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SYNOPSIS: In a review and meta-analysis of 19 studies regarding use of omega-3 fatty acids for treating anxiety, researchers showed improvement in anxiety symptoms with these nutrients. The effect appears most significant in a clinically diagnosed subpopulation.
SOURCE: Su K, Tseng P, Lin P, et al. Association of use of omega-3 polyunsaturated fatty acids with changes in severity of anxiety symptoms: A systematic review and meta-analysis. JAMA Netw Open 2018;1:e182327.
“Many lamentable effects this fear causeth in men, as to be red, pale, tremble, sweat; it makes sudden cold and heat come over all the body, palpitation of the heart, syncope, etc.”1
— Robert Burton, 1621
Described almost 400 years ago by Robert Burton in The Anatomy of Melancholy, anxiety today holds the dubious distinction of ranking as the most common psychiatric condition. General anxiety disorder, panic disorder (with or without agoraphobia), separation anxiety disorder, social anxiety disorder, medication- or substance-induced anxiety, and specific phobias are among the disorders of anxiety described in the Diagnostic and Statistical Manual of Mental Disorders. With prevalence of anxiety approaching one-third of the population, the healthcare costs and related indirect economic impact of anxiety disorders are significant. There are many options for intervention, but underrecognition and undertreatment often lead to worsening and prolongation of symptoms.2,3
It may be useful to consider how to distinguish anxiety from disorders of anxiety. As an emotional state, anxiety may occur as a healthy response to stress or unexpected events. However, anxiety disorders are diagnosed when the symptoms of anxiety are prolonged and begin to interfere with desired functions of life, such as sleeping, eating, working, and relationships.3
Conventional treatment of anxiety disorders includes psychological therapies (such as cognitive-behavioral therapy) alone or in combination with medication (typically, selective serotonin reuptake inhibitors, although other agents are possible).4 Noting that anxious patients may avoid medication because of inherent heightened concern about side effects and that specific therapies may be difficult to access, Su et al stated that “evidence-based and safer treatments are required.”
Omega-3 polyunsaturated fatty acids (PUFAs) are fatty acids that are important in cell membrane structure as well as multiple other bodily functions. Most significantly, omega-3s help in the formation of signaling molecules that play essential roles in the cardiovascular, immune, endocrine, and pulmonary systems. The three main omega-3 PUFAs are alpha-linoleic acid (ALA) found in plant oils, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). EPA and DHA are found mainly in seafood and some algae. Notably, although ALA can be converted, albeit inefficiently, to EPA and DHA in the body, it is an essential fatty acid, which means that this nutrient is not synthesized naturally by the body. Thus, external sources of these agents — whether from foods or dietary supplements — are vital.5
Depression and anxiety often coexist. Omega-3 PUFAs have been found to have clinical utility in several studies of major depressive disorder.6 In a 2015 literature review of omega-3 PUFAs for depression, Wani et al found conflicting results in studies and pointed to the possibility that there exists a subtype of depression particularly susceptible to intervention with these agents.7 Suominen-Taipale et al noted support from laboratory and some emerging clinical studies on the preventive potential of omega-3 PUFAs in both anxiety and mood disorders.8
Su et al stated that preclinical data from mouse and rat studies support the further exploration of omega-3 PUFAs for treating anxiety. They cited several animal studies with promising results, as well as a smattering of human case studies looking at this relationship. Noting that there had been no systematic review of the literature, Su et al sought to conduct a systematic review and meta-analysis of relevant clinical studies regarding anxiety and the use of omega-3 PUFAs.
Out of 3,584 studies and reports identified for potential inclusion in this review, only 19 studies were of sufficient quality to be included in this meta-analysis. Of the 19 studies, 16 included a placebo and all included a control group. A little more than half of the participants (1,203 participants out of a total respondent count of 2,240 participants) were treated with omega-3 PUFA.
Heterogeneity was a significant obstacle in this meta-analysis, with a wide range of scales used to measure anxiety. Another complicating factor was that the baseline condition of participants differed across the studies. Some studies included persons with a diagnosis of generalized anxiety but others included participants who had symptoms of anxiety caused by primary conditions (including attention deficit disorder, obsessive-compulsive disorder, post-myocardial infarction, post-trauma, Alzheimer’s disease, accidental injury, Parkinson’s disease, and test anxiety). Other studies included respondents recruited from the general population without any diagnosis. Su et al attempted to control for this heterogeneity, but clearly noted this as a limitation of the review.
Several subgroups were analyzed. Given the concerns about heterogeneity, Hedges g and 95% confidence intervals were employed to understand effect sizes. Hedges g is a measure of the difference between identified groups (effect size) and is similar to Cohen’s d. In this case, a Hedges g value of ≥ 0 indicates a higher association of anxiety reduction with omega-3 PUFA (vs. control). (See Tables 1 and 2.)
When combining results of all 19 studies (subgroup 1), there appeared to be a statistically significant association between taking omega-3 PUFAs and reduction of clinical symptoms of anxiety. This association was even stronger when considering only the subgroup of participants with a specific diagnosis.
In addition, the investigators found some evidence that EPA-enriched supplements (> 50-60%) were beneficial in treating depression. However, in this meta-analysis, the more significant association with anxiolytic effect appeared to be with preparations with < 60% EPA.
This ambitious, well-designed meta-analysis consolidated 19 disparate studies linked together by an interest in investigating the effect of omega-3 PUFAs for treatment of anxiety. The results showed an association toward effective anxiolytic action with use of these agents, especially in cases in which there was a defined clinical diagnosis (neuropsychiatric or medical).
As noted previously and discussed by Su et al, the major limitation of this review resides within the heterogeneity of the 19 studies. There is clear evidence that the study authors not only were looking at very different aspects and manifestations of anxiety, but also were using different scales to measure anxiety and response to intervention. Breaking the total group into specific subgroups helps address this deficit, but leads to much smaller numbers in each group, making it difficult to generalize these results.
This dilemma points to the need for more well-designed and robust studies with clear criteria for diagnosis and standardized scales for measurement. For example, anxiety symptoms associated with traumatic events may require a different intervention than anxiety associated with a neurodegenerative disorder such as Parkinson’s disease or Alzheimer’s disease, and these both may differ substantially from interventions needed to address test anxiety. The material and data available now is useful for only preliminary conclusions, but does point to a direction for future work in this area.
When weighing risk and harm, it is noteworthy that there is little harm associated with use of omega-3 PUFAs, especially with doses in the range of 2,000 mg/day.4 On the other hand, the effect of untreated anxiety on clinical conditions is significant and can lead to prolongation or worsening of medical states in conditions as disparate as multiple sclerosis, cardiovascular disease, and pulmonary disease.9,10 In mental illness, untreated anxiety is a risk factor for complications of multiple disorders and is an independent risk factor for suicide.11
Given these considerations, a primary care or integrative provider can solidly recommend that patients with anxiety consider a role for dietary intervention with omega-3 PUFAs. The potential for omega-3 PUFAs in fighting anxiety symptoms may be of particular interest to patients who are hoping to avoid conventional pharmacologic agents, including many women of childbearing age and patients who have multiple comorbidities and are hoping to avoid or minimize polypharmacy.
It is useful to keep in mind that there is no evidence from the studies in this review that omega-3 PUFAs can replace traditional antianxiety agents or therapies, and no evidence to support or discourage a combination of these agents. The take away? There is good evidence to support further investigation into the use of omega-3 PUFAs for the treatment of anxiety. The doses of these agents look to be most efficacious at ≥ 2,000 mg/day. The effect is most pronounced in people with anxiety associated with a clinically diagnosed disorder. There is clear and exciting potential for not only clinical guidelines but also public health interventions to emerge as more robust and rigorous studies examine the role of omega-3 PUFAs treatment of anxiety disorders.
Financial Disclosure: Integrative Medicine Alert’s Executive Editor David Kiefer, MD; Peer Reviewer Suhani Bora, MD; Relias Media Executive Editor Leslie Coplin; Editor Jonathan Springston; and Editorial Group Manager Terrey L. Hatcher report no financial relationships relevant to this field of study.