Association of Stimulants With Dopaminergic Alterations in Users of Cocaine, Amphetamine, and Methamphetamine: A Systematic Review and Meta-analysis

Abhishekh Hulegar Ashok, Yuya Mizuno, Nora Volkow, Oliver David Howes

Research output: Contribution to journalReview articlepeer-review

212 Citations (Scopus)
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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= −0.84; cocaine: −0.87, 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= −0.76; cocaine: −0.73; amphetamine and methamphetamine: −0.81, 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.
Original languageEnglish
JournalJAMA Psychiatry
Early online date15 Mar 2017
Publication statusPublished - May 2017


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