A new study of substance use and TMS response may challenge assumptions about who can benefit from neuromodulation for depression. Researchers found no significant association between reported substance use frequency and improvement in depressive symptoms following transcranial magnetic stimulation.
The findings could support a more individualized approach to evaluating patients who report alcohol, cannabis, nicotine, or certain prescribed substance use. However, the research remains a preprint and has not yet completed peer review.
Why Substance Use Has Complicated TMS Eligibility
TMS uses targeted magnetic pulses to influence activity in brain networks involved in mood regulation. Although it is an established treatment for major depressive disorder, response varies across patients.
Substances such as alcohol, cannabis, benzodiazepines, stimulants, and opioids can alter cortical excitability or plasticity. These effects have raised concerns that substance use could interfere with the neural changes believed to support TMS response. Some clinical recommendations have consequently encouraged abstinence or careful risk assessment before treatment.
Evidence directly connecting low-level substance use with weaker antidepressant outcomes has remained limited. This uncertainty may contribute to inconsistent eligibility decisions and could restrict access for patients who do not have a substance use disorder but report occasional or moderate use.
Examining Substance Use And TMS Response In Clinical Practice
Researchers at Vanderbilt University Medical Center conducted a retrospective cohort study using electronic health records from adults treated for major depressive disorder between 2011 and 2025.
The analysis included 219 TMS treatment courses completed by 212 patients. Participants had a mean age of 47, and 56.6% were female. Their average baseline Patient Health Questionnaire-9 score was 17.6, while the average treatment course included 32.9 TMS sessions.
Investigators categorized reported use of alcohol, cannabis, nicotine, prescription and illicit stimulants, benzodiazepines, opioids, inhalants, psychedelics, and other drugs. Frequency was classified as no use, less than weekly, more than weekly, or daily or more.
A Model Designed To Separate Key Variables
The primary outcome was the change in PHQ-9 scores from before treatment to the end of the TMS course.
Statistical models accounted for baseline depression severity, age, sex, and the number of TMS sessions received. This helped researchers examine whether substance use frequency contributed information beyond factors already associated with treatment outcome.
Alcohol was the most commonly reported substance, followed by prescription benzodiazepines and prescription stimulants. Several illicit substance categories contained too few users to support reliable regression analyses.
Reported Use Did Not Predict Symptom Improvement
Across the substance categories with sufficient data, frequency of use was not significantly associated with PHQ-9 change. Effect sizes were small, ranging from 0.00 to 0.30.
Comparisons between individual frequency levels also produced no statistically significant associations. For most estimates, the plausible range of PHQ-9 differences remained within five points, the threshold the researchers used to represent a minimally important clinical change.
Baseline symptom severity was the more consistent predictor. Patients entering treatment with higher PHQ-9 scores generally showed greater reductions by the end of treatment.
Cortical Effects May Not Translate Directly To Clinical Outcomes
Substances can affect neurotransmission, inhibition, excitation, and brain plasticity. In theory, these changes could influence how the cortex responds to magnetic stimulation.
The current findings suggest that measurable neurophysiological effects do not necessarily produce a clinically meaningful reduction in antidepressant benefit among patients reporting low to moderate use. Substance exposure, dependence, withdrawal, intoxication, and prescribed use are also distinct clinical circumstances that should not be treated as interchangeable.
What Sets This Analysis Apart
Rather than examining a single substance, the study evaluated several categories within a real-world clinical population. It also considered frequency instead of reducing substance use to a simple yes-or-no variable.
Important limitations remain. The retrospective design depended on clinical documentation and self-report, which may underestimate use. The sample was drawn from one academic center, and limited representation in several categories prevented conclusions about heavy or illicit substance use.
Access Decisions Still Require Individual Assessment
These results do not establish that all substance use is safe during TMS or that screening is unnecessary. Clinicians must still consider intoxication, withdrawal, seizure risk, medication interactions, substance use disorder severity, and changes in use during treatment.
The study instead suggests that low-level use alone may not justify automatically excluding an otherwise appropriate patient. Prospective, multicenter research is needed to confirm the result and determine whether particular substances, doses, or patterns affect safety or efficacy.
Citations
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