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The calming powers of chamomile have been frequently studied, including a 2009 study that states chamomile is superior to taking a placebo when treating generalized anxiety disorder. One <anchor>recent study</anchor> confirmed it’s safe for long-term use, and another recent study looked beyond its use for anxiety and confirmed that it also shows potential in anticancer treatments.
Long-term chamomile (Matricaria chamomilla L.) treatment for generalized anxiety disorder: A randomized clinical trial - ScienceDirect
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## Phytomedicine

# Long-term chamomile ( Matricaria chamomilla L.) treatment for generalized anxiety disorder: A randomized clinical trial ☆

Author links open overlay panelJun J.Maoa, Sharon X.Xieb, John R.Keefec, IreneSoellerd, Qing S.Lid, Jay D.Amsterdame

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## Abstract

### Background

Generalized Anxiety Disorder (GAD) is one of the most common anxiety disorders treated in primary care, yet current therapies have limited efficacy and substantial side effects.

### Purpose

### Methods

Outpatients from primary care practices and local communities with a primary diagnosis of moderate-to-severe GAD were enrolled for this two-phase study at a large US academic medical center. During Phase 1, eligible participants received 12 weeks of open-label therapy with chamomile pharmaceutical grade extract 1500mg (500mg capsule 3 times daily). During Phase 2, treatment responders were randomized to either 26 weeks of continuation chamomile therapy or placebo in a double-blinded, placebo-substitution design. The primary outcome was time to relapse during continuation therapy, analyzed using Cox proportional hazards. Secondary outcomes included the proportion who relapsed, treatment-emergent adverse events, and vital sign changes. This study is registered at ClinicalTrials.gov, identifier NCT01072344.

### Results

Between March 1, 2010, and June 30, 2015, we enrolled 179 participants. Of those, 93 (51.9%) were responders and agreed to continue in the double-blind randomized controlled trial. A numerically greater number of placebo-switched ( n = 12/47; 25.5%) versus chamomile-continuation ( n = 7/46; 15.2%) participants relapsed during follow-up. Mean time to relapse was 11.4 ± 8.4 weeks for chamomile and 6.3 ± 3.9 weeks for placebo. Hazard of relapse was non-significantly lower for chamomile (hazard ratio, 0.52; 95% CI, 0.20–1.33; P = 0.16). During follow-up, chamomile participants maintained significantly lower GAD symptoms than placebo ( P = 0.0032), with significant reductions in body weight ( P = 0.046) and mean arterial blood pressure ( P = 0.0063). Both treatments had similar low adverse event rates.

### Conclusions

Long-term chamomile was safe and significantly reduced moderate-to-severe GAD symptoms, but did not significantly reduce rate of relapse. Our limited sample size and lower than expected rate of placebo group relapse likely contributed to the non-significant primary outcome finding. Possible chamomile superiority over placebo requires further examination in large-scale studies.

## Graphical abstract

Image, graphical abstract

## Introduction

Generalized Anxiety Disorder (GAD) is characterized by excessive worry about daily matters and the presence of restlessness, fatigue, difficulty concentrating, irritability, muscle tension, and sleep problems (Andrews et al., 2010). GAD has a lifetime prevalence of approximately 5%, with nearly 9million affected adults in the United States (Kessler et al., 2005). As the second most frequently treated psychiatric disorder in the primary care setting, GAD results in substantial distress and disability comparable only to that of the most frequently treated disorder, major depression (Kessler et al., 1999).

Current psychopharmacological treatments for GAD include benzodiazepines and selective serotonin-reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors (SSRI/SNRIs) (Reinhold and Rickels, 2015), but some patients do not respond to these therapies, while others cannot tolerate their side effects (Mitte et al., 2005). As a result, individuals suffering from anxiety commonly seek out complementary and integrative medicine, including herbal medicine products to treat this disorder (Bystritsky et al., 2012).

Chamomile ( Matricaria chamomilla L.) is one of the most widely used herbal remedies in the world. It is included in the pharmacopoeia of 26 countries (Salamon, 1992). Limited basic science research suggests that chamomile and several of its flavonoid components may have anxiolytic and antidepressant activity (Nakazawa et al., 2003, Reis et al., 2006). Although chamomile is used extensively throughout the world as a calming agent, research in humans is very limited. In the only existing randomized controlled trial, our group found a significantly greater reduction in mean general anxiety symptom scores for chamomile as compared with placebo after 8 weeks of therapy (Amsterdam et al., 2009).

Recognizing that GAD is a recurrent disorder that often requires long-term therapy (Yonkers et al., 2003), we sought to extend our preliminary results by conducting a randomized, double-blind, placebo-substitution, long-term safety and efficacy study of chamomile therapy in GAD. Our primary aim was to examine if long-term chamomile therapy prolonged the time to relapse of anxiety symptoms following recovery from GAD, relative to placebo. Our secondary aim was to evaluate the relative safety and tolerability of long-term chamomile therapy as compared with placebo in participants who had recovered from GAD.

## Section snippets

## Study design

We conducted a randomized controlled trial from March 2010 through June 2015 at the Hospital of the University of Pennsylvania, an academic medical center in Philadelphia. After 12 weeks of open-label therapy with chamomile for moderate to severe GAD (Keefe et al., 2016), treatment responders were randomized to receive 26 weeks of either continuation chamomile or placebo in a double-blinded, placebo-substitution design. This is a well-established design strategy used in prior long-term efficacy

## Results

Between March 1, 2010, and June 30, 2015, we evaluated 394 individuals and enrolled a total of 179 participants. Of these, 93 (51.9%) met criteria for clinical response and were then randomized to either placebo ( n = 47) or chamomile continuation ( n = 46). Among participants who were randomized, 7 (7.5%) were lost to follow-up; 3 (3.2%) were withdrawn by the PI due to non-compliance; 19 (20.4%) met criteria for relapse; and 64 (68.8%) were no longer clinically ill by the Week 38 follow-up (Fig.

## Discussion

GAD is a common chronic psychological disorder seen in primary and mental health care settings. Current psychopharmacological treatments have both limited efficacy and substantial side effects (Mitte et al., 2005, Reinhold and Rickels, 2015), and many patients self-medicate with herbal supplements to alleviate chronic anxiety (McIntyre et al., 2015). To our knowledge,very little research has been conducted to date that evaluatesthe long-term safety andefficacy ofherbal medicinesfor anxiety. In

## Conclusions

Our study is the first long-term placebo-controlled trial of chamomile conducted in humans. Chamomile appeared to be safe, with few mild side effects that were indistinguishable from placebo. Continued use of chamomile was associated with a non-significant reduction in GAD relapse among responders to initial therapy, in addition to significantly better GAD symptoms and improved psychological well-being. Furthermore, long-term chamomile use may be associated with improved blood pressure and

## Conflict of interest

The authors declare that they have no conflict of interest.

## Funding

This study is supported by grants from the National Institutes of Health (NIH) / National Center for Complementary and Integrative Health [Grant Number R01 AT005074], and NIH / National Cancer Institute [Cancer Center Support Grant Number P30 CA008748].

## Acknowledgments

We thank all of the clinical coordinators and research assistants for their dedication to clinical trial coordination, data collection, and management. We also thank Kenneth Rockwell Jr., PharmD, MS, Director of Research Pharmacy, University of Pennsylvania School of Medicine and the staff at the Penn Investigational Drug Service for their contributions in study drug preparation and dispensing. We thank the Swedish Herbal Institute for processing, producing, and providing the standardized oral

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## Cited by (92)

2023, Journal of Herbal Medicine

Show abstract

Chamomile has been reported to possess anti-inflammatory, antioxidant, antinociceptive, antimutagenic, sedative, anxiolytic, antispasmodic properties. While the potential therapeutic benefits of chamomile have been discussed broadly, little is known about the potential utility of chamomile in the acute care setting, namely among postoperative and other hospitalized patients. This narrative review aims to explore the potential benefits of chamomile in the inpatient setting.

A PubMed literature search was conducted for original research articles that discussed the clinical application of chamomile toward conditions commonly encountered in the inpatient setting. Study participant population, dosage, type of chamomile preparation, relevant findings, and adverse events were extracted. Potential benefits of chamomile for the inpatient setting were synthesized from pertinent study results.

Of the 22 articles selected for review, only five publications enrolled inpatients. Consequently, many conclusions were drawn from outpatient studies. Chamomile may alleviate six commonly encountered inpatient conditions: (1) anxiety and depression, (2) impaired sleep quality, (3) gastrointestinal dysfunction, (4) acute and chronic pain, (5) nausea and vomiting, and (6) diabetes. Reported adverse events were rare and rated mild.

This narrative review suggests chamomile may be a promising herbal therapy for a variety of conditions commonly encountered in postoperative and hospitalized patients.

2023, International Journal of Surgery Open

Show abstract

Surgical extraction of the impacted lower third molar is one of the most common surgical procedures in dentistry. Postoperative pain usually reaches its intensity 12 h after the procedure and adversely affects the patient's quality of life for many days. Chamomile anti-inflammatory and pain-relieving properties have been introduced in the medical literature. The present study aimed to investigate the efficacy of chamomile gel in reducing postoperative pain and symptoms after impacted lower third molar surgeries.

This study was a triple-blinded placebo-controlled randomised clinical trial with a split-mouth crossover design. The study included 70 impacted lower third molars in 35 patients (13 males and 22 females) with a mean age of 22.29 (±3.00) years. Participants’ extraction sides were randomly allocated into the study groups. Each participant was enrolled twice, i.e., into the study and control groups with a washout period of 3 weeks between the two surgeries. Postoperative pain, need for analgesics, symptoms severity (PoSSe), and wound healing were evaluated.

Gingival healing was significantly better in chamomile group compared to control group (P < 0.001). There were no significant differences in post-extraction alveolar osteitis between chamomile and control group (P = 0.314). VAS results showed significant differences in mean pain scores, with significant decrease in chamomile groups (P < 0.05). Moreover, analgesic consumption was significantly higher in placebo group (P < 0.05). Mean PoSSe scores were 16.8 (±9.4) in the chamomile group, versus 41.1 (±9.9) in the control.

Within the limitations of the present study, it was concluded that intra-socket application of chamomile gel might effectively improve healing, and reduce pain levels, postoperative symptoms severity, and analgesics consumption after surgical extraction of impacted lower third molars.

2023, Child and Adolescent Psychiatric Clinics of North America

2024, BMC Complementary Medicine and Therapies

2024, International Journal of Molecular Sciences

2024, Jundishapur Journal of Natural Pharmaceutical Products

Trial registration number: NCT01072344 at ClinicalTrials.gov. FDA: IND 107,206.

© 2016 Elsevier GmbH. All rights reserved.

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