The Efficacy of Transcutaneous Auricular Vagus Nerve Stimulation in Individuals With Tiletamine Use Disorder (taVNS-Tiletami)

Effect of Transcutaneous Auricular Vagus Nerve Stimulation on Patients With Tiletamine Use Disorder: A Randomized Double-Blind Sham-Controlled Trial

Participants diagnosed with tiletamine use disorder will be assigned to active or sham taVNS for 5 days. Clinical outcomes ( e.g., behavioral paradigms measures and clinical scales ) and physiological markers (e.g., EEG and ECG) will be evaluated at baseline, post-treatment, and 3-month follow-ups to determine therapeutic efficacy and mechanisms of action.

Study Overview

• Status: Not yet recruiting
• Conditions: Substance Use Disorder (SUD); Tiletamine Use Disorder; Drug Craving
• Intervention / Treatment: Device: Transcutaneous Auricular Vagus Nerve Stimulation; Device: Sham Stimulation

Detailed Description

Tiletamine use disorder has emerged as a significant public health concern characterized by persistent psychological craving and high relapse rates. This randomized, double-blind, sham-controlled clinical trial aims to evaluate whether transcutaneous auricular vagus nerve stimulation (taVNS) can reduce craving levels and improve other outcomes in individuals with tiletamine dependence. Multimodal assessments including electroencephalography (EEG), electrocardiography (ECG) , behavioral paradigms measures and clinical scales will be conducted before and after the treatment.

This study seeks to establish a non-invasive vagus nerve stimulation strategy for substance use disorders and explore the treatment mechanism.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jiang Du, M.D, Ph.D; Phone Number: +8618017311220; Email: dujiangdou@163.com

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200030
      • Shanghai Mental Health Center
      • Contact: Jiang Du, M.D, Ph.D; Phone Number: +86 021 6490 6315; Email: dujiangdou@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18-60 years ≥6 years of education[7.1] DSM-5 diagnosis of substance use disorder related to tiletamine Tiletamine use ≥6 months and ≥1 time/week Ability to provide informed consent Willingness to complete follow-up assessments

Exclusion Criteria:

• Severe cognitive impairment History of epilepsy, brain injury, neurological disease or serious psychiatric disease Use of cognition-enhancing medications within 6 months Other psychoactive substance abuse within past 5 years (except nicotine) Metal implants in the head or severe skin sensitivity

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active taVNS; Intervention: Transcutaneous Auricular Vagus Nerve Stimulation Stimulation site: Left cymba conchae Frequency: 20 Hz Pulse width: 500 μs Intensity: 0.5-4 mA (perceptible but non-painful) Session duration: 40 minutes Frequency: 4 sessions/day Treatment course: 5 days (20 sessions)	Device: Transcutaneous Auricular Vagus Nerve Stimulation; The stimulation duration is 40 minutes per session, administered four times daily for 5 consecutive days (20 sessions in total).
Sham Comparator: Sham taVNS; Intervention: Sham Stimulation Site: Ipsilateral earlobe Same device appearance and parameters Minimal sensory stimulation without vagal activation Same treatment schedule as active group	Device: Sham Stimulation; Identical device appearance and parameters, with minimal sensory stimulation and no vagal activation. The treatment schedule is identical to that of the active group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of depressive symptoms	The PHQ-9, fully known as the Patient Health Questionnaire-9, is a self-report assessment tool developed based on the diagnostic criteria in the American Diagnostic and Statistical Manual of Mental Disorders for screening and evaluating the severity of depression. The scale consists of nine items corresponding to the core symptoms of depression. Respondents rate the frequency of symptoms experienced over the past two weeks on a scale of 0 to 3. The total score ranges from 0 to 27, with higher scores indicating potentially more severe depressive symptoms.	Baseline, immediately after the intervention,one month after the intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of stress symptoms	PSS stands for the Perceived Stress Scale. It is used to assess an individual's subjective perceptions of stress and the frequency of stress-related thoughts and feelings over the past month. The scale consists of 14 items, with derived 10-item and 4-item versions also available, and uses a five-point scoring system from 0 to 4, ranging from "never" to "very often". It provides a quick measure of an individual's perceived stress level. The total score ranges from 0 to 56, corresponding to three stress levels: normal (0-28), elevated (29-42), and high (43-56). The scale helps identify stress status and provides guidance for adjusting support resources.	Baseline, immediately after the intervention, one month after the intervention,
Change of the sleep quality	Sleep quality will be measured by the Pittsburgh Sleep Quality Index (PSQI). The total score of PSQI ranges from 0 to 21, in which higher scores mean poorer sleep quality.	Baseline, immediately after the intervention, one month after the intervention,
Change of the anxiety symptoms	The GAD-7 is a self-report scale for assessing anxiety symptoms. It consists of seven items assessing: 1. nervousness or anxiety; 2. uncontrollable worry; 3. excessive worry; 4. difficulty relaxing; 5. restlessness; 6. irritability; and 7. a sense of imp	Baseline, immediately after the intervention, one month after the intervention,
Change of the risky decision-making performance	Risky decision-making performance will be assessed using the Balloon Analogue Risk Task (BART). Higher average pumps in the BART indicate greater risk-taking propensity. Electroencephalography (EEG) will be used to measure neural electrical signals, where increases in relevant electrophysiological indicators may reflect heightened individual sensitivity to negative feedback. Higher frequency of continued dice rolls indicates greater risk propensity. Neural activity features related to the task will be analyzed, with specific patterns associated with risk evaluation and reward processing.	Baseline, immediately after the intervention
Changes in Negative Reinforcement Learning Behaviour	A negative reinforcement learning paradigm was used to assess avoidance-reversal learning behaviour. Behavioural response bias and learning rate were used to characterise negative reinforcement behavioural traits and negative reinforcement learning ability. EEG was recorded simultaneously, and changes in relevant electrophysiological indicators may serve as electrophysiological markers of changes in negative reinforcement learning behaviour.	Baseline, immediately after the intervention,
The change of alcohol craving	Alcohol craving will be measured by the alcohol craving Visual Analog Scale (VAS). The total score of VAS ranged from 0 to 10, in which higher scores mean a higher level of alcohol craving.	Baseline, immediately after the intervention, one month after the intervention,
The change of alcohol use	The AUDIT (the Alcohol Use Disorders Identification Test) consists of 10 items covering drinking frequency, alcohol consumption, alcohol dependence-related symptoms, and adverse consequences caused by alcohol use. Respondents complete the questionnaire based on their recent drinking behaviour, with each item scored according to different response levels. The total score ranges from 0 to 40. Higher scores indicate a higher risk of alcohol-related problems, and the scale can be used to identify hazardous drinking, harmful drinking, and potential risk of alcohol dependence.	Baseline, immediately after the intervention, one month after the intervention,
The changes of Resilience	The China version of the Connor-Davidson Resilience Scale (CD-RISC) consists of 25 items and includes three dimensions: tenacity (13 items), strength (8 items), and optimism (4 items). The scale uses a 5-point Likert scoring method, with scores from 0 to 4 representing "not true at all", "rarely true", "sometimes true", "often true", and "true nearly all the time", respectively. The total score ranges from 0 to 100, with higher scores indicating greater psychological resilience. The internal consistency coefficient of the Chinese version is 0.91.	Baseline, immediately after the intervention, one month after the intervention,
The condition of childhood experiences	Adverse Childhood Experiences (ACEs) includes 25 clinical items and 3 validity items. The scale uses a 5-point scoring system, ranging from "never true" to "very often true". Each subscale score ranges from 5 to 25 and is calculated by summing the scores of the items within that subscale. The total CTQ score is calculated by summing the subscale scores. Higher scores indicate more severe reported childhood maltreatment.	Baseline
The change of nicotine dependence	The FTND is a self-report scale used to assess the severity of nicotine dependence among smokers. The scale usually consists of six items. The total score ranges from 0 to 10, with higher scores indicating more severe nicotine dependence. It can be used to assess the level of smoking addiction and support the development of smoking cessation interventions.	Baseline, immediately after the intervention, one month after the intervention,
Change of the self-control ability	Self-control ability will be measured using the Self-Control Scale (SCS). Higher scores of SCS indicate better self-regulation and impulse control.	Baseline, immediately after the intervention, one month after the intervention,
The changes of impulsive behavior	UPPS-P Impulsive Behavior Scale (UPPS-P) includes 59 items rated on a 4-point Likert scale. Respondents indicate their agreement or disagreement with statements using a 4-point scale (1 = Agree Strongly, 4 = Disagree Strongly). Scoring involves calculating a mean score for each of the five subscales (scaled 1-4) and a total impulsivity score.	Baseline, immediately after the intervention, one month after the intervention,
The changes of morningness-eveningness	The Chinese version of the 5-item Morningness-Eveningness Questionnaire (rMEQ-5). The Chinese version of the MEQ-5 consists of five items selected from the Chinese version of the MEQ-19, namely items 1, 7, 10, 18, and 19.	Baseline, immediately after the intervention, one month after the intervention,
The change of impulsiveness	The Barratt Impulsiveness Scale (BIS) consists of 30 items. Each item is rated according to the frequency of occurrence using a 4-point scoring method: rarely/never = 1, occasionally = 2, often = 3, and almost always/always = 4.	Baseline, immediately after the intervention, one month after the intervention,
The change of somatic symptom	The Somatic Symptom Scale (SSS) consists of 20 items and is a self-report scale using a 4-point rating system (Table 1). A total raw score above 40 is considered positive.	Baseline, immediately after the intervention, one month after the intervention,
The change of behavioral inhibition/activation	The Behavioral Inhibition/Activation System Scale (BIS/BAS Scale) uses a 4-point scoring system, where 1 indicates "strongly agree" and 4 indicates "strongly disagree". Higher scores indicate greater activation of the behavioral inhibition system and behavioral activation system.	Baseline, immediately after the intervention, one month after the intervention,

Collaborators and Investigators

• Sponsor: Shanghai Mental Health Center

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: July 1, 2026
• First Submitted That Met QC Criteria: July 1, 2026
• First Posted (Actual): July 8, 2026

Study Record Updates

• Last Update Posted (Actual): July 8, 2026
• Last Update Submitted That Met QC Criteria: July 1, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Neuromodulation; EEG; Addiction; HRV; taVNS; Drug Craving; Brain-Heart Coupling; Tiletamine Dependence
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Compulsive Behavior; Impulsive Behavior; Behavior; Substance-Related Disorders; Behavior, Addictive
• Other Study ID Numbers: JDu-019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No