Acupuncture for Combat-Related Posttraumatic Stress Disorder: A Randomized Clinical Trial

Michael Hollifield; An-Fu Hsiao; Tyler Smith; Teresa Calloway; Tanja Jovanovic; Besa Smith; Kala Carrick; Seth D. Norrholm; Andrea Munoz; Ruth Alpert; Brianna Caicedo; Nikki Frousakis; Karen Cocozza

doi:10.1001/jamapsychiatry.2023.5651

Original Investigation

February 21, 2024

Acupuncture for Combat-Related Posttraumatic Stress Disorder: A Randomized Clinical Trial

Michael Hollifield, MD^1,2; An-Fu Hsiao, MD, PhD^1,3; Tyler Smith, PhD⁴; et al Teresa Calloway, MATCM, LAc^1,5; Tanja Jovanovic, PhD⁶; Besa Smith, PhD⁴; Kala Carrick, MS¹; Seth D. Norrholm, PhD⁶; Andrea Munoz, PsyD¹; Ruth Alpert, BA¹; Brianna Caicedo, BA¹; Nikki Frousakis, PhD¹; Karen Cocozza, DACM, LAc⁷

Author Affiliations Article Information

¹Tibor Rubin VA Medical Center, Long Beach, California
²Department of Psychiatry and Behavioral Sciences, George Washington School of Medicine & Health Sciences, Washington, DC
³Department of Medicine, Health Policy Research Institute and General Internal Medicine, University of California, Irvine
⁴Analydata, San Diego, California
⁵Yo San University of Traditional Chinese Medicine, Los Angeles, California
⁶Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan
⁷Susan Samueli Integrative Health Institute, University of California, Irvine

JAMA Psychiatry. 2024;81(6):545-554. doi:10.1001/jamapsychiatry.2023.5651

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Key Points

Question Is verum acupuncture delivered over 12 to 15 weeks more efficacious than sham (minimal) needling for reducing posttraumatic stress disorder (PTSD) symptoms or fear-potentiated startle response in veterans with PTSD?

Findings In this randomized clinical trial including 93 participants, verum acupuncture resulted in a larger reduction in PTSD symptom severity than sham from the beginning to the end of treatment in both the intention-to-treat and treatment-completed models, and a larger reduction in fear-potentiated startle extinction after treatment.

Meaning The findings indicate that verum acupuncture had a large pretreatment to posttreatment effect and was clinically and statistically superior to sham needling for reducing PTSD symptoms and enhancing fear extinction.

Abstract

Importance Current interventions for posttraumatic stress disorder (PTSD) are efficacious, yet effectiveness may be limited by adverse effects and high withdrawal rates. Acupuncture is an emerging intervention with positive preliminary data for PTSD.

Objective To compare verum acupuncture with sham acupuncture (minimal needling) on clinical and physiological outcomes.

Design, Setting, and Participants This was a 2-arm, parallel-group, prospective blinded randomized clinical trial hypothesizing superiority of verum to sham acupuncture. The study was conducted at a single outpatient-based site, the Tibor Rubin VA Medical Center in Long Beach, California, with recruitment from April 2018 to May 2022, followed by a 15-week treatment period. Following exclusion for characteristics that are known PTSD treatment confounds, might affect biological assessment, indicate past nonadherence or treatment resistance, or indicate risk of harm, 93 treatment-seeking combat veterans with PTSD aged 18 to 55 years were allocated to group by adaptive randomization and 71 participants completed the intervention protocols.

Interventions Verum and sham were provided as 1-hour sessions, twice weekly, and participants were given 15 weeks to complete up to 24 sessions.

Main Outcomes and Measures The primary outcome was pretreatment to posttreatment change in PTSD symptom severity on the Clinician-Administered PTSD Scale-5 (CAPS-5). The secondary outcome was pretreatment to posttreatment change in fear-conditioned extinction, assessed by fear-potentiated startle response. Outcomes were assessed at pretreatment, midtreatment, and posttreatment. General linear models comparing within- and between-group were analyzed in both intention-to-treat (ITT) and treatment-completed models.

Results A total of 85 male and 8 female veterans (mean [SD] age, 39.2 [8.5] years) were randomized. There was a large treatment effect of verum (Cohen d, 1.17), a moderate effect of sham (d, 0.67), and a moderate between-group effect favoring verum (mean [SD] Δ, 7.1 [11.8]; t₉₀ = 2.87, d, 0.63; P = .005) in the intention-to-treat analysis. The effect pattern was similar in the treatment-completed analysis: verum d, 1.53; sham d, 0.86; between-group mean (SD) Δ, 7.4 (11.7); t₆₉ = 2.64; d, 0.63; P = .01). There was a significant pretreatment to posttreatment reduction of fear-potentiated startle during extinction (ie, better fear extinction) in the verum but not the sham group and a significant correlation (r = 0.31) between symptom reduction and fear extinction. Withdrawal rates were low.

Conclusions and Relevance The acupuncture intervention used in this study was clinically efficacious and favorably affected the psychobiology of PTSD in combat veterans. These data build on extant literature and suggest that clinical implementation of acupuncture for PTSD, along with further research about comparative efficacy, durability, and mechanisms of effects, is warranted.

Trial Registration ClinicalTrials.gov Identifier: NCT02869646

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2 Comments for this article

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March 1, 2024

Acupuncture for Combat-Related Posttraumatic Stress Disorder

Hantong Hu, M.D | The Third Affiliated Hospital of Zhejiang Chinese Medical University

To the Editor,

I read with great interest the randomized controlled trial by Hollifield et al. on acupuncture for combat-related posttraumatic stress disorder (PTSD).[1] The study's promising findings contribute significantly to the field. However, we would like to highlight some key concerns.

First, the age restriction to 18-55 years for the included participants should be further justified, as excluding older adults will significantly limit the study's generalizability and it is not a common approach in acupuncture trials. If the authors imposed this age restriction to minimize confounding factors related to significant changes in the autonomic nervous system (ANS) in older individuals, we suggest the authors perform subgroup analyses based on different age stratifications to better elucidate potential ANS-related confounders. Moreover, reporting secondary outcomes related to ANS function, such as heart rate variability (HRV)[2], would be informative to explore the neural mechanisms underlying the efficacy of acupuncture and moxibustion. Additionally, it is worth noting that the study did not report several secondary and exploratory outcomes as claimed in the previously published study protocol.[3] It would be of interest to know the reasons for this omission.

Second, the original study protocol[3] and the published paper[1] do not specify whether participants were permitted to use rescue medications during the trial, such as emergency medication for panic attacks. It is also unclear whether dosages of concurrent medications for anxiety, depression, or PTSD were recorded and analyzed because they are not reported. Reporting on changes in psychotropic medication dosages could provide meaningful insights into acupuncture's potential interaction with pharmacotherapy, particularly whether it has a "detoxifying and enhancing" effect on psychotropic medications.

Finally, future research directions could include a three-arm design with an active control, comparisons with first-line PTSD treatments, and mechanistic studies to elucidate the roles of meridian versus individual point selection, point fatigue, dose-response effects, and impacts on biological pathways implicated in PTSD. Given the established efficacy of acupuncture for PTSD in this trial, these sophisticated follow-up studies can refine methodology and optimize acupuncture's clinical application for managing PTSD.

REFERENCES
1. Hollifield, M.; Hsiao, A.-F.; Smith, T.; et al. Acupuncture for Combat-Related Posttraumatic Stress Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2024, doi:10.1001/jamapsychiatry.2023.5651.
2. Gullett, N.; Zajkowska, Z.; Walsh, A.; et al. Heart Rate Variability (HRV) as a Way to Understand Associations between the Autonomic Nervous System (ANS) and Affective States: A Critical Review of the Literature. Int J Psychophysiol. 2023; 192:35–42, doi:10.1016/j.ijpsycho.2023.08.001.
3. Hollifield, M.; Hsiao, A.-F.; Carrick, K.; et al. Acupuncture for Combat Post-Traumatic Stress Disorder: Trial Development and Methodological Approach for a Randomized Controlled Clinical Trial. Trials. 2021; 22(1):594. doi:10.1186/s13063-021-05394-3.

CONFLICT OF INTEREST: None Reported

May 3, 2024

Comment on Acupuncture for Combat-Related Posttraumatic Stress Disorder

LIMING CHEN, - | Qi Kong, MD [a], Li-Ming Chen, MD, PhD[b], Pei-Hao Yin MD, PhD[a]

A Putuo Hospital, Shanghai University of Traditional Chinese Medicine
B Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine

Dear editor:
Hollifield et al have recently confirmed positive effects of acupuncture on Combat-Related Posttraumatic Stress Disorder (PTSD)1. While this study provides sufficient data, there are still parts that need to be explored in further research.
First, this study took about five years. The persistence of the authors' team with this trial is admirable. However, the extended duration of the trial was not conducive to maintaining the stability of the team. It is of considerable concern that acupuncture is a treatment modality based on specialized skill, and the experiences of the acupuncturist may affect the treatment effect2. In order to ensure the quality control, it is necessary to mention these aspects in trials with long time spans.
Second, the section of the study on power calculations refers to the use of the PSS-SR scale and CAPS-5 (DSM-5 version) conversions where equal percentile equivalence is used. This is one of the most popular methods3 and provides a reference for the use of different outcomes in the pilot or further study.
Finally, a total of 64 adverse events were reported in this trial. Although these adverse reactions are stated to be unrelated to the trial, they should be described in more detail. In addition, acupuncture is an invasive procedure. Mild acupuncture pain is difficult to avoid when the patient is awake4. It may be necessary to state whether this may cause stress or other adverse on patients with PTSD.
The trial maintained strict inclusion and exclusion criteria, allowing for extended case collection. On this basis, they used adaptive randomization due to anticipation of the characteristics of patients with Combat-Related PTSD. We appreciate the long-term persistence and methodological rigor of the author team. This result will be an important piece of evidence for acupuncture in psychiatric disorders.

Reference
1. Hollifield M, Hsiao AF, Smith T, et al. Acupuncture for Combat-Related Posttraumatic Stress Disorder: A Randomized Clinical Trial. JAMA Psychiatry. Published online February 21, 2024. doi:10.1001/jamapsychiatry.2023.5651
2. Devereaux PJ, Bhandari M, Clarke M, et al. Need for expertise based randomised controlled trials. BMJ. 2005;330(7482):88.
3. van Steenoven I, Aarsland D, Hurtig H, et al. Conversion between Mini‐Mental State Examination, Montreal Cognitive Assessment, and Dementia Rating Scale‐2 scores in Parkinson’s disease. Mov Disord. 2014;29(14):1809-1815. doi:10.1002/mds.26062
4. Capili B, Anastasi JK, Geiger JN. Adverse Event Reporting in Acupuncture Clinical Trials Focusing on Pain. Clin J Pain. 2010;26(1):43-48. doi:10.1097/AJP.0b013e3181b2c985

CONFLICT OF INTEREST: None Reported

Acupuncture for Combat-Related Posttraumatic Stress Disorder: A Randomized Clinical Trial

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