This study examined the immunoregulatory effects of cis-9,10-octadecenoamide (CODA), a recently identified endogenous sleep-inducing brain lipid. CODA displays structural and functional similarities to anandamide, the endogenous ligand for the cannabinoid receptors. CODA proved to be immunosuppressive. It inhibited proliferation of anti-CD3- and ConA-activated primary lymphocytes and proliferation of T- and B-cell lines. Complete inhibition occurred at concentrations of 100 microM. This effect was stereospecific, since the trans-stereo isomer of CODA did not inhibit proliferation at identical concentrations. A further control compound, octadecanamide, identical to cis-9,10-octadecenoamide, besides lacking the 9,10 carbon double bond, also did not affect proliferation. The antiproliferative effects of CODA occurred rapidly, since 24-h exposure to CODA was sufficient for complete inhibition of proliferation. CODA and anandamide worked synergistically in inhibiting lymphocyte proliferation. No significant effects of CODA on monocyte functions, as assessed by LPS-induced TNF alpha secretion, could be detected.