Since the first endocannabinoid anandamide was identified in 1992, extensive research has been conducted to characterize the elements of the tightly controlled endocannabinoid signaling system. While it was established that the activity of endocannabinoids are terminated by a two-step process that includes cellular uptake and degradation, there is still a continuing debate about the mechanistic role of these processes in inactivating anandamide signals. Full article

Starting from an historical overview of lasting Cannabis use over the centuries, we will focus on a description of the cannabinergic system, with a comprehensive analysis of chemical and pharmacological properties of endogenous and synthetic cannabimimetic analogues. The metabolic pathways and the signal transduction mechanisms, activated by cannabinoid receptors stimulation, will also be discussed. In particular, we will point out the action of cannabinoids and endocannabinoids on the different neuronal networks involved in reproductive axis, and locally, on male and female reproductive tracts, by emphasizing the pivotal role played by this system in the control of fertility. Full article

N-acylethanolamides (NAEs) are naturally occurring signaling lipids consisting of amides and esters of long-chain polyunsaturated fatty acids. Usually they are present in a very small amounts in many mammalian tissues and cells, including human reproductive tracts and fluids. Recently, the presence of N-arachidonoylethanolamide (anandamide, AEA), the most characterised member of endocannabinoids, and its congeners palmitoylethanolamide (PEA) and oleylethanolamide (OEA) in seminal plasma, oviductal fluid, and follicular fluids was demonstrated. AEA has been shown to bind not only type-1 (CB1) and type-2 (CB2) cannabinoid receptors, but also type-1 vanilloid receptor (TRPV1), while PEA and OEA are inactive with respect to classical cannabinoid CB1 and CB2 but activate TRPV1 or peroxisome proliferator activate receptors (PPARs). This review concerns the most recent experimental data on PEA and OEA, endocannabinoid-like molecules which appear to exert their action exclusively on sperm cells with altered features, such as membrane characteristics and kinematic parameters. Their beneficial effects on these cells could suggest a possible pharmacological use of PEA and OEA on patients affected by some forms of idiopathic infertility. Full article

The endocannabinoids anandamide and 2-arachydonoylglycerol (2-AG) are lipids naturally derived from membrane precursors which bind cannabinoid receptors (CB₁, CB₂). This endocannabinoid system is disturbed in schizophrenia. Indeed, there seems to be an association between schizophrenia and polymorphisms of the CB₁ receptor gene. Moreover, CB₁ receptors are found in higher density in the prefrontal cortex, hippocampus and basal ganglia of patients with schizophrenia. Similarly, anandamide levels are increased in the cerebrospinal fluid (CSF) and in the serum of schizophrenia patients, including during the prodromal state, suggesting that they may play a protective role in psychosis homeostasis. Future studies are needed to further explore the role of the endocannabinoid system in the pathophysiology of schizophrenia. Full article

This review discusses the role of the cannabinoid system in cartilage tissue and endeavors to establish if targeting the cannabinoid system has potential in mesenchymal stem cell based tissue-engineered cartilage repair strategies. The review discusses the potential of cannabinoids to protect against the degradation of cartilage in inflamed arthritic joints and the influence of cannabinoids on the chondrocyte precursors, mesenchymal stem cells (MSCs). We provide experimental evidence to show that activation of the cannabinoid system enhances the survival, migration and chondrogenic differentiation of MSCs, which are three major tenets behind the success of a cell-based tissue-engineered cartilage repair strategy. These findings highlight the potential for cannabinoids to provide a dual function by acting as anti-inflammatory agents as well as regulators of MSC biology in order to enhance tissue engineering strategies aimed at cartilage repair. Full article

Chemotherapy-induced nausea and vomiting (CINV) is a complex pathophysiological condition and consists of two phases. The conventional CINV neurotransmitter hypothesis suggests that the immediate phase is mainly due to release of serotonin (5-HT) from the enterochromaffin cells in the gastrointestinal tract (GIT), while the delayed phase is a consequence of release of substance P (SP) in the brainstem. However, more recent findings argue against this simplistic neurotransmitter and anatomical view of CINV. Revision of the hypothesis advocates a more complex, differential and overlapping involvement of several emetic neurotransmitters/modulators (e.g. dopamine, serotonin, substance P, prostaglandins and related arachidonic acid derived metabolites) in both phases of emesis occurring concomitantly in the brainstem and in the GIT enteric nervous system (ENS) [1]. No single antiemetic is currently available to completely prevent both phases of CINV. The standard antiemetic regimens include a 5-HT₃ antagonist plus dexamethasone for the prevention of acute emetic phase, combined with an NK₁ receptor antagonist (e.g. aprepitant) for the delayed phase. Although NK₁ antagonists behave in animals as broad-spectrum antiemetics against different emetogens including cisplatin-induced acute and delayed vomiting, by themselves they are not very effective against CINV in cancer patients. Cannabinoids such as D⁹-THC also behave as broad-spectrum antiemetics against diverse emetic stimuli as well as being effective against both phases of CINV in animals and patients. Potential side effects may limit the clinical utility of direct-acting cannabinoid agonists which could be avoided by the use of corresponding indirect-acting agonists. Cannabinoids (both phyto-derived and synthetic) behave as agonist antiemetics via the activation of cannabinoid CB₁ receptors in both the brainstem and the ENS emetic loci. An endocannabinoid antiemetic tone may exist since inverse CB₁ agonists (but not the corresponding silent antagonists) cause nausea and vomiting. Full article

There is an increasing recognition that the endocannabinoid system is the crucial cytokine-hormone system regulating early human pregnancy. The synchronous development of the fertilized embryo and the endometrium to ensure timely implantation has been shown to be one of the pivotal steps to successful implantation. This development is thought to be regulated by a finely balanced relationship between various components of the endocannabinoid system in the endometrium, the embryo and the Fallopian tube. In addition, this system has also been shown to be involved in the regulation of the development and maturation of the gametes prior to fertilization. In this review, we will examine the evidence from animal and human studies to support the role of the endocannabinoid system in gametogenesis, fertilization, implantation, early pregnancy maintenance, and in immunomodulation of pregnancy. We will discuss the role of the cannabinoid receptors and the enzymes involved in the synthesis and degradation of the key endocannabinoid ligands (e.g., anandamide and 2-arachinoylglycerol) in early reproduction. Full article

Cogent evidence shows that cannabis plays a variable role on behavioral regulation and the pathophysiology of most psychiatric conditions. Accordingly, cannabis has been alternatively shown to exacerbate or ameliorate mental symptoms, depending on its composition and route of consumption, as well as specific individual and contextual characteristics. The vulnerability to the psychological effects of cannabis is influenced by a complex constellation of genetic and environmental factors. In the present article, we will review the current evidence on the pharmacological, individual and situational factors that have been documented to affect the behavioral and psychiatric effects of cannabinoids. Full article

Cannabinoid pharmacology has made important advances in recent years after the cannabinoid system was discovered. Studies in experimental models and in humans have produced promising results using cannabinoid-based drugs for the treatment of obesity and cancer, as well as neuroinflammatory and chronic inflammatory diseases. Moreover, as we discuss here, additional studies also indicates that these drugs have immunosuppressive and anti-inflammatory properties including modulation of immune cell function. Thus, manipulation of the endocannabinoid system in vivo may provide novel therapeutic strategies against inflammatory disorders. At least two types of cannabinoid receptors, cannabinoid 1 and cannabinoid 2 receptors are expressed on immune cells such as dendritic cells (DC). Dendritic cells are recognized for their critical role in initiating and maintaining immune responses. Therefore, DC are potential targets for cannabinoid-mediated modulation. Here, we review the effects of cannabinoids on DC and provide some perspective concerning the therapeutic potential of cannabinoids for the treatment of human diseases involving aberrant inflammatory processes. Full article

The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia. We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD) and vascular dementia (VD). Numerous studies have demonstrated an involvement of the cannabinoid system in neurotransmission, neuropathology and neurobiology of dementias. In addition, several candidate compounds have demonstrated efficacy in vitro. However, some of the substances produced inconclusive results in vivo. Therefore, only few trials have aimed to replicate the effects seen in animal studies in patients. Indeed, the literature on cannabinoid administration in patients is scarce. While preclinical findings suggest causal treatment strategies involving cannabinoids, clinical trials have only assessed the suitability of cannabinoid receptor agonists, antagonists and cannabidiol for the symptomatic treatment of dementia. Further research is needed, including in vivo models of dementia and human studies. Full article

The endogenous antinociceptive descending pathway represents a circuitry of the supraspinal central nervous system whose task is to counteract pain. It includes the periaqueductal grey (PAG)-rostral ventromedial medulla (RVM)-dorsal horn (DH) axis, which is the best characterized pain modulation system through which pain is endogenously inhibited. Thus, an alternative rational strategy for silencing pain is the activation of this anatomical substrate. Evidence of the involvement of cannabinoid receptors (CB) in the supraspinal modulation of pain can be found in several studies in which intra-cerebral microinjections of cannabinoid ligands or positive modulators have proved to be analgesic in different pain models, whereas cannabinoid receptor antagonists or antisense nucleotides towards CB1 receptors have facilitated pain. Like opioids, cannabinoids produce centrally-mediated analgesia by activating a descending pathway which includes PAG and its projection to downstream RVM neurons, which in turn send inhibitory projections to the dorsal horn of the spinal cord. Indeed, several studies underline a supraspinal regulation of cannabinoids on g-aminobutyric acid (GABA) and glutamate release which inhibit and enhance the antinociceptive descending pathway, respectively. Cannabinoid receptor activation expressed on presynaptic GABAergic terminals reduces the probability of neurotransmitter release thus dis-inhibiting the PAG-RVM-dorsal horn antinociceptive pathway. Cannabinoids seem to increase glutamate release (maybe as consequence of GABA decrease) and to require glutamate receptor activation to induce antinociception. The consequent outcome is behavioral analgesia, which is reproduced in several pain conditions, from acute to chronic pain models such as inflammatory and neuropathic pain. Taken together these findings would suggest that supraspinal cannabinoid receptors have broad applications, from pain control to closely related central nervous system diseases such as anxiety and depression. Full article

Phytocannabinoids present in Cannabis plants are well known to exert potent anti-inflammatory and immunomodulatory effects. Previously, we have demonstrated that the psychoactive D9-tetrahydrocannabinol (THC) and the non-psychotropic cannabidiol (CBD) modulate mitogen-induced Th1-type immune responses in peripheral blood mononuclear cells (PBMC). The suppressive effect of both cannabinoids on mitogen-induced tryptophan degradation mediated by indoleamine-2,3-dioxygenase (IDO), suggests an additional mechanism by which antidepressive effects of cannabinoids might be linked to the serotonergic system. Here, we will review the role of tryptophan metabolism in the course of cell mediated immune responses and the relevance of cannabinoids in serotonergic signaling. We conclude that in particular the non-psychotropic CBD might be useful for the treatment of mood disorders in patients with inflammatory diseases, since this cannabinoid seems to be safe and its effects on activation-induced tryptophan degradation by CBD were more potent as compared to THC. Full article

Although previously thought of as the peripheral cannabinoid receptor, it is now accepted that the CB₂ receptor is expressed in the central nervous system on microglia, astrocytes and subpopulations of neurons. Expression of the CB₂ receptor in the brain is significantly lower than that of the CB₁ receptor. Conflicting findings have been reported on the neurological effects of pharmacological agents targeting the CB₂ receptor under normal conditions. Under inflammatory conditions, CB₂ receptor expression in the brain is enhanced and CB₂ receptor agonists exhibit potent anti-inflammatory effects. These findings have prompted research into the CB₂ receptor as a possible target for the treatment of neuroinflammatory and neurodegenerative disorders. Neuroinflammatory alterations are also associated with neuropsychiatric disorders and polymorphisms in the CB₂ gene have been reported in depression, eating disorders and schizophrenia. This review will examine the evidence to date for a role of brain CB₂ receptors in neuropsychiatric disorders. Full article

Cannabis contains the psychoactive component delta⁹-tetrahydrocannabinol (delta⁹-THC), and the non-psychoactive components cannabidiol (CBD), cannabinol, and cannabigerol. It is well-known that delta⁹-THC and other cannabinoid CB₁ receptor agonists are neuroprotective during global and focal ischemic injury. Additionally, delta⁹-THC also mediates psychological effects through the activation of the CB₁ receptor in the central nervous system. In addition to the CB₁ receptor agonists, cannabis also contains therapeutically active components which are CB₁ receptor independent. Of the CB₁ receptor-independent cannabis, the most important is CBD. In the past five years, an increasing number of publications have focused on the discovery of the anti-inflammatory, anti-oxidant, and neuroprotective effects of CBD. In particular, CBD exerts positive pharmacological effects in ischemic stroke and other chronic diseases, including Parkinson’s disease, Alzheimer’s disease, and rheumatoid arthritis. The cerebroprotective action of CBD is CB₁ receptor-independent, long-lasting, and has potent anti-oxidant activity. Importantly, CBD use does not lead to tolerance. In this review, we will discuss the therapeutic possibility of CBD as a cerebroprotective agent, highlighting recent pharmacological advances, novel mechanisms, and therapeutic time window of CBD in ischemic stroke. Full article

Cannabinoids are used clinically on a subacute basis as prophylactic agonist antiemetics for the prevention of nausea and vomiting caused by chemotherapeutics. Cannabinoids prevent vomiting by inhibition of release of emetic neurotransmitters via stimulation of presynaptic cannabinoid CB₁ receptors. Cannabis-induced hyperemesis is a recently recognized syndrome associated with chronic cannabis use. It is characterized by repeated cyclical vomiting and learned compulsive hot water bathing behavior. Although considered rare, recent international publications of numerous case reports suggest the contrary. The syndrome appears to be a paradox and the pathophysiological mechanism(s) underlying the induced vomiting remains unknown. Although some traditional hypotheses have already been proposed, the present review critically explores the basic science of these explanations in the clinical setting and provides more current mechanisms for the induced hyperemesis. These encompass: (1) pharmacokinetic factors such as long half-life, chronic exposure, lipid solubility, individual variation in metabolism/excretion leading to accumulation of emetogenic cannabinoid metabolites, and/or cannabinoid withdrawal; and (2) pharmacodynamic factors including switching of the efficacy of Δ⁹-THC from partial agonist to antagonist, differential interaction of Δ⁹-THC with Gs and Gi signal transduction proteins, CB₁ receptor desensitization or downregulation, alterations in tissue concentrations of endocannabinoid agonists/inverse agonists, Δ⁹-THC-induced mobilization of emetogenic metabolites of the arachidonic acid cascade, brainstem versus enteric actions of Δ⁹-THC, and/or hypothermic versus hyperthermic actions of Δ⁹-THC. In addition, human and animal findings suggest that chronic exposure to cannabis may not be a prerequisite for the induction of vomiting but is required for the intensity of emesis. Full article

Exogenous cannabinoids or receptor antagonists may influence many cellular and systemic host responses. The anti-inflammatory activity of cannabinoids may compromise host inflammatory responses to acute viral infections, but may be beneficial in persistent infections. In neurons, where innate antiviral/pro-resolution responses include the activation of NOS-1, inhibition of Ca²⁺ activity by cannabinoids, increased viral replication and disease. This review examines the effect(s) of cannabinoids and their antagonists in viral infections. Full article