In this study, the daily administration of 3 g of long-chain n-3 PUFAs for a period of 3 months significantly decreased feelings of anger in a population of substance abusers by comparison with the administration of a placebo. Anger scores did not return to baseline values during the 3 months that followed treatment discontinuation. These results support the observation made by others that supplements of long-chain n-3 PUFAs can diminish hostility levels in groups of non psychiatric individuals and in borderline patients (Hamazaki et al., 1996
, 2003; Zanarini, 2003
). The influence of n-3 PUFAs on aggression was also demonstrated in an animal model. Rats fed a diet deficient in n-3 PUFAs for 15 weeks after weaning had a significantly increased score on a test for aggression associated with a 36% reduction in DHA in brain phospholipids (DeMar et al., 2006
In the small group of participants in the present investigation, significant associations were found between low intakes of fish and of long-chain n-3 PUFAs prior to the start of the study and a history of assaultive behavior. Sixty percent of the patients who had reported having assaulted others stated eating from 8 to 42 g of fish daily. None of the patients eating more than this amount reported a history of assaultive behavior. These data are consistent with a cross-national study showing that rates of homicides are lower in countries where the consumption of foods rich in PUFAs such as fish is high (Hibbeln and Salem, 2001
). They also give support to cross-sectional studies that reported a reduced plasma DHA level in violent male subjects with antisocial personality (Virkkunen et al., 1987
), and a lower likelihood of high hostility in young adults whose dietary intake of DHA and of fish was high (Irribaren et al., 2004
). If in the present study, there was a causal link between deficient diets and violence, it would imply that patients’ poor dietary habits had been long-lasting. We followed for one year a group of substance abusers and observed that their diets changed little during that period (unpublished). Taken together, existing literature and the present study data suggest that the insufficient intake of long-chain n-3 PUFAs may be one of the factors contributing to increased violence in some individuals. It should, however, be noted that in this study, some patients who did not report violent behaviors, had fish and long-chain n-3 PUFAs intakes as low as those of violent patients. It may be that only some individuals are vulnerable to diverse influences, one of which could be an insufficient intake of long-chain n-3 PUFAs.
Recommendations for the intake of n-3 PUFAs necessary to cover human requirements are still in the process of being determined and will have to await the completion of additional trials. These recommendations vary from country to country and depend in part on the amount of n-6 PUFAs present in different diets because n-6 PUFAs influence tissue concentrations of n-3 PUFAs. Based on a review of major epidemiological studies conducted in the US, the daily intake of EPA and DHA recommended by ISSFAL (International Society for the Study of Fatty Acids and Lipids, 2004
) for cardiovascular health is 500 mg. More recently, Hibbeln et al. (2006)
have proposed that the daily dietary allowance of long-chain n-3 PUFAs that would protect the US population against both cardiovascular and major psychiatric diseases should be higher than the ISSFAL recommendation and should be as high as 3.5 g per day for a 2000 Kcal diet. Participants in the present study consumed only an average of 149 mg of long-chain n-3 PUFAs daily, or 30% of the ISSFAL recommendation and 3.7% of the Hibbeln et al.’s recommendation Their intake of EPA and DHA was most likely even lower because in our calculations of long-chain n-3 PUFAs, DPA was included. Depending on the estimations of what amounts to healthy long-chain n-3 PUFAs consumption, the reported intakes of patients taken as a group could be rated as being either deficient or very deficient. The long-chain n-3 PUFAs intakes of patients who had assaulted others were even lower and amounted to 18% and 2.6% of the ISSFAL and Hibbeln et al.’s recommendations, respectively.
It has been suggested that n-3 PUFAs could decrease stress (Bradbury et al, 2004
) and could be effective in the treatment of a wide variety of psychiatric disorders, including mood disorders, attention deficit and hyperactivity disorders, Alzheimer’s disease, dementia and schizophrenia. The effects of n-3 PUFAs have been reviewed recently (Alessandri et al., 2004
; Young et al., 2005
; Berger et al., 2006
; Parker et al., 2006
; Peet, 2005
). This apparent multitude of effects could be understood in light of the extraordinary complexity and diversity of actions of PUFAs (Alessandri et al., 2004
; Young and Conquer, 2005
). They are components of neuronal membrane phospholipids and modulate their dynamic properties. The conformation of proteins embedded in the membrane bi-layer is influenced by its lipid components. These proteins have important functions as they act as receptors and transporters and can alter the passage of ions. Neuronal membrane fluidity that can be altered by their PUFA composition can thus affect the function of neurotransmitters systems. Upon stimulation, both n-6 and n-3 PUFAs can also be cleaved from membrane phospholipids under the influence of phospholipases and can be converted via different pathways to mediators that have opposing effects. AA derived mediators are vasoconstrictive, pro-aggregant and pro-inflammatory whereas EPA derived mediators have vasodilating, anti-aggregating and anti-inflammatory actions. Finally, PUFAs and their metabolites regulate gene transcriptions. All of the actions of PUFAs have probably not yet been completely elucidated.
In light of this diversity of actions, it could be hypothesized that different mechanisms could have played a role in the decrease in anger scores observed in this study. Modifications of serotonergic neurotransmission that have been implicated in violence might be one of the modes of action of n-3 PUFA supplementation (Mann, 1995
). Higher concentrations of plasma DHA were found to predict higher levels of CSF 5-HIAA in healthy controls and late onset alcoholics (Hibbeln et al., 1998
). This finding suggests that increasing DHA consumption may increase brain serotonin. In the animal literature, it has been shown that modifying the PUFA composition of the diet can influence neurotransmitter level. The supplementation of AA and DHA in the diet of piglets increased the frontal cortex concentrations of 5-HT and dopamine (de la Pressa Owens and Innis, 2000
). Decreasing PUFA levels was found to affect 5-HT as well. Rats fed a diet deficient in n-3 PUFAs had an increase in 5-HT receptor density in the frontal cortex with no changes in binding activity (Delion et al., 1996
). These changes were similar to those reported by Stanley and Mann (1983)
among suicide victims. In other studies, diets low in PUFAs induced decreased concentrations of 5-HT and 5-HIAA in several brain regions including the cortex (Olsson et al., 1998
) and decreased amounts of 5-HT released during synaptic transmission (Kodas et al., 2004
). Other mechanisms might be at play as well because a combination of DHA and EPA or EPA alone appear to have a greater efficacy than DHA alone (Alessandri et al., 2004
). One could wonder why EPA, which is not abundant in neuronal membranes, appears more effective than DHA alone (Hibbeln and Salem, 2001
). It has been suggested that EPA could play a role in brain function by counteracting the AA-mediated signaling. EPA could, for example, competitively attenuate the formation of the n-6 derived eicosanoids that mediate immune-inflammatory responses that have been linked to the pathophysiology of mood disorders (Maes and Smith, 1998
; Raison et al., 2006
). EPA could also counteract the vasoconstrictive effects of AA, thereby increasing blood flow in the brain.
There are few data about the eventual persistence of the behavioral effects of n-3 PUFA supplementation after the administration of the supplements has been discontinued. In this study, anger scores remained reduced for 3 months following treatment discontinuation. This could be attributed to the persistent central effects of n-3 PUFAs. It is also possible that fatty acids were stored in fatty tissues and continued to be released from these stores and thus continued to influence patients’ feelings.
The present study has some limitations. The number of participants was small and some of them received medications. It should be pointed out that medication doses remained stable during the study and that a number of other studies of the efficacy of n-3 PUFAs supplementation in mood disorders involved individuals on standard medication who experienced further improvements that were attributed to the PUFA supplements.
This study, which needs to be replicated in larger samples, showed that the daily administration of 3 g of long-chain n-3 PUFAs for a period of 3 months significantly decreased feelings of anger by comparison with the administration of a placebo. This decrease appeared to persist for 3 months after treatment discontinuation. These data give support to emerging evidence that long chain n-3 PUFAs could play a role in hostility and violence. Angry feelings can lead to aggressive behaviors and in this small population sample, the group of patients who had a history of violent encounters with others reported significantly lower intakes of fish and of long-chain n-3 PUFAs than patients who had not exhibited violent behaviors. N-3 PUFAs supplements, that are both inexpensive and well tolerated, could be considered as treatment adjuncts for patients displaying aggressive behaviors. Moreover, n-3 PUFAs have been shown to be beneficial to general physical health and have been specifically recommended for the prevention of cardiovascular diseases (Kris-Etherton et al., 2002