I feel as if this topic must have arisen on this board before, but I could not -- with a cursory glance -- find a mention of it. Fish oil seems to be something of a "no-brainer" supplement, with benefits on virtually every health-related parameter imaginable. And indeed, many on this board take considerable doses of fish oil regularly. However, many on this board also suffer from HPA-related maladies, particularly those characterized by a hypoactive stress response.
Though I'd not have hypothesized a relationship between fish oil (EPA/DHA) supplementation and the HPA, it seems a substantial one exists. I can't say I've performed a comprehensive review of the literature, but here's what's turned up. Note that the first two studies are very new; they were published online just a week ago.
(PMID: 20466437) This study compared patients with major depression treated with either 1g EPA/day, 20mg fluoxetine/day, or a combination of the two treatments. The findings showed that all three treatments tended to decrease HPA activity and, in particular, plasma cortisol. This may seem unsurprising, given that major depression of the melancholic type is associated with a hyperactive HPA, but the authors found that cortisol suppression was not correlated with symptom improvement. In other words, the drugs -- not the resolution of symptoms -- led to HPA suppression. And indeed, the authors noted that EPA itself may show efficacy in depression specifically by reducing HPA activity. It should be noted that the authors found that EPA was as effective as fluoxetine in symptomatic improvement.
(PMID: 20303394) This study compared the effects of exercise and DHA intake in [healthy] rats. They looked at leptin, ghrelin, AMPK, and SIRT1 in addition to HPA-related parameters, but I will not mention these findings. The authors found:
-In the hypothalamus, exercise increased GR expression whereas DHA reduced GR expression. Exercise and DHA together had no effect.
-In the hippocampus, GR expression was increased by DHA, exercise, and their combination.
-In the hypothalamus, 11betaHSD1 was increased only by DHA, with no changes in the other groups.
-In the hippocampus, 11betaHSD1 was increased by DHA, exercise, and their combination.
To oversimplify GR dynamics extensively, GR binding in the hypothalamus reduces HPA output, whereas GR binding in the hippocampus increases HPA output. Moreover, 11betaHSD1 (which converts corticosterone to cortisol, and thus has a positive effect on local cortisol concentrations) in the hypothalamus tends to reduce HPA output by increasing negative feedback, whereas 11betaHSD1 in the hippocampus tends to increase HPA output by increasing GR binding. In short, DHA has unclear effects in the hypothalamus (decreased GR but increased 11betaHSD-1) but positive effects on the hippocampus (increased GR and increased 11betaHSD1).
(PMID: 17055120) Healthy men were administered LPS, a commonly employed endotoxin. LPS alone caused massive HPA activation, leading to fever, increased ACTH, increased plasma cortisol, and cytokine release. Fish oil (17% EPA, 11% DHA) administration for 3-4 weeks beforehand blunted fever as well as ACTH and cortisol plasma levels, but had no effect on cytokine release.
(PMID: 12909818) "Seven human volunteers were studied on two occasions, before and after 3 weeks of supplementation with 7.2 g/day fish oil." (Fish oil was 17% EPA, 11% DHA). "After 3 weeks of a diet supplemented with n-3 fatty acids, the stimulation by mental stress of plasma epinephrine, cortisol, energy expenditure, and plasma non esterified fatty acids concentrations, were all significantly blunted." This effect is presumably mediated by the CNS.
(PMID: 11237197) In study 1, 41 college students took either a DHA capsule (1.5g DHA) or a control capsule daily for 3 months. The study ended in the middle of the mental stress of final exams. In the control group, hostility had increased significantly compared to the start of the study, whereas in the DHA group no change was found.
In study 2, plasma catecholamines and cortisol were measured for 7 students from the previous study. The authors note: "In study 2 the students were under a continuous stress of final exams that lasted for two mon throughout the whole study period. The plasma cortisol did not change in either group, but the norepinephrine concentration was significantly decreased in the DHA group (-31%), whereas it stayed at the same level in the control group."
It's seemingly undeniable that fish oil has numerous health benefits, but the HPA-related effects of EPA and DHA are neither positive (in conditions of hypoactive HPA activity) nor equal. Based on the above, admittedly limited, evidence, it would seem that EPA has a direct effect reducing HPA activity in response to stress. Its effects on baseline HPA activity are unclear. On the other hand, DHA seems to have conflicting molecular effects on the HPA, and the only study examining its cortisol- and catecholamine-related effects found no change in cortisol and a decrease in NE vs. control during a period of mental stress. It does seem, however, that fish oil containing 17% EPA and 11% DHA does reduce HPA activity in response to both mental and immunological stress.