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

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 < .001) for stimulants combined and -0.87 (95% CI, -1.15 to -0.60; P < .001) for cocaine. In addition, there was a significant decrease in dopamine transporter availability: the effect size was -0.91 (95% CI, -1.50 to -0.32; P < .01) for stimulants combined and -1.47 (95% CI, -1.83 to -1.10; P < .001) for amphetamine and methamphetamine. There was also a significant decrease in D2/D3 receptor availability: the effect size was -0.76 (95% CI, -0.92 to -0.60; P < .001) for stimulants combined, -0.73 (95% CI, -0.94 to -0.53; P < .001) for cocaine, and -0.81 (95% CI, -1.12 to -0.49; P < .001) for amphetamine and methamphetamine. Consistent alterations were not found in vesicular monoamine transporter, dopamine synthesis, or D1 receptor studies.

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.

Figure 1. Studies of dopamine release in stimulant users. The forest plot shows the effect sizes estimated using a random effects model and 95% confidence intervals of the percentage change in the difference of change in D2/3 binding after challenge. There was an overall decrease in dopamine release in stimulant users relative to controls with a large to very large effect size (−0.84 [95% CI, −1.08 - −0.60], p<0.001)

Schrantee et al. 2015 and Wang et al. 2012 studied amphetamine-like stimulant users. The remaining studies included cocaine users.

Figure 2. Studies of dopamine transporter availability. The forest plot shows the effects sizes estimated using a random effects model and 95% confidence intervals of the difference between amphetamine/methamphetamine users and controls. There was an overall decrease in the dopamine transporter availability in methamphetamine users relative to controls (−0.91 [95% CI, −1.5 - −0.32], p <0.01)

Figure 3. Studies of dopamine receptor availability. The forest plot shows the effect sizes estimated using a random effects model and 95% confidence intervals of D2/3 receptor binding potentials. There was an overall decrease in dopamine receptor availability compared to controls (−0.76 [95% CI, −0.92 - −0.60], p<0.001).

Figure 4. A summary of dopaminergic alterations in stimulant users

Summary of the synaptic location of the major dopaminergic findings from our meta-analyses and findings from studies of other aspects of the dopamine system. 1. Based on study by Wu et al. 1997 2. Based on study by Boileau et al. 2008 & 2015 3. Based on study by Narendran et al. 2012 and Johanson et al. 2006 4. Meta-analysis finding with effect size of −0.81 [95% CI, −1.34 - −0.29], p<0.01 5. Meta-analysis finding with effect size of −0.91 [95% CI, −1.50 - −0.32], p<0.01 6. Meta-analysis finding with effect size of −0.71 [95% CI, −0.91 - −0.52], p<0.001