Association of Stimulant Use With Dopaminergic Alterations in Users of Cocaine, Amphetamine, or Methamphetamine: A Systematic Review and Meta-analysis.

TLDR: Data suggest that both presynaptic and postsynaptic aspects of the dopamine system in the striatum are down-regulated in stimulant users, and this has implications for future drug development.

Abstract: Importance Stimulant use disorder is common, affecting between 0.3% and 1.1% of the population, and costs more than $85 billion per year globally. There are no licensed treatments to date. Several lines of evidence implicate the dopamine system in the pathogenesis of substance use disorder. Therefore, understanding the nature of dopamine dysfunction seen in stimulant users has the potential to aid the development of new therapeutics. Objective To comprehensively review the in vivo imaging evidence for dopaminergic alterations in stimulant (cocaine, amphetamine, or methamphetamine) abuse or dependence. Data Sources The entire PubMed, EMBASE, and PsycINFO databases were searched for studies from inception date to May 14, 2016. Study Selection Case-control studies were identified that compared dopaminergic measures between stimulant users and healthy controls using positron emission tomography or single-photon emission computed tomography to measure striatal dopamine synthesis or release or to assess dopamine transporter availability or dopamine receptor availability. Data Extraction and Synthesis Demographic, clinical, and imaging measures were extracted from each study, and meta-analyses and sensitivity analyses were conducted for stimulants combined, as well as for cocaine and for amphetamine and methamphetamine separately if there were sufficient studies. Main Outcomes and Measures Differences were measured in dopamine release (assessed using change in the D2/D3 receptor availability after administration of amphetamine or methylphenidate), dopamine transporter availability, and dopamine receptor availability in cocaine users, amphetamine and methamphetamine users, and healthy controls. Results A total of 31 studies that compared dopaminergic measures between 519 stimulant users and 512 healthy controls were included in the final analysis. In most of the studies, the duration of abstinence varied from 5 days to 3 weeks. There was a significant decrease in striatal dopamine release in stimulant users compared with healthy controls: the effect size was −0.84 (95% CI, −1.08 to −0.60; P P P P P P P Conclusions and Relevance Data suggest that both presynaptic and postsynaptic aspects of the dopamine system in the striatum are down-regulated in stimulant users. The commonality and differences between these findings and the discrepancies with the preclinical literature and models of drug addiction are discussed, as well as their implications for future drug development.

Full text

Title: Association of Stimulants With Dopaminergic Alterations in Users of
Cocaine, Amphetamine, and Methamphetamine: A Systematic Review and
Meta-analysis
Authors
Abhishekh H Ashok MBBS
1,2,3
, Yuya Mizuno MD
3,4
, Nora D Volkow MD
5
, Oliver D
Howes MRCPsych MD PhD
1,2,3
Affiliation
1
Psychiatric Imaging Group, MRC London Institute of Medical Sciences Centre (LMS), Du
Cane Road, London, UK
2
Psychiatric Imaging Group, Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial
College London, Du Cane Road, London, UK
3
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's
College London, London, UK
4
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
5
National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse,
Bethesda, USA
Word count: 3598
Corresponding Author
Abhishekh H Ashok, MBBS
Department of psychosis studies
Institute of Psychiatry, Psychology and Neurosciences
Kings College London
16 De Crespigny Park, London SE5 8AF
Email: abhishekh.ashok@kcl.ac.uk
Ph: 02083833703
Oliver D Howes D.M., Ph.D., M.A., B. M. B.Ch., MRCPsych
Professor, Psychiatric Imaging Group, MRC London Institute of Medical Sciences Centre
(LMS), Du Cane Road, London W12 0NN. (Email: oliver.howes@lms.mrc.ac.uk)
Ph: +44 (0)20 8383 3298
Date of revision 12 January 2017

Abstract:
Importance: Stimulant use disorder is common, affecting between 0.3 to 1.1% of the
population, and costs over $85 billion per year globally. There are currently no licensed
treatments. Several lines of evidence implicate the dopamine system in the pathophysiology of
substance use disorder. Thus understanding the nature of dopamine dysfunction seen in
stimulant users has the potential to aid the development of new therapeutics.
Objective: To comprehensively review the in-vivo imaging evidence for dopaminergic
alterations in stimulant (cocaine or amphetamine/methamphetamine) drug abuse or
dependence.
Data sources: The entire PubMed, EMBASE and PsycINFO databases were searched for
studies from inception date to May 14, 2016.
Study selection: A total of 31 studies were identified that compared dopaminergic measures
between 519 stimulant users and 512 controls using positron emission tomography or
single-photon emission computed tomography to measure striatal dopamine synthesis or
release, or dopamine transporter or receptor availability.
Data extraction and synthesis: Demographic, clinical and imaging measures were extracted
from each study and meta-analyses and sensitivity analyses were conducted for stimulants
combined and cocaine and amphetamines separately where there were sufficient studies.
Main Outcomes and Measures: We determined the difference in dopamine release
(assessed using change in the D2/3 receptor availability following administration of
amphetamine or methylphenidate), transporter and receptor availability in cocaine,
amphetamine and methamphetamine users and healthy controls.
Results: In majority of the studies the duration of abstinence varied from 5 days to 3 weeks.

There was a significant decrease in striatal dopamine release (stimulants combined: Hedges
g= −.84; cocaine: −.87, both p<0.001), dopamine transporter availability (stimulants
combined: Hedges g= −0.91, p<0.01; amphetamine and methamphetamine: Hedges g:
−1.47, p<0.001) and D2/3 availability (stimulants combined: Hedges g= −.; cocaine:
−0.73; amphetamine and methamphetamine: −.81, all p<0.001). We did not find consistent
alterations in vesicular monoamine transporter, dopamine synthesis or D1 receptor studies.
Conclusion and relevance: Our data suggest that both pre and post-synaptic aspects of the
dopamine system in the striatum are down-regulated in stimulant users. We discuss the
commonality and difference between these findings and the discrepancies with the
preclinical literature as well as their implications for future drug development.

Introduction:
According to World Health Organization estimates amphetamine-like stimulants
(predominantly methamphetamine and amphetamine) and cocaine are the second and
fourth most common forms of illicit substance abuse respectively (world drug report 2015;
https://www.unodc.org). The world-wide prevalence of amphetamine-like stimulant use
was estimated at between 0.3-1.1 percent in 2015 (between 13.8 million and 53.8 million
users), and for cocaine it was 0.3-0.4 percent of the population aged 15-64 (between 13
million and 20 million users) (world drug report 2015; https://www.unodc.org). Stimulant
use is thus a significant burden to society
1
. Dopamine dysregulation is hypothesized to
underlie addictive behaviour
2-6
and stimulants such as amphetamine and cocaine act on
dopamine transporters and increase extracellular dopamine
7-10
. Furthermore, preclinical
models show that the acute rewarding effects of stimulant drugs are linked to the release of
dopamine in the nucleus accumbens measured using micro-dialysis or fast scan cyclic
voltammetry
6,11
. Positron emission tomography (PET) and single photon emission
computed tomography (SPECT) enable us to measure dopaminergic function in-vivo in
humans
12
. Using these imaging tools, human studies have found that stimulant drugs
increase synaptic dopamine levels in the whole striatum (including ventral striatum which
includes the nucleus accumbens) and that increases are associated with the subjective
perception of drug reward in non-drug abusing controls
13,14
. However, determining the
dopaminergic effects of stimulants in human stimulant users is essential as the
neurobiological mechanisms may be different. A number of studies have investigated
dopamine release, dopamine transporter and dopamine receptor levels in stimulant
addiction. However, to our knowledge, there has not been a previous meta-analysis of these
findings. Thus we aimed to synthesize the PET and SPECT imaging findings on dopaminergic

function in cocaine and amphetamine-like (amphetamine and methamphetamine) stimulant
addiction and to consider their implications for its treatment. Since both drugs are known to
increase extracellular dopamine levels, either by blocking (cocaine) or reversing
(amphetamine/methamphetamine) the dopamine transporter, we pooled the data
10
. We
group findings into studies of dopamine release, dopamine transporter availability, and
dopamine receptor availability. We focus on the whole striatum as it is richly innervated
with dopaminergic neurons and reliably imaged with PET and SPECT in humans
15
.
Methods:
Study selection
To be included in the meta-analysis, an article needed to investigate the striatal
dopaminergic system in cocaine or amphetamine-like stimulant users (this included
amphetamine and methamphetamine) and a control group, including the mean and
standard deviations for both groups (see supplementary figures 1 and 2 for the study
selection and supplementary methods for further details on the search and inclusion
criteria). We focused on amphetamine and methamphetamine as these are the most widely
used amphetamine-like drugs.
Data extraction
The main outcome measure was the difference in the dopaminergic imaging index between
stimulant users and controls. The following variables were extracted from all the studies:
authors, year of publication, subject characteristics of the control and stimulant users group
(group size, age, sex, substance use characteristics, comorbid substance abuse, method of
abstinence confirmation, duration of abstinence, diagnosis), imaging characteristics