This clinical study is testing whether a new non-invasive brain stimulation method, called temporal interference (TI), can reduce nicotine cravings and usage in people who vape. TI delivers mild electrical currents to the scalp in a way that targets deep brain areas involved in addiction, without the need for surgery.

In this randomized controlled trial, participants will be assigned to one of three groups: TI stimulation to the nucleus accumbens, TI stimulation to the anterior insula, or a placebo (sham) condition. Each participant will attend a single stimulation session after 8 hours of nicotine abstinence and will use a custom vape device that measures real-time nicotine inhalation. Craving levels will be reported during and after the session.

The study aims to determine whether TI to the insula or nucleus accumbens is more effective at decreasing cravings and nicotine inhalation, and whether either is more effective than sham stimulation. For one week after the session, participants will use a smartphone app to track nicotine use and cravings. The primary hypothesis is that TI stimulation to deep brain regions will reduce both nicotine craving and actual use, immediately after stimulation and over the following week, compared to the sham condition.

Substance use disorders (SUDs) are difficult to treat effectively, with high relapse rates despite behavioral and pharmacological interventions. Previous clinical and case studies have shown that direct stimulation of deep brain regions-including the nucleus accumbens (NAcc) and anterior insula (AI)-can produce rapid, sustained reductions in addictive behaviors. Deep brain stimulation (DBS) of the NAcc has resulted in remission of opioid and alcohol use, while disruption of the AI has led to spontaneous loss of cigarette addiction. Although highly effective, DBS is invasive, expensive, and inaccessible to most patients. This randomized controlled clinical trial will evaluate whether temporal interference non-invasive deep brain stimulation (TI-NDBS) to the NAcc or AI can modulate deep brain activity and reduce nicotine craving and use in individuals who vape nicotine. TI uses two high-frequency electrical currents that intersect to create a low-frequency envelope capable of stimulating deep brain structures while sparing the overlying cortex. Pilot studies conducted by the investigators have shown that TI can safely and effectively activate the NAcc, as confirmed by increased BOLD signal during fMRI. In this study, 120 to 150 nicotine-dependent adults will be randomized to receive TI to the NAcc, TI to the AI, or sham stimulation. All participants will abstain from nicotine for at least 8 hours prior to the session, then undergo 60 minutes of stimulation while using a custom vape device that measures vapor inhalation in real time. Craving will be self-reported every 10 minutes. The primary outcome is a reduction in craving or nicotine use during the stimulation session. Secondary outcomes include changes in craving and use over the following week, assessed via ecological momentary assessment (EMA) three times daily using a smartphone app. Participants will also complete pre- and post-session assessments of cognitive function, emotional state, and stimulation experience. TI stimulation will be delivered with gradual current ramping to reduce discomfort, and previous pilot data support its tolerability. Findings from this study will provide early evidence of the safety and efficacy of TI-NDBS as a novel, low-cost, and scalable treatment for nicotine dependence, with potential applications in other addiction and psychiatric disorders involving deep brain circuitry.

Inclusion Criteria:

• Between the ages of 21 and 50
• Nicotine dependent and vape at least 15 mg nicotine per day
• Must have a phone with internet access
• Participants must have at least a 6th grade education and be able to speak and read English

Exclusion Criteria:

• History of seizures, seizure disorders, or familial history of seizure disorders
• History of intractable migraine or complicated migraine syndromes
• History of suicide attempts or active suicidal ideation (past month)
• History of cardiac arrhythmias, prolonged QT, pacemakers, or cardiovascular disorders
• Hypertension with systolic BP >150mmHgCentral nervous system structural lesions (tumors, MS, strokes, etc.)
• Active neuropsychiatric disorders (schizophrenia, bipolar, active psychosis, dementia, etc.)
• History of head trauma with loss of consciousness, skull fractures, subdural hematomas
• Active opioid, cocaine, and/or methamphetamine use
• Active severe cannabis use disorder
• Active alcohol use disorder or history of alcohol withdrawal
• Metal implants in the head or under the scalp (excluding dental implants)
• Current smoking cessation treatment or medications affecting reward processing
• Pregnancy

Participants will receive either active or sham stimulation with ramping protocols designed to mimic sensory experience across conditions. Participants are blinded to condition, and self-reported outcomes are collected through blinded survey methods.