Category Archives: Uncategorized

Stress-induced modulation of endocannabinoid signaling leads to delayed strengthening of synaptic connectivity in the amygdala.

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Image result for pnas“Even a brief exposure to severe stress strengthens synaptic connectivity days later in the amygdala, a brain area implicated in the affective symptoms of stress-related psychiatric disorders. However, little is known about the synaptic signaling mechanisms during stress that eventually culminate in its delayed impact on the amygdala. Hence, we investigated early stress-induced changes in amygdalar synaptic signaling in order to prevent its delayed effects.

Whole-cell recordings in basolateral amygdala (BLA) slices from rats revealed higher frequency of miniature excitatory postsynaptic currents (mEPSCs) immediately after 2-h immobilization stress. This was replicated by inhibition of cannabinoid receptors (CB1R), suggesting a role for endocannabinoid (eCB) signaling.

Stress also reduced N-arachidonoylethanolamine (AEA), an endogenous ligand of CB1R. Since stress-induced activation of fatty acid amide hydrolase (FAAH) reduces AEA, we confirmed that oral administration of an FAAH inhibitor during stress prevents the increase in synaptic excitation in the BLA soon after stress.

Although stress also caused an immediate reduction in synaptic inhibition, this was not prevented by FAAH inhibition. Strikingly, FAAH inhibition during the traumatic stressor was also effective 10 d later on the delayed manifestation of synaptic strengthening in BLA neurons, preventing both enhanced mEPSC frequency and increased dendritic spine-density.

Thus, oral administration of an FAAH inhibitor during a brief stress prevents the early synaptic changes that eventually build up to hyperexcitability in the amygdala. This framework is of therapeutic relevance because of growing interest in targeting eCB signaling to prevent the gradual development of emotional symptoms and underlying amygdalar dysfunction triggered by traumatic stress.”

https://www.ncbi.nlm.nih.gov/pubmed/31843894

https://www.pnas.org/content/early/2019/12/13/1910322116

Cannabinoids and dystonia: an issue yet to be defined.

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 “Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and postures. Besides motor manifestations, patients with dystonia also display non-motor signs and symptoms including psychiatric and sensory disturbances.

Symptomatic treatment of motor signs in dystonia largely relies on intramuscular botulinum toxin injections and, in selected cases, on deep brain stimulation. Oral medications and physical therapy offer a few benefits only in a minority of patients.

Cannabinoids have been shown to be a complementary treatment in several neurological disorders but their usefulness in dystonia have not been systematically assessed. Given recent policy changes in favor of cannabis use in clinical practice and the request for alternative treatments, it is important to understand how cannabinoids may impact people with dystonia.

Reviewing the evidence so far available and our own experience, cannabinoids seem to be effective in single cases but further studies are required to improve our understanding on their role as complementary treatment in dystonia.”

https://www.ncbi.nlm.nih.gov/pubmed/31848779

https://link.springer.com/article/10.1007%2Fs10072-019-04196-5

Beta-caryophyllene enhances wound healing through multiple routes.

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 Image result for plos one“Beta-caryophyllene is an odoriferous bicyclic sesquiterpene found in various herbs and spices.

Recently, it was found that beta-caryophyllene is a ligand of the cannabinoid receptor 2 (CB2). Activation of CB2 will decrease pain, a major signal for inflammatory responses.

We hypothesized that beta-caryophyllene can affect wound healing by decreasing inflammation. Here we show that cutaneous wounds of mice treated with beta-caryophyllene had enhanced re-epithelialization.

The treated tissue showed increased cell proliferation and cells treated with beta-caryophyllene showed enhanced cell migration, suggesting that the higher re-epithelialization is due to enhanced cell proliferation and cell migration. The treated tissues also had up-regulated gene expression for hair follicle bulge stem cells. Olfactory receptors were not involved in the enhanced wound healing. Transient Receptor Potential channel genes were up-regulated in the injured skin exposed to beta-caryophyllene. Interestingly, there were sex differences in the impact of beta- caryophyllene as only the injured skin of female mice had enhanced re-epithelialization after exposure to beta-caryophyllene.

Our study suggests that chemical compounds included in essential oils have the capability to improve wound healing, an effect generated by synergetic impacts of multiple pathways.”

https://www.ncbi.nlm.nih.gov/pubmed/31841509

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216104

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142

Medicinal Use of Cannabis in Children and Pregnant Women.

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 Image result for Rambam Maimonides Med J.“The increasing medicinal use of cannabis during recent years has largely overlooked children and pregnant women due to litigious and ethical concerns.

However, over the last few years medicine has observed increasing numbers of children treated with cannabis for autism spectrum disorder (ASD) and fetal alcohol spectrum disorder (FASD), and pregnant women treated for hyperemesis gravidarum (HG).

This review provides an account of major findings discovered through this research.

Specifically, cannabis may offer therapeutic advantages to behavioral symptoms of autism spectrum disorder and fetal alcohol spectrum disorder, and to the severe nausea and vomiting in hyperemesis gravidarum.

The use of medical cannabis in children and pregnant women should be further discussed and researched in this patient population.”

https://www.ncbi.nlm.nih.gov/pubmed/31826800

Cannabinoids and the expanded endocannabinoid system in neurological disorders.

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 Related image“Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ9-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics.

These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor.

The discovery of CB2 and of endogenous cannabinoid receptor ligands (endocannabinoids) raised new possibilities for safe targeting of this endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded endocannabinoid system – known as the endocannabinoidome – that includes several mediators that are biochemically related to the endocannabinoids, and their receptors and metabolic enzymes.

The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and endocannabinoids in neurological diseases into the limelight.

In this Review, we provide an overview of the endocannabinoid system and the endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma.”

https://www.ncbi.nlm.nih.gov/pubmed/31831863

“The existence of the endocannabinoidome explains in part why some non-euphoric cannabinoids, which affect several endocannabinoidome proteins, are useful for the treatment of neurological disorders, such as multiple sclerosis and epilepsy.”

https://www.nature.com/articles/s41582-019-0284-z

Therapeutic potential of natural psychoactive drugs for central nervous system disorders: A perspective from polypharmacology.

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“In drug development, the creation of highly selective ligands has been unsuccessful for the treatment of central nervous system disorders.

Multi-target ligands, from the polypharmacology paradigm, are being proposed as treatments for these complex disorders, since they offer enhanced efficacy and a strong safety profile.

Natural products are the best examples of multi-target compounds, so they are of high interest within this paradigm.

Additionally, recent research on psychoactive drugs of natural origin, such as ayahuasca and cannabis, has demonstrated promising therapeutic potential for the treatment of some psychiatric and neurological disorders.

In this text, we describe how research on psychoactive drugs can be effectively combined with the polypharmacology paradigm, providing ayahuasca and cannabis research as examples.”

https://www.ncbi.nlm.nih.gov/pubmed/31830883

http://www.eurekaselect.com/177382/article

Cannabis-based medicines and the perioperative physician.

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Image result for perioperative medicine

“Cannabis use for medicinal purposes was first documented in 2900 BC in China, when Emperor Shen Nong described benefit for rheumatism and malaria and later in Ancient Egyptian texts.

Discussion in medical journals, the mainstream and social media around the use of cannabis for medicinal and non-medicinal purposes has increased recently, especially following the legalisation of cannabis for recreational use in Canada and the UK government’s decision to make cannabis-based medicines (CBMs) available for prescription by doctors on the specialist register.

The actual, social and economic legitimisation of cannabis and its medicinal derivatives makes it likely increasing numbers of patients will present on this class of medicines. Perioperative physicians will require a sound understanding of their pharmacology and evidence base, and may wish to exploit this group of compounds for therapeutic purposes in the perioperative period.

The increasing availability of cannabis for both recreational and medicinal purposes means that anaesthetists will encounter an increasing number of patients taking cannabis-based medications. The existing evidence base is conflicted and incomplete regarding the indications, interactions and long-term effects of these substances.

Globally, most doctors have had little education regarding the pharmacology of cannabis-based medicines, despite the endocannabinoid system being one of the most widespread in the human body.

Much is unknown, and much is to be decided, including clarifying definitions and nomenclature, and therapeutic indications and dosing. Anaesthetists, Intensivists, Pain and Perioperative physicians will want to contribute to this evidence base and attempt to harness such therapeutic benefits in terms of pain relief and opiate-avoidance, anti-emesis and seizure control.

We present a summary of the pharmacology of cannabis-based medicines including anaesthetic interactions and implications, to assist colleagues encountering these medicines in clinical practice.”

https://www.ncbi.nlm.nih.gov/pubmed/31827774

“In summary, cannabinoids may improve pain relief as part of multi-modal approach. As the evidence base increases, CBMs could become part of the perioperative teams’ armamentarium to help provide an opiate sparing multimodal analgesia regime as well as having a role in the management of common post-operative complications such as nausea and vomiting.”

 https://perioperativemedicinejournal.biomedcentral.com/articles/10.1186/s13741-019-0127-x

Missing Pieces to the Endocannabinoid Puzzle.

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Image result for trends in molecular medicine“The most bioactive ingredient of cannabis (Cannabis sativa or indica) extracts, Δ9-tetrahydrocannabinol (THC), was identified in the 1960s as one of more than 110 phytocannabinoids. It activates receptors of chemically different endogenous ligands (endocannabinoids) that, unlike THC, are metabolized by several enzymes of the endocannabinoid system. Here, the complexity of the plant-derived and endogenous cannabinoids (eCBs) is discussed, to better appreciate the challenge of: (i) dissecting their mutual interactions; (ii) understanding their impact on human pathophysiology; and (iii) exploiting them for human disease. To this aim, missing pieces to the eCB puzzle must be urgently found, by solving the 3D structures of key components, and interrogating noncanonical modes of regulation and trafficking of these lipid signals.”

https://www.ncbi.nlm.nih.gov/pubmed/31822395

https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(19)30293-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS147149141930293X%3Fshowall%3Dtrue

Untargeted characterization of extracts from Cannabis sativa L. cultivars by gas and liquid chromatography coupled to mass spectrometry in high resolution mode.

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Talanta“Elucidation of Cannabis composition is required to evaluate the potential of this plant for pharmacological uses, but also for implementation in breeding programs with agronomical purposes. The aim of the present study was to develop a method for untargeted analysis of polar and non-polar Cannabis extracts.

For this purpose, extracts from 17 cultivars of Cannabis sativa L. were analyzed by gas chromatography-time-of-flight/mass spectrometry (GC-TOF/MS) and liquid chromatography quadrupole time-of-flight tandem mass spectrometry (LC-QTOF MS/MS) in high resolution mode.

One hundred sixty-nine compounds were identified in the extracts by searching MS and MS/MS information. Among identified families, there were mainly cannabinoids, terpenoids, lipids and flavonoids, but also some interesting compounds such as amino and organic acids, among others.

Relative contents of terpenoids and cannabinoids in the same cultivars grown in greenhouse and field were compared. Compositional differences in the profile of terpenoids and cannabinoids between both types of grown conditions were found.”

https://www.ncbi.nlm.nih.gov/pubmed/31816756

https://www.sciencedirect.com/science/article/abs/pii/S0039914019310173?via%3Dihub

Structure-Effect Relationships of Novel Semi-Synthetic Cannabinoid Derivatives.

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Image result for frontiers in pharmacology“As a library of cannabinoid (CB) derivatives with (-)-trans–cannabidiol (CBD) or (-)-trans-cannabidivarin (CBDV) scaffold, we synthesized nine novel cannabinoids: 2-hydroxyethyl cannabidiolate (2-HEC), 2-hydroxypentyl cannabidiolate (2-HPC), 2,3-dihydroxypropyl cannabidiolate (GCBD), cyclohexyl cannabidiolate (CHC), n-hexyl-cannabidiolate (HC), 2-(methylsulfonamido)ethyl cannabidiolate (NMSC), 2-hydroxyethyl cannabidivarinolate (2-HECBDV), cyclohexyl cannabidivarinolate (CHCBDV), and n-hexyl cannabidivarinolate (HCBDV). Their binding and intrinsic effects at the CB1- and CB2-receptors and the effects on inflammatory signaling cascades were investigated in in vitro and ex vivo cell models.

Materials and Methods: Binding affinity was studied in membranes isolated from CB-receptor-transfected HEK293EBNA cells, intrinsic functional activity in Chinese hamster ovary (CHO) cells, and activation of nuclear factor κB (NF-κB) and nuclear factor of activated T-cells (NFAT) in phorbol 12-myristate 13-acetate (PMA)/ionomycin (IO)-treated Jurkat T-cells. Inhibition of interleukin (IL)-17-induced pro-inflammatory cytokines and chemokines [IL-6, IL-1β, CC-chemokine ligand 2 (CCL2), and tumor necrosis factor (TNF)-α] was studied in RAW264.7 macrophages at the RNA level. Pro-inflammatory cytokine (IL-1β, IL-6, IL-8, and TNF-α) expression and prostaglandin E2 (PGE2) expression were investigated at the protein level in lipopolysaccharide (LPS)-treated primary human monocytes.

Results: Derivatives with long aliphatic side chains at the ester position at R1 [HC (5)] as well as the ones with polar side chains [2-HECBDV (7), NMSC (6), and 2-HEC (1)] can be selective for CB2-receptors. The CBDV-derivatives HCBDV and CHCBDV demonstrated specific binding at CB1- and CB2-receptors at nanomolar concentrations. 2-HEC, 2-HPC, GCBD, and NMSC were agonists at CB2-receptor and antagonists at CB1-receptor. CHC bound both receptors at submicromolar ranges and was an agonist for these receptors. 2-HECBDV was an agonist at CB2-receptor and an antagonist at the CB1-receptor despite its modest affinity at this receptor (micromolar range). NMSC inhibited NF-κB and NFAT activity, and 2-HEC, 2-HPC, and GCBD dose-dependently inhibited PMA/IO-stimulated NFAT activation. CHC and HC dose-dependently reduced IL-1β and CCL2 messenger RNA (mRNA) expression. NMSC inhibited IL-1β, CCL2, and TNF-α at lower doses. At higher doses, it induced a pronounced increase in IL-6 mRNA. 2-HEC, 2-HPC, and GCBD dose-dependently inhibited LPS-induced IL-1β, TNF-α, and IL-6 synthesis. NMSC further increased LPS-stimulated IL-1β release but inhibited IL-8, TNF-α, and PGE2.

Conclusion: The CBD- and CBDV-derivatives studied are suitable for targeting CB-receptors. Some may be used as selective CB2 agonists. The length of the aliphatic rest at R2 of CBD (pentyl) and CBDV (propyl) did not correlate with the binding affinity. Higher polarity at R1 appeared to favor the agonistic activity at CB2-receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/31824305

https://www.frontiersin.org/articles/10.3389/fphar.2019.01284/full