Cranial electrotherapy stimulation, also known as cranial electrical stimulation, transcranial electrical stimulation, or electrical stimulation therapy, is a non-invasive method of brain stimulation. This therapy utilizes a device to deliver weak pulses of electrical current to the brain via electrodes located on the earlobes, mastoid processes, or scalp. Cranial electrotherapy stimulation is believed to affect brain regions associated with emotion regulation, pain, hormone production, and other related functions. Cranial electrotherapy stimulation aims to improve conditions such as anxiety, depression, insomnia, fibromyalgia, Alzheimer’s disease, and additional pain-related disorders.
A number of cranial electrical stimulators have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. These devices include, but are not limited to, the following: CES Ultra™ HealthPax; Alpha-Stim® Neurotone; LISS Cranial Stimulator; Transcranial Electrotherapy Stimulator-A (TESA) and the Cervella™ Cranial Electrotherapy Stimulator (CES).
Use of cranial electrotherapy stimulation is considered EXPERIMENTAL/INVESTIGATIVE for all indications due to the lack of clinical evidence demonstrating an impact on improved health outcomes.
Home use of cranial electrotherapy stimulation devices is considered EXPERIMENTAL/INVESTIGATIVE for all indications due to the lack of clinical evidence demonstrating an impact on improved health outcomes.
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No additional statements.
Summary of Evidence
Cranial electrotherapy stimulation (CES) has been suggested for treatment of various psychological and physiological conditions. The published clinical evidence evaluating CES for these conditions is minimal and of poor quality, and also lacks long-term data. In addition, professional societies do not address CES for any purpose. Therefore, cranial electrotherapy stimulation is considered experimental/investigative for all indications, due to the lack of clinical evidence demonstrating an impact on improved health outcomes.
Rationale
Cranial electrotherapy stimulation (CES), also known as cranial electrical stimulation and transcranial electrical stimulation, is a noninvasive and nonpharmacological procedure that involves application of transcutaneous alternating pulsed current to the head via electrodes to affect brain function. Interest in CES began in the early 1900s on the theory that weak pulses of electrical current have a calming effect on the central nervous system. The technique was further developed in the 1950s as a treatment for anxiety and depression and use of CES later spread to the United States as a treatment for various psychological and physiological conditions. Presently, the mechanism of action is thought to be the modulation of activity in brain networks by direct action in the hypothalamus, limbic system, and/or the reticular activating system. CES is hypothesized to improve relaxation, increase mental alertness and clarity, reduce fatigue, and to decrease anxiety, obsessive-compulsive behaviors, and ruminative thoughts. CES treatment can be administered in a clinic or office or may be self-directed in the patient’s home.
Several devices for CES have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process.
In 2023, Morriss et al published results for the multicenter, double-blind, randomized, controlled Alpha-Stim-D trial that evaluated the Alpha-Stim Anxiety Insomnia and Depression (AID) device. Patients with moderate to severe major depression received 8 weeks of once daily treatment with Alpha-Stim AID or a sham device. Patients without recent/prior antidepressant use were eligible, although only about 15% of patients had not used antidepressants in the prior 3 months. At week 16, the primary endpoint (the 17-item Hamilton Depression Rating Scale) had decreased by a mean of 5.9 points with Alpha-Stim AID and 6.5 points with the sham device (difference, -0.6; 95% CI, -1.0 to 2.2; p=0.46). The decreases in both groups were clinically important, but the difference between groups was not significant. Adverse events and tolerability were similar between groups. It is unclear whether patients in the sham device group were allowed to use concurrent antidepressants or behavioral therapy. The researchers concluded that Active Alpha-Stim AID was safe and acceptable, however it was no more clinically effective than sham treatment in major depression.
In 2021, Kim et al published results for a 3-week randomized, double-blind, sham-controlled trial evaluating the effectiveness of home-based CES (n=25) versus sham treatment (n=29) in nonclinical patients with daily anxiety. Novel, headphone-like, in-ear electrodes were used in this study. Results demonstrated a significant reduction in anxiety scores using the State Anxiety Inventory (SAI) with CES versus sham stimulation treatment. Depression inventory scores did not significantly differ between groups. Limitations of this study included the use of a small sample of nonclinical patients, short follow-up, post-randomization withdrawals that did not contribute data to the analysis, and the unclear clinical significance of a decreased anxiety inventory score.
Barclay and Barclay (2014) published results for a randomized, double-blind, sham-controlled trial evaluating the effectiveness of 1 hour of daily CES for patients with anxiety (n=115) and comorbid depression (n=23). Analysis of covariance showed a significant advantage of active CES over sham for both anxiety (p=0.001) and depression (p=0.001) over 5 weeks of treatment. The mean decrease in the Hamilton Rating Scale for Anxiety score was 32.8% for active CES and 9.1% for sham. The mean decrease in the Hamilton Rating Scale for Depression score was 32.9% for active CES and 2.6% for sham. However, because key health outcomes were not addressed and, as noted in a Veterans Affairs Evidence Synthesis Program review in 2018 by Shekelle et al, due to the serious methodological limitations of this study (i.e., unclear sham credibility), the strength of this evidence is low. This systematic review published by Shekelle et al explored the benefits and harms of CES for adult patients with chronic painful conditions, depression, anxiety, and insomnia. 26 randomized trials met eligibility criteria, however most trials had small sample sizes and short durations; all had high risk of bias due to inadequate blinding. The review showed that evidence is insufficient that CES has clinically important effects on fibromyalgia, headache, neuromusculoskeletal pain, degenerative joint pain, depression, or insomnia; low-strength evidence suggests modest benefit in patients with anxiety and depression.
In a smaller, double-blind, sham-controlled, randomized pilot study (n=30), Mischoulon et al (2015) found no significant benefit of CES as adjunctive therapy in patients with treatment-resistant major depression. Both the active and sham groups demonstrated improvement of about 3-5 points in HAM-D-17 scores (p<0.05 for both) over the 3 weeks of the study, suggesting a strong placebo effect, and no significant differences were observed between groups. Remission rates were 12% for CES, and 15% for sham, a nonsignificant difference. CES was deemed safe, with good tolerability, however limitations include a small sample size, short follow-up, and lack of an active comparator therapy. The researchers concluded that future studies are needed that compare against other CES devices.
In 2015, results from a sham-controlled, double-blind randomized trial published by Lyon et al found no significant benefit of CES with the Alpha-Stim device for symptoms of depression, anxiety, pain, fatigue, and sleep disturbances in women receiving chemotherapy for breast cancer. This phase 3 trial randomized 167 women with early-stage breast cancer to 1 hour of daily CES or to sham stimulation beginning within 48 hours of the first chemotherapy session and continuing until 2 weeks after chemotherapy ended (range, 6 to 32 weeks). Stimulation intensity was below the level of sensation. Active and sham devices were factory preset, and neither evaluators nor patients were aware of the treatment assignment. Outcomes were measured using validated questionnaires that assessed pain, anxiety, and depression, fatigue, and sleep disturbance. There were no significant differences between the active and sham CES groups during treatment. However, the trial might have been limited by low symptoms levels at baseline, resulting in a floor effect, and the low level of stimulation. The researchers concluded that although there was no evidence for the routine use of CES during the chemotherapy period for symptom management in women with breast cancer, further symptom management modalities should be evaluated to mitigate symptoms of depression, anxiety, fatigue, pain, and sleep disturbances over the course of chemotherapy.
In 2021, Price et al published a meta-analysis evaluating CES for the treatment of depression and/or anxiety and depression. Five RCTs and 12 open-label, non-randomized studies that utilized Alpha-Stim were included. When considering pooled data from RCTs, results demonstrated that the mean depression level at posttest for the CES group was -0.69 standard deviations lower than the mean depression level for the sham stimulation group, which corresponds to a medium effect size. Pooled data from nonrandomized studies showed a smaller effect of -0.43 standard deviations in favor of CES. The reviewers concluded that CES has a small to medium significant effect in symptoms of depression across moderate to severe patients in civilian, military, veterans, advanced cancer, and pediatric populations.
In 2020, Ahn et al published a small double-blind, randomized, sham-controlled, single center pilot study evaluating the feasibility and efficacy of remotely supervised CES via secure videoconferencing in 30 older adults with chronic pain due to knee osteoarthritis. Mean age was 59.43 years. CES was delivered via the Alpha-Stim M Stimulator, which was preset at 0.1 mA at a frequency of 0.5 Hz, and applied for 1 hour daily on weekdays for 2 weeks. The sham electrodes were identical in appearance and placement, but the stimulator did not deliver electrical current. All 30 participants completed the study and were included in the outcome analyses. For the primary outcome of clinical pain at 2 weeks as assessed by a Numeric Rating Scale, a significantly greater reduction occurred in the active CES group (-17.00 vs +5.73; p<0.01). No patients reported any adverse effects. Important relevancy limitations include lack of assessment of important health outcomes or long-term efficacy. An important conduct and design limitation is that it is unclear how convincing the sham procedure was as it did not involve any feature designed to simulate a tingling sensation and give the patient the feeling of being treated (i.e., subtherapeutic amplitude, initial current slowly turned to zero). Thus, findings may be subject to the placebo effect. This trial was also limited by the small number of participants and very short duration. These limitations preclude drawing conclusions based on these findings.
A Cochrane literature review by O’Connell et al (2014) evaluated noninvasive brain stimulation techniques for chronic pain. Reviewers identified 11 randomized trials of CES for chronic pain. A meta-analysis of 5 trials (n=270 participants) found no significant difference in pain scores between active and sham stimulation (standard mean difference [SMD], -0.24; 95% CI, -0.48 to 0.01) for the treatment of chronic pain. A 2018 update by O’Connell et al did not find additional trials for CES.
Klawansky et al (1995) published a meta-analysis of 14 RCTs comparing CES with sham for the treatment of various psychological and physiological conditions: anxiety (eight trials), brain dysfunction (two trials), headache (two trials), and insomnia (two trials). The meta-analysis of anxiety showed CES to be significantly more effective than sham treatment (p<0.05). Most studies failed to report all data necessary for meta-analysis. Moreover, in all but two trials, the therapist was not blinded and knew which patients were receiving CES or sham treatment. The reviewers strongly recommended that future trials of CES report complete data and incorporate therapist blinding to avoid possible bias.
A Cochrane review by Bronfort et al (2004) assessed noninvasive treatments for headaches. They identified 1 poor quality, placebo-controlled, randomized trial (n=100) of CES for a migraine or a tension-type headache. Results from the trial showed greater reductions in pain intensity in the CES group than in the placebo group (effect size, 0.4; 95% CI, 0.0 to 0.8). The reviewers concluded that further research is needed using scientifically rigorous methods. A 2014 update to this review has been withdrawn due to the desire to replace the review with 3 separate reviews; however, these were unable to be completed.
Shill et al (2011) studied the effects of noninvasive transcranial electrical stimulation on the motor and psychological symptoms of early Parkinson's disease. Twenty-three patients were treated with 10 days of placebo versus active treatment and then followed for 14 weeks. Results showed no benefit of CES with the Nexalin device for motor or psychological symptoms in a crossover study of 23 patients with early Parkinson disease. The treatment was well tolerated without device-related adverse events. The reviewers commented that despite the study results, nonpharmacological approaches should continue to be pursued in Parkinson's disease, as they are generally well received by patients.
Technology Assessments
Hayes evaluates a wide range of medical technologies and provides evidence-based assessments to determine impacts on patient safety and health outcomes. The Hayes Rating has become the industry’s benchmark and reflects the strength and direction of the evidence regarding a medical technology. The Hayes Rating is D2 for the use of cranial electrical stimulation (CES) for reduction in pain and improvement in function in adults with fibromyalgia, indicating insufficient published evidence to assess the safety and/or impact on health outcomes. The Hayes Rating is also D2 for use of CES for the treatment of chronic pain associated with spinal cord injury.
In addition, in 2023, Hayes published an Evidence Analysis Research Brief to evaluate the evidence related to CES for treatment of posttraumatic stress disorder (PTSD). A review of the clinical evidence suggested that there currently is not enough published peer-reviewed literature to evaluate the evidence related to CES for treatment of PTSD.
Practice Guidelines & Position Statements
No guidelines or statements have been identified that address CES.
Reference List
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