Cranial Electrotherapy Stimulation for Anxiety

Overseen By Tad Brunye, Ph.D.

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Tufts University

Must not be taking: Prescription medications

Disqualifiers: Neurological, Psychological, Cardiac, Hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 23

Duration: 4-6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how Cranial Electrotherapy Stimulation (CES) can help manage acute stress in Soldiers. Participants will undergo 20 CES sessions, and researchers will measure and compare their stress responses, such as heart rate and anxiety levels, to those receiving a sham (fake) CES treatment. The aim is to determine if the real CES treatment provides noticeable stress relief. Ideal candidates are Soldiers who have not used CES before and are free from conditions like anxiety disorders or a history of head injuries.

As an unphased trial, this study offers Soldiers the opportunity to contribute to innovative research on stress management techniques.

Do I have to stop taking my current medications for the trial?

Yes, you must stop taking prescription medications, except for oral contraceptives, to participate in the trial.

Will I have to stop taking my current medications?

Yes, you will need to stop taking prescription medications, except for oral contraceptives, to participate in this trial.

What prior data suggests that Cranial Electrotherapy Stimulation is safe for Soldiers?

Research shows that Cranial Electrotherapy Stimulation (CES) is generally safe. Studies have found that CES can reduce anxiety symptoms in many patients, with only moderate side effects. One study found that CES could also help treat anxiety, depression, and sleep issues.

Most research suggests that CES is safe, with few experiencing serious side effects. However, some studies indicate that its effectiveness might not surpass a placebo for certain conditions. Overall, CES appears to be a safe option for those considering trials, though its effectiveness can vary. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about Cranial Electrotherapy Stimulation (CES) for anxiety because it offers a non-invasive way to potentially reduce symptoms without the side effects commonly associated with medications like SSRIs and benzodiazepines. Unlike these traditional treatments, CES uses low-level electrical currents to stimulate the brain, which can be administered at home using a small device. This approach not only simplifies the treatment process but also opens up possibilities for quicker relief, making it an appealing option for those who experience side effects from or are resistant to standard medications.

What evidence suggests that Cranial Electrotherapy Stimulation is effective for anxiety?

Research has shown that Cranial Electrotherapy Stimulation (CES) can help reduce anxiety. In this trial, participants will receive either Active CES or Sham CES. One study found that people using CES had lower anxiety levels than those who received no treatment. Another study found that CES users experienced less anxiety compared to those using a fake device. CES has also been moderately effective in reducing anxiety in people with various anxiety disorders. These findings suggest that CES may help lower anxiety by affecting the brain's electrical activity. ^{1 3 6 7 8}

Who Is on the Research Team?

Kana Okano, Ph.D.

Principal Investigator

Tufts University

Are You a Good Fit for This Trial?

This trial is for individuals aged 18-40 who have never used Cranial Electrotherapy Stimulation (CES) and can sit and stand freely. They must be willing to have their data stored for future research. People with hypertension, insomnia, brain conditions, pregnancy plans during the study, history of brain injury or illness, use of certain medications (excluding oral contraceptives), nursing mothers, or those with neurological/psychological disorders are excluded.

Inclusion Criteria

Agree to have their data stored in a repository (database) for future use

I can sit and stand without help.

I have never used or been treated with CES.

Exclusion Criteria

I am taking prescription medications other than birth control pills.

I have a history of neurological or psychological disorders.

I have a history of heart disease or irregular heartbeats.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Baseline Assessment

Participants complete a baseline measure assessing their biochemical, physiological, emotional, and behavioral responses to a stressful lethal force decision making task

1 day

1 visit (in-person)

Treatment

Participants complete 20 sessions of Cranial Electrotherapy Stimulation (CES) over four to six weeks

4-6 weeks

20 visits (in-person)

Follow-up

Participants complete a follow-up measure assessing their biochemical, physiological, emotional, and behavioral responses to the same stressful lethal force decision making task

Within 5 days after treatment

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Active CES
• Sham CES

Trial Overview The study tests how 20 sessions of CES affect soldiers' stress responses by measuring biochemical markers like salivary alpha amylase and cortisol, physiological indicators such as heart rate variability, emotional state anxiety levels, and cognitive task performance before and after the treatment compared to a Sham CES group.

How Is the Trial Designed?

Group I: Active CES Active Control 1 Intervention

Active Cranial Electrotherapy Stimulation (CES)

Group II: Sham CES Placebo Group 1 Intervention

Sham Cranial Electrotherapy Stimulation (CES)

Active CES is already approved in United States for the following indications:

Approved in United States as Cranial Electrotherapy Stimulation for:

• Anxiety
• Depression
• Insomnia
• Post-traumatic stress disorder
• Headache

Who Is Running the Clinical Trial?

Tufts University

Lead Sponsor

Trials

271

Recruited

595,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Published Research Related to This Trial

This study is the first placebo-controlled double-blind cross-over trial assessing the efficacy of levetiracetam (LEV) in treating Electric Status Epilepticus during Sleep (ESES) in children, involving 18 patients.

Levetiracetam significantly reduced the mean spike index from 56 to 37, demonstrating a strong treatment effect (p<0.0002), indicating its potential effectiveness in managing ESES similar to its use in treating epileptic seizures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of levetiracetam on focal nocturnal epileptiform activity during sleep--a placebo-controlled double-blind cross-over study. Larsson, PG., Bakke, KA., Bjørnæs, H., et al.[2018]

Electrical cranial stimulation (CES) significantly reduces symptoms of anxiety, depression, and insomnia, with a strong effect size of -0.96 for anxiety based on a meta-analysis of 8 randomized controlled trials involving 337 participants.

The 'Alpha-Stim' device used for CES was particularly effective in alleviating anxiety compared to sham controls, and the treatment was well-accepted, showing no increased risk of dropout compared to control groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of electrical cranial stimulation for treatment of psychiatric symptoms in patients with anxiety: A systematic review and meta-analysis. Chung, FC., Sun, CK., Chen, Y., et al.[2023]

Cranial electrotherapy stimulation is an effective treatment for anxiety, depression, and insomnia, supported by over 40 years of research and more than 100 clinical studies.

The device has a very low incidence of adverse effects (less than 1%), which are generally mild and self-limiting, making it a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cranial electrotherapy stimulation for treatment of anxiety, depression, and insomnia. Kirsch, DL., Nichols, F.[2022]

ESES/CSWS is a rare childhood epilepsy disorder characterized by continuous epileptiform activity during sleep, with an incidence of 0.2-0.5% among all childhood epilepsies, and it leads to neuropsychological regression and motor impairment.

There is currently no consensus on the best treatment for ESES/CSWS, as no controlled clinical trials exist; however, various treatment options like antiepileptic drugs, steroids, and dietary changes are reviewed, highlighting the need for a personalized therapeutic approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapy of encephalopathy with status epilepticus during sleep (ESES/CSWS syndrome): an update. Veggiotti, P., Pera, MC., Teutonico, F., et al.[2017]

Cranial Electrotherapy Stimulation (CES) using novel in-ear electrodes significantly reduced state-anxiety symptoms in a 3-week study with nonclinical volunteers, compared to a sham treatment.

EEG analysis revealed that CES increased theta power in the left frontal region and high-beta activity in specific brain areas, suggesting that CES may positively influence brain activity related to anxiety management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of cranial electrotherapy stimulation with novel in-ear electrodes on anxiety and resting-state brain activity: A randomized double-blind placebo-controlled trial. Kim, J., Kim, H., Kim, DH., et al.[2021]

The Italian version of the Liverpool Adverse Events Profile (iLAEP) was validated as a reliable tool for monitoring adverse events of antiepileptic drugs (AEDs) in 204 patients, showing high internal consistency and a quick completion time of about 9 minutes.

The iLAEP effectively predicts treatment discontinuation, with a cutoff score of 36.5 indicating a significant risk of dropout, as patients scoring above this threshold had a 20.27-fold increased risk of stopping their AED treatment within 3 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liverpool Adverse Events Profile: Italian validation and predictive value for dropout from antiepileptic treatment in people with epilepsy. Romoli, M., Eusebi, P., Siliquini, S., et al.[2019]

The case of a 7-year-old girl with sleep electrical status epilepticus (SESE) revealed that SESE may be associated with hypersomnia and nocturnal enuresis, suggesting it could be an intrinsic sleep disorder rather than just an EEG finding.

Neuropsychological assessments indicated significant language deficits and potential limbic system involvement, highlighting the need for systematic testing for sleep disorders in children with SESE, as it may lead to neuropsychological consequences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Electrical status epilepticus during sleep]. Ortega, JJ., Belda, VJ., Tripiana, JL., et al.[2009]

Cranial electrotherapy stimulation (CES) significantly reduced depression scores in participants, improving from an average of 31.3 to 10.8 on the Beck depression inventory-II, indicating its efficacy in alleviating depressive symptoms.

CES also positively impacted stress response by flattening the cortisol slope and increasing bedtime cortisol levels, suggesting it may serve as an effective adjunctive therapy for stress management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of cranial electrotherapy stimulation on improving depressive symptoms in people with stress: A randomized, double-blind controlled study. Lee, M., Kim, Y., Yoon, IY., et al.[2023]

Cranial electrostimulation (CES) was found to be significantly more effective than sham treatment for anxiety based on a meta-analysis of 14 randomized controlled trials, indicating its potential as a therapeutic intervention for anxiety disorders.

The review highlighted concerns about the quality of the studies, including a lack of complete data reporting and insufficient blinding of therapists, which could introduce bias in the results; thus, future research should address these issues to improve reliability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-analysis of randomized controlled trials of cranial electrostimulation. Efficacy in treating selected psychological and physiological conditions. Klawansky, S., Yeung, A., Berkey, C., et al.[2019]

Cranial electrotherapy stimulation (CES) significantly reduces anxiety symptoms in patients, showing a moderate effect size based on a systematic review of 11 randomized control trials involving 794 participants.

CES is well-tolerated with no severe side effects reported, making it a safe option for reducing both anxiety and depressive symptoms in patients with anxiety disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Tolerability of Cranial Electrotherapy Stimulation in the Treatment of Anxiety: A Systemic Review and Meta-Analysis. Ching, PY., Hsu, TW., Chen, GW., et al.[2022]

In a study of 7973 patients requiring emergent sedation for behavioral emergencies, serious adverse events (SAEs) were rare, occurring in only 2.1% of cases, with cardiac arrest happening in just 0.1% of patients.

Ketamine was associated with a higher frequency of invasive airway placements and severe oxygen desaturation compared to benzodiazepines and antipsychotics, but it also resulted in fewer patients needing additional sedation, indicating a complex risk-benefit profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events following emergent prehospital sedation of patients with behavioral emergencies: A retrospective cohort study. Brown, LH., Crowe, RP., Pepe, PE., et al.[2023]

The NEAT12 device, which uses cranial electrotherapy stimulation (CES) techniques, appears to positively influence brain activity in a 42-year-old male patient recovering from alcohol dependence, particularly by upregulating activity in the Cingulate Gyrus, a region associated with substance use disorders.

Pre- and post-treatment qEEG analysis showed significant changes in brain wave patterns, including a decrease in delta waves and an increase in alpha waves, suggesting that NEAT12 may help normalize electrical activity in the brain during protracted abstinence from alcohol, indicating potential as an anti-craving therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative Electroencephalography Analysis (qEEG) of Neuro-Electro-Adaptive Therapy 12™ [NEAT12] Up-Regulates Cortical Potentials in an Alcoholic during Protracted Abstinence: Putative Anti-Craving Implications. Waite, RL., Oscar-Berman, M., RBraverman, E., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9218324/

Efficacy and Tolerability of Cranial Electrotherapy Stimulation ... We found CES is effective in reducing anxiety symptoms with moderate effect size in patients with both primary and secondary anxiety.

2. thelancet.com thelancet.com/journals/lanpsy/article/PIIS2215-0366(23)00007-X/fulltext

Clinical effectiveness of active Alpha-Stim AID versus sham ... Both the active Alpha-Stim AID and sham Alpha-Stim AID groups, after 8 weeks of treatment, showed a clinically important mean improvement in the ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01533415

Use of Alpha-Stim Cranial-electrotherapy Stimulation (CES ... H¹ : The active CES treatment group has significantly lower anxiety scores on the HAM-A and HAM-D17 than the sham group at the endpoint of the study.

4. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK493135/

The Effectiveness and Risks of Cranial Electrical Stimulation ... Compared to receiving nothing, subjects treated with 20 minutes of CES reported a greater reduction in state anxiety score (22.2 vs 1.3). We could draw no ...

5. frontiersin.org frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2023.1157473/full

Efficacy of electrical cranial stimulation for treatment ... The therapeutic effectiveness of CES was significantly better than that in the control groups for anxiety (ES=-0.96, p <0.00001, eight trials, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10115990/

Efficacy of electrical cranial stimulation for treatment ... Our study supported the use of CES for symptoms of anxiety, depression, and insomnia in those suffering from anxiety with fair acceptability.

7. hsrd.research.va.gov hsrd.research.va.gov/publications/esp/CES.pdf

The Effectiveness and Risks of Cranial Electrical Stimulation ... The evidence is insufficient to support conclusions that CES has clinically important effects on headache, fibromyalgia, neuromuscular pain, depression, PTSD, ...

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2468171722000060

Cranial electrotherapy stimulation in the treatment of ... Symptomatic improvement of 25 % or more was reported for anxiety (66.7 % of respondents), PTSD (62.5 % of respondents), insomnia (65.3 % of respondents), and ...