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Figure 1.
Studies of Dopamine Release in Stimulant Users
Studies of Dopamine Release in Stimulant Users

Shown are the effect sizes estimated using a random-effects model and 95% CIs of the percentage change in the difference for D2/D3 binding change after challenge. There was an overall decrease in dopamine release in stimulant users relative to healthy controls, with a large to very large effect size (−0.84; 95% CI, −1.08 to −0.60; P < .001). Schrantee et al21 and Wang et al22 studied amphetamine-like stimulant users. The remaining studies17-20,23 included cocaine users.

Figure 2.
Studies of Dopamine Transporter Availability in Amphetamine and Methamphetamine Users and in Cocaine Users
Studies of Dopamine Transporter Availability in Amphetamine and Methamphetamine Users27-35 and in Cocaine Users24-26

Shown are the effect sizes estimated using a random-effects model and 95% CIs of the difference between amphetamine and methamphetamine users and healthy controls. There was an overall decrease in dopamine transporter availability in methamphetamine users relative to healthy controls (effect size, −0.91; 95% CI, −1.50 to −0.32; P < .01).

Figure 3.
Studies of Dopamine Receptor Availability in Cocaine Users, Amphetamine and Methamphetamine Users, and Stimulant Users Overall
Studies of Dopamine Receptor Availability in Cocaine Users,17-20,23,37,43-48 Amphetamine and Methamphetamine Users,21,22,38-42 and Stimulant Users Overall

Shown are the effect sizes estimated using a random-effects model and 95% CIs of D2/D3 receptor binding potentials. There was an overall decrease in dopamine receptor availability compared with healthy controls (effect size, −0.76; 95% CI, −0.92 to −0.60; P < .001).

Figure 4.
Summary of Dopaminergic Alterations in Stimulant Users
Summary of Dopaminergic Alterations in Stimulant Users

The synaptic location of the major dopaminergic findings is summarized from our meta-analysis and the results from studies of other aspects of the dopamine system. VMAT2 indicates vesicular monoamine transporter 2. The upward arrow indicates increased in stimulant users compared with controls; the downward arrow indicates decreased in stimulant users compared with controls.
aBased on the study by Wu et al.49
bBased on studies by Boileau et al51 and by Boileau et al.52
cBased on studies by Narendran et al50 and by Johanson et al.28
dMeta-analysis finding, with effect size of −0.91 (95% CI, −1.50 to −0.32; P < .01).
eMeta-analysis finding, with effect size of −0.84 (95% CI, −1.08 to −0.60; P < .001).
fMeta-analysis finding, with effect size of −0.76 (95% CI, −0.92 to −0.60; P < .001).

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Original Investigation
Meta-analysis
May 2017

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

Author Affiliations
  • 1Psychiatric Imaging Group, Medical Research Council London Institute of Medical Sciences Centre, London, England
  • 2Psychiatric Imaging Group, Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, England
  • 3Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, England
  • 4Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
  • 5National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland
  • 6National Institute on Drug Abuse, Bethesda, Maryland
JAMA Psychiatry. 2017;74(5):511-519. doi:10.1001/jamapsychiatry.2017.0135
Key Points

Question  What is the nature of in vivo differences in dopaminergic function between stimulant users and healthy controls?

Findings  In this systematic review and meta-analysis, dopamine release, dopamine transporter availability, and D2/D3 receptor availability in the striatum were all lower in stimulant users compared with healthy controls, with large effect sizes.

Meaning  The dopamine system shows generalized differences in long-term cocaine and amphetamine and methamphetamine stimulant use.

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.

Introduction

According to World Drug Report 2015 estimates, amphetamine-like stimulants (predominantly amphetamine and methamphetamine) and cocaine are the second and fourth most common forms of illicit substance abuse, respectively.1 The worldwide prevalence of amphetamine-like stimulant use was estimated at 0.3% to 1.1% in 2015 (between 13.8 million and 53.8 million users), and for cocaine it was 0.3% to 0.4% of the population aged 15 to 64 years (between 13 million and 20 million users).1 Stimulant use disorder costs more than $85 billion per year globally.2 Therefore, stimulant use poses a significant burden to society.2 Dopamine dysregulation is hypothesized to underlie addictive behavior,3-7 and stimulants like amphetamine and cocaine act on dopamine transporters and increase extracellular dopamine.8-11 Furthermore, preclinical models show that the short-term rewarding effects of stimulant drugs are linked to the release of dopamine in the nucleus accumbens measured using microdialysis or fast-scan cyclic voltammetry.7,12 Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) enable us to measure dopaminergic function in vivo in humans.13 Using these imaging tools, human studies14,15 have found that stimulant drugs increase synaptic dopamine levels in the whole striatum (including ventral striatum, which encompasses the nucleus accumbens) and that increases are associated with the subjective perception of drug reward in controls who are not abusing drugs. However, determining the dopaminergic effects of stimulants in human stimulant users is essential because the neurobiological mechanisms may be different. Many studies have investigated dopamine release, dopamine transporter levels, and dopamine receptor levels in stimulant addiction. However, to our knowledge, there has not been a previous meta-analysis of these findings. Therefore, 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. Because these drugs are known to increase extracellular dopamine levels either by blocking (cocaine) or reversing (amphetamine and methamphetamine) the dopamine transporter, we pooled the data.11 We group the findings into studies of dopamine release, dopamine transporter availability, and dopamine receptor availability. We focus on the whole striatum because it is richly innervated with dopaminergic neurons and reliably imaged with PET and SPECT in humans.16

Methods
Study Selection

The entire PubMed, EMBASE, and PsycINFO databases were searched for studies from inception date to May 14, 2016. To be included in the meta-analysis, an article needed to investigate the striatal dopaminergic system in cocaine or amphetamine-like stimulant users (including amphetamine and methamphetamine) and a control group, with the means (SDs) for both groups. (Further details on the study selection and search and inclusion criteria are provided in the eAppendix in the Supplement). We focused on amphetamine and methamphetamine because these entities 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 healthy controls. The following variables were extracted from all the studies: authors, year of publication, and participant characteristics of the healthy control and stimulant users groups (group size, age, sex, substance use specifics, comorbid substance abuse, method of abstinence confirmation, duration of abstinence, and diagnosis). In addition, we recorded imaging characteristics (method, radiotracer, scanner type, and resolution), route of administration of drug challenge, and modeling method.

Data Analysis

The main outcome measure was the effect size for the dopaminergic imaging index for the whole striatum in the stimulant users (cocaine and amphetamine-like stimulant studies combined) using a random-effects model. Separate secondary meta-analyses were conducted for the studies of dopamine release, dopamine transporter availability, and dopamine receptor availability in cocaine and amphetamine-like substance users to determine if the effects were consistent across categories of stimulants. Publication bias was assessed using funnel plots and regression tests. Heterogeneity was estimated using the I2 statistic (I2 statistics ≤50% indicate low to moderate heterogeneity, whereas I2 statistics >50% indicate moderate to high heterogeneity). Leave-one-out sensitivity analyses were conducted. P < .05 (2-tailed) was considered statistically significant (the eAppendix in the Supplement provides further methodological details).

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.

Dopamine Release

There were 7 studies17-23 (5 in cocaine users and 2 in amphetamine-like stimulant users) assessing dopamine release in 164 stimulant users and 139 healthy controls. The meta-analysis showed a significant reduction in dopamine release in the stimulant users relative to healthy controls, with an effect size of −0.84 (95% CI, −1.08 to −0.60; P < .001) (Figure 1). This reduction was also seen when the meta-analysis was restricted to cocaine users, with an effect size of −0.87 (95% CI, −1.15 to −0.60; P < .001). There were too few studies of amphetamine-like stimulant users for a meta-analysis, but the effect sizes in the 2 studies21,22 were in the same direction, with standardized mean differences of −1.05 (95% CI, −1.76 to −0.34) and −0.40 (95% CI, −1.11 to 0.32). The results of heterogeneity and sensitivity analyses are provided in the eAppendix in the Supplement.

Dopamine Transporter Availability

There were 12 studies (3 in cocaine users24-26 and 9 in amphetamine-like stimulant users27-35) assessing dopamine transporter availability in 177 stimulant users and 191 healthy controls. The meta-analysis showed a significant reduction in dopamine transporter availability in the stimulant users relative to healthy controls, with an effect size of −0.91 (95% CI, −1.50 to −0.32; P < .01) (Figure 2). For subanalysis, there were 9 studies27-35 in amphetamine-like stimulant users assessing dopamine transporter availability in 108 stimulant users and 126 healthy controls. The meta-analysis showed significantly reduced dopamine transporter availability in amphetamine-like stimulant users, with an effect size of −1.47 (95% CI, −1.83 to −1.10; P < .001). There were 5 studies24-26,36,37 in cocaine users. One study36 was excluded because it included cocaine users with potential central nervous system comorbidity (human immunodeficiency virus infection). This exclusion left too few studies for a separate meta-analysis in cocaine users. The results of these studies were inconsistent, with the 2 PET studies26,37 (in which there was an overlap of samples) showing no significant difference in dopamine transporter availability in cocaine users, while the 2 SPECT studies24,25 reported elevated dopamine transporter availability in cocaine users who were abstinent in the short term. The 2 SPECT studies in cocaine users had durations of abstinence of a maximum of 4 days25 and a mean of 7 days.24 Residual cocaine could block radiotracer binding to dopamine transporter, resulting in a slight underestimation of dopamine transporter levels in these studies. The results of heterogeneity and sensitivity analyses are provided in the eAppendix in the Supplement.

Dopamine Receptor Availability

There were 19 studies (7 studies21,22,38-42 in amphetamine-like stimulant users and 12 studies17-20,23,37,43-48 in cocaine users) assessing dopamine receptor availability in 342 stimulant users and 321 healthy controls. The meta-analysis revealed an overall reduction in D2/D3 receptor availability in stimulant users relative to healthy controls, with an effect size of −0.76 (95% CI, −0.92 to −0.60; P < .001) (Figure 3). In the separate analyses, a reduction in D2/D3 receptor availability was noted in cocaine users (effect size, −0.73; 95% CI, −0.94 to −0.53; P < .001) and amphetamine-like stimulant users (effect size, −0.81; 95% CI, −1.12 to −0.49; P < .001) relative to healthy controls. The results of heterogeneity and sensitivity analyses are provided in the eAppendix in the Supplement.

Other Dopaminergic Measures

There was only one study49 in stimulant users using 6-[18F]fluoro-dihydroxy-phenylalanine ([18F]-DOPA) assessing dopamine synthesis capacity. This study showed reduced dopamine synthesis capacity in cocaine users, and the estimated effect size was found to be 0.46 (95% CI, −0.46 to 1.39). We could not identify any studies on dopamine synthesis capacity in amphetamine-like stimulant users. Four studies assessed vesicular monoamine transporter 2 (VMAT2) availability, with inconsistent findings: 2 studies showed significantly reduced VMAT2 availability, one in cocaine users with 2 weeks of abstinence (effect size, 1.60; 95% CI, 0.68-2.52)50 and the other in methamphetamine abusers after 3 months of abstinence (effect size, 1.68; 95% CI, 0.86-2.50).28 However, 2 studies51,52 in recently abstinent methamphetamine users (mean duration of abstinence, 2.6 days and 19 days, respectively) showed elevated VMAT2 levels (effect size, 1.16; 95% CI, 0.56-1.76). Moreover, given that methamphetamine interacts with VMAT2 at the same site as the PET tracers and because of the short duration of abstinence, it is possible that VMAT2 levels were underestimated in some individuals.

There was one study53 on stimulant users and D1 receptors, which used [11C]NNC112 to compare cocaine abusers with controls. Although there were no differences in D1 receptors between groups, the availability of D1 receptors in cocaine abusers was negatively associated with the choice to self-administer cocaine by the cocaine abusers.

Discussion

To our knowledge, this study is the first meta-analysis of the nature of dopaminergic dysfunction in stimulant users. Our main findings are that dopamine release, dopamine transporter availability, and D2/D3 receptor availability are all lower in vivo in stimulant users compared with healthy controls, with large to very large effect sizes (effect size, −0.84, −0.91, and −0.76, respectively). This finding indicates that there is a generalized down-regulation of the dopaminergic system in stimulant users, as shown in Figure 4. Our sensitivity analyses of the dopamine D2/D3 receptor availability and dopamine release findings showed consistent results, and we noted low heterogeneity across studies of cocaine and amphetamine-like drugs and across differing radiotracers and techniques. However, there was a difference between results in amphetamine and methamphetamine users compared with cocaine users in dopamine transporter availability. In amphetamine and methamphetamine users, large and consistent reductions in dopamine transporter availability were observed. In contrast, for cocaine users, despite that the limited number of studies prevented subanalysis, 2 studies26,37 showed no difference in dopamine transporter availability and 2 other studies24,25 demonstrated elevated dopamine transporter availability, both in acutely abstinent cocaine users in the short term. This result may point to a mechanistic difference between the effects of amphetamine-like drugs and cocaine on dopamine transporters, consistent with preclinical findings,54 and highlights the need for more studies in cocaine users. Cocaine is known to act primarily by blocking dopamine transporters, while amphetamine competitively inhibits dopamine reuptake at dopamine transporters and increases dopamine transporter–mediated reverse transport of dopamine from the cytoplasm into the synaptic cleft independent of action potential–evoked vesicular release.8-10 It has also been suggested that the action of amphetamine depends on its concentration, with amphetamine acting primarily as a dopamine transporter blocker at low concentrations and reversing dopamine transport at high concentrations.8 In addition, amphetamine-like stimulants are known to trigger internalization of plasmalemmal dopamine transporter.55 Finally, cocaine, amphetamine, and methamphetamine are also known to act on serotonin and norepinephrine transporters, although their affinities for these transporters are different.56 Given these pharmacological differences in stimulants, there could be variations in dopaminergic effects between stimulants that are masked by pooling studies.

Specific issues affect interpretation of the results herein. For studies of D2/D3 receptors, the tracers generally used do not distinguish between D2 and D3 receptors or between the high-affinity and low-affinity forms of the D2 receptor, therefore the reduction could reflect a change in 1 or more of these entities. However, 2 studies44,46 used [11C]PHNO, which is selective for the D2 high-affinity form and shows a higher affinity for D3 receptors over D2 receptors. These studies did not demonstrate significant differences between stimulant users and controls in the striatum. This result suggests that the reduction in our meta-analysis reflects a reduction in the low-affinity form of the D2 receptor availability. Also, given that the radiotracers used to measure D2/D3 receptor availability are sensitive to endogenous dopamine levels,57 a possible interpretation of our finding of reduced D2/D3 receptor levels is that this result reflects elevated synaptic dopamine levels. However, a dopamine depletion study43 in cocaine users has shown that baseline synaptic levels are also reduced, which indicates that the reduction in D2/D3 receptor availability represents a reduction in D2/D3 receptor levels. Furthermore, our findings taken together with the observation of reductions in synaptic dopamine levels43 and dopamine synthesis capacity49 suggest that there is a generalized reduction in presynaptic dopaminergic activity. With the available data, however, we could not specifically rule out the possibility of up-regulation of the D3 receptor.

Limitations

In common with other meta-analyses58-62 of psychiatric imaging studies, variations exist among the studies analyzed herein. These include differences in the sample characteristics (eg, the inclusion of current or abstinent users, comorbid use of other substances like nicotine and alcohol, and variations in the durations of abstinence) and in the methods (particularly in the radiotracer used and delineation of the striatum) (eAppendix in the Supplement).

Nevertheless, there was low heterogeneity across the analyses, with the exception of dopamine transporter availability, and the random-effects model we used allows for variations in effects. Furthermore, if anything, these differences between studies would obscure rather than account for the effects we observed. A general limitation of the literature, apparent in the funnel plots, is that there are few studies with large sample sizes. In addition, there have been few studies on dopamine release, and we could not investigate potential differences between oral and intravenous routes of drug challenge to elicit dopamine release. Although in absolute terms the oral challenge studies showed lower release than those using an intravenous route, both indicated blunted release in stimulant users compared with healthy controls.

Implications for Understanding Stimulant Misuse and Dependence

Preclinical investigations using in vivo microdialysis and chronoamperometry conclusively demonstrated that acute administration of stimulants increases extracellular dopamine concentrations in the striatum and nucleus accumbens.12 Furthermore, in vivo fast-scan cyclic voltammetry and implantable microsensor studies,7,12 which are able to quantify the dopamine signaling over a subsecond timescale, have demonstrated that stimulants increase phasic dopamine release. In addition, human in vivo imaging studies have shown evidence consistent with the concept that acute exposure to stimulants leads to increased synaptic dopamine through cue-induced dopamine release or blockade of dopamine transporter and that this is linked to a subjective high63 and craving.64,65 Moreover, change in in vivo dopaminergic imaging indexes after amphetamine administration has been shown to be directly related to change in microdialysis measures,66 providing convergence across methods. Therefore, there is consistency between the preclinical and clinical findings indicating that short-term administration of stimulants results in increased extracellular dopamine by stimulating release (amphetamines) or by dopamine transporter blockade (cocaine).

Our meta-analysis demonstrates a consistent reduction in dopamine release in people who have been exposed to chronic stimulant use. In contrast, preclinical models of long-term use are inconsistent, with some studies showing no change in basal dopamine output after withdrawal of chronic amphetamine67-71 and cocaine,72-75 while other studies76-79 have reported increases in dopamine output after cocaine withdrawal. Therefore, the first major implication of our meta-analysis is that the findings in many preclinical models of chronic use do not reflect what is seen in the human studies. This result suggests caution in extrapolating from preclinical models and may explain the failure to develop treatments for stimulant addiction based on them. There are a several potential explanations for this inconsistency, including differences in the dosing regimens and durations used in preclinical models relative to human use patterns. Nevertheless, this discrepancy suggests that we need to develop new preclinical models that reproduce the dopaminergic changes seen in the human condition.

Our findings show reductions in both presynaptic and postsynaptic aspects of the dopaminergic system, suggesting a generalized down-regulation. One potential explanation for the reduction in dopamine release and transporter availability (seen in amphetamine and methamphetamine users only) could be a loss of dopamine neurons or damage to the dopaminergic terminals. Evidence exists that both cocaine and amphetamines induce apoptosis, as indexed by activation of caspases, loss of mitochondrial potential, cytochrome c release, and oxidative stress.80 In addition to this finding, amphetamine and methamphetamine induce dopaminergic neuron damage through the formation of quinones and free radicals.81-83 Preclinical models with methamphetamine have shown evidence of dopamine terminal damage that recovers with detoxification.84,85 In humans, dopamine transporters recover with detoxification in methamphetamine abusers,6,35 which was interpreted to indicate that dopamine neurons were not lost. Moreover, the only postmortem study86 we could identify, which was in methamphetamine abusers, showed evidence of reduction in dopamine transporters but not of dopamine neuronal loss. However, preliminary evidence from 2 epidemiological studies87,88 that methamphetamine abuse might increase the risk for Parkinson disease suggests that in some cases its abuse might accelerate age-associated dopamine neuronal degeneration.89

It has been suggested that recurrent drug use causes tolerance by various mechanisms, including dopamine receptor alterations, changes in second-messenger systems, and altered regulation of dopamine neuron function.90-92 Therefore, it is possible that the dopaminergic differences noted in our meta-analysis could be due to the development of tolerance through 1 or more of these mechanisms. Preclinical studies have also demonstrated that dopaminergic synaptic transmission is modulated by glutamatergic and γ-aminobutyric acid–ergic neurons.92 Neuroimaging studies investigating these interactions are needed to determine if this modulation is the case in humans.

Three alternative basic models are possible to account for both our presynaptic and postsynaptic findings. The first model is that recurrent stimulant use results in adaptive changes in the dopamine system that lead to reduced firing of dopamine neurons, potentially similar to the depolarization blockade that is seen after a period of successive firing,93 with consequently reduced dopamine synthesis and release. In this context, reduced transporter levels may be compensatory in response to reduced tonic dopamine levels in the synapse. The reduction in D2/D3 receptor levels is less easy to understand in the context of the presynaptic reductions. However, D2/D3 receptors undergo internalization after activation by dopamine, and this occurrence would reduce radiotracer binding, at least to several of the tracers used in the studies in our analyses.94,95 Therefore, the reduction in D2/D3 receptor availability could reflect a compensatory increase in internalized D2/D3 receptors, which would reduce the number of D2/D3 receptors available to bind to dopamine. Recurrent exposure may lead to loss of these internalized receptors and long-term transcriptional changes that reduce receptor availability.

The second model is that reductions underlie the pathogenesis of stimulant misuse and precede its onset. Therefore, individuals at risk of stimulant misuse may have reductions in dopamine release, transporter levels, and D2/D3 receptor levels secondary to genetic or environmental risk factors. Reductions in D2/D3 receptor levels and reduced release of dopamine in response to stimulants could mean that an individual is less sensitive to the effects of taking a stimulant, leading to escalating use. However, it is less easy to see how reduced dopamine transporter levels fit with this model because they would be expected to prolong the effects of stimulants. Longitudinal studies on the effects of stimulant drugs in patients with attention-deficit/hyperactivity disorder showed down-regulation of dopamine release with long-term exposure,96 which indicates that some of the changes are driven by long-term drug exposures.

The final model, a hybrid, may best account for our findings. Evidence suggests that reduced D2/D3 receptor levels may precede and predispose to the onset of stimulant misuse but also show further reductions during stimulant use,97 and similar effects may be seen with dopamine release and transporter levels. In our meta-analysis, dopaminergic alterations are marked even in the studies of several months’ abstinence, with evidence suggesting that dopamine receptor density and release are still down-regulated after 9 months of abstinence.35 This result suggests that effects may persist, with implications for understanding relapse. Our findings also support the opponent-process model.98

This observation highlights a fundamental issue raised by our meta-analysis, namely, that current findings do not address the temporal relationship between down-regulation in the dopamine system and phase of addiction. Future longitudinal human PET studies, as well as preclinical studies that investigate changes in the dopamine system before and during stimulant misuse and after abstinence, are needed to test these models (eAppendix in the Supplement). In addition, such investigations will help to identify biomarkers to guide treatment and predict outcomes.

Clinical Implications of Our Findings

Our data identify several clear targets for treatment interventions. Given our finding of a large effect size reduction, D2/D3 receptors stand out. That they stand out as a target for treatment intervention is further supported by studies20,22 in cocaine users and methamphetamine users showing that lower dopamine D2/D3 receptor availability at baseline predicts relapse after treatment. Our data support the development of drugs that target the presynaptic dopaminergic system to restore tonic striatal dopamine release, which is necessary for the function of the striatocortical indirect pathway, a key system disrupted in addiction.6 Recent preclinical evidence shows that administration of the dopamine precursor levodopa restored the aberrant dopaminergic signaling in a cocaine addiction animal model7,98 and by preliminary clinical evidence demonstrating that inhibiting dopamine reuptake (eg, with bupropion hydrochloride, modafinil, or mazindol) or inhibiting dopamine metabolism (eg, with selegiline hydrochloride or disulfiram) might hold some promise in the treatment of stimulant addiction.99 Strategies to up-regulate striatal D2 receptors have been shown in animal models to protect against compulsive stimulant drug intake.100 Therefore, interventions that lead to D2 up-regulation, such as physical activity, as recently shown in a preliminary study101 in methamphetamine abusers, merit further investigation. Several dopaminergic treatments have been tested to treat stimulant use disorder, with limited success to date.102-104 Our findings may also explain why strategies to block dopamine neurotransmission (eg, using dopamine receptor antagonists105) have largely been disappointing to date, because dopamine receptor levels are already low, and the results suggest that methods to increase dopamine receptor levels or sensitivity could have potential.

Conclusions

There is robust evidence for down-regulated presynaptic and postsynaptic dopamine function in stimulant addiction, with large effect sizes. These findings suggest that future drug development should target the restoration of dopaminergic function as a goal for the treatment of stimulant addiction.

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Article Information

Accepted for Publication: January 24, 2017.

Corresponding Author: Oliver D. Howes, MRCPsych, MD, PhD, Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, Du Cane Road, London W12 0NN, England (oliver.howes@lms.mrc.ac.uk).

Published Online: March 15, 2017. doi:10.1001/jamapsychiatry.2017.0135

Author Contributions: Drs Ashok and Mizuno had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Ashok, Volkow, Howes.

Acquisition, analysis, or interpretation of data: Ashok, Mizuno, Howes.

Drafting of the manuscript: Ashok, Mizuno, Howes.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Ashok, Mizuno, Howes.

Obtained funding: Howes.

Administrative, technical, or material support: Ashok.

Study supervision: Howes.

Conflict of Interest Disclosures: Dr Ashok reported conducting research funded by the Medical Research Council and King’s College London. Dr Mizuno reported receiving manuscript fees or speaker’s honoraria from Sumitomo Dainippon Pharma, Astellas, and Yoshitomi Yakuhin; reported receiving fellowship grants from Astellas Foundation for Research on Metabolic Disorders, Japanese Society of Clinical Neuropsychopharmacology, and Mochida Memorial Foundation for Medical and Pharmaceutical Research; and reported receiving consultant fees from Bracket within the past 3 years. Dr Volkow reported being director of the National Institute on Drug Abuse and reported conducting research as an intramural scientist that is funded by the National Institute on Alcohol Abuse and Alcoholism. Dr Howes reported conducting research funded by the Medical Research Council, the National Institute for Health Research, and the Maudsley Charity and reported receipt of investigator-initiated research funding from or participation in advisory or speaker meetings organized by AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Lundbeck, Lyden-Delta, Servier, and Roche.

Funding/Support: This study was funded by grant MC-A656-5QD30 from the Medical Research Council, by grant 666 from the Maudsley Charity, by grant 094849/Z/10/Z from the Brain & Behavior Research Foundation, by the Wellcome Trust (Dr Howes), and by a King’s College London scholarship (Dr Ashok).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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