The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome.
In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period.
The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence interval [CI], −41.1 to −5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient’s overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.
Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375.)”
“The high and increasing prevalence of medical marijuana consumption in the general population invites the need for quality evidence regarding its safety and efficacy. Herein, we synthesize extant literature pertaining to the phytocannabinoid cannabidiol (CBD) and its brain effects.
The principle phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) and CBD are the major pharmacologically active cannabinoids. The effect of CBD on brain systems as well as on phenomenological measures (e.g. cognitive function) are distinct and in many cases opposite to that of Δ9-THC.
Cannabidiol is without euphoriant properties, and exerts antipsychotic, anxiolytic, anti-seizure, as well as anti-inflammatory properties.
It is essential to parcellate phytocannabinoids into their constituent moieties as the most abundant cannabinoid have differential effects on physiologic systems in psychopathology measures. Disparate findings and reports related to effects of cannabis consumption reflect differential relative concentration of Δ9-THC and CBD.
Existing literature, notwithstanding its deficiencies, provides empirical support for the hypothesis that CBD may exert beneficial effects on brain effector systems/substrates subserving domain-based phenomenology. Interventional studies with purified CBD are warranted with a call to target-engagement proof-of-principle studies using the research domain criteria (RDoC) framework.” https://www.ncbi.nlm.nih.gov/pubmed/28501518
“Cannabidiol (CBD) is a cannabinoid component of marijuana that has no significant activity at cannabinoid receptors or psychoactive effects. There is considerable interest in CBD as a therapy for epilepsy.
Almost a third of epilepsy patients are not adequately controlled by clinically available anti-seizure drugs (ASDs). Initial studies appear to demonstrate that CBD preparations may be a useful treatment for pharmacoresistant epilepsy.
The National Institute of Neurological Disorders and Stroke (NINDS) funded Epilepsy Therapy Screening Program (ETSP) investigated CBD in a battery of seizure models using a refocused screening protocol aimed at identifying pharmacotherapies to address the unmet need in pharmacoresistant epilepsy. Applying this new screening workflow, CBD was investigated in mouse 6 Hz 44 mA, maximal electroshock (MES), corneal kindling models and rat MES and lamotrigine-resistant amygdala kindling models.
Following intraperitoneal (i.p.) pretreatment, CBD produced dose-dependent protection in the acute seizure models; mouse 6 Hz 44 mA (ED50 164 mg/kg), mouse MES (ED50 83.5 mg/kg) and rat MES (ED50 88.9 mg/kg). In chronic models, CBD produced dose-dependent protection in the corneal kindled mouse (ED50 119 mg/kg) but CBD (up to 300 mg/kg) was not protective in the lamotrigine-resistant amygdala kindled rat. Motor impairment assessed in conjunction with the acute seizure models showed that CBD exerted seizure protection at non-impairing doses.
The ETSP investigation demonstrates that CBD exhibits anti-seizure properties in acute seizure models and the corneal kindled mouse. However, further preclinical and clinical studies are needed to determine the potential for CBD to address the unmet needs in pharmacoresistant epilepsy.” https://www.ncbi.nlm.nih.gov/pubmed/28478594
“Cannabidiol (CBD) is a cannabinoid component from Cannabis sativa that does not induce psychotomimetic effects and possess anti-inflammatory properties. In the present study we tested the effects of CBD in a periodontitis experimental model in rats. Morphometrical analysis of alveolar bone loss demonstrated that CBD-treated animals presented a decreased alveolar bone loss. These results indicate that CBD may be useful to control bone resorption during progression of experimental periodontitis in rats.” https://www.ncbi.nlm.nih.gov/pubmed/19070683
“The balance between detrimental, pro-aging, often stochastic processes and counteracting homeostatic mechanisms largely determines the progression of aging. There is substantial evidence suggesting that the endocannabinoid system (ECS) is part of the latter system because it modulates the physiological processes underlying aging.
The activity of the ECS declines during aging, as CB1 receptor expression and coupling to G proteins are reduced in the brain tissues of older animals and the levels of the major endocannabinoid 2-arachidonoylglycerol (2-AG) are lower. However, a direct link between endocannabinoid tone and aging symptoms has not been demonstrated.
Here we show that a low dose of Δ9-tetrahydrocannabinol (THC) reversed the age-related decline in cognitive performance of mice aged 12 and 18 months. This behavioral effect was accompanied by enhanced expression of synaptic marker proteins and increased hippocampal spine density.
THC treatment restored hippocampal gene transcription patterns such that the expression profiles of THC-treated mice aged 12 months closely resembled those of THC-free animals aged 2 months. The transcriptional effects of THC were critically dependent on glutamatergic CB1 receptors and histone acetylation, as their inhibition blocked the beneficial effects of THC.
Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat age-related cognitive impairments.”
“A double-blind study was performed comparing 5 mg delta-9-tetrahydrocannabinol (THC) p.o., 50 mg codeine p.o., and placebo in a patient with spasticity and pain due to spinal cord injury. The three conditions were applied 18 times each in a randomized and balanced order. Delta-9-THC and codeine both had an analgesic effect in comparison with placebo. Only delta-9-THC showed a significant beneficial effect on spasticity. In the dosage of THC used no altered consciousness occurred.”
“It has been suggested that the endocannabinoid system elicits neuroprotection against excitotoxic brain damage.
In the present study the therapeutic potential of AM 404 on ischaemia-induced neuronal injury was investigated in vivo and compared with that of the classical cannabinoid receptor type 1 (CB1) agonist, Δ9-tetraydrocannabinol (THC), using a model of transient global cerebral ischaemia in the gerbil.
Our findings demonstrate that AM 404 and THC reduce neuronal damage caused by bilateral carotid occlusion in gerbils and that this protection is mediated through an interaction with CB1 and opioid receptors.
Endocannabinoids might form the basis for the development of new neuroprotective drugs useful for the treatment of stroke and other neurodegenerative pathologies.
There is some evidence from experiments with mice that increasing anandamide or 2-arachidonoyl glycerol content may lead to neuroprotection.
Collectively, our data demonstrate that AM 404 and THC protect against neuronal ischaemia-induced injury through a mechanism involving cannabinoid and opioid receptors but not vanilloid receptors.”
“Extensive basic science research has identified the potential therapeutic benefits of active compounds extracted from the Cannabis sativa L. plant (the cannabinoids). It is recognized that a significant proportion of patients suffering with the debilitating symptoms of pain and spasticity in multiple sclerosis or other conditions smoke cannabis despite the legal implications and stigma associated with this controlled substance. GW Pharmaceuticals have developed Sativex (GW- 1000-02), a combined cannabinoid medicine that delivers and maintains therapeutic levels of two principal cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), via an oromucosal pump spray, that aims to minimize psychotropic side effects.” https://www.ncbi.nlm.nih.gov/pubmed/16969427
“Sativex has proved to be well tolerated and successfully self-administered and self-titrated in both healthy volunteers and patient cohorts. Clinical assessment of this combined cannabinoid medicine has demonstrated efficacy in patients with intractable pain (chronic neuropathic pain, pain due to brachial plexus nerve injury, allodynic peripheral neuropathic pain and advanced cancer pain), rheumatoid arthritis and multiple sclerosis (bladder problems, spasticity and central pain), with no significant intoxication-like symptoms, tolerance or withdrawal syndrome.” https://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summaryn_pr?p_JournalId=4&p_RefId=1021517
“Sativex(®) (nabiximols, USAN name) oromucosal spray contains the two main active constituents of Cannabis sativa, tetrahydrocannabinol and cannabidiol in a 1:1 molecular ratio, and acts as an endocannabinoid system modulator.” https://www.ncbi.nlm.nih.gov/pubmed/21449855
“Abuse potential and psychoactive effects of δ-9-tetrahydrocannabinol and cannabidiol oromucosal spray (Sativex), a new cannabinoid medicine. Evidence to date suggests that abuse or dependence on Sativex is likely to occur in only a very small proportion of recipients.” https://www.ncbi.nlm.nih.gov/pubmed/21542664