Why are there still no treatments for methamphetamine use disorder?

Methamphetamine use disorder is a significant and growing health problem in the US—yet unlike opioid use disorder, there’s currently no evidence-based pharmacotherapy for methamphetamine dependence.

An NIH report referred to it as “one of the most commonly misused stimulant drugs in the world.”^[] An article published by JAMA Psychiatry in 2020 predicted that methamphetamine use disorder may be the “next substance use crisis” in the US—and possibly the world.^[]

So how can physicians address this challenge?

Scope of the problem

The National Survey on Drug Use and Health estimates that more than 14.7 million Americans have tried methamphetamine at least once. The JAMA Psychiatry article estimated that 1.86 million Americans used methamphetamine in 2018.

Neuroimaging studies have shown that the activity of the dopamine system is impaired in those who misuse methamphetamine. Decreases in motor speed and verbal learning commonly occur in frequent users. Structural and functional changes in the brain also impact emotion and memory.

Methamphetamine use disorder is also a public health burden, leading to the increased transmission of infectious diseases such as hepatitis and HIV, as well as societal ills including increased crime, child neglect, and unemployment.

"In the wake of the opioid crisis, methamphetamine has re-emerged as a challenge to mental health providers and researchers alike," according to the authors of the NIH report.  

Behavioral treatments

Unlike opioid use disorder, which can be treated pharmacologically and behaviorally, there are no approved medications to treat methamphetamine dependence, the NIH notes.

“Although medications have proven effective in treating some substance use disorders, there are currently no medications that counteract the specific effects of methamphetamine or that prolong abstinence from and reduce the misuse of methamphetamine by an individual addicted to the drug,” the agency wrote.

Instead, it highlighted behavioral therapies as most effective, including cognitive-behavioral and contingency management interventions.

The Matrix Model, for instance, is a 16-week comprehensive behavioral treatment approach that involves various facets, such as individual counseling, behavioral therapy, 12-step support, drug testing, use of non-drug-related activities, and family support.

Contingency management interventions—in which incentives are given to those individuals who manage or treat their methamphetamine use—have also proven effective.

In a review published in PLOS ONE, Canadian researchers found that contingency management is likely most effective at treating this condition, with interventions such as anticonvulsants, disulfiram, antipsychotics, and acupuncture proving ineffective.^[]

“The strongest evidence-based approach for the treatment of stimulant use disorder at this time remains contingency management interventions," the authors continued. "While treating stimulant use disorder with psychostimulants has shown some favorable results, high-quality clinical trials and meta-analyses are needed to determine the clinical utility of psychostimulants and other pharmacotherapies to address the growing need for stimulant treatments.”

Bupropion and naltrexone

Individually, these agents have been somewhat effective in treating methamphetamine use disorder in clinical trials. Bupropion is an antidepressant with stimulant-like effects that affects the norepinephrine and dopamine systems. It may target the dysphoria of withdrawal from methamphetamine that causes its continued misuse.

In the Accelerated Development of Additive Treatment for Methamphetamine Disorder (ADAPT-2) trial, researchers publishing in the NEJM tested the use of naltrexone plus bupropion in treating amphetamine misuse.^[]

In the experimental group, patients with moderate to severe methamphetamine use disorder were given injectable naltrexone (380 mg q3 weeks) plus oral extended-release bupropion (450 mg qd) for two 6-week stages.

Researchers performed the trial in two stages. In the first stage (n = 403), 16.5% of the patients in the naltrexone–bupropion group versus 3.4% in the placebo group exhibited response. In the second stage (n = 225), these numbers were 11.4% and 1.8%, respectively.

Adverse events included gastrointestinal disorders, malaise, and tremors. In total, 13.6% of those patients receiving naltrexone-bupropion and 2.5% receiving placebo exhibited an overall treatment effect over 12 weeks.

Contingency management concerns

According to the authors of an article published in Health Affairs, “The principles behind contingency management are intuitive, given what is known about the neurobiologic basis of addiction.^[] Drugs highjack the brain’s reward system during prolonged periods of drug use. Monetary rewards as part of contingency management that are tied to abstinence or other treatment objectives (for example, adherence to treatment activities) provide competing reinforcers.”

Despite their success, contingency management programs are rarely available in the US. It’s unlawful to provide more than nominal payments to patients who are being treated with federal or state dollars. The Centers for Medicare and Medicaid Services caps incentive payments to $75 a year. Under federal laws, more substantial payments may be considered inducement or kickbacks.

The problem with smaller incentives is that the National Institute on Drug Abuse has found that it takes more money for patients to abstain from methamphetamine use—between $400 and $500 a year.

Due to the lack of available medical treatments for methamphetamine use disorder, and the effectiveness of behavior therapies, physicians should consider referring patients with this disorder to counselors and specialists for further treatment. The NIH report adds that "mental health professionals need to be trained in recognizing early cardiovascular and cerebrovascular warning signs to mitigate the mortality associated with methamphetamine use disorder."

Meanwhile, more research is needed. "Parsing the disorder into different processes, e.g. craving or mood-related alterations, and targeting the neural systems and biological pathways underlying these processes may lead to greater success in identifying disease modifying interventions," the agency wrote.