Simultaneous Assessment of Serum Levels and Pharmacologic Effects of Cannabinoids on Endocannabinoids and N-Acylethanolamines by Liquid Chromatography-Tandem Mass Spectrometry.

Introduction: The primary compounds of Cannabis sativa, delta-9-tetrahydrocannabinol (Δ9-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, Δ9-THC, and 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol, a major metabolite of Δ9-THC. Our method was applied to explore pharmacokinetic and pharmacodynamic effects from intraperitoneal injections of Δ9-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 (R2>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.

Cannabidiol as a treatment option for schizophrenia: recent evidence and current studies.

PURPOSE OF REVIEW: The most recent studies published or initiated in the last 18 months, investigating cannabidiol in the treatment of symptoms of schizophrenia and related conditions are summarized, including observed tolerability and reported side-effects. RECENT FINDINGS: Recent studies focused on patients with sub-acute psychotic syndromes of schizophrenia, clinical high-risk state for psychosis (CHR-P), or frequent cannabis users, as well as cognitive functioning in chronic schizophrenia. There is further, although not consistent evidence for cannabidiol-reducing positive symptoms, but not negative symptoms. Evidence for improvement of cognition was weaker, with one study reporting a worsening. Regarding side effects and tolerability, cannabidiol induced sedation in one study, with the other studies indicating good tolerability, even at high doses. SUMMARY: Recent clinical trials added further evidence for an antipsychotic potential of cannabidiol. In general, studies following trial designs as suggested by regulators in schizophrenia are needed in sufficient numbers to clarify the safety and efficacy of cannabidiol herein. In addition, such studies will further elucidate its ability to target specific aspects of the syndrome, such as negative or cognitive symptoms. Furthermore, aiming for an add-on treatment with cannabidiol will require further studies to identify potentially useful or even harmful combinations.