Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.

These findings support the hypothesis of an involvement of anandamide in cognitive processes impaired in schizophrenia and are consistent with a protective effect of elevated anandamide levels herein.

We suggest that the protective upregulation of endocannabinoid signalling reflects either a hereditary trait or mirrors a modulating response to genetically influenced cerebral function involving, e.g., other neurotransmitters or energy metabolism.

Background:In contrast to delta-9-tetrahydrocannabinol, the phytocannabinoid cannabidiol does not exert psychotomimetic effects. Cannabidiol was suggested a re-uptake inhibitor of anandamide and potential antipsychotic properties have been hypothesized for it. We therefore performed a clinical trial to investigate thesis hypothesis and to clarify the underlying link to the neurobiology of schizophrenia.Methods:We performed an explorative, 4-week, double-blind, controlled clinical trial on the effects of purified cannabidiol in acute schizophrenia compared to the antipsychotic amisulpride. The antipsychotic properties of both drugs were the primary target of the study. Furthermore, side-effects and anxiolytic capabilities of both treatments were investigated.Results:42 patients fulfilling DSM-IV criteria of acute paranoid schizophrenia participated in the study. Both treatments were associated with a significant decrease of psychotic symptoms after 2 and 4 weeks as assessed by BPRS and PANSS. However, there was no statistical difference between both treatment groups. In contrast, cannabidiol induced significantly less side effects (EPS, increase in prolactin, weight gain) when compared to amisulpride.Conclusions:Cannabidiol revealed substantial antipsychotic properties in acute schizophrenia. This is in line with our suggestion of an adaptive role of the endocannabinoid system in paranoid schizophrenia, and raises further evidence that this adaptive mechanism may represent a valuable target for antipsychotic treatment strategies.The Stanley Medical Research Institute (00-093 to FML) and the Koeln Fortune Program (107/2000 + 101/2001 to FML) funded this study.

Based on the contribution of the endocannabinoid system to the pathophysiology of schizophrenia, the primary pro-psychotic ingredient of Cannabis sativa, Δ-9tetrahydrocannabinol (Δ-9-THC), is used in preclinical as well as clinical research to mimic schizophrenia-like symptoms. While it is common to administer lipid-based formulations of Δ-9-THC in human studies orally, intraperitoneal injections of waterbased solutions are used in animal models. Because of the poor water solubility of Δ-9-THC, solubilizers such as ethanol and/or emulsifiers are needed for these preparations. In order to test whether a lipid-based solvent would be superior over a waterbased vehicle in rats, we compared the effects on locomotor activity and prepulse inhibition (PPI) of the acoustic startle reaction, as well as pharmacokinetic data obtained from rats' serum and brain tissue samples. Up to 50 mg/kg Δ-9-THC in the lipid-based formulation was not able to induce any behavioral alterations, while already 5 mg/kg of the water-based Δ-9-THC preparation significantly reduced locomotor activity. This also induced a small but significant PPI reduction, which was prepulse intensity dependent. Interestingly, the reflexive motor response to the startle stimulus was not affected by the water-based Δ-9-THC solution. Analysis of serum and brain Δ-9-THC levels by high-performance liquid chromatography/mass spectrometry revealed that although the final concentration reached in the brain was comparable for both pharmaceutical preparations, the water-based formulation achieved a faster kinetic. We, therefore, conclude that the slope of the Δ-9-THC concentration-time curve and the resulting cannabinoid receptor type 1 activation per time unit are responsible for the induction of behavioral alterations.

Introduction: Chronic stress causes a variety of physiological and behavioral alterations, including social impairments, altered endocrine function, and an increased risk for psychiatric disorders. Thereby, social stress is one of the most effective stressful stimuli among mammals and considered to be one of the major risk factors for the onset and progression of neuropsychiatric diseases. For analyzing the effects of social stress in mice, the resident/intruder paradigm of social defeat is a widely used model. Although the chronic social defeat stress model has been extensively studied, little is known about the effects of repeated or chronic social defeat stress on the endocannabinoid system (ECS). The present study aimed to understand the effects of chronic social stress on anxiety behavior and the levels of endocannabinoids (ECs) and two N-acylethanolamines (NAEs) in different brain regions of mice. Materials and Methods: Two-month-old, male C57Bl/6J mice were exposed to chronic psychosocial stress for 3 weeks. The effects of stress on anxiety behavior were measured using the light-dark box and hole board test. The EC levels of 2-arachidonoyl glycerol (2-AG) and anandamide (N-arachidonoylethanolamine [AEA]), as well as the levels of two NAEs (oleoylethanolamide [OEA] and palmitoylethanolamide), were analyzed by liquid chromatography-tandem mass spectrometry in the hippocampus, cerebellum, and cortex. Results: In comparison with control mice (n = 12), mice exposed to social defeat stress (n = 11) showed increased anxiety behaviors in the light-dark box and hole board test and gained significantly more weight during the experimental period. Additionally, chronic social stress induced differential alterations in the brain levels of 2-AG and AEA. More precisely, 2-AG levels were higher in the cortex and cerebellum, whereas reduced AEA levels were found in the hippocampus. Furthermore, we observed lower OEA levels in the hippocampus. Conclusion:The current study confirms that the ECS plays an essential role in stress responses, whereby its modulation seems to be brain region dependent.

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Introduction: The primary compounds of Cannabis sativa , delta-9-tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (CBD), inflict a direct influence on the endocannabinoid system-a complex lipid signaling network with a central role in neurotransmission and control of inhibitory and excitatory synapses. These phytocannabinoids often interact with endogenously produced endocannabinoids (eCBs), as well as their structurally related N -acylethanolamines (NAEs), to drive neurobiological, nociceptive, and inflammatory responses. Identifying and quantifying changes in these lipid neuromodulators can be challenging owing to their low abundance in complex matrices. Materials and Methods: This article describes a robust liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for the extraction and quantification of the eCBs anandamide and 2-arachidonoylglycerol, along with their congener NAEs oleoylethanolamine and palmitoylethanolamine, and phytocannabinoids CBD, Δ 9 -THC, and 11-Nor-9-carboxy-Δ 9 -tetrahydrocannabinol, a major metabolite of Δ 9 -THC. Our method was applied to explore pharmacokinetic and pharmacodynamic effects from intraperitoneal injections of Δ 9 -THC and CBD on circulating levels of eCBs and NAEs in rodent serum. Results: Detection limits ranged from low nanomolar to picomolar in concentration for eCBs (0.012–0.24 pmol/mL), NAEs (0.059 pmol/mL), and phytocannabinoids (0.24–0.73 pmol/mL). Our method displayed good linearity for calibration curves of all analytes ( R 2 >0.99) as well as acceptable accuracy and precision, with quality controls not deviating >15% from their nominal value. Our LC-MS/MS method reliably identified changes to these endogenous lipid mediators that followed a causal relationship, which was dependent on both the type of phytocannabinoid administered and its pharmaceutical preparation. Conclusion: We present a rapid and reliable method for the simultaneous quantification of phytocannabinoids, eCBs, and NAEs in serum using LC-MS/MS. The accuracy and sensitivity of our assay infer it can routinely monitor endogenous levels of these lipid neuromodulators in serum and their response to external stimuli, including cannabimimetic agents.