Institute for Medical Statistics, Informatics, and Epidemiology, University of Cologne, Cologne, Germany
Changes from baseline in Positive and Negative Symptoms Scale (PANSS) scores determined using mixed effects repeated measures model analysis (adjusted for baseline). (a) PANSS total score. (b) PANSS-positive score. (c) PANSS-negative score. (d) PANSS general score. Data show predicted means and s.e. at each weak. Statistical significance is calculated between groups ( † P ⩽ 0.05, †† P ⩽ 0.01 and ††† P ⩽ 0.001) and vs baseline (that is, 0; * CBD, # AMI; *** /### P ⩽ 0.05, ** /## P ⩽ 0.01, * /# P ⩽ 0.001).
Meltzer HY, Arvanitis L, Bauer D, Rein W . Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry 2004; 161: 975–984.
Our results provide evidence that the non-cannabimimetic constituent of marijuana, cannabidiol, exerts clinically relevant antipsychotic effects that are associated with marked tolerability and safety, when compared with current medications. Although a plethora of pharmacological mechanisms have recently been suggested relevant for the antipsychotic effect of cannabidiol 31 the primary pharmacological mechanism through which cannabidiol exerts this antipsychotic effect in humans is unclear at present. However, the significant association observed in cannabidiol-treated patients between improvement of clinical symptoms and serum anandamide levels suggests that the ability of cannabidiol to inhibit the FAAH activity and enhance intrinsic anandamide signaling might be a functionally relevant component of its antipsychotic properties. Although only serum levels of anandamide were assessed in this study in comparison with cerebrospinal fluid samples, 13, 32 the systemic effect of cannabidiol on FAAH inhibition is highly likely to be reflected in this compartment. In addition, while serum values of endocannabinoids have been found less useful in early stages of schizophrenia, they have been reported valuable in more chronic cases. 33, 34 Our interpretation is supported by two sets of clinical data. First, in a relatively large cohort of antipsychotic-naïve schizophrenic patients (n=47), cerebrospinal anandamide levels were found to be inversely correlated with psychotic symptoms. 13 Second, high-risk subjects for psychosis 35 who exhibited lower cerebrospinal levels of anandamide also showed a higher risk for transiting to frank psychosis. 32 As is often the case in this type of study, we cannot exclude that cannabidiol may reduce psychotic symptoms through complementary or even alternative mechanisms to FAAH inhibition, including interactions with serotonin 5-HT1A receptors, 36 GPR55 receptors 37 and transient receptor potential vanilloid-1 receptors. 19 Nevertheless, our results do provide a rationale for additional clinical testing of selective FAAH inhibitors in schizophrenia.
The ‘valid for safety’ set encompassed all patients who were randomized and received any study medication. On the basis of this the treatment-emergent adverse events were compared among treatment groups using Fisher’s exact test. Owing to the exploratory nature of the study, all analyses were performed without adjustment for multiplicity. Statistical analyses were done using IBM SPSS Statistics 19 (Somers, NY, USA) and R 2.12.1 (Vienna, Austria; Sasabuchi test, Fieller’s confidence interval).
Scatton B, Sanger DJ . Pharmacological and molecular targets in the search for novel antipsychotics. Behav Pharmacol 2000; 11: 243–256.
Leweke FM, Schneider U, Thies M, Münte TF, Emrich HM . Effects of synthetic Δ 9 -tetrahydrocannabinol on binocular depth inversion of natural and artificial objects in man. Psychopharmacology 1999; 142: 230–235.
Ryberg E, Larsson N, Sjogren S, Hjorth S, Hermansson NO, Leonova J et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 2007; 152: 1092–1101.
Accepted : 30 January 2012
In 1993 an enzyme we called anandamide amidase, now named called FAAH, was shown to break AEA down to arachidonic acid and ethanolamine (Figure (Figure1) 1 ) in the membrane fractions of most rat tissues except in leg and heart muscle (Deutsch and Chin, 1993). This activity was reported in liver microsomes for fatty acid amides, other than anandamide (Bachur and Udenfriend, 1966; Schmid et al., 1985). This lack of breakdown activity in muscle was fortuitous for the success of the vas deferens assay that was employed in the discovery of AEA in 1992 (Devane et al., 1992; Pertwee et al., 1995). In our original assay we used thin layer chromatography with AEA radio-labeled in the arachidonate portion of the molecule, but later ethanolamine labeled AEA simplified the assay procedure by permitting measurement of radiolabel without a thin layer chromatography step (Omeir et al., 1995). Cloning of the enzyme permitted more detailed molecular studies including ones that showed uniquely two serine residues in the active site (Omeir et al., 1999; Patricelli et al., 1999) and that FAAH was localized to the endoplasmic reticulum (Cravatt et al., 1996). FAAH is the main player in AEA inactivation although other pathways have been implicated in the metabolism of AEA as well (van der Stelt et al., 2002; Rahman et al., 2014).
Anandamide breakdown (anandamide amidase, FAAH)
The work of my laboratory had been generously funded by the National Institute on Drug Abuse, intermittently, since the early 1980s. These grants funded the work for the discovery of FAAH, the study of its inhibitors, the identification of the FABPs as AEA carriers and most recently, the drug discovery program for FABP inhibitors (NIH 035923). Dr. Hillery, Rapaka and Volkow have always been generous with their advice over the years.
In 1993 we were the first to show, with rather rudimentary experiments, that AEA was actively taken up in neuroblastoma and glioma cells (Deutsch and Chin, 1993). In 1994 the uptake of AEA was confirmed and the mechanism was postulated to involve an ATP independent active membrane transporter (Di Marzo et al., 1994). The hypothesis of an AEA transmembrane transporter became dogma for many years and the “hunt” still goes on for this “putative” anandamide membrane transporter (AMT) also called the “putative endocannabinoid membrane transporter (EMT, Ligresti et al., 2010; Nicolussi et al., 2014; Nicolussi and Gertsch, 2015). Many of the AMT (EMT) proposals have fallen by the wayside. For example, a paper first showed uptake was FAAH independent and then a decade later it was proposed that a FAAH fragment called FLAT (FAAH-like anandamide transporter) was the transmembrane transporter (Fegley et al., 2004; Fu et al., 2012), the latter being questioned (Leung et al., 2013; Björklund et al., 2014; Fowler, 2014). The evidence for a transmembrane transporter was based on enzyme saturation kinetics in cell culture, uptake studies in cells and the physiological effects of “membrane transporter inhibitors.” Many dozens of such inhibitors were proposed. However, it was shown that the kinetics of uptake of AEA can show saturation owing to the passage of hydrophobic AEA through the water layer surrounding the cell and that many of these transport inhibitors were in fact FAAH inhibitors or FAAH substrates or bound to receptors confounding the mechanism of their physiological effects (Glaser et al., 2003; Alexander and Cravatt, 2006; Bojesen and Hansen, 2006; Nicolussi and Gertsch, 2015). Furthermore, it was demonstrated that AEA can freely pass through an artificial membrane without the aid of any protein (Figure (Figure2, 2 , Bojesen and Hansen, 2005; Di Pasquale et al., 2009; Kaczocha et al., 2012a; Fowler, 2013, 2015). A transmembrane protein transporter has not been identified to date and the effects of these inhibitors appear to occur downstream and many of the so-called transporter inhibitors were in fact FAAH or FABP inhibitors.