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and That What Mean? Has CBD Properties. Antioxidant Does Neuroprotective



  • and That What Mean? Has CBD Properties. Antioxidant Does Neuroprotective
  • US6630507B1 - Cannabinoids as antioxidants and neuroprotectants - Google Patents
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  • CBD Has Antioxidant and Neuroprotective Properties. What Does That Mean? by ECHO What does it mean that CBD is neuroprotective?. CBD, like Δ9-THC, is a major phytocannabinoid accounting for up to . antioxidant mechanisms independently of cannabinoid receptors. [99] A clinical study from using 15 subjects with HD reported an average daily dose of CBD of 10 mg/kg/day per . Antidepressant and neuroprotective properties. Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous The neuroprotective properties of CBD do not appear to be exerted by the the plant Cannabis sativa in which it may represent up to 40% of cannabis extracts [1]. Rosenthal R, Axelrod J. Neuroprotective antioxidants from marijuana.

    and That What Mean? Has CBD Properties. Antioxidant Does Neuroprotective

    Some of the research on these antagonists has focused on cannabinoids, a subset of which have been found to be NMDA receptor antagonists. The HU dimethylheptyl cannabinoid, has severe side effects, including fatigue, thirst, headache, and hypotension. Subjects who received this synthetic cannabinoid with a dimethylheptyl group experienced marked psychomotor retardation, and were unwilling or incapable of assuming an erect position. THC tetrahydrocannabinol is another of the cannabinoids that has been shown to be neuroprotective in cell cultures, but this protection was believed to be mediated by interaction at the cannabinoid receptor, and so would be accompanied by undesired psychotropic side effects.

    Although it has been unclear whether cannabimimetic activity plays a role in neuroprotection against glutamate induced neurological injury, the teaching in this field has clearly been that a cannabinoid must at least be an antagonist at the NMDA receptor to have neuroprotective effect. Hence cannabidiol 2-[3-methyl 1-methylethenyl cyclohexenyl]pentyl-1,3-benzenediol or CBD , a cannabinoid devoid of psychoactive effect Pharm.

    Cannabidiol has been studied as an antiepileptic Carlini et al. No signs of toxicity or serious side effects have been observed following chronic administration of cannabidiol to healthy volunteers Cunha et al. Hence in spite of its potential use in treating glaucoma and seizures, cannabidiol has not been considered a neuroprotective agent that could be used to prevent glutamate induced damage in the central nervous system.

    It is an object of this invention to provide a new class of antioxidant drugs, that have particular application as neuroprotectants, although they are generally useful in the treatment of many oxidation associated diseases. Yet another object of the invention is to provide a subset of such drugs that can be substantially free of psychoactive or psychotoxic effects, are substantially non-toxic even at very high doses, and have good tissue penetration, for example crossing the blood brain barrier.

    It has surprisingly been found that cannabidiol and other cannabinoids can function as neuroprotectants, even though they lack NMDA receptor antagonist activity. This discovery was made possible because of the inventor's recognition of a previously unanticipated antioxidant property of the cannabinoids in general and cannabidiol in particular that functions completely independently of antagonism at the NMDA, AMPA and kainate receptors.

    Hence the present invention includes methods of preventing or treating diseases caused by oxidative stress, such as neuronal hypoxia, by administering a prophylactic or therapeutically effective amount of a cannabinoid to a subject who has a disease caused by oxidative stress. The cannabinoid may be a cannabinoid other than THC, HU, or other potent cannabinoid receptor agonists. The cannabinoid may also be other than HU or any other NMDA receptor antagonist that has previously been reported.

    A potent cannabinoid receptor agonist is one that has an EC 50 at the cannabinoid receptor of 50 nM or less, but in more particular embodiments nM or nM or less. In disclosed embodiments the cannabinoid is not psychoactive, and is not psychotoxic even at high doses. In some particularly disclosed embodiments, the cannabinoid is selected from the group: In other embodiments, the cannabinoid is one of the following: The C ring is aromatic, and the B ring can be a pyran.

    Particular embodiments are dibenzo pyrans and cyclohexenyl benzenediols. This high lipid solubility enhances penetration of the drug into the CNS, as reflected by its volume of distribution V d of 1.

    Particular embodiments may also be highly water soluble derivatives that are able to penetrate the CNS, for example carboxyl derivatives. R are independently selected from the group of H, substituted or unsubstituted alkyl, especially lower alkyl, for example unsubstituted C 1 -C 3 alkyl, hydroxyl, alkoxy, especially lower alkoxy such as methoxy or ethoxy, substituted or unsubstituted alcohol, and unsubstituted or substituted carboxyl, for example COOH or COCH 3.

    In other embodiments R can also be substituted or unsubstituted amino, and halogen. In other particular embodiments, the cannabinoids are one of the following: In yet other embodiments of the invention, the cannabinoids are. Particular examples of nonpsychoactive cannabinoids that fall within this definition are cannabidiol and. In more particular embodiments, the cannabinoid is used to prevent or treat an ischemic or neurodegenerative disease in the central nervous system of a subject, by administering to the subject a therapeutically effective amount of a cannabinoid to protect against oxidative injury to the central nervous system.

    The cannabinoid may be any of the compounds set forth above, or more specifically. The invention also includes an assay for selecting a cannabinoid to use in treating a neurological disease by determining whether the cannabinoid is an antioxidant. Once it has been determined that the cannabinoid is an antioxidant, an antioxidant effective amount of the cannabinoid is administered to treat the neurological disease, such as a vascular ischemic event in the central nervous system, for example the type caused by a neurovascular thromboembolism.

    Similarly, the method of the present invention includes determining whether a disease is caused by oxidative stress, and if the disease is caused by oxidative stress, administering the cannabinoid in a therapeutically effective antioxidant amount. The invention also includes identifying and administering antioxidant and neuroprotective compounds such as cannabidiol which selectively inhibit the enzyme activity of both 5- and lipoxygenase more than the enzyme activity of lipoxygenase.

    In addition, such compounds posses low NMDA antagonist activity and low cannabinoid receptor activity. Assays for selecting compounds with the desired effect on lipoxygenase enzymes, and methods for using identified compounds to treat neurological or ischemic diseases are also provided.

    Such diseases may include a vascular ischemic event in the central nervous system, for example a thromboembolism in the brain, or a vascular ischemic event in the myocardium. Useful administration of the compounds involves administration both during and after an ischemic injury.

    These and other objects of the invention will be understood more clearly by reference to the following detailed description and drawings. The voltage at which initial peaks occur is an indication of antioxidant activity. This invention provides antioxidant compounds and compositions, such as pharmaceutical compositions, that include cannabinoids that act as free radical scavengers for use in prophylaxis and treatment of disease.

    The invention also includes methods for using the antioxidants in prevention and treatment of pathological conditions such as ischemia tissue hypoxia , and in subjects who have been exposed to oxidant inducing agents such as cancer chemotherapy, toxins, radiation, or other sources of oxidative stress. The compositions and methods described herein are also used for preventing oxidative damage in transplanted organs, for inhibiting reoxygenation injury following reperfusion of ischemic tissues for example in heart disease , and for any other condition that is mediated by oxidative or free radical mechanisms of injury.

    In particular embodiments of the invention, the compounds and compositions are used in the treatment of ischemic cardiovascular and neurovascular conditions, and neurodegenerative diseases.

    However the present invention can also be used as an antioxidant treatment in non-neurological diseases. Molecular oxygen is essential for aerobic organisms, where it participates in many biochemical reactions, including its role as the terminal electron acceptor in oxidative phosphorylation.

    However excessive concentrations of various forms of reactive oxygen species and other free radicals can have serious adverse biological consequences, including the peroxidation of membrane lipids, hydroxylation of nucleic acid bases, and the oxidation of sulfhydryl groups and other protein moieties.

    Biological antioxidants include tocopherols and tocotrieneols, carotenoids, quinones, bilirubin, ascorbic acid, uric acid, and metal binding proteins. However these endogenous antioxidant systems are often overwhelmed by pathological processes that allow permanent oxidative damage to occur to tissue. Free radicals are atoms, ions or molecules that contain an unpaired electron, are usually unstable, and exhibit short half-lives.

    Reactive oxygen species ROS is a collective term, designating the oxygen radicals e. The hydroxyl radical sets off chain reactions and can interact with nucleic acids. Increased production of these poisonous metabolites in certain pathological conditions is believed to cause cellular damage through the action of the highly reactive molecules on proteins, lipids and DNA. In particular, ROS are believed to accumulate when tissues are subjected to ischemia, particularly when followed by reperfusion.

    It is evident to those of skill in the art that most pathological conditions are multifactorial, and that assigning or identifying the predominant causal factors for any particular condition is frequently difficult. Oxidative associated diseases include, without limitation, free radical associated diseases, such as ischemia, ischemic reperfusion injury, inflammatory diseases, systemic lupus erythematosis, myocardial ischemia or infarction, cerebrovascular accidents such as a thromboembolic or hemorrhagic stroke that can lead to ischemia or an infarct in the brain, operative ischemia, traumatic hemorrhage for example a hypovolemic stroke that can lead to CNS hypoxia or anoxia , spinal cord trauma, Down's syndrome, Crohn's disease, autoimmune diseases e.

    The present invention is believed to be particularly beneficial in the treatment of oxidative associated diseases of the CNS, because of the ability of the cannabinoids to cross the blood brain barrier and exert their antioxidant effects in the brain. In particular embodiments, the pharmaceutical composition of the present invention is used for preventing, arresting, or treating neurological damage in Parkinson's disease, Alzheimer's disease and HIV dementia; autoimmune neurodegeneration of the type that can occur in encephalitis, and hypoxic or anoxic neuronal damage that can result from apnea, respiratory arrest or cardiac arrest, and anoxia caused by drowning, brain surgery or trauma such as concussion or spinal cord shock.

    Antioxidants can act by scavenging biologically important reactive free radicals or other reactive oxygen species. OH, HOCl, ferryl, peroxyl, peroxynitrite, and alkoxyl , or by preventing their formation, or by catalytically converting the free radical or other reactive oxygen species to a less reactive species.

    Relative antioxidant activity can be measured by cyclic voltametry studies of the type disclosed in Example 5 and FIG.

    The voltage at which the first peak occurs is an indication of the voltage at which an electron is donated, which in turn is an index of antioxidant activity. Since oxidative damage is generally cumulative, there is no minimum threshold level or dose with respect to efficacy. However, minimum doses for producing a detectable therapeutic or prophylactic effect for particular disease states can be established.

    Cannabinoids also include compounds that have a characteristic dibenzopyran ring structure of the type seen in THC and cannabinoids which do not possess a pyran ring such as cannabidiol. Many other cannabinoids are similarly disclosed in Agurell et al. Psychoactivity is not meant to include non-cannabinoid receptor mediated effects such as the anxiolytic effect of CBD. In the presence of a sufficient concentration of antagonist, an agonist cannot activate its receptor.

    When the receptor is activated for a longer than normal period of time, this may cause neurotoxicity, as in the case of NMDA, AMPA and kainate receptors see Examples 3 and 4. This term is further exemplified by groups such as methyl, ethyl, n-propyl, isobutyl, t-butyl, pentyl, pivalyl, heptyl, adamantyl, and cyclopentyl.

    Alkyl groups can either be unsubstituted or substituted with one or more substituents, e. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl or 2-methylpropyl , cyclopropylmethyl, i-amyl, n-amyl, hexyl and heptyl.

    Lower alkyl groups can also be unsubstituted or substituted, where a specific example of a substituted alkyl is 1,1-dimethyl heptyl. An alcohol may be either linear or branched, such as isopropyl alcohol. In an unsubstituted alkoxy, the R is an unsubstituted alkyl. Arylalkoxys are a subset of substituted alkoxys. Examples of useful substituted alkoxy groups are: A particular aryloxy group is phenoxy.

    HetAr is a heteroaryl group, and R is a straight-chain or branched chain aliphatic group. Example of arylaklyl groups include benzyl and furfuryl. Arylalkyl groups can optionally be unsubstituted or substituted with, e. A particular amino group is —NH 2. The following examples show that both nonpsychoactive cannabidiol, and psychoactive cannabinoids such as THC, can protect neurons from glutamate induced death, by a mechanism independent of cannabinoid receptors. Cannabinoids are also be shown to be potent antioxidants capable of preventing ROS toxicity in neurons.

    Dihydrorhodamine was supplied by Molecular Probes Eugene, Oreg. T-butyl hydroperoxide, tetraethylammonium chloride, ferric citrate and sodium dithionite were all purchased from Aldrich WI. Solutions of cannabinoids, cyclothiazide and other lipophiles were prepared by evaporating a 10 mM ethanolic solution under a stream of nitrogen in a siliconized microcentrifuge tube. Dimethyl sulfoxide DMSO, less than 0. After evaporation, 1 ml of culture media was added and the drug was dispersed using a high power sonic probe.

    Cannabidiol reduces ab-induced neuroinflammation and promotes hippocampal neurogenesis through PPARc involvement. Prospects for cannabinoid therapies in basal ganglia disorders. The effect of cannabis on urge incontinence in patients with multiple sclerosis: Role of endogenous cannabinoids in synaptic signaling. Friedman D, Devinsky O. Cannabinoids in the treatment of epilepsy.

    Gaoni Y, Mechoulam R. Isolation structure and partial synthesis of an active constituent of hashish. J Am Chem Soc. Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson's disease: Importance of antioxidant and cannabinoid receptor-independent properties.

    Cannabinoid receptors in the human brain: Gloss D, Vickrey B. Cochrane Database Syst Rev. The multiplicity of action of cannabinoids: Implications for treating neurodegeneration.

    Grinspoon L, Bakalar JB. The use of cannabis as a mood stabilizer in bipolar disorder: Anecdotal evidence and the need for clinical research. Guo J, Ikeda SR. Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons. A unified critical inventory. Hermann D, Schneider M. Potential protective effects of cannabidiol on neuroanatomical alterations in cannabis users and psychosis: Phytocannabinoids as novel therapeutic agents in CNS disorders.

    Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: Endocannabinoids and vascular function. J Pharmacol Exp Ther. International Union of Pharmacology.

    Classification of cannabinoid receptors. A review of the evidence for efficacy of complementary and alternative medicines in MS. Potential for the treatment of neuronal hyperexcitability. Iffland K, Grotenhermen F. Safety and Side Effects of Cannabidiol— A review of clinical data and relevant animal studies. Meta-analysis of cannabis based treatments for neuropathic and multiple sclerosis-related pain.

    Curr Med Res Opin. A promising drug for neurodegenerative disorders? Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. A typical responsiveness of the orphan receptor GPR55 to cannabinoid ligands.

    Prolonged CNS hyperexcitability in mice after a single exposure to deltatetrahydrocannabinol. Kim D, Thayer SA. Efficacy and safety of medical marijuana in selected neurologic disorders, Report of the Guideline Development Subcommittee of the American Academy of Neurology.

    Dopamine modulation of state-dependent endocannabinoid release and long-term depression in the striatum. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. From phytocannabinoids to cannabinoid receptors and endocannabinoids: Pleiotropic physiological and pathological roles through complex pharmacology.

    Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. An endocannabinoid tone limits excitotoxicity in vitro and in a model of multiple sclerosis.

    Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cell Mol Life Sci. Cannabidiol induces intracellular calcium elevation and cytotoxicity in oligodendrocytes.

    Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis. Breast Cancer Res Treat. Handbook of Cannabis and Related Pathologies. Cannabidiol protects oligodendrocyte progenitor cells from inflammation-induced apoptosis by attenuating endoplasmic reticulum stress.

    Stereospecific synthesis of - -delta 1- and - -delta 1 6 -tetrahydrocannabinols. The structure of cannabidiol. Insights into pathophysiology and therapy from a mouse model of Dravet syndrome. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Emerging strategies for exploiting cannabinoid receptor agonists as medicines. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Immunohistochemical localization of the neural cannabinoid receptor in rat brain.

    Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: Actions on signals involved in angiogenesis and metastasis. Cannabinoid facilitation of fear extinction memory recall in humans. Prevention of Alzheimer's disease pathology by cannabinoids: Neuroprotection mediated by blockade of microglial activation. Supraspinal modulation of pain by cannabinoids: The role of GABA and glutamate. An uncontrolled, open-label, 2-year extension trial. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis.

    Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with untreated newly diagnosed temporal lobe epilepsy.

    Ronesi J, Lovinger DM. Induction of striatal long-term synaptic depression by moderate frequency activation of cortical afferents in rat. Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: Relevance for Huntington's disease.

    Cannabidiol reduced the striatal atrophy caused 3-nitropropionic acid in vivo by mechanisms independent of the activation of cannabinoid, vanilloid TRPV1 and adenosine A2A receptors. TRB3 links ER stress to autophagy in cannabinoid anti-tumoral action. Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. Delta 9 - tetrahydrocannabinol-induced catalepsy-like immobilization is mediated by decreased 5-HT neurotransmission in the nucleus accumbens due to the action of glutamate-containing neurons.

    Hallucinogens of Plant Origin. A promising impact for traumatic brain injury. Therapeutic modalities for treatment resistant depression: Focus on vagal nerve stimulation and ketamine.

    Endocannabinoids and traumatic brain injury. Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma. Cannabidiol inhibits angiogenesis by multiple mechanisms. Delta 9 -tetrahydrocannabinol alone and combined with cannabidiol mitigate fear memory through reconsolidation disruption. On disruption of fear memory by reconsolidation blockade: Evidence from cannabidiol treatment.

    Sativex-like combination of phytocannabinoids is neuroprotective in malonate-lesioned rats, an inflammatory model of Huntington's disease: Role of CB1 and CB2 receptors. Endocannabinoids and beta-amyloid-induced neurotoxicity in vivo: Effect of pharmacological elevation of endocannabinoid levels. Effect of cannabinoids on platelet serotonin uptake. Guidelines for prescribing medical marijuana. The world anti-doping code international standard prohibited list. Jan, [Last accessed on Jan 29].

    Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on patients. Deltatetrahydrocannabinol for nighttime agitation in severe dementia. Maternal separation produces alterations of forebrain brain-derived neurotrophic factor expression in differently aged rats. Depression and anxiety are co-morbid but dissociable in mild Parkinson's disease: A prospective longitudinal study of patterns and predictors.

    Cannabis in the Management and Treatment of Seizures and Epilepsy: A Scientific Review Pre-publication release for public domain dissemination. Endogenous cannabinoids mediate retrograde signaling at hippocampal synapses. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis CAMS study: Multicentre randomised placebo-controlled trial.

    Cannabinoids in multiple sclerosis CAMS study: Safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry. Brain-derived neurotrophic factor serum levels in heroin-dependent patients after 26 weeks of withdrawal. The similar antiox idant abilities of canna-. The antiox idative properties of cannabinoids suggest a.

    A lthough cannabidiol was similar in neuropro-. The lack of psycho-. Further more, the abilit y of can-. NMDAr may reduce the oc currence of tox icit y or side effects. In vivo studies to examine the ef ficac y of. A The ef fect of cannabidiol on ox idative tox icit y in neuronal cultures.

    Ter t -butyl hydroperox ide-induced tox icit y was examined in the. B Comparison of antiox idants and cannabidiol for their abilit y to prevent glutamate tox icit y in neurons. M were examined in a model of A MPA y k ainate receptor-dependent tox icit y.

    Each experiment represents the mean of four replicate s repeated on three oc casions. See Mater ials and Methods for further ex periment al det ails.

    Sign ificant dif ferences bet ween cannabidiol and other antiox idants are indicated w ith. M, Leonoudak is, D. Ventra, C, Porcellini, A. Van Bockst aele, E. N Psychophar macol. Within this complex framework, CBD exhibits positive effects in situations in which glutamatergic signaling, particularly that mediated by N-methyl-D-aspartate acid receptor NMDAR , plays a critical role. Thus, CBD ex- hibits antioxidant properties and protects neurons from glutamate-induced death but without cannabinoid receptor activation or NMDAR antagonism [13].

    CBD diminishes the neural damage caused by ischemic stroke [14] and chronic diseases, including Parkinson's and Alzheimer's dis- eases [15][16][17]. Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor. Cannabidiol CBD , the major non-psychotomimetic compound present in the Cannabis sativa plant, exhibits therapeutic potential for various human diseases, including chronic neurodegenerative diseases, such as Alzheimer's and Parkinson's, ischemic stroke, epilepsy and other convulsive syndromes, neuropsychiatric disorders, neuropathic allodynia and certain types of cancer.

    CBD does not bind directly to endocannabinoid receptors 1 and 2, and despite research efforts, its specific targets remain to be fully identified. The in vivo administration of CBD or BD enhanced morphine-evoked supraspinal antinociception, alleviated NMDA-induced convulsive syndrome, and reduced the infarct size caused by permanent unilateral middle cerebral artery occlusion. Neuroprotective Properties of CBD CBD shows neuroprotective properties following different insults in animal models involving neurodegeneration, mainly due to its antioxidant [88, 89], antiapoptotic [90,91], and anti-inflammatory properties [92][93][94].

    In a rat model of Parkinson's disease, CBD provided neuroprotection against the progressive degeneration of nigrostriatal dopaminergic neurons [89,95]. Cannabidiol and Cannabis Use Disorder. Cannabis use disorders CUD represent a serious public health problem in occidental societies. Despite their devastating social, health, and economic impact, to date no pharmacological treatment has been approved for the clinical management of cannabis dependence.

    Haloperidol, however, increased lipid peroxidation and iNOS mRNA expression and reduced catalase activity in the striatum. CBD, despite its well-described antioxidant effects Hampson et al. However, it attenuated the increase in iNOS mRNA expression and the reduction of catalase activity promoted by haloperidol. The chronic use of drugs that reduce the dopaminergic neurotransmission can cause a hyperkinetic movement disorder called tardive dyskinesia TD.

    The pathophysiology of this disorder is not entirely understood but could involve oxidative and neuroinflammatory mechanisms. Cannabidiol CBD , the major non-psychotomimetic compound present in Cannabis sativa plant, could be a possible therapeutic alternative for TD. This phytocannabinoid shows antioxidant, anti-inflammatory and antipsychotic properties and decreases the acute motor effects of classical antipsychotics.

    The present study investigated if CBD would attenuate orofacial dyskinesia, oxidative stress and inflammatory changes induced by chronic administration of haloperidol in mice. The results showed that the male Swiss mice treated daily for 21 days with haloperidol develop orofacial dyskinesia. Daily CBD administration before each haloperidol injection prevented this effect. Mice treated with haloperidol showed an increase in microglial activation and inflammatory mediators in the striatum.

    These changes were also reduced by CBD. On the other hand, the levels of the anti-inflammatory cytokine IL increased in the striatum of animals that received CBD and haloperidol. Regarding oxidative stress, haloperidol induced lipid peroxidation and reduced catalase activity. This latter effect was attenuated by CBD. Evidence indicates that CBD has antioxidant, antiapoptotic, and neuroprotective properties [24] [25][26][27][28] reviewed in ref.

    Our previous studies showed that CBD is able to improve iron- induced memory deficits 10 and regulate markers of synaptic viability and mitochondrial dynamics in the hippocampus of iron-overloaded rats Antiapoptotic effects of cannabidiol in an experimental model of cognitive decline induced by brain iron overload.

    Iron accumulation in the brain has been recognized as a common feature of both normal aging and neurodegenerative diseases. Cognitive dysfunction has been associated to iron excess in brain regions in humans. We have previously described that iron overload leads to severe memory deficits, including spatial, recognition, and emotional memory impairments in adult rats. In the present study we investigated the effects of neonatal iron overload on proteins involved in apoptotic pathways, such as Caspase 8, Caspase 9, Caspase 3, Cytochrome c, APAF1, and PARP in the hippocampus of adult rats, in an attempt to establish a causative role of iron excess on cell death in the nervous system, leading to memory dysfunction.

    Cannabidiol CBD , the main non-psychotropic component of Cannabis sativa, was examined as a potential drug to reverse iron-induced effects on the parameters analyzed.

    These results suggest that iron can trigger cell death pathways by inducing intrinsic apoptotic proteins. The reversal of iron-induced effects by CBD indicates that it has neuroprotective potential through its anti-apoptotic action. Stilbenoids and cannabinoids from the leaves of Cannabis sativa f. Three new stilbenoids , and 16 known stilbenoids and cannabinoids were isolated from the leaves of Hemp Cannabis sativa L. These isolated compounds exhibited cytotoxic effects on human cancer cells via inhibiting cancer cells proliferation and inducing cell death.

    Among them, compound 4, 5, 10, 12, 13, 15, and 19 displayed broad-spectrum cytotoxicity, and 1, 7, and 11 displayed selectivity in inhibition efficiency on MCF-7 and A cells, which suppressed significantly cancer cells proliferation by inducing cell death. Their effects of compounds on improving reverse cholesterol transport RCT were evaluated by isotope-tracing and western blotting. Results showed that the three stilbenoids showed cytotoxicity above 1.

    They could improve [3H]-cholesterol efflux from Raw The three stilbenoids could also significantly improve the protein expressin of ABCA1. However, they showed no significant effect on PCSK9. The above results indicated that these stilbenoids may elevate the transfer of cholesterol to hepatocytes by improving proteins expression of SR-B1 and LDLR, and the synthesis of bile acid by increasing protein expression of CYP7A1.

    In conclusion, HM1 showed lower cytotoxicity and higher activity on improving RCT-related proteins expression. Our study suggests that It may be explored as a novel lipid-lowering drug and as beneficial ingredient in health functional foods and pharmaceuticals. Oct Practical Neurol. Click here to listen to the Podcast The one-third of people who do not gain seizure control through current treatment options need a revolution in epilepsy therapeutics. The general population appears to be showing a fundamental and rapid shift in its opinion regarding cannabis and cannabis-related drugs.

    It is quite possible that cannabidiol, licensed in the USA for treating rare genetic epilepsies, may open the door for the widespread legalisation of recreational cannabis. It is important that neurologists understand the difference between artisanal cannabidiol products available legally on the high street and the cannabidiol medications that have strong trial evidence. In the UK in there are multiple high-profile reports of the response of children taking cannabis-derived medication, meaning that neurologists are commonly asked questions about these treatments in clinic.

    We address what an adult neurologist needs to know now, ahead of the likely licensing of Epidiolex in the UK in Cannabis Therapeutics and the Future of Neurology. Neurological therapeutics have been hampered by its inability to advance beyond symptomatic treatment of neurodegenerative disorders into the realm of actual palliation, arrest or reversal of the attendant pathological processes.

    While cannabis-based medicines have demonstrated safety, efficacy and consistency sufficient for regulatory approval in spasticity in multiple sclerosis MS , and in Dravet and Lennox-Gastaut Syndromes LGS , many therapeutic challenges remain. This review will examine the intriguing promise that recent discoveries regarding cannabis-based medicines offer to neurological therapeutics by incorporating the neutral phytocannabinoids tetrahydrocannabinol THC , cannabidiol CBD , their acidic precursors, tetrahydrocannabinolic acid THCA and cannabidiolic acid CBDA , and cannabis terpenoids in the putative treatment of five syndromes, currently labeled recalcitrant to therapeutic success, and wherein improved pharmacological intervention is required: The inherent polypharmaceutical properties of cannabis botanicals offer distinct advantages over the current single-target pharmaceutical model and portend to revolutionize neurological treatment into a new reality of effective interventional and even preventative treatment.

    Toward a New Age. Among the many cannabinoids in the cannabis plant, cannabidiol CBD is a compound that does not produce the typical subjective effects of marijuana. The aim of the present review is to describe the main advances in the development of the experimental and clinical use of cannabidiol CBD in neuropsychiatry.

    A non-systematic search was performed for studies dealing with therapeutic applications of CBD, especially performed by Brazilian researchers. CBD was shown to have anxiolytic, antipsychotic and neuroprotective properties.

    In addition, basic and clinical investigations on the effects of CBD have been carried out in the context of many other health conditions, including its potential use in epilepsy, substance abuse and dependence, schizophrenia, social phobia, post-traumatic stress, depression, bipolar disorder, sleep disorders, and Parkinson. CBD is an useful and promising molecule that may help patients with a number of clinical conditions.

    Controlled clinical trials with different neuropsychiatric populations that are currently under investigation should bring important answers in the near future and support the translation of research findings to clinical settings.

    There are many cannabis strains that vary widely in the composition of cannabinoids, terpenes, flavonoids, and other compounds. These components work synergistically to produce wide variations in benefits, side effects, and strain characteristics.

    Knowledge of the individual medicinal properties of the cannabinoids, terpenes, and flavonoids is necessary to cross-breed strains to obtain optimal standardized synergistic compositions. Review the medical literature involving major and minor cannabinoids, primary and secondary terpenes, and flavonoids that underlie the synergistic entourage effects of cannabis.

    Summarize the individual medicinal benefits of these substances, including analgesic and anti-inflammatory properties. There is also supporting evidence that cannabis may assist in opioid detoxification and weaning, thus making it a potential weapon in battling the opioid epidemic. Cannabis science is a rapidly evolving medical sector and industry with increasingly regulated production standards.

    Further research is anticipated to optimize breeding of strain-specific synergistic ratios of cannabinoids, terpenes, and other phytochemicals for predictable user effects, characteristics, and improved symptom and diseasetargeted therapies.

    Cannabidiol CBD exhibits neuroprotective properties in many experimental systems. However, development of CBD as a drug has been confounded by the following: The design strategy for KLS was to increase hydrophilicity while optimizing neuroprotective potency against oxidative stress toxicity relevant to hepatic encephalopathy. The protective responses of CBD and KLS were compared in dissociated rat hippocampal cultures co-treated with toxic levels of ethanol and ammonium acetate.

    This comparison revealed that KLS was fold more potent than CBD in preventing neuronal toxicity from the combined toxin treatment, while both compounds exhibited complete protective efficacy back to control values. Both compounds can act through mNCX. KLS may provide an alternative to CBD as a therapeutic candidate to treat diseases associated with oxidative stress. Jul J Neurochem. In this study we analyzed the involvement of the cyclic AMP cAMP -protein kinase A system in the regulation of interleukin 6 production by cultured cortical astrocytes.

    Vasoactive intestinal peptide strongly increased, in a dose-dependent manner, interleukin 6 production. This effect was reduced when protein kinase A was blocked by KT; it was not affected by calphostin C, a protein kinase C inhibitor.

    Forskolin caused a concentration-dependent increase in interleukin 6 release that was also inhibited by KT Because prostaglandins are believed to play a role in interleukin 6 production, we tried to determine whether the stimulatory effects of vasoactive intestinal peptide and forskolin on cytokine release might be mediated by stimulation of prostaglandin production in cortical astrocytes.

    Conversely, forskolin concentration-dependently stimulated the production of both prostaglandins, an effect that was blocked by indomethacin. Indomethacin did not affect either vasoactive intestinal peptide- or forskolin-stimulated interleukin 6 production. In conclusion, we provide evidence that vasoactive intestinal peptide increases interleukin 6 production by astrocytes through the stimulation of the cAMP-protein kinase A pathway, an effect that is reproduced by cAMP analogues.

    In addition, we point out that prostaglandins are not involved in vasoactive intestinal peptide- and forskolin-mediated induction of interleukin 6 production in cultured astrocytes. Inhibition of free radical production or free radical scavenging protects from the excitotoxic cell death mediated by glutamate in cultures of cerebellar granule neurons. Glutamate kills sensitive neurons through several steps downstream to receptor activation: Inhibition of nitric oxide synthase NOS and phospholipase A2 PLA2 were effective in decreasing cell death and the combined treatments showed some degree of additivity.

    By contrast, inhibition of xanthine oxidase XO with allopurinol was uneffective. A synergistic effect was demonstrated by the combination of vitamin E and C. On the other hand, antioxidants did not increase the protection granted by enzyme inhibitors, suggesting that they act downstream to NOS and PLA2. Finally, a moderate protection was obtained by blocking protein synthesis with cycloheximide, suggesting a partial contribution of apoptotic mechanisms to the excitotoxic cell death.

    Qualitative and quantitative assessments of cell survival have indicated that: These findings suggest that HU holds a unique position among putative neuroprotectant agents in that it combines NMDA receptor antagonistic activity and free radical scavenging abilities in a single molecule.

    Antinociceptive activity of intrathecally administered cannabinoids alone, and in combination with morphine, in mice. The antinociceptive effects of various cannabinoids, alone and in combination with opiates, were evaluated in antinociceptive tests in mice. The cannabinoids tested produce marked antinociceptive effects after i. Respective ED50 values in the tail-flick test were 0.

    US6630507B1 - Cannabinoids as antioxidants and neuroprotectants - Google Patents

    Additional ingredients may be added to further adjust properties such as color, Furthermore, CBD is known to be a reasonably potent antioxidant, which This means that enriching a natural hemp extract with pure (often synthetic) .. and (–) Δ9-tetrahydrocannabinol are neuroprotective antioxidants. And furthermore, CBD was non-psychoactive, meaning that it doesn't get you high. Unlike THC, CBD is unique in that it has a wide range of effects on many of the body's most important Neuroprotective and Antioxidant Effects . disease: importance of antioxidant and cannabinoid receptor-independent properties. CBD, otherwise known as Cannabidiol, is one of the less CBD is completely non-psychoactive, meaning it will not make you feel “stoned” or “high. a ton of antioxidant and neuroprotective properties, which opens the.



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