Exploring cutting-edge research that might finally provide medical solutions to one of our most persistent addiction crises
In the shadow of the opioid crisis, another drug epidemic has been steadily growing—one for which doctors have no FDA-approved medications to offer. Stimulant use disorder, encompassing addictions to methamphetamine and cocaine, contributed to nearly 110,000 overdose deaths in 2022 alone, with many fatalities involving the dangerous combination of stimulants with synthetic opioids like fentanyl 4 6 . Despite the staggering toll, when someone seeks help for stimulant addiction, healthcare providers must rely on behavioral interventions alone while hoping for scientific breakthroughs. This article explores the cutting-edge research that might finally provide medical solutions to one of our most persistent addiction crises.
The numbers behind stimulant dependence reveal a public health emergency of dramatic proportions:
people in the United States had a substance use disorder in 2021, with stimulant disorders representing a growing segment 4
of people with substance use disorders received treatment in 2021 4
Overdose deaths involving psychostimulants like methamphetamine doubled from 2019 to 2021 5
Deaths involving both opioids and stimulants occurred 22 times more frequently in 2021 than a decade earlier 6
Perhaps most alarming is the disproportionate impact on rural communities, where people report nearly twice the likelihood of past-year methamphetamine use compared to those in urban settings 1 .
Visualization: Stimulant Use Trends (2019-2023)
Without FDA-approved medications, what treatments are available today? The standard of care for stimulant use disorder is contingency management—a behavioral approach where patients receive rewards such as gift cards for drug-free urine tests 6 . In January 2025, the Substance Abuse and Mental Health Services Administration took a significant step by increasing the annual reward limit from $75 to $750 per person, recognizing that higher amounts (typically $400-$560) produce better outcomes 6 .
In parallel, clinicians increasingly practice off-label prescribing—using medications approved for other conditions to treat stimulant dependence. Recent guidelines from leading professional societies conditionally recommend several medications, particularly when patients have co-occurring disorders 1 .
| Medication | Evidence Status | Particularly Recommended For |
|---|---|---|
| Bupropion | Mixed study results, conditional recommendation | Co-occurring tobacco use disorder or depressive disorder |
| Mirtazapine | Moderate evidence for reducing methamphetamine use | Co-occurring depressive disorder |
| Topiramate | Mixed study results, conditional recommendation | Co-occurring alcohol use disorder |
| Methylphenidate (long-acting) | Shows promise, especially for cocaine use disorder | Co-occurring ADHD |
| Naltrexone-Bupropion Combination | Conditional recommendation | Co-occurring tobacco use, depressive, or alcohol use disorders |
A 2025 study of rural primary care clinics found that approximately 1 in 7 patients with stimulant use disorder received prescriptions for these off-label medications, suggesting gradual adoption of these practices 1 .
In August 2025, researchers at Virginia Commonwealth University (VCU) published groundbreaking research in the Journal of Neuroscience that might eventually lead to the first medication specifically designed for cocaine use disorder 2 . The discovery centers on dopamine, the brain's key reward chemical, and how cocaine hijacks this system.
The VCU team, led by Dr. Lankupalle Jayanthi and Dr. Sammanda Ramamoorthy, has studied cocaine's effects for over 25 years. They explain that stimulants like cocaine disrupt the careful balance between two proteins that regulate dopamine:
Control how much dopamine nerve cells release
Act as "molecular vacuums," sucking dopamine back into nerve cells after its release 2
Cocaine creates a vicious cycle by increasing levels of a peptide called dynorphin, which makes kappa opioid receptors hypersensitive to dopamine. This triggers dopamine transporters to work in overdrive, vacuuming up dopamine so efficiently that everyday pleasures no longer bring satisfaction. The result: users experience negative emotions and intensified drug cravings 2 .
The VCU team made two crucial preliminary discoveries. First, they found that kappa opioid receptors activate dopamine transporters through phosphorylation—a process where a phosphate group is added to the transporter's structure. Second, they identified the exact location where this occurs: a specific amino acid called threonine-53 2 .
Their groundbreaking experiment tested a simple hypothesis: what if they could block phosphorylation at this specific site?
Researchers developed genetically modified mice with altered dopamine transporters. The key modification was replacing threonine-53 with alanine, an amino acid that cannot bind to phosphate groups
Both normal mice and those with modified transporters received injections of a drug that activates kappa opioid receptors
Researchers monitored the mice for signs of aversiveness and reward-seeking behavior—typical responses to kappa opioid activation
The team measured phosphorylation levels and dopamine transporter activity in both groups 2
The results were striking. Normal mice showed increased phosphorylation at the threonine-53 site, heightened transporter activity, and displayed the expected aversive and reward-seeking behaviors. However, mice with the modified dopamine transporters showed neither the molecular changes nor the behavioral responses 2 .
| Measurement | Normal Mice | Genetically Modified Mice |
|---|---|---|
| Phosphorylation at threonine-53 site | Significantly increased | No increase |
| Dopamine transporter activity | Working in overdrive | Normal activity levels |
| Behavioral responses to kappa opioid activation | Strong aversion and reward-seeking | No significant behavioral changes |
This breakthrough suggests that targeting threonine-53 phosphorylation could block key mechanisms behind cocaine addiction without disrupting normal dopamine function.
The VCU experiment exemplifies the sophisticated tools modern neuroscientists use to unravel addiction's complexity. Here are key components from their research and the broader field:
| Research Tool | Function/Purpose |
|---|---|
| Genetically modified animal models | Allows researchers to study specific molecular mechanisms by altering single genes |
| Kappa opioid receptor agonists/antagonists | Compounds that either activate or block kappa opioid receptors to study their function |
| Phosphorylation site mapping | Techniques to identify exactly where phosphate groups attach to proteins |
| mRNA-based drugs (minigenes) | Emerging approach to produce therapeutic peptides that interfere with specific molecular interactions |
| Dopamine transporter activity assays | Methods to measure how efficiently dopamine transporters are functioning |
The VCU team is now developing an mRNA-based minigene therapy that would produce peptides matching the threonine-53 phosphorylation site. These "decoy" peptides would attract kappa opioid receptors, protecting the actual dopamine transporters from being sent into overdrive 2 .
While researchers pursue new medications, our very definition of successful treatment is evolving. A 2024 analysis by the National Institute on Drug Abuse (NIDA) found that reducing stimulant use—even without complete abstinence— delivers significant health improvements 9 .
The study analyzed data from 13 clinical trials involving over 2,000 people with stimulant use disorders. It revealed that more participants achieved reduced use (18%) than complete abstinence (14%). Most importantly, this reduction was associated with substantial benefits:
decrease in drug craving
decrease in drug-seeking behaviors
decrease in depression severity 9
This evidence supports what many in recovery have known all along: small steps matter. As NIDA Director Dr. Nora Volkow explained, "Embracing measures of success in addiction treatment beyond abstinence supports more individualized approaches to recovery" 9 .
The search for medications to treat stimulant dependence is advancing on multiple fronts. Beyond the VCU research, NIDA's "$100,000 Start an SUD Startup" Challenge is funding innovative approaches to substance use disorder treatment, including novel technologies and treatment models 8 . Additionally, the repurposing of existing medications continues to show promise, with researchers investigating drugs originally developed for other conditions 8 .
From the molecular insights at VCU to the evolving understanding of treatment success at NIDA, researchers are building a comprehensive toolkit that may eventually offer medical solutions to match the behavioral interventions available today.
The path forward recognizes that addiction is a treatable brain disorder, not a moral failing. As science continues to unravel its complexity, millions await the day when a diagnosis of stimulant use disorder comes with proven medical treatments and realistic pathways to recovery.
References will be listed here in the final version.