic
Critical revision of the manuscript for important and Health (NSDUH) releases. Accessed March 5, trogocytosis and spine head filopodia induction.
intellectual content: Stewart. 2020. http://www.samhsa.gov/data/release/2018- Nat Commun. 2018;9(1):1228. doi:10.1038/s41467-
Administrative, technical, or material support: Both national-survey-drug-use-and-health-nsduh- 018-03566-5
authors. releases
19. Boyle CC, Kuhlman KR, Dooley LN, et al.
Supervision: Paulus. 7. Ma J, Bao YP, Wang RJ, et al. Effects of Inflammation and dimensions of reward processing
Conflict of Interest Disclosures: Dr Paulus medication-assisted treatment on mortality among following exposure to the influenza vaccine.
reported serving as an advisor to Spring Care Inc, a opioids users: a systematic review and Psychoneuroendocrinology. 2019;102:16-23. doi:10.
behavioral health startup, and receiving royalties meta-analysis. Mol Psychiatry. 2019;24(12):1868- 1016/j.psyneuen.2018.11.024
for an article about methamphetamine in 1883. doi:10.1038/s41380-018-0094-5
20. Felger JC, Li Z, Haroon E, et al. Inflammation is
UpToDate. No other disclosures were reported. 8. Carroll KM, Weiss RD. The role of behavioral associated with decreased functional connectivity
Funding/Support: This work has been supported interventions in buprenorphine maintenance within corticostriatal reward circuitry in depression.
in part by the William K. Warren Foundation, grant treatment: a review. Am J Psychiatry. 2017;174(8): Mol Psychiatry. 2016;21(10):1358-1365. doi:10.
U01 DA041089 from the National Institute on Drug 738-747. doi:10.1176/appi.ajp.2016.16070792 1038/mp.2015.168
Abuse, and grant award 1P20GM121312 from the 9. Moszczynska A, Callan SP. Molecular, behavioral, 21. Kohno M, Link J, Dennis LE, et al.
National Institute of General Medical Sciences and physiological consequences of Neuroinflammation in addiction: a review of
Center. methamphetamine neurotoxicity: implications for neuroimaging studies and potential
Role of the Funder/Sponsor: The funding sources treatment. J Pharmacol Exp Ther. 2017;362(3):474- immunotherapies. Pharmacol Biochem Behav.
had no role in the design and conduct of the study; 488. doi:10.1124/jpet.116.238501 2019;179:34-42. doi:10.1016/j.pbb.2019.01.007
collection, management, analysis, and 10. Barr AM, Panenka WJ, MacEwan GW, et al. The 22. Yu S, Zhu L, Shen Q, Bai X, Di X. Recent
interpretation of the data; preparation, review, or need for speed: an update on methamphetamine advances in methamphetamine neurotoxicity
approval of the manuscript; and decision to submit addiction. J Psychiatry Neurosci. 2006;31(5):301-313. mechanisms and its molecular pathophysiology.
the manuscript for publication. 11. Yang X, Wang Y, Li Q, et al. The main molecular Behav Neurol. 2015;2015:103969. doi:10.1155/2015/
Disclaimer: The content is solely the responsibility mechanisms underlying methamphetamine- 103969
of the authors and does not necessarily represent induced neurotoxicity and implications for 23. Liberti MV, Locasale JW. The Warburg effect:
the official views of the National Institutes of pharmacological treatment. Front Mol Neurosci. how does it benefit cancer cells? Trends Biochem Sci.
Health. 2018;11:186. doi:10.3389/fnmol.2018.00186 2016;41(3):211-218. doi:10.1016/j.tibs.2015.12.001
Additional Contributions: April C. May, MA, 12. Fischer F, Hamann A, Osiewacz HD. 24. Hu Y, Salmeron BJ, Krasnova IN, et al.
Department of Psychiatry, University of California, Mitochondrial quality control: an integrated Compulsive drug use is associated with imbalance
San Diego, provided assistance with creating the network of pathways. Trends Biochem Sci. 2012;37 of orbitofrontal- and prelimbic-striatal circuits in
figures. She was not compensated for her (7):284-292. doi:10.1016/j.tibs.2012.02.004 punishment-resistant individuals. Proc Natl Acad Sci
contribution. 13. Borgmann K, Ghorpade A. Methamphetamine U S A. 2019;116(18):9066-9071. doi:10.1073/pnas.
augments concurrent astrocyte mitochondrial 1819978116
REFERENCES stress, oxidative burden, and antioxidant capacity: 25. Lyoo IK, Yoon S, Kim TS, et al. Predisposition to
1. Chomchai C, Chomchai S. Global patterns of tipping the balance in HIV-associated and effects of methamphetamine use on the
methamphetamine use. Curr Opin Psychiatry. 2015; neurodegeneration. Neurotox Res. 2018;33(2):433- adolescent brain. Mol Psychiatry. 2015;20(12):1516-
28(4):269-274. doi:10.1097/YCO. 447. doi:10.1007/s12640-017-9812-z 1524. doi:10.1038/mp.2014.191
0000000000000168 14. Ropek N, Al-Serori H, Mišík M, et al. 26. Hall MG, Alhassoon OM, Stern MJ, et al. Gray
2. Stoneberg DM, Shukla RK, Magness MB. Global Methamphetamine (“crystal meth”) causes matter abnormalities in cocaine versus
methamphetamine trends: an evolving problem. Int induction of DNA damage and chromosomal methamphetamine-dependent patients:
Crim Justice Rev. 2017;28(2):136-161. doi:10.1177/ aberrations in human derived cells. Food Chem a neuroimaging meta-analysis. Am J Drug Alcohol
1057567717730104 Toxicol. 2019;128:1-7. doi:10.1016/j.fct.2019.03.035 Abuse. 2015;41(4):290-299. doi:10.3109/00952990.
3. Piper BJ, Ogden CL, Simoyan OM, et al. Trends in 15. Wang X, Northcutt AL, Cochran TA, et al. 2015.1044607
use of prescription stimulants in the United States Methamphetamine activates toll-like receptor 4 to 27. Baicy K, London ED. Corticolimbic
and Territories, 2006 to 2016. PLoS One. 2018;13 induce central immune signaling within the ventral dysregulation and chronic methamphetamine
(11):e0206100. doi:10.1371/journal.pone.0206100 tegmental area and contributes to extracellular
dopamine increase in the nucleus accumbens shell.

E6 JAMA Psychiatry Published online April 8, 2020 (Reprinted) jamapsychiatry.com

© 2020 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a Paris Sud University User on 04/08/2020

 Neurobiology, Clinical Presentation, and Treatment of Methamphetamine Use Disorder Review Clinical Review & Education

abuse. Addiction. 2007;102(suppl 1):5-15. doi:10. methamphetamine-dependent patients and 54. Chen Y, Zhang J, Sun Y. The relationship
1111/j.1360-0443.2006.01777.x healthy controls. Psychopharmacology (Berl). 2018; between childhood abuse and depression in a
28. London ED, Kohno M, Morales AM, Ballard ME. 235(7):2113-2121. doi:10.1007/s00213-018-4910-z sample of Chinese people who use
Chronic methamphetamine abuse and 41. Basterfield C, Hester R, Bowden SC. methamphetamine. Int J Clin Health Psychol. 2019;
corticostriatal deficits revealed by neuroimaging. A meta-analysis of the relationship between 19(3):181-188. doi:10.1016/j.ijchp.2019.06.003
Brain Res. 2015;1628(pt A):174-185. doi:10.1016/j. abstinence and neuropsychological functioning in 55. Simpson JL, Grant KM, Daly PM, Kelley SG,
brainres.2014.10.044 methamphetamine use disorder. Neuropsychology. Carlo G, Bevins RA. Psychological burden and
29. Kim YT, Lee JJ, Song HJ, et al. Alterations in 2019;33(5):739-753. doi:10.1037/neu0000552 gender differences in methamphetamine-
cortical activity of male methamphetamine abusers 42. Moallem NR, Courtney KE, Ray LA. The dependent individuals in treatment. J Psychoactive
performing an empathy task: fMRI study. Hum relationship between impulsivity and Drugs. 2016;48(4):261-269. doi:10.1080/
Psychopharmacol. 2010;25(1):63-70. doi:10.1002/ methamphetamine use severity in a community 02791072.2016.1213470
hup.1083 sample. Drug Alcohol Depend. 2018;187:1-7. doi:10. 56. Akindipe T, Wilson D, Stein DJ. Psychiatric
30. Aron JL, Paulus MP. Location, location: using 1016/j.drugalcdep.2018.01.034 disorders in individuals with methamphetamine
functional magnetic resonance imaging to pinpoint 43. Cservenka A, Ray LA. Self-reported attentional dependence: prevalence and risk factors. Metab
brain differences relevant to stimulant use. Addiction. and motor impulsivity are related to age at first Brain Dis. 2014;29(2):351-357. doi:10.1007/s11011-
2007;102(suppl 1):33-43. doi:10.1111/j.1360-0443. methamphetamine use. Addict Behav. 2017;65:7-12. 014-9496-5
2006.01778.x doi:10.1016/j.addbeh.2016.09.008 57. Svingen L, Dykstra RE, Simpson JL, et al.
31. Paulus MP, Hozack N, Frank L, Brown GG, 44. Wang TY, Fan TT, Bao YP, et al. Pattern and Associations between family history of substance
Schuckit MA. Decision making by related factors of cognitive impairment among use, childhood trauma, and age of first drug use in
methamphetamine-dependent subjects is associated chronic methamphetamine users. Am J Addict. persons with methamphetamine dependence.
with error-rate-independent decrease in prefrontal 2017;26(2):145-151. doi:10.1111/ajad.12505 J Addict Med. 2016;10(4):269-273. doi:10.1097/
and parietal activation. Biol Psychiatry. 2003;53(1): ADM.0000000000000233
45. Rubenis AJ, Fitzpatrick RE, Lubman DI,
65-74. doi:10.1016/S0006-3223(02)01442-7 Verdejo-Garcia A. Sustained attention but not 58. McKetin R, Kothe A, Baker AL, Lee NK, Ross J,
32. Harlé KM, Zhang S, Ma N, Yu AJ, Paulus MP. effort-based decision-making predicts treatment Lubman DI. Predicting abstinence from
Reduced neural recruitment for Bayesian motivation change in people with methamphetamine use after residential
adjustment of inhibitory control in methamphetamine dependence. J Subst Abuse Treat. rehabilitation: findings from the Methamphetamine
methamphetamine dependence. Biol Psychiatry 2018;95:48-54. doi:10.1016/j.jsat.2018.09.007 Treatment Evaluation Study. Drug Alcohol Rev.
Cogn Neurosci Neuroimaging. 2016;1(5):448-459. 2018;37(1):70-78. doi:10.1111/dar.12528
46. Rubenis AJ, Fitzpatrick RE, Lubman DI,
doi:10.1016/j.bpsc.2016.06.008 Verdejo-Garcia A. Impulsivity predicts poorer 59. Yimsaard P, Maes MM, Verachai V, Kalayasiri R.
33. Kohno M, Loftis JM, Huckans M, Dennis LE, improvement in quality of life during early Pattern of methamphetamine use and the time lag
McCready H, Hoffman WF. The relationship treatment for people with methamphetamine to methamphetamine dependence. J Addict Med.
between interleukin-6 and functional connectivity dependence. Addiction. 2018;113(4):668-676. doi: 2018;12(2):92-98. doi:10.1097/ADM.
in methamphetamine users. Neurosci Lett. 2018; 10.1111/add.14058 0000000000000371
677:49-54. doi:10.1016/j.neulet.2018.04.037 47. Hart CL, Gunderson EW, Perez A, et al. Acute 60. Chen LY, Strain EC, Alexandre PK, Alexander
34. Harlé KM, Yu AJ, Paulus MP. Bayesian physiological and behavioral effects of intranasal GC, Mojtabai R, Martins SS. Correlates of
computational markers of relapse in methamphetamine in humans. nonmedical use of stimulants and
methamphetamine dependence. Neuroimage Clin. Neuropsychopharmacology. 2008;33(8):1847-1855. methamphetamine use in a national sample. Addict
2019;22:101794. doi:10.1016/j.nicl.2019.101794 doi:10.1038/sj.npp.1301578 Behav. 2014;39(5):829-836. doi:10.1016/j.addbeh.
2014.01.018
35. Stewart JL, Connolly CG, May AC, Tapert SF, 48. McKetin R, Dawe S, Burns RA, et al. The profile
Wittmann M, Paulus MP. Striatum and insula of psychiatric symptoms exacerbated by 61. Ellis MS, Kasper ZA, Cicero TJ. Twin epidemics:
dysfunction during reinforcement learning methamphetamine use. Drug Alcohol Depend. the surging rise of methamphetamine use in
differentiates abstinent and relapsed 2016;161:104-109. doi:10.1016/j.drugalcdep.2016.01. chronic opioid users. Drug Alcohol Depend. 2018;
methamphetamine-dependent individuals. Addiction. 018 193:14-20. doi:10.1016/j.drugalcdep.2018.08.029
2014;109(3):460-471. doi:10.1111/add.12403 49. Wang Z, Li WX, Zhi-Min L. Similarity and 62. Otten R, Mun CJ, Dishion TJ. The social
36. Gowin JL, Harlé KM, Stewart JL, Wittmann M, difference in drug addiction process between exigencies of the gateway progression to the use of
Tapert SF, Paulus MP. Attenuated insular processing heroin- and methamphetamine-dependent users. illicit drugs from adolescence into adulthood.
during risk predicts relapse in early abstinent Subst Use Misuse. 2017;52(4):459-467. doi:10. Addict Behav. 2017;73:144-150. doi:10.1016/j.
methamphetamine-dependent individuals. 1080/10826084.2016.1245331 addbeh.2017.05.011
Neuropsychopharmacology. 2014;39(6):1379-1387. 50. Grant KM, LeVan TD, Wells SM, et al. 63. Kandel D, Kandel E. The Gateway Hypothesis
doi:10.1038/npp.2013.333 Methamphetamine-associated psychosis. of substance abuse: developmental, biological and
37. Gowin JL, Ernst M, Ball T, et al. Using J Neuroimmune Pharmacol. 2012;7(1):113-139. doi: societal perspectives. Acta Paediatr. 2015;104(2):
neuroimaging to predict relapse in stimulant 10.1007/s11481-011-9288-1 130-137. doi:10.1111/apa.12851
dependence: a comparison of linear and machine 51. Lecomte T, Dumais A, Dugré JR, Potvin S. The 64. Hser YI, Evans E, Huang D, Brecht ML, Li L.
learning models. Neuroimage Clin. 2019;21:101676. prevalence of substance-induced psychotic Comparing the dynamic course of heroin, cocaine,
doi:10.1016/j.nicl.2019.101676 disorder in methamphetamine misusers: and methamphetamine use over 10 years. Addict
38. Moeller SJ, Paulus MP. Toward biomarkers of a meta-analysis. Psychiatry Res. 2018;268:189-192. Behav. 2008;33(12):1581-1589. doi:10.1016/j.addbeh.
the addicted human brain: using neuroimaging to doi:10.1016/j.psychres.2018.05.033 2008.07.024
predict relapse and sustained abstinence in 52. Lappin JM, Roxburgh A, Kaye S, et al. Increased 65. Brecht ML, Herbeck D. Time to relapse
substance use disorder. Prog Neuropsychophar- prevalence of self-reported psychotic illness following treatment for methamphetamine use:
macol Biol Psychiatry. 2018;80(pt B):143-154. doi: predicted by crystal methamphetamine use: a long-term perspective on patterns and predictors.
10.1016/j.pnpbp.2017.03.003 evidence from a high-risk population. Int J Drug Drug Alcohol Depend. 2014;139:18-25. doi:10.1016/
39. Hart CL, Marvin CB, Silver R, Smith EE. Is Policy. 2016;38:16-20. doi:10.1016/j.drugpo.2016.10. j.drugalcdep.2014.02.702
cognitive functioning impaired in 018 66. Lanyon C, Nambiar D, Higgs P, Dietze P, Quinn
methamphetamine users? a critical review. 53. Salo R, Flower K, Kielstein A, Leamon MH, B. Five-year changes in methamphetamine use,
Neuropsychopharmacology. 2012;37(3):586-608. doi: Nordahl TE, Galloway GP. Psychiatric comorbidity in dependence, and remission in a community-
10.1038/npp.2011.276 methamphetamine dependence. Psychiatry Res. recruited cohort. J Addict Med. 2019;13(2):159-165.
40. Wang LJ, Chen CK, Lin SK, Chen YC, Xu K, 2011;186(2-3):356-361. doi:10.1016/j.psychres.2010. doi:10.1097/ADM.0000000000000469
Huang MC. Cognitive profile of ketamine- 09.014 67. Huang MC, Yang SY, Lin SK, et al. Risk of
dependent patients compared with cardiovascular diseases and stroke events in

jamapsychiatry.com (Reprinted) JAMA Psychiatry Published online April 8, 2020 E7

© 2020 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a Paris Sud University User on 04/08/2020

 Clinical Review & Education Review Neurobiology, Clinical Presentation, and Treatment of Methamphetamine Use Disorder

methamphetamine users: a 10-year follow-up 78. Härtel-Petri R, Krampe-Scheidler A, 87. Rawson RA, Chudzynski J, Gonzales R, et al.
study. J Clin Psychiatry. 2016;77(10):1396-1403. doi: Braunwarth WD, et al. Evidence-based guidelines The impact of exercise on depression and anxiety
10.4088/JCP.15m09872 for the pharmacologic management of symptoms among abstinent methamphetamine-
68. Lappin JM, Darke S, Farrell M. Stroke and methamphetamine dependence, relapse dependent individuals in a residential treatment
methamphetamine use in young adults: a review. prevention, chronic methamphetamine-related, setting. J Subst Abuse Treat. 2015;57:36-40. doi:10.
J Neurol Neurosurg Psychiatry. 2017;88(12):1079- and comorbid psychiatric disorders in post-acute 1016/j.jsat.2015.04.007
1091. doi:10.1136/jnnp-2017-316071 settings. Pharmacopsychiatry. 2017;50(3):96-104. 88. Campbell AN, Nunes EV, Matthews AG, et al.
doi:10.1055/s-0043-105500 Internet-delivered treatment for substance abuse:
69. Kevil CG, Goeders NE, Woolard MD, et al.
Methamphetamine use and cardiovascular disease. 79. Chan B, Freeman M, Kondo K, et al. a multisite randomized controlled trial. Am J
Arterioscler Thromb Vasc Biol. 2019;39(9):1739-1746. Pharmacotherapy for methamphetamine/ Psychiatry. 2014;171(6):683-690. doi:10.1176/appi.
doi:10.1161/ATVBAHA.119.312461 amphetamine use disorder—a systematic review ajp.2014.13081055
and meta-analysis. Addiction. 2019;114(12):2122-2136. 89. US Food and Drug Administration. FDA permits
70. Neeki MM, Kulczycki M, Toy J, et al. Frequency doi:10.1111/add.14755
of methamphetamine use as a major contributor marketing of mobile medical application for
toward the severity of cardiomyopathy in adults 80. Xiaoshan T, Junjie Y, Wenqing W, et al. substance use disorder. Published September 14,
ⱕ50 years. Am J Cardiol. 2016;118(4):585-589. doi: Immunotherapy for treating methamphetamine, 2017. Accessed March 5, 2020. https://www.fda.
10.1016/j.amjcard.2016.05.057 heroin and cocaine use disorders. Drug Discov Today. gov/news-events/press-announcements/fda-
Published online August 13, 2019. doi:10.1016/j. permits-marketing-mobile-medical-application-
71. Schürer S, Klingel K, Sandri M, et al. Clinical drudis.2019.07.009 substance-use-disorder
characteristics, histopathological features, and
clinical outcome of methamphetamine-associated 81. Khoramizadeh M, Effatpanah M, Mostaghimi A, 90. Cook R, Quinn B, Heinzerling K, Shoptaw S.
cardiomyopathy. JACC Heart Fail. 2017;5(6):435-445. Rezaei M, Mahjoub A, Shishehgar S. Treatment of Dropout in clinical trials of pharmacological
doi:10.1016/j.jchf.2017.02.017 amphetamine abuse/use disorder: a systematic treatment for methamphetamine dependence: the
review of a recent health concern. Daru. 2019;27 role of initial abstinence. Addiction. 2017;112(6):
72. Paratz ED, Zhao J, Sherwen AK, Scarlato RM, (2):743-753. doi:10.1007/s40199-019-00282-3 1077-1085. doi:10.1111/add.13765
MacIsaac AI. Is an abnormal ECG just the tip of the
ICE-berg? examining the utility of 82. De Crescenzo F, Ciabattini M, D’Alò GL, et al. 91. Keith JR, Rapgay L, Theodore D, Schwartz JM,
electrocardiography in detecting Comparative efficacy and acceptability of Ross JL. An assessment of an automated EEG
methamphetamine-induced cardiac pathology. psychosocial interventions for individuals with biofeedback system for attention deficits in a
Heart Lung Circ. 2017;26(7):684-689. doi:10.1016/j. cocaine and amphetamine addiction: a systematic substance use disorders residential treatment
hlc.2016.11.005 review and network meta-analysis. PLoS Med. setting. Psychol Addict Behav. 2015;29(1):17-25. doi:
2018;15(12):e1002715. doi:10.1371/journal.pmed. 10.1037/adb0000016
73. Darke S, Duflou J, Lappin J, Kaye S. Clinical and 1002715
autopsy characteristics of fatal methamphetamine 92. Liang Y, Wang L, Yuan TF. Targeting withdrawal
toxicity in Australia. J Forensic Sci. 2018;63(5):1466- 83. Alammehrjerdi Z, Briggs NE, Biglarian A, Mokri symptoms in men addicted to methamphetamine
1471. doi:10.1111/1556-4029.13710 A, Dolan K. A randomized controlled trial of brief with transcranial magnetic stimulation:
cognitive behavioral therapy for regular a randomized clinical trial. JAMA Psychiatry. 2018;
74. Gladden RM, O’Donnell J, Mattson CL, Seth P. methamphetamine use in methadone treatment. 75(11):1199-1201. doi:10.1001/jamapsychiatry.2018.
Changes in opioid-involved overdose deaths by J Psychoactive Drugs. 2019;51(3):280-289. doi:10. 2383
opioid type and presence of benzodiazepines, 1080/02791072.2019.1578445
cocaine, and methamphetamine—25 states, 93. Young KD, Siegle GJ, Zotev V, et al.
July-December 2017 to January-June 2018. MMWR 84. Harada T, Tsutomi H, Mori R, Wilson DB. Randomized clinical trial of real-time fMRI amygdala
Morb Mortal Wkly Rep. 2019;68(34):737-744. doi: Cognitive-behavioural treatment for neurofeedback for major depressive disorder:
10.15585/mmwr.mm6834a2 amphetamine-type stimulants (ATS)–use disorders. effects on symptoms and autobiographical memory
Cochrane Database Syst Rev. 2018;12:CD011315. recall. Am J Psychiatry. 2017;174(8):748-755. doi:
75. Gouzoulis-Mayfrank E, Härtel-Petri R, Hamdorf doi:10.1002/14651858.CD011315.pub2 10.1176/appi.ajp.2017.16060637
W, Havemann-Reinecke U, Mühlig S, Wodarz N.
Methamphetamine-related disorders. Dtsch Arztebl 85. Martínez-Vispo C, Martínez Ú, López-Durán A, 94. Wang D, Zhou C, Chang YK. Acute exercise
Int. 2017;114(26):455-461. doi:10.3238/arztebl.2017. Fernández Del Río E, Becoña E. Effects of ameliorates craving and inhibitory deficits in
0455 behavioural activation on substance use and methamphetamine: an ERP study. Physiol Behav.
depression: a systematic review. Subst Abuse Treat 2015;147:38-46. doi:10.1016/j.physbeh.2015.04.008
76. Lee NK, Jenner L, Harney A, Cameron J. Prev Policy. 2018;13(1):36. doi:10.1186/s13011-018-
Pharmacotherapy for amphetamine dependence: 95. Glasner-Edwards S, Mooney LJ, Ang A, et al.
0173-2 Mindfulness based relapse prevention for stimulant
a systematic review. Drug Alcohol Depend. 2018;
191:309-337. doi:10.1016/j.drugalcdep.2018.06.038 86. Wang D, Zhou C, Zhao M, Wu X, Chang YK. dependent adults: a pilot randomized clinical trial.
Dose-response relationships between exercise Mindfulness (N Y). 2017;8(1):126-135. doi:10.1007/
77. Morley KC, Cornish JL, Faingold A, Wood K, intensity, cravings, and inhibitory control in s12671-016-0586-9
Haber PS. Pharmacotherapeutic agents in the methamphetamine dependence: an ERPs study.
treatment of methamphetamine dependence. Drug Alcohol Depend. 2016;161:331-339. doi:10.
Expert Opin Investig Drugs. 2017;26(5):563-578. 1016/j.drugalcdep.2016.02.023
doi:10.1080/13543784.2017.1313229

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© 2020 American Medical Association. All rights reserved.

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