2006; Moreira and Guimaraes, 2005], and in humans [Hallak et al. 2011]. Cannabis users with detectable levels of both CBD and delta-9 tetrahydrocannabinol (THC) in hair samples reported a lower incidence of schizophrenia-like symptoms than those in whom THC alone was detected [Morgan and Curran, 2008]. Furthermore, acute intoxication Inhibitors,research,lifescience,medical with cannabis containing low CBD led to impairments in recall, whereas high CBD cannabis

did not induce any cognitive deficits [Morgan et al. 2010]. CBD has been shown to have the opposite B-Raf assay effect to THC on neural activation measured using fMRI during an emotional processing task and a verbal memory task [Bhattacharyya et al. 2010; Fusar-Poli et al. 2009], and pretreatment with CBD significantly attenuates the psychotogenic effects of THC [Bhattacharyya et al. 2010; Karniol et al. 1974]. Preliminary work suggests that CBD is effective as an antipsychotic in patients with schizophrenia [Zuardi et al. 2006], although it had no additional beneficial effect in a small open-label study of clozapine-resistant Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical patients [Zuardi et al. 2006]. The mechanism of action of CBD has not yet been elucidated completely. It has been demonstrated that CBD antagonizes the inhibitory effect of endocannabinoids and THC on GABA and glutamate transmission, mediated via CB1 receptors [Godino Mdel et al. 2007; Neu et al. 2007]. Given the hypothesized

mechanism of ketamine action on GABA and glutamate systems, it is possible that the enhancement of GABA-A function is its primary mode of action in reducing Inhibitors,research,lifescience,medical ketamine-induced effects (Figure 6). However, a CB1 antagonist was not found to be effective in patients with schizophrenia [Meltzer et al. 2004], and there is growing evidence that some of the beneficial effects of CBD, like minocycline, may be mediated via inhibition

of p38 MAP kinase [El-Remessy et al. 2008; Esposito et al. 2006]. Drugs targeting glutamate in schizophrenia: Drugs in development GlyT1 Inhibitors,research,lifescience,medical inhibitors Several pharmaceutical companies have published data on GlyT1 receptor inhibitors (see Table 1). Roche reported in a press release that their GlyT1 inhibitor, RG1678, was successful in treating negative symptoms in a phase II drug trial, but they have not published any further data on this compound at present [Pinard et al. 2010]. Johnson and Johnson have reported that Sclareol the GlyT1 inhibitor, R231857, improved scopolamine-induced cognitive impairments in healthy volunteers [Liem-Moolenaar et al. 2010]. Schering-Plough report that they are investigating the effects of Org 25935 on negative symptoms, but no data have yet been released to the public domain. One concerning potential side effect of glycine transporter inhibitors is respiratory depression, although it is not clear whether this affects all compounds in this class [Perry et al. 2008].