The purpose of the present study was to examine the effect of the serotonin releasing amphetamine derivatives methylenedioxymethamphetamine (MDMA), methylenedioxyamphetamine (MDA) and fenfluramine (FEN) on immunity in rats. Similar to MDA and MDMA, FEN reduced the number of circulating lymphocytes, provoked a suppression of Con A-stimulated lymphocyte proliferation and total IFN-gamma and IL-10 production in diluted whole blood cultures. Thus the non-psychostimulant amphetamine derivative FEN, shares the ability of the psychostimulant methylenedioxy-substituted amphetamine derivatives to alter these indices of immune function in the rat. However, when Con A-stimulated cytokine production was normalised for the number of lymphocytes in culture in order to examine cytokine production at a cellular level, the effect of the amphetamine derivatives begins to diverge. FEN shares with MDMA and MDA the ability to suppress production of the Th2 type cytokine IL-10. However the effect of these drugs on Th1 type cytokine secretion was much more complex. While the methylendioxy-substituted amphetamines increases the secretion of the Th1 type cytokine IL-2 without altering the related Th1 type cytokine IFN-gamma, FEN did not alter IL-2 secretion, but suppressed IFN-gamma secretion. In addition to these effects on T-cell responses, all three drugs inhibited LPS-induced TNF-alpha secretion from diluted whole blood cultures suggesting that macrophage activity is impaired following treatment. In all, these data extend our previous findings concerning the effects of MDMA on the immune system and demonstrate that the related serotonin releasers MDA and FEN also provoke immunological changes in rats.