In this study, the daily administration of 2.250 g of EPA and 500 mg of DHA for 3 months was accompanied by significant decreases in anger and anxiety scores in a group of substance abusers. These changes were associated with increases in plasma levels of EPA and DHA but an increase in EPA was more robustly correlated with low end-of-trial anxiety scores and an increase in DHA was more robustly correlated with low end-of-trial anger scores.
The present data provide further support to emerging evidence of a link between n-3 PUFAs and hostility. Rates of homicides are greater in countries with lower seafood intake (Hibbeln, 2001
). This is consistent with a study showing that a reduced plasma level of DHA predicted greater hostility in violent male subjects with antisocial personality (Virkkunen et al., 1987
) and with other data showing that young adults whose dietary intake of DHA and fish was high had a lower likelihood of high hostility (Iribarren et al., 2004
). Few studies have investigated the effects of n-3 supplements on hostility or aggression. In one study, DHA supplementation with oil capsules prevented an increase in aggression at times of stress among Japanese students (Hamazaki et al., 1996
) but had no effect in non-stressful situations (Hamazaki et al., 1998
). Similar findings by the same authors were reported in an elderly cohort of white-collar workers but not in rural villagers (Hamazaki et al., 2002
). In a study of women with untreated borderline personality disorder, ethyl ester EPA was found to diminish aggression and hostility measures as well as the severity of depressive symptoms (Zanarini and Frankenburg, 2003
). Prisoners treated with supplements of vitamins, minerals and n-6 and n-3 PUFAs had fewer disciplinary incidents than those who had received a placebo (Gesch et al., 2002
There is a limited amount of information about the effects of n-3 PUFAs in anxiety. The present data are among the first suggesting the possible existence of a relationship between EPA and anxiety in humans. Yehuda et al. (2005)
who investigated the effects of the administration of a mixture of n-3 and n-6 PUFAs on test anxiety in college students observed an improvement in variables associated with this type of anxiety (i.e., appetite, mood, concentration, fatigue, academic organization, and sleep). They also observed a decrease in elevated cortisol levels. Green et al. (2006)
found decreased levels of most n-3 PUFAs in the red blood cell membranes of patients with social anxiety disorder. Furthermore, their data suggest the existence of a relationship between the degree of n-3 PUFA deficiency and the severity of the anxiety disorder. Fux et al. (2004)
, on the other hand found EPA to be ineffective in a preliminary study of 11 patients with obsessive-compulsive disorder treated with selective serotonin reuptake inhibitors. Preclinical studies have shown that the administration of EPA decrease anxiety-like behaviors in rodents. The inflammatory-sickness response, stress and anxiety-like behaviors and stimulation of corticosterone secretion induced in rats by interleukin-1beta, the most potent proinflammatory cytokine, were found to be significantly reversed by the administration of EPA (Song et al., 2004
In light of the discrepant results yielded by different studies using comparable amounts of n-3 PUFAs to treat mood disorders, one could wonder whether participants in some of these studies could have been unresponsive because they were not deficient in n-3 PUFAs. This was not the case in the present study as lower anger and anxiety scores at the end of the trial were associated with more important changes from baseline in EPA and DHA. Unlike most therapeutic agents, FAs are available from dietary sources but the upper limits of plasma concentrations of EPA and DHA beyond which additional increments would become ineffective have not yet been determined. Within the FA ranges observed in this study, no ceiling effect was observed and the magnitude of EPA and DHA changes appeared sufficient to induce psychological effects.
Little is presently known about the nature of the specific mechanisms underlying the efficacy of EPA and DHA in different psychiatric disorders. N-3 PUFAs have extraordinarily complex and diverse effects ranging from modifications of the biophysical properties of neuronal membranes that lead to alterations in receptor activity and signal transduction to the production of potent eicosanoids that control immune-inflammatory responses and blood flow as well as the regulation of gene expression. EPA and DHA are generally used in the treatment of one specific, more or less well delineated psychiatric condition. In the present study, changes in two psychological dimensions were assessed simultaneously and an attempt was made to determine the relative contribution of EPA and DHA to these changes. Increases in EPA (but not in DHA) were found to be robustly correlated with end-of-trial low anxiety scores whereas increases in DHA were more robustly correlated with low anger scores. It would be tempting to speculate that the modes of action of LC n-3 PUFAs could be different for anger and anxiety. The stress and anxiety-like behaviors and the stimulation of corticosterone induced in rats by interleukin-1beta were found to be significantly reversed by the administration of EPA (Song et al., 2004
). On the other hand, modifications of serotonin (5-HT) neurotransmission have been implicated in violence and increasing DHA consumption may increase brain 5-HT neurotransmission as indicated by a study showing that higher concentrations of plasma DHA predicted higher levels of cerebrospinal fluid 5-HIAA (5-Hydroxyindole Acetic Acid) in healthy controls and late onset alcoholics (Hibbeln et al., 1998
). It can be pointed out, however, that a small number of subjects took part in the present study. The correlation between EPA increases and anger that was not significant could have become significant if a larger number of subjects had been included, raising the possibility that DHA and EPA could act in synergy on the modulation of hostility.
The present data need to be confirmed in larger samples. Studies are needed to determine the effectiveness of EPA and DHA administered separately and in combination in different psychiatric conditions. The most effective doses of these two PUFAs need to be determined. These doses might depend on the pre-trial plasma levels of n-3 PUFAs as it is possible that non-deficient individuals might be non-responders. Ideally, n-3 PUFAs should be measured prior to the start of therapeutic interventions. Doses of EPA and DHA will also depend on the pre-trial levels of PUFAs of the n-6 series as they compete with PUFAs of the n-3 series for conversion to biologically active derivatives. Recommendations might thus vary as a function of the country of origin of individuals who are candidates for treatment. The duration of treatment needed to restore PUFAs to healthy levels and whether supplementation can be replaced by sound dietary habits should also be investigated.