Cannabinoids such as Δ(9) - tetrahydrocannabinol, the major psychoactive component of marijuana and hashish, primarily act via cannabinoid CB(1) and CB(2) receptors to produce characteristic behavioural effects in humans. Due to the tractability of rodent models for electrophysiological and behavioural studies, most of the studies of cannabinoid receptor action have used rodent cannabinoid receptors. While CB(1) receptors are relatively well-conserved among mammals, human CB(1) (hCB(1) ) differs from rCB(1) and mCB(1) receptors at 13 residues, which may result in differential signalling. In addition, two hCB(1) splice variants (hCB(1a) and hCB(1b) ) have been reported, diverging in their amino-termini relative to hCB(1) receptors. In this study, we have examined hCB(1) signalling in neurones. hCB(1) , hCB(1a) hCB(1b) or rCB(1) receptors were expressed in autaptic cultured hippocampal neurones from CB(1) (-/-) mice. Such cells express a complete endogenous cannabinoid signalling system. Electrophysiological techniques were used to assess CB(1) receptor-mediated signalling. KEY RESULTS Expressed in autaptic hippocampal neurones cultured from CB(1) (-/-) mice, hCB(1) , hCB(1a) and hCB(1b) signal differentially from one another and from rodent CB(1) receptors. Specifically, hCB(1) receptors inhibit synaptic transmission less effectively than rCB(1) receptors. Our results suggest that cannabinoid receptor signalling in humans is quantitatively very different from that in rodents. As the problems of marijuana and hashish abuse occur in humans, our results highlight the importance of studying hCB(1) receptors. They also suggest further study of the distribution and function of hCB(1) receptor splice variants, given their differential signalling and potential impact on human health. This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.