Efficacy of Cannabinoids in a Pre-Clinical Drug-Screening Platform for Alzheimer’s Disease.

“Finding a therapy for Alzheimer’s disease (AD) is perhaps the greatest challenge for modern medicine. The chemical scaffolds of many drugs in the clinic today are based upon natural products from plants, yet Cannabis has not been extensively examined as a source of potential AD drug candidates.

Here, we determine if a number of non-psychoactive cannabinoids are neuroprotective in a novel pre-clinical AD and neurodegeneration drug-screening platform that is based upon toxicities associated with the aging brain.

This drug discovery paradigm has yielded several compounds in or approaching clinical trials for AD. Eleven cannabinoids were assayed for neuroprotection in assays that recapitulate proteotoxicity, loss of trophic support, oxidative stress, energy loss, and inflammation. These compounds were also assayed for their ability to remove intraneuronal amyloid and subjected to a structure-activity relationship analysis. Pairwise combinations were assayed for their ability to synergize to produce neuroprotective effects that were greater than additive.

Nine of the 11 cannabinoids have the ability to protect cells in four distinct phenotypic neurodegeneration screening assays, including those using neurons that lack CB1 and CB2 receptors. They are able to remove intraneuronal Aβ, reduce oxidative damage, and protect from the loss of energy or trophic support. Structure-activity relationship (SAR) data show that functional antioxidant groups such as aromatic hydroxyls are necessary but not sufficient for neuroprotection. Therefore, there is a need to focus upon CB1 agonists that have these functionalities if neuroprotection is the goal.

Pairwise combinations of THC and CBN lead to a synergistic neuroprotective interaction.

Together, these results significantly extend the published data by showing that non-psychoactive cannabinoids are potential lead drug candidates for AD and other neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/31104297

https://link.springer.com/article/10.1007%2Fs12035-019-1637-8

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Effect of Cannabis Use on HIV DNA during Suppressive ART.

Infectious Diseases Society of America

“Cannabis use is frequent among people living with HIV and is associated with reduced systemic inflammation. We observed a faster HIV DNA decay during antiretroviral therapy among cannabis users, compared to no drug use. No cannabis-effect was observed on cellular HIV RNA transcription.”

https://www.ncbi.nlm.nih.gov/pubmed/31074488

 

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Cannabinoid Regulation of Fear and Anxiety: an Update.

 

“Anxiety- and trauma-related disorders are prevalent and debilitating mental illnesses associated with a significant socioeconomic burden. Current treatment approaches often have inadequate therapeutic responses, leading to symptom relapse. Here we review recent preclinical and clinical findings on the potential of cannabinoids as novel therapeutics for regulating fear and anxiety.

RECENT FINDINGS:

Evidence from preclinical studies has shown that the non-psychotropic phytocannabinoid cannabidiol and the endocannabinoid anandamide have acute anxiolytic effects and also regulate learned fear by dampening its expression, enhancing its extinction and disrupting its reconsolidation. The findings from the relevant clinical literature are still very preliminary but are nonetheless encouraging. Based on this preclinical evidence, larger-scale placebo-controlled clinical studies are warranted to investigate the effects of cannabidiol in particular as an adjunct to psychological therapy or medication to determine its potential utility for treating anxiety-related disorders in the future.”

https://www.ncbi.nlm.nih.gov/pubmed/31030284

https://link.springer.com/article/10.1007%2Fs11920-019-1026-z

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Future Aspects for Cannabinoids in Breast Cancer Therapy.

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“Cannabinoids (CBs) from Cannabis sativa provide relief for tumor-associated symptoms (including nausea, anorexia, and neuropathic pain) in the palliative treatment of cancer patients.

Additionally, they may decelerate tumor progression in breast cancer patients.

Indeed, the psychoactive delta-9-tetrahydrocannabinol (THC), non-psychoactive cannabidiol (CBD) and other CBs inhibited disease progression in breast cancer models.

The effects of CBs on signaling pathways in cancer cells are conferred via G-protein coupled CB-receptors (CB-Rs), CB1-R and CB2-R, but also via other receptors, and in a receptor-independent way.

THC is a partial agonist for CB1-R and CB2-R; CBD is an inverse agonist for both.

In breast cancer, CB1-R expression is moderate, but CB2-R expression is high, which is related to tumor aggressiveness. CBs block cell cycle progression and cell growth and induce cancer cell apoptosis by inhibiting constitutive active pro-oncogenic signaling pathways, such as the extracellular-signal-regulated kinase pathway.

They reduce angiogenesis and tumor metastasis in animal breast cancer models. CBs are not only active against estrogen receptor-positive, but also against estrogen-resistant breast cancer cells. In human epidermal growth factor receptor 2-positive and triple-negative breast cancer cells, blocking protein kinase B- and cyclooxygenase-2 signaling via CB2-R prevents tumor progression and metastasis.

Furthermore, selective estrogen receptor modulators (SERMs), including tamoxifen, bind to CB-Rs; this process may contribute to the growth inhibitory effect of SERMs in cancer cells lacking the estrogen receptor.

In summary, CBs are already administered to breast cancer patients at advanced stages of the disease, but they might also be effective at earlier stages to decelerate tumor progression.”

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[Significance of the endocannabinoid system in migraine].

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“Based on the traditional pain-relieving effect of Cannabis species an endogenous cannabinoid like system was discovered in the human body. Endocannabinoids have important role in the homeostasis of the body, such as stress response and mood control, feeding behaviour, energy balance and metabolism, immunological processes, and also play important role in controlling pain processing. Previous studies suggested that an endocannabinoid dysfunction, namely endocannabinoid deficit, might contribute to the development of migraine and its chronification. Although, the exact nature of the relationship between migraine and endocannabinoid system is not fully understood yet, in this brief review we summarise research results suggesting that the endocannabinoid system may be a potential drug target in the migraine therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/30962405

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Cannabinoid Actions on Neural Stem Cells: Implications for Pathophysiology.

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“With the increase of life expectancy, neurodegenerative disorders are becoming not only a health but also a social burden worldwide. However, due to the multitude of pathophysiological disease states, current treatments fail to meet the desired outcomes. Therefore, there is a need for new therapeutic strategies focusing on more integrated, personalized and effective approaches. The prospect of using neural stem cells (NSC) as regenerative therapies is very promising, however several issues still need to be addressed. In particular, the potential actions of pharmacological agents used to modulate NSC activity are highly relevant. With the ongoing discussion of cannabinoid usage for medical purposes and reports drawing attention to the effects of cannabinoids on NSC regulation, there is an enormous, and yet, uncovered potential for cannabinoids as treatment options for several neurological disorders, specifically when combined with stem cell therapy. In this manuscript, we review in detail how cannabinoids act as potent regulators of NSC biology and their potential to modulate several neurogenic features in the context of pathophysiology.”

https://www.ncbi.nlm.nih.gov/pubmed/30959794

https://www.mdpi.com/1420-3049/24/7/1350

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Cannabidiol as adjunctive treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome.

“Epilepsy is one of the most common chronic disorders of the brain affecting around 70 million people worldwide. Treatment is mainly symptomatic, and most patients achieve long-term seizure control. Up to one-third of the affected subjects, however, are resistant to anticonvulsant therapy.

Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are severe, refractory epilepsy syndromes with onset in early childhood. Currently available interventions fail to control seizures in most cases, and there remains the need to identify new treatments.

Cannabidiol (CBD) is the first in a new class of antiepileptic drugs. It is a major chemical of the cannabis plant, which has antiseizure properties in absence of psychoactive effects.

This article provides a critical review of the pharmacology of CBD and the most recent clinical studies that evaluated its efficacy and safety as adjunctive treatment of seizures associated with LGS and DS.”

https://www.ncbi.nlm.nih.gov/pubmed/30938373

https://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=4&p_RefId=2909248&p_IsPs=N

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Update on Antiepileptic Drugs 2019.

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“This article is an update from the article on antiepileptic drug (AED) therapy published in the last Continuum issue on epilepsy and is intended to cover the vast majority of agents currently available to the neurologist in the management of patients with epilepsy. Treatment of epilepsy starts with AED monotherapy. Knowledge of the spectrum of efficacy, clinical pharmacology, and modes of use for individual AEDs is essential for optimal treatment for epilepsy. This article addresses AEDs individually, focusing on key pharmacokinetic characteristics, indications, and modes of use.

RECENT FINDINGS:

Since the previous version of this article was published, three new AEDs, brivaracetam, cannabidiol, and stiripentol, have been approved by the US Food and Drug Administration (FDA), and ezogabine was removed from the market because of decreased use as a result of bluish skin pigmentation and concern over potential retinal toxicity.Older AEDs are effective but have tolerability and pharmacokinetic disadvantages. Several newer AEDs have undergone comparative trials demonstrating efficacy equal to and tolerability at least equal to or better than older AEDs as first-line therapy. The list includes lamotrigine, oxcarbazepine, levetiracetam, topiramate, zonisamide, and lacosamide. Pregabalin was found to be less effective than lamotrigine. Lacosamide, pregabalin, and eslicarbazepine have undergone successful trials of conversion to monotherapy. Other newer AEDs with a variety of mechanisms of action are suitable for adjunctive therapy. Most recently, the FDA adopted a policy that a drug’s efficacy as adjunctive therapy in adults can be extrapolated to efficacy in monotherapy. In addition, efficacy in adults can be extrapolated for efficacy in children 4 years of age and older. Both extrapolations require data demonstrating that an AED has equivalent pharmacokinetics between its original approved use and its extrapolated use. In addition, the safety of the drug in pediatric patients has to be demonstrated in clinical studies that can be open label. Rational AED combinations should avoid AEDs with unfavorable pharmacokinetic interactions or pharmacodynamic interactions related to mechanism of action.

SUMMARY:

Knowledge of AED pharmacokinetics, efficacy, and tolerability profiles facilitates the choice of appropriate AED therapy for patients with epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/30921021

https://insights.ovid.com/crossref?an=00132979-201904000-00014

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Daily Practice Managing Resistant Multiple Sclerosis Spasticity With Delta-9-Tetrahydrocannabinol: Cannabidiol Oromucosal Spray: A Systematic Review of Observational Studies.

 Image result for journal of central nervous system disease“Spasticity is one of the most common symptoms in people with multiple sclerosis (MS). Conventional anti-spasticity agents have limitations in their efficacy and tolerability.

Delta-9-tetrahydrocannabinol: cannabidiol (THC:CBD) spray, a cannabinoid-based medicine, is approved as an add-on therapy for MS spasticity not adequately controlled by other anti-spasticity medications. The results from randomized controlled trials (RCTs) have demonstrated a reduction in the severity of spasticity and associated symptoms. However, RCTs do not always reflect real-life outcomes. We systematically reviewed the complementary evidence from non-interventional real-world studies.

METHODS:

A systematic literature review was conducted to identify all non-RCT publications on THC:CBD spray between 2011 and 2017. Data on study design, patient characteristics, effectiveness, and safety outcomes were extracted from those publications meeting our inclusion criteria.

RESULTS:

In total, we reviewed 14 real-world publications including observational studies and treatment registries. The proportion of patients reaching the threshold of minimal clinical important difference (MCID), with at least a 20% reduction of the spasticity Numeric Rating Scale (NRS) score after 4 weeks ranged from 41.9% to 82.9%. The reduction in the mean NRS spasticity score after 4 weeks was maintained over 6-12 months. The average daily dose was five to six sprays. Delta-9-tetrahydrocannabinol: cannabidiol was well tolerated in the evaluated studies in the same way as in the RCTs. No new or unexpected adverse events or safety signals were reported in everyday clinical practice.

CONCLUSIONS:

The data evaluated in this systematic review provide evidence for the efficacy and safety of THC:CBD in clinical practice and confirm results obtained in RCTs.”

https://www.ncbi.nlm.nih.gov/pubmed/30886530

https://journals.sagepub.com/doi/10.1177/1179573519831997

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The endocannabinoid system in migraine: from bench to pharmacy and back.

 Image result for curr opin neurol“Migraine is a common, highly disabling disorder. Its treatment involves acute and preventive therapy. Many of available preventive medications are not well tolerated, which results in poor compliance and limited effectiveness. Cannabinoids have been proposed for the treatment of migraine but their efficacy and tolerability are controversial.

RECENT FINDINGS:

Cannabinoids modulate functions and activity of signaling pathways that have a key role in pain control. Growing preclinical evidence and initial clinical findings suggest that modulation of the endocannabinoid system, via endogenous or exogenous cannabinoids may be relevant for migraine via multiple mechanisms.

SUMMARY:

The endocannabinoid system qualifies as an interesting area of research worth exploration in the quest for therapeutic targets for the treatment of migraine.”

https://www.ncbi.nlm.nih.gov/pubmed/30883435

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