Cannabis as an anticonvulsant

BMJ Journals“There are records of the cannabis plant being used for medicinal purposes in ancient times, and in the 19th century it was used as an effective anti-epileptic drug (AED) in children.

However, because of its abuse potential, most countries imposed laws restricting its cultivation and use, and this has greatly inhibited research into possible therapeutic uses.

Things are now changing, and cannabis derivatives are now used legally to treat, for example, pain, nausea and spasticity.

The plant contains over 100 biologically active compounds, and recently it has been possible to isolate these and identify the neurochemical mechanisms by which some of them operate: one in particular, cannabidiol”

https://www.ncbi.nlm.nih.gov/pubmed/29449212

http://adc.bmj.com/content/early/2018/02/15/archdischild-2018-314921

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The Cannabinoids Δ8THC, CBD, and HU-308 Act via Distinct Receptors to Reduce Corneal Pain and Inflammation

Mary Ann Liebert, Inc. publishers

“Corneal injury can result in dysfunction of corneal nociceptive signaling and corneal sensitization.

Activation of the endocannabinoid system has been reported to be analgesic and anti-inflammatory.

The purpose of this research was to investigate the antinociceptive and anti-inflammatory effects of cannabinoids with reported actions at cannabinoid 1 (CB1R) and cannabinoid 2 (CB2R) receptors and/or noncannabinoid receptors in an experimental model of corneal hyperalgesia.

Topical cannabinoids reduce corneal hyperalgesia and inflammation.

The antinociceptive and anti-inflammatory effects of Δ8THC are mediated primarily via CB1R, whereas that of the cannabinoids CBD and HU-308, involve activation of 5-HT1A receptors and CB2Rs, respectively.

Cannabinoids could be a novel clinical therapy for corneal pain and inflammation resulting from ocular surface injury.”

https://www.ncbi.nlm.nih.gov/pubmed/29450258

http://online.liebertpub.com/doi/abs/10.1089/can.2017.0041

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Cannabis for paediatric epilepsy: challenges and conundrums.

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“Research is expanding for the use of cannabidiol as an anticonvulsant drug. The mechanism of cannabidiol in paediatric epilepsy is unclear but is thought to play a role in modulation of synaptic transmission. Evidence for its efficacy in treating epilepsy is limited but growing, with a single pharmaceutical company-funded randomised double-blind controlled trial in children with Dravet syndrome. Progress towards the use of medicinal cannabinoids incorporates a complex interplay of social influences and political and legal reform. Access to unregistered but available cannabidiol in Australia outside of clinical trials and compassionate access schemes is state dependent and will require Therapeutic Goods Administration approval, although the cost may be prohibitive. Further clinical trials are needed to clearly define efficacy and safety, particularly long term.”

https://www.ncbi.nlm.nih.gov/pubmed/29438649

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Plasma N-acylethanolamine and endocannabinoid levels in burning mouth syndrome: potential role in disease pathogenesis.

Journal of Oral Pathology & Medicine

“The objective was to measure endocannabinoid (eCB) ligands and non-cannabinoid N-acylethanolamine (NAE) molecules in plasma from individuals with burning mouth syndrome (BMS), and to determine if plasma eCB/NAE levels correlated with pain, inflammation and depressive symptomatology in this cohort.

RESULTS:

Plasma levels of PEA, but not OEA, AEA or 2-AG, were significantly elevated in patients with BMS, when compared to plasma from healthy individuals. Plasma PEA, OEA and AEA levels correlated with depressive symptomatology.

CONCLUSIONS:

This is the first evidence to indicate that circulating eCB/NAE levels are altered in BMS.”

https://www.ncbi.nlm.nih.gov/pubmed/29436743

http://onlinelibrary.wiley.com/doi/10.1111/jop.12692/abstract

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Role of the endocannabinoid system in the formation and development of depression.

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“Two types of cannabinoid (CB) receptors have been described in the human body: CB1 and CB2 receptors. CB1 receptor distribution may be related to the cannabinoid functions of memory and cognition regulation as well as motor control.

In addition, the endocannabinoid system (ECS) related to CB1 receptors may be involved in human emotion regulation, especially depression occurrence. Indeed, CB1 receptors are all distributed in depression associated neuroanatomical structures and neural circuits.

Both animal experiments and clinical studies have demonstrated that impairment of the ECS pathway is present in depression models and patients, and application of both CB1 receptor agonists and anandamide (cannabinoid-like substance) degradation inhibitors produce similar biochemical and behavioral effects as antidepressants.

These findings provide a solid basis for understanding the ECS role in the formation and development of depression. Therefore, it can be inferred that the ECS may have an important function in both depression treatment and the effects of antidepressants.”

https://www.ncbi.nlm.nih.gov/pubmed/29441900

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Cannabinoid-induced cell death in endometrial cancer cells: involvement of TRPV1 receptors in apoptosis.

Journal of Physiology and Biochemistry

“Among a variety of phytocannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most promising therapeutic compounds. Besides the well-known palliative effects in cancer patients, cannabinoids have been shown to inhibit in vitro growth of tumor cells.

Likewise, the major endocannabinoids (eCBs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), induce tumor cell death.

The purpose of the present study was to characterize cannabinoid elements and evaluate the effect of cannabinoids in endometrial cancer cell viability.

These data indicate that cannabinoids modulate endometrial cancer cell death.

Selective targeting of TPRV1 by AEA, CBD, or other stable analogues may be an attractive research area for the treatment of estrogen-dependent endometrial carcinoma.

Our data further support the evaluation of CBD and CBD-rich extracts for the potential treatment of endometrial cancer, particularly, that has become non-responsive to common therapies.”

https://www.ncbi.nlm.nih.gov/pubmed/29441458

https://link.springer.com/article/10.1007%2Fs13105-018-0611-7

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Learning and Memory is Modulated by Cannabidiol When Administered During Trace Fear-Conditioning.

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“Cannabidiol (CBD) is thought to have therapeutic potential for treating psychiatric conditions that affect cognitive aspects of learning and memory, including anxiety and post-traumatic stress disorder (PTSD).

Studies have shown that CBD enhances extinction of fear memory when given after conditioning. This led us to hypothesize that CBD, if administered prior to fear conditioning, might modulate cognitive learning and memory processes in additional ways that would further guide its potential use for treating PTSD.

Therefore, we designed a study to investigate effects of CBD on fear learning and memory when administered to mice prior to administering a trace fear conditioning protocol which imposes cognitive demands on the learning and memory process.

Overall, the memory-modulating effects of a single pre-conditioning dose of CBD, which we show here, demonstrate the need to more fully characterize its basic effects on memory, suggest caution when using it clinically as an anxiolytic, and point to a need for more research into its potential as a therapeutic for treating memory-loss disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/29432803

https://www.sciencedirect.com/science/article/pii/S1074742718300224

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Efficacy of artisanal preparations of cannabidiol for the treatment of epilepsy: Practical experiences in a tertiary medical center.

“Medically refractory epilepsy continues to be a challenge worldwide, and despite an increasing number of medical therapies, approximately 1 in 3 patients continues to have seizures.

Cannabidiol (CBD), one of many constituents of the Cannabis sativa or marijuana plant, has received renewed interest in the treatment of epilepsy. While highly purified CBD awaits Food and Drug Administration (FDA) approval, artisanal formulations of CBD are readily available and are seeing increased use in our patient population.

Although randomized controlled trials of CBD are ongoing and promising, data regarding artisanal formulations of CBD are minimal and largely anecdotal. Here, we report a retrospective study to define the efficacy of artisanal CBD preparations in children with epilepsy.

Given the known interaction between CBD and clobazam, we also conducted a subgroup comparison to determine if clobazam use was related to any beneficial effects of CBD. Additionally, we compared response rates with CBD and with clobazam alone within an overlapping patient cohort. A pediatric cohort with epilepsy of 108 patients was identified through a medical record search for patients using CBD oil.

The addition of CBD resulted in 39% of patients having a >50% reduction in seizures, with 10% becoming seizure-free. The responder rate for clobazam was similar. No patients achieved CBD monotherapy, although the weaning of other antiepileptic drugs (AEDs) became possible in 22% of patients. A comparable proportion had AED additions during CBD therapy. With concomitant use of clobazam, 44% of patients had a 50% reduction in seizures upon addition of CBD compared with 33% in the population not taking clobazam; this difference was not statistically significant. The most common reported side effect of CBD was sedation in less than 4% of patients, all of whom were also taking clobazam.

Increased alertness and improved verbal interactions were reported in 14% of patients in the CBD group and 8% of patients in the CBD and clobazam group. Benefits were more marked in the CBD alone group, in contrast to the CBD and clobazam group, but this difference was not statistically significant.

In summary, these findings support efficacy of artisanal CBD preparations in seizure reduction with few significant side effects. The response to CBD was independent of concurrent clobazam use, although clobazam may contribute to the sedation seen with concurrent CBD use.”

“In this retrospective study, we report that artisanal CBD is helpful in the treatment of medically refractory seizures.”
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Chronic High Doses of Cannabinoids Promote Hippocampal Neurogenesis

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“Hippocampal neurogenesis is suppressed following chronic administration of the major drugs of abuse (including opiates, alcohol, nicotine, and cocaine). However, CB1-knockout mice display significantly decreased hippocampal neurogenesis, suggesting that CB1 receptors activated by endogenous, plant-derived, or synthetic cannabinoids may promote hippocampal neurogenesis.

Cannabinoids can regulate the proliferation of hippocampal NS/PCs by acting on CB1 receptors. They found that both the synthetic cannabinoid HU210 and the endocannabinoid anandamide profoundly promote embryonic hippocampal NS/PC proliferation. Chronic, but not acute, HU210 significantly increases the number of newborn hippocampal neurons in adult rats by promoting NS/PC proliferation.

A significant increase was observed in the hipoppocampal newborn neurons of mice following twice-daily HU210 injection for 10 days.

This suggests that cannabinoids are the only illicit drug that can promote adult hippocampal neurogenesis following chronic  administration.”

Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects.” https://www.jci.org/articles/view/25509

http://www.science20.com/science_why_not/blog/chronic_high_doses_cannabinoids_promote_hippocampal_neurogenesis

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Role for neuronal nitric-oxide synthase in cannabinoid-induced neurogenesis.

Role for neuronal nitric-oxide synthase in cannabinoid-induced neurogenesis.“Cannabinoids, acting through the CB1 cannabinoid receptor (CB1R), protect the brain against ischemia and related forms of injury.

This may involve inhibiting the neurotoxicity of endogenous excitatory amino acids and downstream effectors, such as nitric oxide (NO).

Cannabinoids also stimulate neurogenesis in the adult brain through activation of CB1R.

Because NO has been implicated in neurogenesis, we investigated whether cannabinoid-induced neurogenesis, like cannabinoid neuroprotection, might be mediated through alterations in NO production.” https://aggregator.leafscience.org/role-for-neuronal-nitric-oxide-synthase-in-cannabinoid-induced-neurogenesis/

“Nitric oxide negatively regulates mammalian adult neurogenesis.”  http://www.pnas.org/content/100/16/9566.long

“Thus, cannabinoids appear to stimulate adult neurogenesis by opposing the antineurogenic effect of NO.” http://jpet.aspetjournals.org/content/jpet/319/1/150.full.pdf

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