Prostaglandins, Leukotrienes and Essential Fatty Acids 75 (2006) 309–314 Relationship between omega-3 fatty acids and plasma neuroactive steroids in alcoholism, depression and controls L.R.G. Nieminen a , K.K. Makino a , N. Mehta a , M. Virkkunen b , H.Y. Kim a , J.R. Hibbeln a,Ã a National Institutes of Health, National Institutes on Alcoholism and Alcohol Abuse, Laboratory of Membrane Biophysics and Biochemistry, Bethesda, MD 20814, USA b Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland Abstract Deficiency in the long-chain o-3 fatty acid, docosahexaenoic acid (DHA) has been associated with increased corticotropin releasing hormone and may contribute to hypothalamic pituitary axis (HPA) hyperactivity. Elevated levels of the neuroactive steroids, allopregnanolone (3a,5a-THP) and 3a,5a-tetrahydrodeoxycorticosterone (THDOC) appear to counter-regulate HPA hyperactivity. Plasma essential fatty acids and neurosteroids were assessed among 18 male healthy controls and among 34 male psychiatric patients with DSM-III alcoholism, depression, or both. Among all subjects, lower plasma DHA was correlated with higher plasma THDOC (r ¼0.3, Po0.05) and dihydroprogesterone (DHP) (r ¼0.52, Po0.05). Among psychiatric patients lower DHA was correlated with higher DHP (r ¼0.60, Po0.01), and among healthy controls lower plasma DHA was correlated with higher THDOC (r ¼0.83, Po0.01) and higher isopregnanolone (3b,5a-THP) (r ¼0.55, Po0.05). In this pilot observational study, lower long-chain o-3 essential fatty acid status was associated with higher neuroactive steroid concentrations, possibly indicating increased feedback inhibition of the HPA axis. r 2006 Elsevier Ltd. All rights reserved. 1. Introduction A growing body of clinical and epidemiological data suggests that the o-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) may be effective in the treatment and or prevention of depressive disorders [1]. Depressive disorders have been associated with excessive responses to stress and hyperactivity of the hypothalamic pituitary adrenal (HPA) axis [2]. However, few studies have examined a putative link between o-3 fatty acids, HPA hyperactiv- ity and stress response. Hibbeln et al. [3] demonstrated that lower plasma levels of DHA predicted higher levels of corticotropin releasing hormone (CRH) in cerebrospinal fluid, suggesting that deficiency in DHA may facilitate excessive stress re- sponses and HPA hyperactivity. In support of this interpretation, DHA deficient rats had exaggerated distress behaviors compared to DHA adequate rats during administration of CRH and were normalized upon restoration of dietary DHA [4]. At least two double-blind placebo-controlled intervention trials with human subjects have demonstrated a stress protective benefit of supple- mentation with o-3’s. Among Japanese students, supple- mentation with DHA attenuated stress-induced increases in aggression and hostility [5]. Among stressed university staff, both o-3 and placebo significantly reduced perceived stress, however only the o-3 group was significantly better compared to the no-treatment con- trols. The latter study had several methodological limitations, including the use of olive oil as placebo, and therefore should be interpreted cautiously [6]. Excessive stress response and HPA hyper-activation may be reflected in concentrations of brain and plasma ARTICLE IN PRESS www.elsevier.com/locate/plefa 0952-3278/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.plefa.2006.07.012 Ã Corresponding author. NIAAA, 31 Center drive, 31/1B 58, Bethesda, MD 20892, USA. Tel.: +301 435 4028; fax: +301 402 0016. E-mail address: jhibbeln@mail.nih.gov (J.R. Hibbeln).