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

Gastrointestinal Adverse Events of Cannabinoid 1 Receptor Inverse Agonists suggest their Potential Use in Irritable Bowel Syndrome with Constipation: A Systematic Review and Meta-Analysis.

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 Image result for J Gastrointestin Liver Dis“Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal (GI) disorders characterized by pain and impaired bowel movements. Currently available drugs show limited efficacy.

Cannabinoid 1 receptor (CB1) inverse agonists (CB1-RAN) cause diarrhea and may be candidates for the treatment of constipation-predominant IBS (IBS-C). We evaluated the effects of CB1-RAN in clinical trials for their potential use in IBS-C.

METHODS:

Database search identified all clinical trials published up to May 2018 that reported rimonabant and taranabant treatment for at least one month and detailed the GI adverse events (AEs). Categorical outcomes (subgroups of AEs) were analyzed using the odds ratio (OR).

RESULTS:

Eighteen trials met the inclusion criteria. Rimonabant 20 mg produced significantly more overall AEs (OR=1.35, CI: 1.19-1.52, p<0.0001), psychiatric events (OR=1.79, CI: 1.46-2.21, p<0.001) and GI AEs (OR=2.05, CI: 1.65-2.55, p<0.001) compared to placebo. Taranabant at doses ranging from 0.5 to 8 mg produced significantly more overall AEs (OR=1.36, CI: 1.13-1.64, p<0.002), psychiatric AEs (1.82, CI: 1.54-2.16, p<0.001) and GI AEs (OR=1.75, CI: 1.29-2.37, p<0.001) compared to placebo.

CONCLUSIONS:

The approach to target CB1 in the gut for the treatment of IBS-C or chronic constipation seems a promising therapeutic option. Prospective clinical trials on the possible targeting of CB1 and the endocannabinoid system are warranted.”

https://www.ncbi.nlm.nih.gov/pubmed/31826058

https://www.jgld.ro/jgld/index.php/jgld/article/view/265

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

Cannabidiol Improves Cognitive Impairment and Reverses Cortical Transcriptional Changes Induced by Ketamine, in Schizophrenia-Like Model in Rats.

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 Image result for Mol Neurobiol.“Cannabidiol (CBD), a non-psychotropic cannabinoid, demonstrates antipsychotic-like and procognitive activities in humans and in animal models of schizophrenia.

The mechanisms of these beneficial effects of CBD are unknown. Here, we examined behavioral effects of CBD in a pharmacological model of schizophrenia-like cognitive deficits induced by repeated ketamine (KET) administration. In parallel, we assessed transcriptional changes behind CBD activities in the prefrontal cortex (PFC), the main brain area linked to schizophrenia-like pathologies.

Male Sprague-Dawley rats were injected for 10 days with KET followed by 6 days of CBD. The cognitive performance was evaluated in the novel object recognition test followed by PFC dissections for next-generation sequencing (RNA-Seq) analysis and bioinformatics.

We observed that KET-induced learning deficits were rescued by CBD (7.5 mg/kg).

Similarly, CBD reversed transcriptional changes induced by KET. The majority of the genes affected by KET and KET-CBD were allocated to astroglial and microglial cells and associated with immune-like processes mediating synaptogenesis and neuronal plasticity. These genes include C1qc, C1qa, C1qb, C2, and C3 complement cascade elements, Irf8 factor and Gpr84, Gpr34, Cx3cr1, P2ry12, and P2ry6 receptors. The main pathway regulators predicted to be involved included TGFβ1 and IFNγ. In addition, CBD itself upregulated oxytocin mRNA in the PFC.

The present data suggest that KET induces cognitive deficits and transcriptional changes in the PFC and that both effects are sensitive to a reversal by CBD treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/31823199

https://link.springer.com/article/10.1007%2Fs12035-019-01831-2

Cannabis Use in Children With Pantothenate Kinase-Associated Neurodegeneration.

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 SAGE Journals“Pantothenate kinase-associated neurodegeneration is characterized by severe, progressive dystonia. This study aims to describe the reported usage of cannabis products among children with pantothenate kinase-associated neurodegeneration.

METHODS:

A cross-sectional, 37-item survey was distributed in April 2019 to the families of 44 children who participate in a clinical registry of individuals with pantothenate kinase-associated neurodegeneration.

RESULTS:

We received 18 responses (40.9% response rate). Children were a mean of 11.0 (SD 4.3) years old. The 15 respondents with dystonia or spasticity were on a median of 2 tone medications (range 0-9). Seven children had ever used cannabis (38.9%). The most common source of information about cannabis was other parents. Children who had ever used cannabis were on more tone medications, were more likely to have used opiates, were less likely to be able to roll, and less likely to sit comfortably, than children who had never used cannabis. Four children reported moderate or significant improvement in dystonia with cannabis. Other areas reported to be moderate or significantly improved were pain (n = 3), sleep (n = 4), anxiety (n = 3), and behavior (n = 2). Adverse effects included sadness (n = 1), agitation/behavior change (n = 1), and tiredness (n = 1).

CONCLUSION:

Cannabis use was commonly reported among children with pantothenate kinase-associated neurodegeneration whose parents responded to a survey, particularly when many other dystonia treatments had been tried. Physicians should be aware that parents may treat their child with severe, painful dystonia with cannabis. Placebo-controlled studies of products containing cannabidiol and 9-tetrahydrocannabinol are needed for pediatric tone disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31823681

https://journals.sagepub.com/doi/abs/10.1177/0883073819890516?journalCode=jcna

More evidence of cannabis efficacy in restless legs syndrome.

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Image result for Sleep Breath journal “Restless legs syndrome (RLS) is one of the most disabling and sometimes painful sensorimotor ailment of the nervous system that has only in recent years become more widely accepted as a clinical disorder with its own distinct features. Usually, symptoms respond well to dopamine agonists, anticonvulsants, or opiates, but still a subset of patients remains refractory to medical therapy and/or reports serious side effects.

Recently, patients’ statement of a remarkable and total remission of RLS symptoms following cannabis use has been reported. Here, we confirm and extend these findings to more patients with RLS.

The antinociceptive effect of marijuana has been documented in many painful neurological conditions, and the potential benefit of cannabis use in patients with refractory RLS should therefore be questioned by robust clinical trials.”

https://www.ncbi.nlm.nih.gov/pubmed/31820197

https://link.springer.com/article/10.1007%2Fs11325-019-01978-1

Characteristics of Dispensary Patients that Limit Alcohol after Initiating Cannabis.

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Publication Cover “Many patients have reported that they decrease their use of opioids after starting medical cannabis (MC) but less is known for alcohol.

The objective of this exploratory study was to identify any factors which differentiate alcohol abaters from those that do not modify their alcohol use after starting MC (non-abaters).

Comparisons were made to identify any demographic, dosing, or health history characteristics which differentiated alcohol abaters (N = 47) from non-abaters (N = 65). Respondents selected from among a list of 37 diseases/health conditions (e.g. diabetes, sleep disorders).

Abaters and non-abaters were indistinguishable in terms of sex, age, or prior drug history. A greater percentage of abaters (59.6%) than non-abaters (40.6%, p < .05) reported using MC two or more times per day. Abaters were more likely to be employed (68.1%) than non-abaters (51.1%, p < .05). Abaters also reported having significantly more health conditions and diseases (3.3 ± 2.0) than non-abaters (2.4 ± 1.4, p < .05).

This small study offers some insights into the profile of patients whose self-reported alcohol intake decreased following initiation of MC. Additional prospective or controlled research into the alcohol abatement phenomenon following MC may be warranted.”

https://www.ncbi.nlm.nih.gov/pubmed/31813342

https://www.tandfonline.com/doi/abs/10.1080/02791072.2019.1694199?journalCode=ujpd20