NIDA Session Highlights Promising Strategies for Methamphetamine Use Disorder

While the United States continues to grapple with the opioid crisis, which has seen a renewed uptick in the wake of COVID-19, it is also dealing with another crisis—the methamphetamine crisis. Recent data from the Centers for Disease Control and Prevention and National Institute on Drug Abuse (NIDA) has shown a rise in methamphetamine use and deaths in both men and women, across age groups, and across ethnicities (with minority groups being the hardest hit). And unlike opioid use disorder mitigation, there are no approved medications available to help in the methamphetamine battle.

That may soon change, according to speakers at a NIDA-sponsored session on treatment advances in methamphetamine use disorder.

“NIDA has invested over three decades of research testing over 60 different drugs in hundreds of randomized, controlled trials for methamphetamine use disorder, with no success,” said Madhukar Trivedi, M.D., professor of psychiatry at UT Southwestern Medical Center. “The problem is certainly not a lack of trying.”

Trivedi said that a few years back, he led a working group to identify new strategies for developing methamphetamine treatments, and there was a consensus to both explore novel therapies but also look at existing medications that might complement each other in combination. The combination that seemed most promising was naltrexone and bupropion—they both target cravings but via different mechanisms. (Naltrexone is approved for opioid use disorder and alcohol use disorder, and bupropion is approved for smoking cessation.)

Last year, Trivedi and colleagues published the results of a large clinical trial of 400 adults, finding that the naltrexone-bupropion combination was almost six times more effective at achieving methamphetamine abstinence (confirmed with urine screens) than placebo. He noted the data pointed to the combination therapy being as effective as the individual medications.

Kathleen Brady, M.D., Ph.D., a professor of psychiatry and vice president of research at the Medical University of South Carolina, discussed a current NIDA effort to test transcranial magnetic stimulation (TMS) as a treatment for methamphetamine use disorder. TMS shows promise as an addiction treatment because its magnetic energy may help restore dysfunctional reward pathways. A number of studies have shown that TMS is indeed effective in the short term at reducing craving and withdrawal symptoms, primarily in nicotine addiction (so much that the FDA cleared TMS for as an adjunct for smoking cessation last year). There have also been a handful of positive studies testing TMS for methamphetamine or cocaine cravings, which set the stage for the current NIDA trial.

Brady is leading a multisite group that will enroll 160 adults with methamphetamine or cocaine use disorder and randomize them to 30 sessions of TMS or sham stimulation over eight weeks; the exact dosing schedule will be flexible to work with participant schedules to limit dropouts. Brady noted that the primary goal of the study is feasibility: “Can we get people with a substance use problem to come in 30 times to a clinic, sometimes twice in a day?” she said. The study will also explore the efficacy of TMS at reducing not just cravings but also stimulant use. She said that about 30 participants are enrolled thus far.

Finally, Manish Jha, M.D., an assistant professor of psychiatry at UT Southwestern Medical Center, discussed a study he is proposing to test another novel strategy—ketamine—for methamphetamine use disorder. A couple of recently published studies have demonstrated that a single ketamine infusion can boost the effects of a mindfulness-based intervention in people with cocaine dependence or alcohol use disorder, supporting the idea that this agent makes the brain more receptive to information. The study for alcohol use disorder also found that ketamine without accompanying mindfulness was still effective at promoting abstinence, suggesting the medication itself may have an effect.

Jha is hoping to enroll 120 adults with methamphetamine use disorder for a 12-week study in which participants will receive 18 ketamine or placebo (midazolam) infusions over six weeks, followed by a six-week follow-up. He noted that it is an intense treatment regimen, but given how intractable addiction can be, it might be what’s required.

In her discussion following the session, NIDA Director Nora Volkow, M.D., noted that these three large trials showcase the power of NIDA’s Clinical Trials Network, a coordinated group of academic centers that have the infrastructure to initiate trials of promising agents fairly quickly.

Volkow also commented on the interesting connection that all three trials involve treatments (ketamine, TMS, and bupropion) that were first proven to help with depression. “It makes you wonder if some of the outcomes are due to improvements in depressive symptomology like dysphoria,” she said. The explanation might be as simple as people feel a little better after treatment with ketamine or TMS such that they don’t need to reach for a drug as often.

She hoped that NIDA could launch more trials that look at positive outcomes of substance use treatments that go beyond abstinence, which is the key metric the FDA uses for approving addiction treatments. “It’s like saying the only valid outcome for antidepressant trials is complete remission,” she said. She suggested that other harm-reduction variables such as reduced usage, better mood, or improved sleep can be meaningful to people in real-world settings. ■