Cannabinoid Modulation of the Stressed Hippocampus.

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“Exposure to stressful situations is one of the risk factors for the precipitation of several psychiatric disorders, including Major Depressive Disorder, Posttraumatic Stress Disorder and Schizophrenia.

The hippocampal formation is a forebrain structure highly associated with emotional, learning and memory processes; being particularly vulnerable to stress. Exposure to stressful stimuli leads to neuroplastic changes and imbalance between inhibitory/excitatory networks. These changes have been associated with an impaired hippocampal function.

Endocannabinoids (eCB) are one of the main systems controlling both excitatory and inhibitory neurotransmission, as well as neuroplasticity within the hippocampus.

Cannabinoids receptors are highly expressed in the hippocampus, and several lines of evidence suggest that facilitation of cannabinoid signaling within this brain region prevents stress-induced behavioral changes.

Also, chronic stress modulates hippocampal CB1 receptors expression and endocannabinoid levels.

Moreover, cannabinoids participate in mechanisms related to synaptic plasticity and adult neurogenesis. Here, we discussed the main findings supporting the involvement of hippocampal cannabinoid neurotransmission in stress-induced behavioral and neuroplastic changes.”

https://www.ncbi.nlm.nih.gov/pubmed/29311804

https://www.frontiersin.org/articles/10.3389/fnmol.2017.00411/full

Practical considerations in medical cannabis administration and dosing.

European Journal of Internal Medicine

“Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical complexity and variability, quality control issues, previous dearth of appropriately powered randomised controlled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise patients pursuing such treatment.

With the advent of pharmaceutical cannabis-based medicines (Sativex/nabiximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology and therapeutics has become untenable.

In this article, the authors endeavour to present concise data on cannabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration (smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain primarily to THC, whose total daily dose-equivalent should generally be limited to 30mg/day or less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of tolerance.

CBD, in contrast to THC, is less potent, and may require much higher doses for its adjunctive benefits on pain, inflammation, and attenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks.

Suggestions are offered on cannabis-drug interactions, patient monitoring, and standards of care, while special cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain, use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and hazardous activities.”

PTL401, a New Formulation Based on Pro-nano Dispersion Technology, Improves Oral Cannabinoids Bioavailability in Healthy Volunteers.

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“There is growing clinical interest in developing and commercializing pharmaceutical-grade cannabinoid products, containing primarily tetrahydrocannabinol (THC) and cannabidiol (CBD). The oral bioavailability of THC and CBD is very low due to extensive “first pass” metabolism.

A novel oral THC and CBD formulation, PTL401, utilizing an advanced self-emulsifying oral drug delivery system, was designed to circumvent the “first pass” effect. In this study, the bioavailability of THC and CBD from the PTL401 capsule was compared with similar doses from a marketed reference oromucosal spray (Sativex®).

No outstanding safety concerns were noted following either administration.

We conclude that PTL401 is a safe and effective delivery platform for both CBD and THC. The relatively faster absorption and improved bioavailability, compared to the oromucosal spray, justifies further, larger scale clinical studies with this formulation.”

Investigating the relationships between alcohol consumption, cannabis use and circulating cytokines: a preliminary analysis.

Alcoholism: Clinical and Experimental Research

“In recent years, human and animal studies have converged to support altered inflammatory signaling as one molecular mechanism underlying the pathophysiology of alcohol use disorders (AUDs). Alcohol binds to receptors on immune cells, triggering signaling pathways that produce pro-inflammatory cytokines. Chronic inflammation is associated with tissue damage, which may contribute to negative effects of AUD.

Conversely, cannabis is associated with decreased inflammatory signaling, and animal studies suggest that cannabinoids may impact alcohol-induced inflammation.

We explored the relationship between self-reported alcohol and cannabis use and circulating levels of the pro-inflammatory cytokines IL-6, IL-8 and IL-1β in the blood.

A positive association between alcohol and IL-6 emerged. We also observed a negative association between cannabis and IL-1β.

These preliminary findings suggest that cannabinoid compounds may serve to mitigate inflammation associated with alcohol use.”

https://www.ncbi.nlm.nih.gov/pubmed/29286537

http://onlinelibrary.wiley.com/doi/10.1111/acer.13592/abstract;jsessionid=CE6DC7E1CC2712861F31EF048D2F7118.f02t04

Cannabidiol Does Not Convert to Δ9-Tetrahydrocannabinol in an In Vivo Animal Model.

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“Introduction: Cannabidiol (CBD) can convert to Δ9-tetrahydrocannabinol (THC) in vitro with prolonged exposure to simulated gastric fluid; however, in vitro conditions may not be representative of the in vivo gut environment. Using the minipig, we investigated whether enteral CBD converts to THC in vivo.

Conclusions: Findings of the present study show that orally dosed CBD, yielding clinically relevant plasma exposures, does not convert to THC in the minipig, a species predictive of human GI tract function.”

Expression of cannabinoid 1 and, 2 receptors and the effects of cannabinoid 1 and, 2 receptor agonists on detrusor overactivity associated with bladder outlet obstruction in rats.

 

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“This study investigated changes in the expression of cannabinoid (CB) receptors and the effects of CB1 and CB2 agonists on detrusor overactivity (DO) associated with bladder outlet obstruction (BOO) in rats.

CONCLUSIONS:

CB1 and CB2 receptors, especially CB1, play a role in the pathophysiology of BOO-associated DO, and could serve as therapeutic targets.”  https://www.ncbi.nlm.nih.gov/pubmed/29284441

“The results of this study suggest that CB1 and CB2 receptors in the bladder, particularly CB1 receptors, play a significant role in the pathophysiology of BOO-associated DO, and could serve as diagnostic biomarker and therapeutic targets in this disorder.”

Role of the endogenous cannabinoid receptor 1 in brain injury induced by chronic intermittent hypoxia in rats.

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“This study investigated the effect of rimonabant, a cannabinoid receptor type 1 (CB1) antagonist, on calcium/calmodulin dependent protein kinase II (CaMKII) and CB1 in chronic intermittent hypoxia (CIH).

Rimonabant had a protective effect against CIH.” https://www.ncbi.nlm.nih.gov/pubmed/29264962

http://www.tandfonline.com/doi/abs/10.1080/00207454.2017.1420069

 

Discovery of Selective Cannabinoid CB2 Receptor Agonists by High-Throughput Screening.

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“The endocannabinoid system (ECS) plays a diverse role in human physiology ranging from the regulation of mood and appetite to immune modulation and the response to pain.

Drug development that targets the cannabinoid receptors (CB1 and CB2) has been explored; however, success in the clinic has been limited by the psychoactive side effects associated with modulation of the neuronally expressed CB1 that are enriched in the CNS. CB2, however, are expressed in peripheral tissues, primarily in immune cells, and thus development of CB2-selective drugs holds the potential to modulate pain among other indications without eliciting anxiety and other undesirable side effects associated with CB1 activation.

As part of a collaborative effort among industry and academic laboratories, we performed a high-throughput screen designed to discover selective agonists or positive allosteric modulators (PAMs) of CB2. Although no CB2 PAMs were identified, 167 CB2 agonists were discovered here, and further characterization of four select compounds revealed two with high selectivity for CB2 versus CB1.

These results broaden drug discovery efforts aimed at the ECS and may lead to the development of novel therapies for immune modulation and pain management with improved side effect profiles.”

https://www.ncbi.nlm.nih.gov/pubmed/29257918

 

Provider Perspectives on Use of Medical Marijuana in Children With Cancer.

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“Although medical marijuana (MM) may have utility in the supportive care of children with serious illness, it remains controversial.

We investigated interdisciplinary provider perspectives on legal MM use in children with cancer.

Most pediatric oncology providers are willing to consider MM use in children with cancer and receive frequent inquiries.” https://www.ncbi.nlm.nih.gov/pubmed/29233937

http://pediatrics.aappublications.org/content/early/2017/12/08/peds.2017-0559.long

“Medical Marijuana For Children With Cancer Broadly Supported By Doctors. An overwhelming majority of health care professionals who care for children with cancer would be willing to help those children get medical marijuana” https://www.forbes.com/sites/tarahaelle/2017/12/12/medical-marijuana-for-children-with-cancer-broadly-supported-by-doctors/#3d31cf08795d

“Most doctors would allow medical marijuana for children with cancer, study finds. A considerable majority of medical physicians would help children treat cancer with medical cannabis, a new study suggests.” http://blog.sfgate.com/smellthetruth/2017/12/12/most-doctors-would-allow-medical-marijuana-for-children-with-cancer-study-finds/

“Clinicians Support Medical Marijuana Use in Children With Cancer, But Lack Knowledge” https://jamanetwork.com/journals/jama/fullarticle/2672986

Extract of Fructus Cannabis Ameliorates Learning and Memory Impairment Induced by D-Galactose in an Aging Rats Model.

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“Hempseed (Cannabis sativa L.) has been used as a health food and folk medicine in China for centuries.

In the present study, we sought to define the underlying mechanism by which the extract of Fructus Cannabis (EFC) protects against memory impairment induced by D-galactose in rats.

To accelerate aging and induce memory impairment in rats, D-galactose (400 mg/kg) was injected intraperitoneally once daily for 14 weeks. EFC (200 and 400 mg/kg) was simultaneously administered intragastrically once daily in an attempt to slow the aging process.

We found that EFC significantly increased the activity of superoxide dismutase, while lowering levels of malondialdehyde in the hippocampus. Moreover, EFC dramatically elevated the organ indices of some organs, including the heart, the liver, the thymus, and the spleen. In addition, EFC improved the behavioral performance of rats treated with D-galactose in the Morris water maze. Furthermore, EFC inhibited the activation of astrocytes and remarkably attenuated phosphorylated tau and suppressed the expression of presenilin 1 in the brain of D-galactose-treated rats.

These findings suggested that EFC exhibits beneficial effects on the cognition of aging rats probably by enhancing antioxidant capacity and anti-neuroinflammation, improving immune function, and modulating tau phosphorylation and presenilin expression.”