http://www.mdpi.com/journal/pharmaceuticals/special_issues/cannabinoids/ Dear Colleagues, We invite authors to submit papers to Pharmaceuticals in the exciting field of Cannabinoid research. This special issue is to include original articles on basic or clinical reserach on the endocannabinoid system (including enocannabinoids and the enzymes involved in their synthesis and degradation), phytocannabinoid (such as THC, CBD, THCV) or cannabis preparations (such as Sativex) in any reserach area, but particularly investigations looking at novel compounds or novel sites of action. We also welcome review articles on complex and controversial areas in cannabinoid pharmacology. Prof. Dr. Rudolf Brenneisen Dr. Saoirse O'Sullivan Guest Editor Submission All manuscripts should be submitted to pharmaceuticals@mdpi.com with a copy to the Guest Editor. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website. Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed Open Access monthly journal published by MDPI.   Please visit the Instructions for Authors page before submitting a manuscript. Article Processing Charges (APC) for publication in this Open Access journal will be waived for well-prepared manuscripts submitted before 30 June 2010. English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections. http://www.mdpi.com/1424-8247/3/11/3355/ 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. http://www.mdpi.com/1424-8247/3/11/3355/ Thu, 28 Oct 2010 00:00:00 CEST Pharmaceuticals 2010-10-28 3 11 Review 3355 3370 1424-8247 Inactivation of Anandamide Signaling: A Continuing Debate 2010-10-28 doi: 10.3390/ph3113355 Hesham Khairy Wael E. Houssen http://www.mdpi.com/1424-8247/3/10/3275/ 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. http://www.mdpi.com/1424-8247/3/10/3275/ Mon, 25 Oct 2010 00:00:00 CEST Pharmaceuticals 2010-10-25 3 10 Review 3275 3323 1424-8247 Cannabinoids and Reproduction: A Lasting and Intriguing History 2010-10-25 doi: 10.3390/ph3103275 Giovanna Cacciola Rosanna Chianese Teresa Chioccarelli Vincenza Ciaramella Silvia Fasano Riccardo Pierantoni Rosaria Meccariello Gilda Cobellis http://www.mdpi.com/1424-8247/3/10/3200/ 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. http://www.mdpi.com/1424-8247/3/10/3200/ Tue, 12 Oct 2010 00:00:00 CEST Pharmaceuticals 2010-10-12 3 10 Review 3200 3211 1424-8247 Endocannabinoids and Human Sperm Cells 2010-10-12 doi: 10.3390/ph3103200 Annarina Ambrosini Rosamaria Fiorini Giovanna Zolese http://www.mdpi.com/1424-8247/3/10/3101/ 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. http://www.mdpi.com/1424-8247/3/10/3101/ Fri, 08 Oct 2010 00:00:00 CEST Pharmaceuticals 2010-10-08 3 10 Review 3101 3126 1424-8247 Endocannabinoids and Schizophrenia 2010-10-08 doi: 10.3390/ph3103101 Joëlle Desfossés Emmanuel Stip Lahcen Ait Bentaleb Stéphane Potvin http://www.mdpi.com/1424-8247/3/9/2970/ 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. http://www.mdpi.com/1424-8247/3/9/2970/ Mon, 06 Sep 2010 00:00:00 CEST Pharmaceuticals 2010-09-06 3 9 Review 2970 2985 1424-8247 Tissue Engineering of Cartilage; Can Cannabinoids Help? 2010-09-06 doi: 10.3390/ph3092970 Aoife Gowran Katey McKayed Manoj Kanichai Cillian White Nissrin Hammadi Veronica Campbell http://www.mdpi.com/1424-8247/3/9/2930/ 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. http://www.mdpi.com/1424-8247/3/9/2930/ Fri, 03 Sep 2010 00:00:00 CEST Pharmaceuticals 2010-09-03 3 9 Review 2930 2955 1424-8247 Mechanisms of Broad-Spectrum Antiemetic Efficacy of Cannabinoids against Chemotherapy-Induced Acute and Delayed Vomiting 2010-09-03 doi: 10.3390/ph3092930 Nissar A. Darmani http://www.mdpi.com/1424-8247/3/9/2910/ 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. http://www.mdpi.com/1424-8247/3/9/2910/ Thu, 02 Sep 2010 00:00:00 CEST Pharmaceuticals 2010-09-02 3 9 Review 2910 2929 1424-8247 From Fertilisation to Implantation in Mammalian Pregnancy—Modulation of Early Human Reproduction by the Endocannabinoid System 2010-09-02 doi: 10.3390/ph3092910 Katerina N. Bambang Tulay Karasu Alpha Gebeh Anthony H. Taylor Timothy H. Marczylo Patricia Lam Jonathon M. Willets Justin C. Konje http://www.mdpi.com/1424-8247/3/9/2799/ 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. http://www.mdpi.com/1424-8247/3/9/2799/ Thu, 26 Aug 2010 00:00:00 CEST Pharmaceuticals 2010-08-26 3 9 Review 2799 2820 1424-8247 Vulnerability Factors for the Psychiatric and Behavioral Effects of Cannabis 2010-08-26 doi: 10.3390/ph3092799 Marco Bortolato Valentina Bini Simone Tambaro http://www.mdpi.com/1424-8247/3/8/2733/ 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. http://www.mdpi.com/1424-8247/3/8/2733/ Mon, 23 Aug 2010 00:00:00 CEST Pharmaceuticals 2010-08-23 3 8 Review 2733 2750 1424-8247 Dendritic Cell Regulation by Cannabinoid-Based Drugs 2010-08-23 doi: 10.3390/ph3082733 Mattias Svensson Puran Chen Oscar Hammarfjord http://www.mdpi.com/1424-8247/3/8/2689/ 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. http://www.mdpi.com/1424-8247/3/8/2689/ Tue, 17 Aug 2010 00:00:00 CEST Pharmaceuticals 2010-08-17 3 8 Review 2689 2708 1424-8247 Cannabinoids and Dementia: A Review of Clinical and Preclinical Data 2010-08-17 doi: 10.3390/ph3082689 Sebastian Walther Michael Halpern http://www.mdpi.com/1424-8247/3/8/2661/ 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. http://www.mdpi.com/1424-8247/3/8/2661/ Mon, 16 Aug 2010 00:00:00 CEST Pharmaceuticals 2010-08-16 3 8 Review 2661 2673 1424-8247 The Role of Cannabinoid Receptors in the Descending Modulation of Pain 2010-08-16 doi: 10.3390/ph3082661 Enza Palazzo Livio Luongo Vito de Novellis Francesco Rossi Sabatino Maione http://www.mdpi.com/1424-8247/3/8/2647/ 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. http://www.mdpi.com/1424-8247/3/8/2647/ Fri, 13 Aug 2010 00:00:00 CEST Pharmaceuticals 2010-08-13 3 8 Review 2647 2660 1424-8247 The Potential Role of Cannabinoids in Modulating Serotonergic Signaling by Their Influence on Tryptophan Metabolism 2010-08-13 doi: 10.3390/ph3082647 Marcel Jenny Sebastian Schröcksnadel Florian Überall Dietmar Fuchs http://www.mdpi.com/1424-8247/3/8/2517/ 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. http://www.mdpi.com/1424-8247/3/8/2517/ Tue, 10 Aug 2010 00:00:00 CEST Pharmaceuticals 2010-08-10 3 8 Review 2517 2553 1424-8247 Brain CB2 Receptors: Implications for Neuropsychiatric Disorders 2010-08-10 doi: 10.3390/ph3082517 Michelle Roche David P Finn http://www.mdpi.com/1424-8247/3/7/2197/ 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. http://www.mdpi.com/1424-8247/3/7/2197/ Thu, 08 Jul 2010 00:00:00 CEST Pharmaceuticals 2010-07-08 3 7 Review 2197 2212 1424-8247 Therapeutic Potential of Non-Psychotropic Cannabidiol in Ischemic Stroke 2010-07-08 doi: 10.3390/ph3072197 Hayakawa Mishima Fujiwara http://www.mdpi.com/1424-8247/3/7/2163/ 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. http://www.mdpi.com/1424-8247/3/7/2163/ Wed, 07 Jul 2010 00:00:00 CEST Pharmaceuticals 2010-07-07 3 7 Review 2163 2177 1424-8247 Cannabinoid-Induced Hyperemesis: A Conundrum—From Clinical Recognition to Basic Science Mechanisms 2010-07-07 doi: 10.3390/ph3072163 Darmani http://www.mdpi.com/1424-8247/3/6/1873/ 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. http://www.mdpi.com/1424-8247/3/6/1873/ Wed, 09 Jun 2010 00:00:00 CEST Pharmaceuticals 2010-06-09 3 6 Review 1873 1886 1424-8247 Cannabinoids and Viral Infections 2010-06-09 doi: 10.3390/ph3061873 Reiss