Feeling euphoric after methamphetamine and showing a stronger brain response to a monetary reward cue were not interchangeable outcomes in a 2025 controlled human study. The drug increased positive subjective effects, but its effects on reward-related imaging signals did not track those feelings in the expected way.
What did participants receive?
Molla and colleagues used a randomized, double-blind, within-subject comparison of a single 20-mg oral methamphetamine dose with placebo. Healthy adults attended separate imaging sessions at least 72 hours apart. Capsules were administered at 9:30 a.m.; participants were taken to a 75-minute MRI session after further assessments at 10:30 a.m.
The study enrolled 101 participants. Thirteen were excluded from imaging analysis because of excessive movement, poor task engagement or technical problems, leaving 88 participants: 47 men and 41 women. Subjective-effect analyses used their own available observations, including some analyses with 101 participants. “Eighty-eight” is the imaging denominator, not a universal denominator for every result.
The task separated anticipation from outcome
During the Monetary Incentive Delay task, cues signaled possible gains, possible losses or neutral outcomes. Participants responded to a target, with successful responses earning a gain or avoiding a loss. The task adjusted target duration to regulate success rates.
The investigators separately examined brain responses while participants anticipated an outcome and when feedback disclosed what occurred. Reward anticipation, loss anticipation and receipt of an outcome are distinct processes. A signal in one phase cannot simply be described as “more reward activity” across the entire task.
Positive feelings increased; the hypothesized imaging pattern did not
Methamphetamine increased drug liking, euphoria and stimulant-like subjective effects compared with placebo. It also increased heart rate. These observations confirm effects under the study conditions; they do not determine what an individual experienced outside the experiment.
In the predefined imaging regions, the clearer drug effect concerned anticipation of monetary loss. Ventral striatal activation increased for loss versus neutral cues, with p = 0.009. The caudate finding during gain anticipation was a nonsignificant trend, p = 0.087. It should not be presented as a demonstrated reward-anticipation increase.
The drug did not significantly change the predefined regional responses during outcome feedback. An exploratory whole-brain analysis found a different signal in the right precuneus during loss feedback. That exploratory result should remain separate from the predefined region-of-interest findings.
A baseline association was not the same as a drug-induced association
| Comparison | Reported result | What it does not establish |
|---|---|---|
| Caudate reward-cue activity under placebo versus later drug-associated euphoria | Positive association, Spearman r = 0.32, p = 0.002 | A validated individual diagnostic test |
| Drug-induced caudate activity change versus euphoria change | No significant association, r = −0.17, p = 0.1 | Proof that all reward mechanisms are independent |
| Thalamic loss-anticipation signal versus stimulant-like ratings | Initial association did not survive multiple-comparison correction | A confirmed relationship after correction |
The placebo-session association concerns differences between people in a baseline condition. The drug-minus-placebo comparison concerns changes produced across conditions. Switching between these comparisons can turn the paper’s actual result into a stronger—and unsupported—mechanistic claim.
Why the null findings matter
The results do not show that methamphetamine has no effect on reward processing. They show that particular imaging and subjective endpoints did not move together as hypothesized at this dose and task. The authors discuss possible explanations involving tonic signaling and cue responses, but the experiment did not directly measure synaptic dopamine.
A 43-person subset had appeared in an earlier report. That earlier imaging sample and this expanded analysis should not be counted as wholly independent replications.
Can these scans identify impairment?
This study did not validate a blood-concentration threshold, a driving-impairment test or a method for reconstructing a person’s state during an earlier event. BOLD imaging, subjective reports and cardiovascular measurements are different endpoints. There was no basis to convert a regional imaging change into an individualized degree of intoxication.
The participants were selected healthy young adults, most with little or no prior stimulant exposure. Generalization to chronic use, other doses, other routes, clinical populations or nonmonetary rewards requires additional evidence.
Primary scientific source
Molla H, DeBrosse J, Keedy S, Lee R, de Wit H. Effects of methamphetamine on two measures of reward: Euphoria and neural activation to reward cues. Neuropsychopharmacology. 2025;50:1298–1304. doi:10.1038/s41386-025-02110-6. Original commentary on the supplied controlled human study.
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