Cannabis is a complex plant, with major compounds such as delta-9- tetrahydrocannabinol and cannabidiol, which have opposing effects. The discovery of its compounds has led to the further discovery of an important neurotransmitter system called the endocannabinoid system. This system is widely distributed in the brain and in the body, and is considered to be responsible for numerous significant functions. There has been a recent and consistent worldwide increase in cannabis potency, with increasing associated health concerns. A number of epidemiological research projects have shown links between dose-related cannabis use and an increased risk of development of an enduring psychotic illness. However, it is...

Background: The ‘‘classic’’ endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the ‘‘eCB deficiency syndrome’’ as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system—ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation. Methodology/Principal Findings: We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and...

Abstract Objectives: This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis. Methods: Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources. Results: Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is...

Medicine continues to struggle in its approaches to numerous common subjective pain syndromes that lack objective signs and remain treatment resistant. Foremost among these are migraine, fibromyalgia, and irritable bowel syndrome, disorders that may overlap in their affected populations and whose sufferers have all endured the stigma of a psychosomatic label, as well as the failure of endless pharmacotherapeutic interventions with substandard benefit. The commonality in symptomatology in these conditions displaying hyperalgesia and central sensitization with possible common underlying pathophysiology suggests that a clinical endocannabinoid deficiency might characterize their origin. Its base hypothesis is that all humans have an underlying endocannabinoid tone that is...

Chronic treatment with Δ 9 -tetrahydrocannabinol (THC) produces tolerance to cannabinoid-mediated behaviors and region-specific adaptation of brain cannabinoid receptors. However, the relationship between receptor adaptation and tolerance is not well understood, and the dose-response relationship of THC-induced cannabinoid receptor adaptation is unknown. This study assessed cannabinoid receptor function in the brain and cannabinoid-mediated behaviors after chronic treatment with different dosing regimens of THC. Mice were treated twice per day for 6.5 days with the following: vehicle, 10 mg/kg THC, or escalating doses of 10 to 20 to 30 or 10 to 30 to 60 mg/kg THC. Tolerance to cannabinoid-mediated locomotor inhibition, ring immobility, antinociception,...

The cannabinoid CB1 and CB2 receptors are Class A G protein-coupled receptors (GPCRs). While many Class A GPCRs have endogenous ligands that are hydrophilic cations (e.g., the serotonin and dopamine receptors), the cannabinoid receptors have neutral, highly lipophilic ligands derived from the fatty acid, arachidonic acid. The most well-studied of these are Narachidonoylethanolamine (anandamide, AEA) and sn-2-arachidonoylglycerol (2-AG). This review focuses on the experimental and computational studies that have been used to probe the nature of endocannabinoid interaction with the cannabinoid receptors. These studies include mutation, SAR and NMR studies, as well as, QSAR, docking and molecular dynamics simulations. Gaps in our knowledge are...

Cannabinoid type 1 receptors (CB1Rs) are functionally active within the laterodorsal tegmental nucleus (LDT), which is critically involved in control of rapid eye movement sleep, cortical arousal, and motivated states. To further characterize the cellular consequences of activation of CB1Rs in this nucleus, we examined whether CB1R activation led to rises in intracellular Ca2? ([Ca2?]i) and whether processes shown in other regions to involve endocannabinoid (eCB) transmission were present in the LDT. Using a combination of Ca2? imaging in multiple cells loaded with Ca2? imaging dye via ‘bulk-loading’ or in single cells loaded with dye via a patch-clamp electrode, we found that WIN 55212-2...

The hypnogenic properties of cannabis have been recognized for centuries, but endogenous cannabinoid (endocannabinoid) regulation of vigilance states is poorly characterized. We report findings from a series of experiments in mice measuring sleep with polysomnography after various systemic pharmacological manipulations of the endocannabinoid system. Rapid, unbiased scoring of vigilance states was achieved using an automated algorithm that we devised and validated. Increasing endocannabinoid tone with a selective inhibitor of monoacyglycerol lipase (JZL184) or fatty acid amide hydrolase (AM3506) produced a transient increase in non-rapid eye movement (NREM) sleep due to an augmentation of the length of NREM bouts (NREM stability). Similarly, direct activation of...

Ageing is characterized by the progressive impairment of physiological functions and increased risk of developing debilitating disorders, including chronic inflammation and neurodegenerative diseases. These disorders have common molecular mechanisms that can be targeted therapeutically. In the wake of the approval of the first cannabinoid-based drug for the symptomatic treatment of multiple sclerosis, we examine how endocannabinoid (eCB) signalling controls — and is affected by — normal ageing and neuroinflammatory and neurodegenerative disorders. We propose a conceptual framework linking eCB signalling to the control of the cellular and molecular hallmarks of these processes, and categorize the key components of endocannabinoid signalling that may serve as...

Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were the first endocannabinoids to be characterized, that bind two G protein-coupled receptors, CB1 and CB2. AEA synthesized by multiple pathways, including NAPE-specific phospholipase D (NAPE-PLD) and degraded by the fatty acid amide hydrolase (FAAH). AEA levels are critical in regulating embryo development and the ‘‘window’’ of implantation. We examined the expression of nape-pld mRNA, CB1 and FAAH in human placenta hypothesizing that their altered signaling may contribute to spontaneous miscarriage. First trimester placentas from women with spontaneous miscarriage (group 1) were matched with placentas from women who underwent termination (group 2). Nape-pld expression was analyzed by RT-PCR; CB1...