UK graduate researcher leads landmark methamphetamine treatment systematic review

LEXINGTON, Ky. (Aug. 18, 2026) — Publishing a paper in a top-tier journal is a major accomplishment for faculty members. For first-year graduate students, it’s almost unheard of.

Alexandra N. Johansen, a chemistry Ph.D. student in the University of Kentucky College of Arts and Sciences, has done exactly that, serving as the lead author of a comprehensive systematic review recently published in Pharmacological Reviews.

The manuscript, titled “Translational Medications Development for Methamphetamine Use Disorder: A Systematic Review of Preclinical, Human Laboratory and Clinical Research,” tackles one of the most pressing public health crises in the Commonwealth: the lack of FDA-approved medications to treat methamphetamine use disorder (MUD).

For Johansen, the achievement reflects how UK empowers its students to take the lead on research with immediate, real-world implications.

“UK has provided me with an exceptional mentor whose guidance and support equipped me to lead a review of this significance so early in my career,” Johansen said. “UK’s commitment to addressing specific issues facing Kentucky and Appalachia enabled me to turn this research into a call to action that can directly impact our communities.”

A neglected crisis

Although much of the national conversation regarding the overdose epidemic has focused on opioids, Johansen’s research highlights a stark reality for Kentuckians. According to the 2025 Kentucky Drug Overdose Fatality Report, methamphetamine was the most frequently identified substance in toxicology reports for overdose deaths — even surpassing fentanyl.

“As researchers, we’ve largely neglected stimulant use disorders,” Johansen said. “Especially in Kentucky, it’s an urgent issue. Methamphetamine use has spiked recently in Appalachia, and it contributes to almost half of all overdose deaths in the state. Finding ways to support people who use methamphetamine is critically important.” 

The disparity in research investment is a primary theme of Johansen’s work. Her review found that although cocaine use disorder is already under-researched, methamphetamine receives even less attention. Her team identified only 25 candidate medications that have been evaluated in randomized, double-blind, placebo-controlled clinical trials for MUD, compared to more than 60 medications for cocaine.

The biological challenge

The systematic review delves into why MUD is so difficult to treat. As a psychoactive drug that speeds up brain activity, methamphetamine boosts the signal of the neurotransmitter monoamine. It does this by binding to vesicular monoamine transporter 2 (VMAT2) and reversing its function. This process floods dopamine, serotonin and norepinephrine into the synapse and simultaneously blocks their reuptake, which prolongs monoamine activity and amplifies signaling for all three neurotransmitters.

These changes result in cardiotoxicity, immune system dysregulation, impaired cognition and dysregulated sleep. Despite these clear dangers, the neurobiological effects are complex and identifying an optimal pharmacological treatment is challenging.

The translational pipeline

The core of Johansen’s research involves evaluating the “translational medications development pipeline.” This process is the roadmap that moves potential treatments from preclinical studies (typically involving rodents) to the human laboratory and, finally, to large-scale clinical trials.

Of the 25 medications Johansen identified in clinical trials, only five — aripiprazole, bupropion, d-amphetamine, modafinil and naltrexone — had been systematically evaluated across all three levels of the research pipeline.

“We wanted to see if the effects of each medication were consistent across contexts,” Johansen said. The review found that most candidate medications failed to show a significant change in methamphetamine use across these research domains, highlighting a “negative predictive validity.” Essentially, if a drug fails in the laboratory setting, it is highly likely to fail in a clinical trial.

This roadmap is intended to prevent the waste of valuable resources on medications that lack a strong translational foundation, thereby highlighting the importance of robust preclinical research. By identifying which pharmacological targets show the most promise — such as those targeting GABA-glutamate systems — Johansen is providing a “most wanted” list for future MUD drug development, similar to the priorities set by the National Institute on Drug Abuse (NIDA) for the opioid crisis.

Empowering students

William W. Stoops, Ph.D., the chair and Dr. William R. Willard Professor in Behavioral Science in the UK College of Medicine and Johansen’s mentor, noted that this publication is remarkably significant for a student so early in her career.

“Having this work accepted in Pharmacological Reviews is a remarkable feat for any scientist, as it is one of the top journals in the field of pharmacology with an impact factor of 20.3,” said Stoops. “It is particularly noteworthy that this project was led by a graduate student, marking her very first, first-author publication since joining our lab at the University of Kentucky.”

The opportunity to lead such a systematic review required a collaborative environment that prioritizes student mentorship, which Johansen found at UK. Johansen worked alongside Stoops and her former mentor from Davidson College, Mark A. Smith, Ph.D. This partnership allowed Johansen to build upon a 2016 review of cocaine use disorder medications and apply those lessons to the methamphetamine crisis.

“At UK, we like to empower graduate students. It’s a joy to see young minds like Alex lead high-impact research that addresses pressing public health challenges,” Stoops said. “By providing Alex this platform so early in her career, we are advancing the search for methamphetamine treatments but also training the next generation of research leaders.”

A call for more realistic outcomes

A major hurdle identified in the systematic review is the current regulatory standard for success. Currently, the general expectation is that a treatment promotes “complete abstinence” — zero drug use — as the primary endpoint for clinical trials involving substance use disorders.

Johansen argues that this bar is unrealistically high and inconsistent with how the medical community treats other conditions. For example, medications for depression are often approved based on a 50% reduction in symptom severity.

“There’s a huge disparity in accepted endpoints for substance use disorder medications development compared to other disorders,” Johansen said. “Some medications for MUD have shown promise. However, according to the current guidance, it’s not enough to actually receive approval, even though these medications may help people.”

The review advocates for “nonabstinence outcomes,” such as a 75% reduction in drug-positive urine screens, which research suggests is associated with improvements in things like quality of life for cocaine use disorder.

The ultimate goal of Johansen’s work is to standardize care for those struggling with stimulants. Unlike opioid use disorder, where medications like methadone and buprenorphine are widely available, there are currently no standardized pharmacological tools for MUD.

“I work in a lab where we do a lot of clinical trials, and people often ask, ‘Is it true there’s no medication to help cut back or quit using methamphetamine?’” Johansen said. “People feel like they can’t get the treatment that they want and that they need right now. As researchers, we haven’t identified the right tools to help them yet.”

By providing a clear analysis of where the research stands and where it needs to go, Johansen has created a framework that could lead to those long-awaited treatments.

Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under Award Numbers R01DA060632 and R01DA064144. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.