Accelerated Brain Stimulation Trial Targets Methamphetamine Addiction

An accelerated course of brain stimulation delivered 50 times in three weeks reduced self-reported methamphetamine craving and depression severity in a small open-label feasibility trial at UT Southwestern Medical Center, Manish Jha, MBBS, of UT Southwestern reported Oct. 12 at the American Society of Functional Neuroradiology meeting in Newport Beach, California. The trial was not designed to test whether the treatment works — its goal was to find out whether people with methamphetamine use disorder would tolerate an intense schedule borrowed from an accelerated protocol for treatment-resistant depression.

Researchers screened 28 people over two years and enrolled 23, of whom 20 had methamphetamine use disorder and three had cocaine use disorder, said Manish Jha, MBBS, of UT Southwestern. Of the 20 with methamphetamine use disorder, 94.7 percent completed at least 45 of the 50 sessions, with a mean of 46.3 sessions. Everyone but one participant finished 45 or more. The study is registered on ClinicalTrials.gov as START-D.

What the protocol involved

Participants received 10-minute sessions of intermittent theta burst stimulation with at least 50 minutes between sessions, for up to 50 sessions across three weeks — a schedule described in the registry record as borrowing elements from the Stanford Accelerated Intelligent Neuromodulation Therapy protocol used for treatment-resistant depression. Before each session, participants were shown images intended to provoke craving.

After 12 visits, participants reported reductions in methamphetamine craving and in overall depression severity. Cue-induced craving, the measure the imagery was designed to move, barely changed. Jha said participants did report an improved ability to resist using after the fourth session of a given day.

"We didn't see much change in cue-induced craving," Jha said. "What did change a bit was the self-reported craving and how much they were craving currently in the moment before the cue craving. So, there may be some signal."

Because the trial was open-label, with no sham comparison group, none of the symptom changes can be attributed to the stimulation rather than to participation in a structured program or to the passage of time. Jha also flagged one design limitation directly: the team stopped following participants one week after treatment ended.

"We did some EEG work every day as they were coming in, but probably one of the mistakes we made in this protocol was ending our follow-up one week after the treatment," he said. "These individuals have pretty unstable lives, and trying to follow them for a month or 3 months is difficult, so we just designed this as a small study."

Why stimulant treatment lags behind opioids

There is no FDA-approved medication for methamphetamine use disorder, and Jha noted that guidelines from the American Society of Addiction Medicine and the American Academy of Addiction Psychiatry do not recommend any drug for stimulant use disorder with high confidence. The strongest pharmaceutical result to date came from a 2021 randomized trial in which extended-release naltrexone combined with bupropion modestly reduced drug use: 13.6 percent of participants who received the treatment had negative urine samples after six weeks, compared with 2.5 percent of the placebo group.

Overdose deaths involving methamphetamine climbed roughly six- to sevenfold in less than a decade, Jha said, and the national overdose decline driven by fewer opioid deaths has not pulled stimulant deaths down with it. "The number of deaths attributable just to stimulants — including methamphetamine and cocaine — has continued to increase," he said, adding that the problem is concentrated in western states including Arizona, New Mexico and California.

The treatment gap matters for people who arrive at care with more than one problem. Stimulant use frequently travels with depression, and options for treatment-resistant depression — including repetitive transcranial magnetic stimulation and esketamine — carry their own access constraints. People seeking care for substance use disorder and co-occurring depression often have to assemble treatment from separate systems.

The adherence problem the accelerated schedule targets

Conventional repetitive transcranial magnetic stimulation is delivered as one session a day, five days a week, for six to eight weeks — 30 or more clinic visits that assume a stable schedule and reliable transportation. A previous trial testing that schedule in people with stimulant use disorder found that only 43.9 percent of participants assigned to the treatment arm attended at least 20 of 30 sessions.

Compressing the course into three weeks is an attempt to fit treatment around lives that are not stable enough for a two-month commitment. The adherence numbers in Jha's trial are the clearest result it produced: the schedule was feasible to deliver, which is the precondition for testing whether it does anything.

What would have to come next

Jha said a multisite randomized controlled trial is needed to replicate and expand the findings. Until then, the results sit where most early neuromodulation data for addiction has sat for years: promising enough to justify a larger blinded study, and too small and too uncontrolled to change what clinicians recommend.

The study's registry record lists an estimated enrollment of 40 participants, a start date of June 2024 and an estimated primary completion in June 2027. Its primary outcome is feasibility rather than symptom change. For a condition with no approved medication and rising death counts, the trial's value may lie less in the craving numbers it reported than in showing that an accelerated protocol can be run at all in a population that has historically dropped out of treatment.