Cannabinoids and the expanded endocannabinoid system in neurological disorders.

 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.

“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.

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.

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.

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

Cannabis Use in Children With Pantothenate Kinase-Associated Neurodegeneration.

 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.

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.

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

Activation of Cannabinoid Receptors Attenuates Endothelin-1-induced Mitochondrial Dysfunction in Rat Ventricular Myocytes.

Image result for Journal of Cardiovascular Pharmacology.“Evidence suggests that activation of the endocannabinoid system offers cardioprotection.

Aberrant energy production by impaired mitochondria purportedly contributes to various aspects of cardiovascular disease. We investigated whether cannabinoid (CB) receptor activation would attenuate mitochondrial dysfunction induced by endothelin-1 (ET1).

Acute exposure to ET1 (4 h) in the presence of palmitate as primary energy substrate induced mitochondrial membrane depolarization, and decreased mitochondrial bioenergetics and expression of genes related to fatty acid oxidation (i.e. peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α, a driver of mitochondrial biogenesis, and carnitine palmitoyltransferase (CPT)-1β, facilitator of fatty acid uptake).

A CB1/CB2 dual agonist with limited brain penetration, CB-13, corrected these parameters. AMP-activated protein kinase (AMPK), an important regulator of energy homeostasis, mediated the ability of CB-13 to rescue mitochondrial function. In fact, the ability of CB-13 to rescue fatty acid oxidation-related bioenergetics, as well as expression of PGC-1α and CPT-1β, was abolished by pharmacological inhibition of AMPK using compound C and shRNA knockdown of AMPKα1/α2, respectively.

Interventions that target CB/AMPK signaling might represent a novel therapeutic approach to address the multi-factorial problem of cardiovascular disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31815823

https://insights.ovid.com/crossref?an=00005344-900000000-98463

The Cannabinoid Receptor Agonist WIN55,212-2 Ameliorates Hippocampal Neuronal Damage After Chronic Cerebral Hypoperfusion Possibly Through Inhibiting Oxidative Stress and ASK1-p38 Signaling.

 “Chronic cerebral hypoperfusion (CCH) is a major contributor to cognitive decline and degenerative processes leading to Alzheimer’s disease, vascular dementia, and aging. However, the delicate mechanism of CCH-induced neuronal damage, and therefore proper treatment, remains unclear.

WIN55,212-2 (WIN) is a nonselective cannabinoid receptor agonist that has been shown to have effects on hippocampal neuron survival. In this study, we investigated the potential roles of WIN, as well as its underlying mechanism in a rat CCH model of bilateral common carotid artery occlusion.

These findings indicated that WIN may be a potential therapeutic agent for ischemic neuronal damage, involving a mechanism associated with the suppression of oxidative stress and ASK1-p38 signaling.”

https://www.ncbi.nlm.nih.gov/pubmed/31808139

https://link.springer.com/article/10.1007%2Fs12640-019-00141-8