Cannabinoid-based Treatments Research Articles

CANNABIDIOL AS A FORM OF TREATMENT FOR PATIENTS WITH POST-TRAUMATIC STRESS DISORDER FROM VICTIMS OF VIOLENCE – INTEGRATIVE REVIEW

Introduction. Violence as a social and public health problem, with a particular focus on its consequences, such as Post-Traumatic Stress Disorder (PTSD). According to the World Health Organization, violence encompasses the intentional use of physical force or power, threatening or harming individuals, groups or communities. Objective: To describe the effects of Cannabidiol on patients with Post-Traumatic Stress due to physical and psychological violence. Methodology: This is an observational and retrospective integrative systematic review, with the exclusion criteria: non-empirical articles, non-indexed publications. A total of 545 articles related to post-traumatic stress and cannabidiol were found and only 13 articles were selected to present the results of this study. Results and discussion: The endogenous endocannabinoid system plays a significant role in the processing and extinction of fear memory. Cannabidiol (CBD), a non-psychoactive component of Cannabis sativa, has shown potential in the treatment of anxiety disorders, including PTSD. CBD interacts with the endocannabinoid system indirectly by increasing the availability of endocannabinoids such as anandamide, which act on CB1 receptors in the brain. This activation of the endocannabinoid system may help reduce the behavioral response to aversive memories and improve fear extinction. Final Thoughts: While early research on the effects of CBD on PTSD is promising, more studies are needed to determine its efficacy and safety, particularly in victims of violence. Sources also emphasize the need for greater awareness and accessibility of cannabinoid-based treatments for those who may benefit from them.

Cannabinoids from C. sativa L.: Systematic Review on Potential Pharmacological Effects against Infectious Diseases Downstream and Multidrug-Resistant Pathogens

Cannabis sativa L. has garnered attention as a potential source for new antimicrobial agents, particularly due to the increased prevalence of microbial resistance to conventional antimicrobials and the emergence of multidrug-resistant pathogens. This review, conducted according to the PRISMA 2020 statement, systematically analyzed the antimicrobial properties of C. sativa extracts and cannabinoids against various bacteria, fungi, viruses, and parasites. Data were collected from the scientific literature (102 papers) and clinical trials (5 studies) from 2014 to June 2024. Findings revealed that cannabinoids, especially CBD, demonstrate significant antimicrobial activity against Gram-positive bacteria like MRSA, Gram-negative bacteria such as Pseudomonas aeruginosa, various Candida species, SARS-CoV-2, and HIV. Additionally, CBD showed efficacy against parasitic infections like Echinococcus granulosus and Leishmania species. These results suggest that cannabinoids may represent a new class of antimicrobial agents with unique and diverse mechanisms of action, potentially effective in broad-spectrum therapies. This study highlights the urgent need for further research and standardized clinical trials to validate these findings and to develop cannabinoid-based treatments. The antimicrobial properties of C. sativa align with WHO priorities and support global health initiatives, offering promising avenues for addressing antimicrobial resistance and improving public health outcomes.

Exploring the Potential of Cannabinoids in the Treatment of Tourette’s Syndrome

Introduction Tourette’s syndrome (TS) is a disorder characterized by repetitive, involuntary movements, and vocalizations known as tics. While there are existing treatment options, there is a growing need for novel pharmacological approaches to manage the symptoms of TS effectively. This study delves into the emerging field of using cannabinoids as a potential treatment for Tourette’s syndrome.Objectives The primary objectives of this review are to examine the current evidence base for the use of cannabinoids in the treatment of Tourette’s syndrome, to assess the biological rationale supporting the use of cannabinoids in managing tic severity, to provide insights into the results of existing clinical trials involving cannabinoids and Tourette’s syndrome, and to draw conclusions regarding the potential efficacy and safety of cannabinoid-based treatments for TS.MethodsNarrative review of the available scientific literature.ResultsThere is a strong biological rationale for how cannabinoids could impact tic severity. The endocannabinoid system plays a crucial role in regulating various physiological processes, including motor control and neurotransmitter release. Activation of cannabinoid receptors in the brain may modulate these processes, potentially reducing tics. While limited, two small randomized, placebo-controlled trials of THC have been conducted in TS patients. These trials suggested potential benefits of cannabis-derived agents in reducing tic frequency and severity. Self-report and examiner rating scales demonstrated significant improvements in tic symptoms. The trials indicated that THC treatment did not result in significant adverse effects in TS patients.ConclusionsThe exploration of cannabinoids as a treatment option for Tourette’s syndrome is promising but requires further investigation. The biological mechanisms through which cannabinoids may affect tic severity in TS are sound, suggesting their potential as a therapeutic option. Existing trials with THC have shown encouraging results, demonstrating a reduction in tics without significant adverse effects. However, the limited number of trials warrants caution in drawing definitive conclusions. Despite the promising findings, the overall efficacy and safety of cannabinoid-based treatments remain largely unknown. Further trials are essential to address dosing, active ingredients, optimal administration, and potential long-term effects. Clinical use should be approached with caution. While early evidence is encouraging, additional rigorous studies are needed to establish the safety and efficacy of cannabinoid-based treatments for this disorder.Disclosure of InterestNone Declared

Cannabinoids for Substance Use Disorder Treatment: What Does the Current Evidence Say?

Background: The prevalence of Substance Use Disorder (SUD) is increasing along with the need to develop approaches to reduce the harm associated with substance use, including investigating alternatives such as cannabinoids, which show promising results, although the current evidence is limited. This scoping review focuses on the limitations and potentials of cannabinoid-based treatments for SUDs. Methods: We examined between-subject randomized controlled trials (RCTs) investigating the use of CBD and THC as pharmacological treatment for SUDs in adults, with the procedures attending the expectations of the Preferred Reporting Items for Scoping reviews and Meta-Analyses (PRISMA) for Scoping Reviews guidelines and assessed risk of bias using the Cochrane Risk of Bias Assessment Tool 2. Results: Ten RCTs were included, with six demonstrating low risk of bias, and positive results were found for treating Cannabis Use Disorder, while contradictory results were found for Opioid Use Disorder, and inconclusive results for treating Cocaine Use Disorder. Conclusions: CBD and THC demonstrate potential for treating some SUDs, but evidence is limited. Robust RCTs with larger samples and longer follow-up periods are necessary to assess carefully developed outcomes for different SUD patients. New cannabinoid-based medications and scientific-based policies may advance SUD treatment. A comprehensive approach to treatment and careful methodological choices may benefit patients with SUD.

A Complete Endocannabinoid Signaling System Modulates Synaptic Transmission between Human Induced Pluripotent Stem Cell–Derived Neurons

The endocannabinoid system (ECS) modulates synaptic function to regulate many aspects of neurophysiology. It adapts to environmental changes and is affected by disease. Thus, the ECS presents an important target for therapeutic development. Despite recent interest in cannabinoid-based treatments, few preclinical studies are conducted in human systems. Human induced pluripotent stem cells (hiPSCs) provide one possible solution to this issue. However, it is not known if these cells have a fully functional ECS. Here, we show that hiPSC-derived neuron/astrocyte cultures exhibit a complete ECS. Using Ca2+ imaging and a genetically encoded endocannabinoid sensor, we demonstrate that they not only respond to exogenously applied cannabinoids but also produce and metabolize endocannabinoids. Synaptically driven [Ca2+]i spiking activity was inhibited (EC50 = 48 ± 13 nM) by the efficacious agonist [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrolol [1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate] (Win 55,212-2) and by the endogenous ligand 2-arachidonoyl glycerol (2-AG; EC50 = 2.0 ± 0.6 µm). The effects of Win 55212-2 were blocked by a CB1 receptor-selective antagonist. Δ9-Tetrahydrocannabinol acted as a partial agonist, maximally inhibiting synaptic activity by 47 ± 14% (EC50 = 1.4 ± 1.9 µm). Carbachol stimulated 2-AG production in a manner that was independent of Ca2+ and blocked by selective inhibition of diacylglycerol lipase. 2-AG returned to basal levels via a process mediated by monoacylglycerol lipase as indicated by slowed recovery in cultures treated with 4-[Bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester (JZL 184). Win 55,212-2 markedly desensitized CB1 receptor function following a 1-day exposure, whereas desensitization was incomplete following 7-day treatment with JZL 184. This human cell culture model is well suited for functional analysis of the ECS and as a platform for drug development. SIGNIFICANCE STATEMENT: Despite known differences between the human response to cannabinoids and that of other species, an in vitro human model demonstrating a fully functional endocannabinoid system has not been described. Human induced pluripotent stem cells (hiPSCs) can be obtained from skin samples and then reprogrammed into neurons for use in basic research and drug screening. Here, we show that hiPSC-derived neuronal cultures exhibit a complete endocannabinoid system suitable for mechanistic studies and drug discovery.

The microglial endocannabinoid system is similarly regulated by lipopolysaccharide and interferon gamma

Perturbation of the endocannabinoid system can have profound effects on immune function and synaptic plasticity. Microglia are one of few cell types with a self-contained endocannabinoid system and are positioned at the interface between the immune system and the central nervous system. Past work has produced conflicting results with respect to the effects of pro-inflammatory conditions on the microglial endocannabinoid system. Thus, we systematically investigated the relationship between the concentration of two distinct pro-inflammatory stimuli, lipopolysaccharide and interferon gamma, on the abundance of components of the endocannabinoid system within microglia. Here we show that lipopolysaccharide and interferon gamma influence messenger RNA abundances of the microglial endocannabinoid system in a concentration-dependent manner. Furthermore, we demonstrate that the efficacy of different synthetic cannabinoid treatments with respect to inhibition of microglia nitric oxide release is dependent on the concentration and type of pro-inflammatory stimuli presented to the microglia. This indicates that different pro-inflammatory stimuli influence the capacity of microglia to synthesize, degrade, and respond to cannabinoids which has implications for the development of cannabinoid-based treatments for neuroinflammation.

The model of care at a leading medical cannabis clinic in Canada

Medical cannabis access has been legalized in more than 30 countries worldwide and popularity among patients is increasing rapidly. Cannabinoid-based treatments have been shown to be beneficial for several symptoms such as chemotherapy-induced nausea and vomiting, spasticity, chronic pain, intractable seizures and insomnia, yet high-quality clinical trials are still limited. As millions of patients now have legal access to medical cannabis, little information is available about the development of best clinical practices and an effective medical cannabis clinic model.A medical cannabis clinic is an innovative and emergent practice model that may be necessary to bridge the gap between patient and healthcare provider interest and existing barriers to the prescription of medical cannabis treatments, such as limited medical education, lack of high-quality clinical research and challenging or evolving regulatory frameworks. In this paper, we describe the model of care and organization of a dedicated medical cannabis clinic operating in Quebec, Canada since 2014. We share the principles of medical cannabis practice, including the structure of its medical and support team, clinic organisation and procedure guidelines. Key clinic statistics and patient demographics are shared with year by year comparison.Operating since 2014, the clinic has endured a rapidly changing regulatory landscape in Canada, overcoming numerous challenges including medical and social stigma, limited funding, resources and institutional support combined with a high demand for services. To support medical cannabis leaders globally, an important knowledge-sharing is required. The clinic has expanded to a network of four clinic sites across Quebec and offers continuing education and preceptorships to health care providers and trainees as well as research services to both academic and industry partners. The description of the clinic offers guidance on medical cannabis treatment and care and discusses possible solutions to associated challenges. The clinic model of care can be adapted to different healthcare settings and regulatory frameworks; it may assist physicians and health care providers in the development of medical cannabis clinics or the implementation of best practices as medical cannabis access continues to evolve.

Hepatic Cannabinoid Signaling in the Regulation of Alcohol-Associated Liver Disease.

PURPOSEThe endocannabinoid system has emerged as a key regulatory signaling pathway in the pathophysiology of alcohol-associated liver disease (ALD). More than 30 years of research have established different roles of endocannabinoids and their receptors in various aspects of liver diseases, such as steatosis, inflammation, and fibrosis. However, pharmacological applications of the endocannabinoid system for the treatment of ALD have not been successful because of psychoactive side effects, despite some beneficial effects. Thus, a more delicate and detailed elucidation of the mechanism linking the endocannabinoid system and ALD may be of paramount significance in efforts to apply the system to the treatment of ALD.SEARCH METHODSThree electronic databases (PubMed, MEDLINE, and Cochrane Library) were used for literature search from November 1988 to April 2021. Major keywords used for literature searches were “cannabinoid,” “cannabinoid receptor,” “ALD,” “steatosis,” and “fibrosis.”SEARCH RESULTSAccording to the inclusion and exclusion criteria, the authors selected 47 eligible full-text articles out of 2,691 searched initially. Studies in the past 3 decades revealed the opposite effects of cannabinoid receptors CB1R and CB2R on steatosis, inflammation, and fibrosis in ALD.DISCUSSION AND CONCLUSIONSThis review summarizes the endocannabinoid signaling in the general physiology of the liver, the pathogenesis of ALD, and some of the potential therapeutic implications of cannabinoid-based treatments for ALD.

Cannabis, the Endocannabinoid System and Immunity-the Journey from the Bedside to the Bench and Back.

The Cannabis plant contains numerous components, including cannabinoids and other active molecules. The phyto-cannabinoid activity is mediated by the endocannabinoid system. Cannabinoids affect the nervous system and play significant roles in the regulation of the immune system. While Cannabis is not yet registered as a drug, the potential of cannabinoid-based medicines for the treatment of various conditions has led many countries to authorize their clinical use. However, the data from basic and medical research dedicated to medical Cannabis is currently limited. A variety of pathological conditions involve dysregulation of the immune system. For example, in cancer, immune surveillance and cancer immuno-editing result in immune tolerance. On the other hand, in autoimmune diseases increased immune activity causes tissue damage. Immuno-modulating therapies can regulate the immune system and therefore the immune-regulatory properties of cannabinoids, suggest their use in the therapy of immune related disorders. In this contemporary review, we discuss the roles of the endocannabinoid system in immunity and explore the emerging data about the effects of cannabinoids on the immune response in different pathologies. In addition, we discuss the complexities of using cannabinoid-based treatments in each of these conditions.

Medical cannabis in supportive cancer care: lessons from Canada.

Medical cannabis, or cannabinoid-based products, continues to grow in popularity globally, driving the evolution of regulatory access frameworks; cancer patients and caregivers often rely on guidance from their physicians regarding cannabinoid-based treatments. But the majority of healthcare practitioners still feel unprepared and insufficiently informed to make reasonable, evidence-based recommendations about medical cannabis. More than 30 countries worldwide have now legalized access to medical cannabis; yet various nations still face arduous regulatory challenges to fulfill the needs of patients, healthcare practitioners, and other medical stakeholders. This has affected the deployment of comprehensive medical cannabis access programs adapted to cultural and social realities. With a 20-year history of legal medical cannabis access and nearly 400,000 registered patients under its federal access program, Canada serves as a model for countries which are developing their regulatory frameworks. The Canadian clinical experience in cannabinoid-based treatments is also a valuable source of lessons for healthcare professionals who wish to better understand the current evidence examining medical cannabis for oncology patients.

The Highs and Lows of Cannabis in Cancer Treatment and Bone Marrow Transplantation.

In the last decade, we have observed an increased public and scientific interest in the clinical applications of medical cannabis. Currently, the application of cannabinoids in cancer patients is mainly due to their analgesic and anti-emetic effects. The direct effects of phyto-cannabinoids on cancer cells are under intensive research, and the data remain somewhat inconsistent. Although anti-proliferative properties were observed in vitro, conclusive data from animal models and clinical trials are lacking. Since immunotherapy of malignant diseases and bone marrow transplantation are integral approaches in hemato-oncology, the immuno-modulatory characteristic of cannabinoids is a fundamental aspect for consideration. The effect of cannabinoids on the immune system is presently under investigation, and some evidence for its immuno-regulatory properties has been shown. In addition, the interaction of cannabinoids and classical cytotoxic agents is a subject for further investigation. Here we discuss the current knowledge of cannabinoid-based treatments in preclinical models and the limited data in oncological patients. Particularly, we address the possible contradiction between the direct anti-tumor and the immune-modulatory effects of cannabinoids. Better understanding of the mechanism of cannabinoids influence is essential to design therapies that will allow cannabinoids to be incorporated into the clinic.

The Potential of Cannabinoid-Based Treatments in Tourette Syndrome.

Novel pharmacological treatments are needed for Tourette syndrome. Our goal was to examine the current evidence base and biological rationale for the use of cannabis-derived medications or medications that act on the cannabinoid system in Tourette syndrome. We conducted a comprehensive literature search of PubMed for randomized controlled trials or clinical trials of cannabis-derived medications in Tourette syndrome. Data regarding the population, intervention, safety profile, and outcomes for each trial were extracted and reported and the evidence supporting use of individual cannabis-derived medications was critiqued. There is a strong biological rationale regarding how cannabis-derived medications could affect tic severity. Anecdotal case reports and series have noted that many patients report that their tics improve after using cannabis. However, only two small randomized, placebo-controlled trials of Δ9-tetrahydrocannabinol have been published; these suggested possible benefits of cannabis-derived agents for the treatment of tics. Trials examining other agents active on the cannabinoid system for tic disorders are currently ongoing. Cannabinoid-based treatments are a promising avenue of new research for medications that may help the Tourette syndrome population. However, given the limited research available, the overall efficacy and safety of cannabinoid-based treatments is largely unknown. Further trials are needed to examine dosing, active ingredients, and optimal mode of administration of cannabis-derived compounds, assuming initial trials suggest efficacy. Clinical use for refractory patients should at the very least be restricted to adult populations, given the uncertain efficacy and risk of developmental adverse effects that cannabinoids may have in children. Even in adult populations, cannabis-derived medications are associated with significant issues such as the effects they have on driving safety and the fact that they cause positive urine drug screens that can affect employment.

Molecular evaluation of the endocannabinoid system in RTT mice-model: implications for cannabinoid-based treatments.

Molecular evaluation of the endocannabinoid system in RTT mice-model: implications for cannabinoid-based treatments.

P.2.029 - Characterisation of a Dravet syndrome knock-in mouse model useful for investigating cannabinoid-based treatments

Dravet syndrome (DS) is a rare pediatric epileptic encephalopathy which, in approximately 60-80% of patients, is caused by mutations in the gene SCN1A that encodes the α1 subunit of the voltage-gated sodium channel NaV1.1 [1]. Clinically, DS patients present different types of epileptic seizures, which are normally accompanied by cognitive impairment and behavioral disturbances such as hyperactivity and autistic traits [2]. These patients are typically resistant to most antiepileptic drugs, but recent preliminary data suggest that a promising therapy for DS may be based on the use of cannabidiol (CBD) [3]. However, this issue has not been investigated in DS mouse models, therefore existing a wide field of research focused on finding biochemical evidences that could justify the beneficial effects of CBD shown in DS patients. The aim of the present study was to characterize a new DS condicional knock-in mouse model, which may be useful for investigate the effects of CBD in DS. This characterization was focused on behavioral and biochemical/histological terms, specifically on postnatal day 25, stage corresponding to early ages in humans, when main features of the disease are presented. Heterozygous conditional knock-in mice (B6(Cg)-Scn1atm1.1Dsf/J) carrying a missense mutation in SCN1A gene, A1783V, were crossed to Cre recombinase mice (Cre B6.Cg-Tg (Syn1-cre)671Jxm/J) generating offspring with A1783V mutation in cre-expressing tissues. At postnatal day 25, behavioural tests were conducted to analyze motor activity (spontaneous activity test), autistic-like traits (social interaction test) and cognitive deficits (Y-maze test). At this age, mice were euthanized and brains collected for biochemical and histopathological analysis. Data are expressed as mean ± SEM (10/15 animals per group in behavioural analysis and 6 animals per group in biochemical and histopathological analysis) and the statistical analysis used was one-way ANOVA followed by Bonferroni test. Behavioral analyses showed that DS mice exhibit hyperactivity in the actimeter reduced social behaviors in the social interaction test and cognitive impairment in the Y-maze test. Biochemical analysis revealed the existence of a partial dysregulation of the endocannabinoid system (ECS), with a decrease in mRNA (measured by qRT-PCR) levels for the CB1 receptor in cerebellum and MAGL hydrolyzing enzyme in prefrontal cortex and cerebellum. We also found an increase of microglia and astrocyte cells in cerebral cortex, striatum and hippocampus of DS mice, revealed by elevated Iba-1 and GFAP immunolabeling, respectively, which suggests that neuroinflammation might be part of DS pathogenesis. Our results reveal that DS mice present behavioral disturbances, a dysregulation of ECS and neuroinflammation events. We hypothesize whether CBD efficay may be associated with the direct or indirect correction of the dysregulation in the ECS, which contains targets for CBD, and also associated with the potent anti-inflammatory effect of CBD. We are currently engaged in pharmacological experiments to investigate if CBD treatment is able to normalize the changes in the ECS, neuroinflammation and behavioral impairment in DS mice.

Neurological Disorders in Medical Use of Cannabis: An Update.

Medical cannabis is increasingly used as a treatment or adjunct treatment with different levels of efficacy in several neurological disorders or related symptoms (such as multiple sclerosis, autism, Parkinson and Alzheimer disease, Tourette's syndrome, Huntington's disease, neuropathic pain, epilepsy, headache), as well as in other medical conditions (e.g. nausea and vomiting, glaucoma, appetite stimulation, cancer, inflammatory conditions, asthma). Nevertheless, a number of neurological adverse effects from use of medical cannabis on the short- and on the longterm have been reported, in addition to other adverse health events. It has been noticed that the use of medical cannabis can lead to a paradoxical effects depending on the amount of delta-9-tetrahydrocannabinol (THC) -like cannabinoids the preparation contain. Accordingly, some neurological disorders or symptoms (e.g. multiple sclerosis, seizures, epilepsy, headache) may be caused or exacerbated by the same treatment supposed to cure them. The current review presents an update of the neurological adverse effects resulting from the use of cannabis for medical purposes, highlighting the need to weigh the benefits and risks, when using cannabinoidbased treatments.

Cannabinoids in the management of spasticity associated with multiple sclerosis

The endocannabinoid system and cannabinoid-based treatments have been involved in a wide number of diseases. In particular, several studies suggest that cannabinoids and endocannabinoids may have a key role in the pathogenesis and therapy of multiple sclerosis (MS). In this study we highlight the main findings reported in literature about the relevance of cannabinoid drugs in the management and treatment of MS. An increasing body of evidence suggests that cannabinoids have beneficial effects on the symptoms of MS, including spasticity and pain. In this report we focus on the effects of cannabinoids in the relief of spasticity describing the main findings in vivo, in the mouse experimental allergic encephalomyelitis model of MS. We report on the current treatments used to control MS symptoms and the most recent clinical studies based on cannabinoid treatments, although long-term studies are required to establish whether cannabinoids may have a role beyond symptom amelioration in MS.

An Overview of Parkinsons Disease and the Cannabinoid System and Possible Benefits of Cannabinoid-Based Treatments

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder with a heterogeneous clinical picture and a variable rate of progression. PD is characterized by degeneration of the pigmented neuromelanin bearing cells of the pars compacta of the substantia nigra that leads to a severe dopaminergic denervation of the striatum. Current treatments for PD rely on dopamine replacement therapy, most commonly with the dopamine precursor levodopa. Despite the many recent advances in the symptomatic treatment of PD, there is still no realistic prospect for a cure. In recent years, new data support the idea of a relevant role for the cannabinoid system in PD. As cannabinoids have neuroprotective properties, they have been proposed as potentially useful neuroprotective substances in PD, as well as to alleviate some symptoms in specific circumstances (i.e. parkinsonian tremor associated with overactivity to the subthalamic nucleus; levodopa-induced dyskinesia). By contrast, CB(1) receptor antagonists might be useful to reduce bradykinesia in patients refractory to classic levodopa treatment. The present article will review all data about the relationship between PD and the cannabinoid system including: i) the usefulness of cannabinoid-related compounds to alleviate some PD symptoms; ii) that cannabinoid-based compounds might provide protection against the progression of neuronal injury characteristic of this disease; iii) the influence of cannabinoids on local inflammatory events associated with the pathogenesis in PD. Collectively, all these evidence support that the management of the cannabinoid system might represent a new approach to the treatment of PD.

A role for endocannabinoids in viral-induced dyskinetic and convulsive phenomena

Dyskinesias and seizures are both medically refractory disorders for which cannabinoid-based treatments have shown early promise as primary or adjunctive therapy. Using the Borna disease (BD) virus rat, an animal model of viral encephalopathy with spontaneous hyperkinetic movements and seizure susceptibility, we identified a key role for endocannabinoids in the maintenance of a balanced tone of activity in extrapyramidal and limbic circuits. BD rats showed significant elevations of the endocannabinoid anandamide in subthalamic nucleus, a relay nucleus compromised in hyperkinetic disorders. While direct and indirect cannabinoid agonists had limited motor effects in BD rats, abrupt reductions of endocannabinoid tone by the CB 1 antagonist SR141716A (0.3 mg/kg, i.p.) caused seizures characterized by myoclonic jerks time-locked to periodic spike/sharp wave discharges on hippocampal electroencephalography. The general opiate antagonist naloxone (NLX) (1 mg/kg, s.c.), another pharmacologic treatment with potential efficacy in dyskinesias or L-DOPA motor complications, produced similar seizures. No changes in anandamide levels in hippocampus and amygdala were found in convulsing NLX-treated BD rats. In contrast, NLX significantly increased anandamide levels in the same areas of normal uninfected animals, possibly protecting against seizures. Pretreatment with the anandamide transport blocker AM404 (20 mg/kg, i.p.) prevented NLX-induced seizures. These findings are consistent with an anticonvulsant role for endocannabinoids, counteracting aberrant firing produced by convulsive agents, and with a functional or reciprocal relation between opioid and cannabinoid tone with respect to limbic convulsive phenomena.

Towards cannabis and cannabinoid treatment of multiple sclerosis

Multiple sclerosis is a common human demyelinating disease of the central nervous system (CNS), and it is thought to involve autoimmune responses to CNS myelin antigens. Current symptomatic therapies for multiple sclerosis are in some cases ineffective and may have a high risk of serious side effects. This has led some multiple sclerosis patients to self-medicate with cannabis, which anecdotal evidence suggests may be beneficial in controlling symptoms such as spasticity, pain, tremor and bladder dysfunction. In support of these claims, results from experimental studies have suggested that cannabinoid-based treatments may be beneficial in a wide number of diseases. Furthermore, recent research in animal models of multiple sclerosis has demonstrated the efficacy of cannabinoids in controlling disease-induced symptoms such as spasticity and tremor, as well as in ameliorating the severity of clinical disease. However, these initially promising results have not yet been fully translated into the clinic. Although cannabinoid treatment of multiple sclerosis symptoms has been shown to be both well tolerated and effective in a number of subjective tests in several small-scale clinical trials, objective measures demonstrating the efficacy of cannabinoids are still lacking. Currently, a number of large-scale phase III clinical trials are under way to further elucidate the use of cannabinoids in the symptomatic treatment of multiple sclerosis. This review highlights the recent advances in our understanding of the endocannabinoid system, discusses both the experimental and clinical evidence for the use of cannabinoids to treat multiple sclerosis and explores possible future strategies of cannabinoid therapy in multiple sclerosis.