Epilepsy and cannabidiol: a guide to treatment.

The growing interest in cannabidiol (CBD), specifically a pure form of CBD, as a treatment for epilepsy, among other conditions, is reflected in recent changes in legislation in some countries. Although there has been much speculation about the therapeutic value of cannabis-based products as an anti-seizure treatment for some time, it is only within the last two years that Class I evidence has been available for a pure form of CBD, based on placebo-controlled RCTs for patients with Lennox-Gastaut syndrome and Dravet syndrome. However, just as we are beginning to understand the significance of CBD as a treatment for epilepsy, in recent years, a broad spectrum of products advertised to contain CBD has emerged on the market. The effects of these products are fundamentally dependent on the purity, preparation, and concentration of CBD and other components, and consensus and standardisation are severely lacking regarding their preparation, composition, usage and effectiveness. This review aims to provide information to neurologists and epileptologists on the therapeutic value of CBD products, principally a purified form, in routine practice for patients with intractable epilepsy.

Cannabis use in people with multiple sclerosis and spasticity: A cross-sectional analysis.

BACKGROUND: Growing evidence supports that cannabinoids relieve MS-related spasticity but little is known about cannabis use among people with MS (PwMS) and spasticity. OBJECTIVE: To characterize cannabis use among PwMS and spasticity. METHODS: As part of baseline data collection for a spasticity intervention trial in Oregon, PwMS and self-reported spasticity answered questions about cannabis use. RESULTS: 54% reported ever using cannabis and 36% currently use. 79% use multiple routes of administration, 58% use at least daily. 79% find cannabis helpful for spasticity and 26% use cannabis and prescribed oral antispasticity medications. CONCLUSIONS: Many PwMS and spasticity use cannabis and report it helps their spasticity.

A role for cannabinoids in the treatment of myotonia? Report of compassionate use in a small cohort of patients.

BACKGROUND: The symptomatic treatment of myotonia and myalgia in patients with dystrophic and non-dystrophic myotonias is often not satisfactory. Some patients anecdotally report symptoms' relief through consumption of cannabis. METHODS: A combination of cannabidiol and tetrahydrocannabinol (CBD/THC) was prescribed as compassionate use to six patients (four patients with myotonic dystrophy types 1 and 2, and 2 patients with CLCN1-myotonia) with therapy-resistant myotonia and myalgia. CBD/THC oil was administered on a low dose in the first 2 weeks and adjusted to a higher dose in the following 2 weeks. Myotonia behaviour scale (MBS), hand-opening time, visual analogue scales (VAS) for myalgia and myotonia, and fatigue and daytime sleepiness severity scale (FSS, ESS) were performed weekly to monitor treatment response. RESULTS: All patients reported an improvement of myotonia especially in weeks 3 and 4 of treatment: MBS improved of at least 2 points in all patients, the hand-opening time variously improved in 5 out of 6 patients. Chronic myalgia was reported by both DM2 patients at baseline, one of them experienced a significant improvement of myalgia under treatment. Some gastrointestinal complaints, as abdominal pain and diarrhoea, improved in 3 patients; however, 4 out of 6 patients reported new-onset constipation. No other relevant side effect was noticed. CONCLUSIONS: These first empirical results suggest a potentially beneficial role of CBD/THC in alleviating myotonia and should encourage further research in this field including a randomized-controlled trial on larger cohorts.

Pure delta-9-tetrahydrocannabinol and its combination with cannabidiol in treatment-resistant Tourette syndrome: A case report.

OBJECTIVES: Anecdotal reports and preliminary studies suggest a therapeutic potential of cannabis in Tourette syndrome. We report the case of a female patient suffering from treatment-resistant Tourette syndrome. METHODS: Guideline-directed antipsychotic treatment with risperidone and aripiprazole as well as pure delta-9-tetrahydrocannabinol had no significant effect on Tourette syndrome symptomatology. RESULTS: Following administration of a daily dosage of 10 mg delta-9-tetrahydrocannabinol combined with 20 mg cannabidiol (CBD), the patient showed a rapid and highly significant improvement in the Yale Global Tic Severity Scale. CONCLUSIONS: It can be speculated whether the beneficial effects may rely on the pharmacological properties of cannabidiol.

Cortical and spinal excitability in patients with multiple sclerosis and spasticity after oromucosal cannabinoid spray.

BACKGROUND: Delta-9-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex®) has been recently approved for the management of treatment-resistant multiple sclerosis (MS) spasticity. Although the symptomatic relief of Sativex® on MS-spasticity has been consistently demonstrated, the pathogenetic implications remain unclear and the few electrophysiological studies performed to address this topic yielded controversial results. We therefore aimed to investigate the mechanisms underpinning the modulation of spastic hypertonia by Sativex®, at both central and spinal levels, through an extensive neurophysiological battery in patients with MS. METHODS: Nineteen MS patients with treatment-resistant spasticity were recruited. Before and after 4weeks of treatment with Sativex® patients were clinically assessed with the Modified Ashworth Scale (MAS) and underwent a large neurophysiological protocol targeting measures of excitability and inhibition at both cortical [e.g., intracortical facilitation (ICF), short (SICI) and long (LICI) intracortical inhibition, cortical silent period (CSP)] and spinal level [e.g., H-reflex, H/M ratio and recovery curve of the H-reflex (HRC)]. A group of 19 healthy subjects served as controls. RESULTS: A significant reduction of the MAS score after 4weeks of Sativex® treatment was detected. Before treatment, an increase in the late facilitatory phase of HRC was recorded in patients compared to the control group, that normalised post treatment. At central level, SICI and LICI were significantly higher in patients compared to healthy subjects. After therapy, a significant strengthening of inhibition (e.g. reduced LICI) and a non-significant facilitation (e.g. marginally increased ICF) occurred, suggesting a modulatory effect of Sativex® on different pathways, predominantly of inhibitory type. Sativex® treatment was well tolerated, with only 3 patients complaining about dizziness and bitter taste in their mouth. DISCUSSION: Our results confirm the clinical benefit of Sativex® on spastic hypertonia and demonstrate that it might modulate both cortical and spinal circuits, arguably in terms of both excitation and inhibition. We suggest that the clinical benefit was likely related to a net increase of inhibition at cortical level that, in turn, might have influenced spinal excitability.

Fat to treat fat: emerging relationship between dietary PUFA, endocannabinoids, and obesity.

Obesity incidence continues to escalate as a global nutrition and health problem. Scientists and clinicians are engaged in numerous research approaches that include behavior, education, applied nutrition studies and clinical therapies to prevent, control and reverse obesity. The common goal is to identify areas of basic and clinical research to understand aspects of human biology that contribute to obesity. In these approaches recent discoveries in biology and advancing technologies are tools employed to prevent and reverse obesity. The purpose of this review article is to present the current knowledge of key components of the endocannabinoid system that contribute to eating, influence systemic energy metabolism, and dietary factors that alter the responses of ligand binding and activation of cannabinoid receptors. Herein the objectives are to (1) describe the relationship between dietary polyunsaturated fatty acids (PUFA) and obesity, (2) explain the role of this signaling system in obesity, and (3) present areas of consequential future research with dietary long chain PUFA. There are several gaps in the knowledge of the role dietary PUFA play in the tone of the endocannabinoid signaling system involving ligands and receptors. Elucidating the PUFA relationship to signaling tone may explain the presumed overstimulation of signaling believed to contribute to over eating, fat accretion and inflammation. Future research in this endeavor must be hypothesis driven utilizing appropriate models for investigations on dietary PUFA, endocannabinoids and obesity.

Endocannabinoid system: potential novel targets for treatment of schizophrenia.

Accumulating epidemiological evidences suggest that cannabis use during adolescence is a potential environmental risk for the development of psychosis, including schizophrenia. Consistently, clinical and preclinical studies, using pharmacological approaches and genetically engineered animals to target endocannabinoid signaling, reveal the multiple varieties of endocannabinoid system-mediated human and animal behaviors, including cognition and emotion. Recently, there has been substantial progress in understanding the molecular mechanisms of the endocannabinoid system for synaptic communications in the central nervous system. Furthermore, the impact of endocannabinoid signaling on diverse cellular processes during brain development has emerged. Thus, although schizophrenia has etiological complexities, including genetic heterogeneities and multiple environmental factors, it now becomes crucial to explore molecular pathways of convergence of genetic risk factors and endocannabinoid signaling, which may provide us with clues to find novel targets for therapeutic intervention. In this review, epidemiological, clinical, and pathological evidences on the role of the endocannabinoid system in the pathophysiologies of schizophrenia will be presented. We will also make a brief overview of the recent progress in understanding molecular mechanisms of the endocannabinoid system for brain development and function, with particular focus on cannabinoid receptor type 1 (CB1R)-mediated cascade, the most well-characterized cannabinoid receptor. Lastly, we will discuss the potential of the endocannabinoid system in finding novel therapeutic targets for prevention and treatment of schizophrenia.

[Pain relief with cannabinoids-- the importance of endocannabinoids and cannabinoids for pain therapy]. / Schmerzlinderung durch Cannabinoide?--Bedeutung des Endocannabinoidsystems und der Cannabinoide für die Schmerztherapie.

The endocannabinoid system reduces sensitization processes. Low doses of cannabinoids may enhance the potency of opioid-drugs and reduce the risk of tolerance to opioids. So far no cannabinoid has been approved for the treatment of acute pain due to lack of consistent data. In contrast, a Cannabis Based Medicine spray consisting of delta9-tetrahydrocannabinol and cannabidiol has been approved for the treatment of neuropathic pain in patients with multiple sclerosis. The adjunct of cannabidiol and the oromucosal formulation increase the therapeutic index of delta9-tetrahydrocannabinol. The differentiation of analgetic effects and cannabimimetic effects may be increased while compounds--such as ajulemic acid--are used which preferentially act on peripheral cannabinoid receptors and exert receptor independent effects. A further approach in this direction is the use of enzymes which metabolize endocannabinoids.

The endocannabinoid system as a target for alkamides from Echinacea angustifolia roots.

Alkamides are the major lipophilic constituents of Echinacea angustifolia roots. Due to their structural similarity with anandamide, we have evaluated their ability to bind to rodent cannabinoid receptors CB1 and CB2 by a standard receptor binding assay using [(3)H]CP-55,940 as a radioligand. The alkamides exhibited selective affinity especially to CB2 receptors and can therefore be considered as CB ligands. Most of the alkamides showed good metabolic stability as indicated by the similarity between affinity to CB1 determined in the presence/absence of the protease inhibitor PMSF. It is suggested that CB2 interactions may be the molecular mode of action of Echinacea alkamides as immunomodulators.