Cannabimimetic plants: are they new cannabinoidergic modulators?

“Phytochemicals and secondary metabolites able to interact with the endocannabinoid system (Cannabimimetics) have been recently described in a broad range of plants and fruits. These findings can open new alternative avenues to explore for the development of novel therapeutic compounds. The cannabinoids regulate many physiological and pathological functions in both animals and plants. Cannabis sativa is the main plant that produces phytocannabinoids inside resins capable to defend the plant from the aggression of parasites and herbivores. Animals produce anandamide and 2-arachidonoyl glycerol, which thanks to binding with main receptors such as type-1 cannabinoid receptor (CB1R) and the type-2 cannabinoid receptor (CB2R) are involved in inflammation processes and several brain functions. Endogenous cannabinoids, enzymes for synthesis and degradation of cannabinoids, and CB1R and CB2R constitute the endocannabinoid system (ECS). Other plants can produce cannabinoid-like molecules such as perrottetinene extracted from Radula perrottetii, or anandamide and 2-arachidonoyl glycerol extracted from some bryophytes. Moreover, several other secondary metabolites can also interact with the ECS of animals and take the name of cannabimimetics. These phytoextracts not derived from Cannabis sativa can act as receptor agonists or antagonist, or enzyme inhibitors of ECS and can be involved in the inflammation, oxidative stress, cancer, and neuroprotection. Finally, given the evolutionary heterogeneity of the cannabimimetic plants, some authors speculated on the fascinating thesis of the evolutionary convergence between plants and animals regarding biological functions of ECS. The review aims to provide a critical and complete assessment of the botanical, chemical and therapeutic aspects of cannabimimetic plants to evaluate their spread in the world and medicinal potentiality.”

https://www.ncbi.nlm.nih.gov/pubmed/30877436

https://link.springer.com/article/10.1007%2Fs00425-019-03138-x

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Second Cannabinoid Receptor Has the Yin to the First Receptor’s Yang

“Understanding the diverse effects that cannabis has on the human body is imperative if we hope to take advantage of its medicinal properties to treat various disorders. As such, elucidating the molecular structure of the receptors that bind endocannabinoids is a critical step toward developing selective drugs that can differentiate between the two known receptors—CB1 and CB2—for these molecules. Since the structure of the CB1 receptor was resolved a few years ago, an international team of researchers led by scientists at the iHuman Institute within ShanghaiTech University has just published the crystal structure of the human type 2 cannabinoid receptor, CB2.

Findings from the new study—published recently in Cell through an article titled “Crystal Structure of the Human Cannabinoid Receptor CB2”—should be helpful in the development of drugs against inflammatory, neurodegenerative, and other diseases. The study authors compared the newly discovered structure to that of the CB1 receptor, deeming the two receptors to be the “yin and yang” of the human endocannabinoid system.”

“Crystal Structure of the Human Cannabinoid Receptor CB1” https://www.cell.com/fulltext/S0092-8674(16)31385-X
“Crystal Structure of the Human Cannabinoid Receptor CB2” https://www.cell.com/cell/pdf/S0092-8674(18)31625-8.pdf
“This study compares newly discovered structures to those of the CB1 receptor, and deems the two receptors to be the Yin and Yang of the human endocannabinoid system, which is a signalling system that regulates biological processes such as pain, immune function, metabolism, and neuronal activities among others.” https://www.worldhealth.net/news/ying-yang-second-cannabinoid-receptor/
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Plant-Based Modulators of Endocannabinoid Signaling.

Journal of Natural Products

“Extracts from Cannabis species have aided the discovery of the endocannabinoid signaling system (ECSS) and phytocannabinoids that possess broad therapeutic potential. Whereas the reinforcing effects of C. sativa are largely attributed to CB1 receptor agonism by Δ9-tetrahydrocannabinol (Δ9-THC), the observed medicinal effects of Cannabis arise from the combined actions of various compounds. In addition to compounds bearing a classical cannabinoid structure, naturally occurring fatty acid amides and esters resembling anandamide and 2-arachidonoyl glycerol isolated from non- Cannabis species are also valuable tools for studying ECSS function. This review highlights the potential of plant-based secondary metabolites from Cannabis and unrelated species as ECSS modulators.”

https://www.ncbi.nlm.nih.gov/pubmed/30816712

https://pubs.acs.org/doi/10.1021/acs.jnatprod.8b00874

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Cannabis and Its Secondary Metabolites: Their Use as Therapeutic Drugs, Toxicological Aspects, and Analytical Determination.

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“Although the medicinal properties of Cannabis species have been known for centuries, the interest on its main active secondary metabolites as therapeutic alternatives for several pathologies has grown in recent years. This potential use has been a revolution worldwide concerning public health, production, use and sale of cannabis, and has led inclusively to legislation changes in some countries. The scientific advances and concerns of the scientific community have allowed a better understanding of cannabis derivatives as pharmacological options in several conditions, such as appetite stimulation, pain treatment, skin pathologies, anticonvulsant therapy, neurodegenerative diseases, and infectious diseases. However, there is some controversy regarding the legal and ethical implications of their use and routes of administration, also concerning the adverse health consequences and deaths attributed to marijuana consumption, and these represent some of the complexities associated with the use of these compounds as therapeutic drugs. This review comprehends the main secondary metabolites of Cannabis, approaching their therapeutic potential and applications, as well as their potential risks, in order to differentiate the consumption as recreational drugs. There will be also a focus on the analytical methodologies for their analysis, in order to aid health professionals and toxicologists in cases where these compounds are present.”

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Complete biosynthesis of cannabinoids and their unnatural analogues in yeast

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“Cannabis sativa L. has been cultivated and used around the globe for its medicinal properties for millennia. Some cannabinoids, the hallmark constituents of Cannabis, and their analogues have been investigated extensively for their potential medical applications. Certain cannabinoid formulations have been approved as prescription drugs in several countries for the treatment of a range of human ailments. However, the study and medicinal use of cannabinoids has been hampered by the legal scheduling of Cannabis, the low in planta abundances of nearly all of the dozens of known cannabinoids, and their structural complexity, which limits bulk chemical synthesis. Here we report the complete biosynthesis of the major cannabinoids cannabigerolic acid, Δ9-tetrahydrocannabinolic acid, cannabidiolic acid, Δ9-tetrahydrocannabivarinic acid and cannabidivarinic acid in Saccharomyces cerevisiae, from the simple sugar galactose. To accomplish this, we engineered the native mevalonate pathway to provide a high flux of geranyl pyrophosphate and introduced a heterologous, multi-organism-derived hexanoyl-CoA biosynthetic pathway. We also introduced the Cannabis genes that encode the enzymes involved in the biosynthesis of olivetolic acid, as well as the gene for a previously undiscovered enzyme with geranylpyrophosphate:olivetolate geranyltransferase activity and the genes for corresponding cannabinoid synthases. Furthermore, we established a biosynthetic approach that harnessed the promiscuity of several pathway genes to produce cannabinoid analogues. Feeding different fatty acids to our engineered strains yielded cannabinoid analogues with modifications in the part of the molecule that is known to alter receptor binding affinity and potency. We also demonstrated that our biological system could be complemented by simple synthetic chemistry to further expand the accessible chemical space. Our work presents a platform for the production of natural and unnatural cannabinoids that will allow for more rigorous study of these compounds and could be used in the development of treatments for a variety of human health problems.”

https://www.nature.com/articles/s41586-019-0978-9

“Yeast can produce THC, CBD, novel cannabinoids”  https://www.upi.com/Science_News/2019/02/28/Yeast-can-produce-THC-CBD-novel-cannabinoids/4411551303863/

“Yeast produce low-cost, high-quality cannabinoids”  https://www.eurekalert.org/pub_releases/2019-02/uoc–ypl022419.php

“Engineered yeast can brew up the active ingredients in cannabis plants”  https://www.newscientist.com/article/2195103-engineered-yeast-can-brew-up-the-active-ingredients-in-cannabis-plants/

“High grade cannabis chemicals produced using brewing yeast”  https://www.independent.co.uk/news/science/cannabis-drug-produced-yeast-marijuana-thc-cbd-medicine-california-a8799576.html

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New Insights in Cannabinoid Receptor Structure and Signaling.

“Cannabinoid has long been used for medicinal purposes. Cannabinoid signaling has been considered the therapeutic targets for treating pain, addiction, obesity, inflammation, and other diseases. Recent studies have suggested that in addition to CB1 and CB2, there are non-CB1 and non-CB2 cannabinoid-related orphan GPCRs including GPR18, GPR55, and GPR119. In addition, CB1 and CB2 display allosteric binding and biased signaling, revealing correlations between biased signaling and functional outcomes. Interestingly, new investigations have indicated that CB1 is functionally present within mitochondria of striated and heart muscles directly regulating intramitochondrial signaling and respiration.

CONCLUSION:

In this review, we summarize the recent progress in cannabinoid-related orphan GPCRs, CB1/CB2 structure, Gi/Gs coupling, allosteric ligands and biased signaling, and mitochondria-localized CB1, and discuss the future promise of this research.”

https://www.ncbi.nlm.nih.gov/pubmed/30767756

http://www.eurekaselect.com/170011/article

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Medicinal Cannabis for Parkinson’s Disease: Practices, Beliefs, and Attitudes Among Providers at National Parkinson Foundation Centers of Excellence.

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“Legalization of the medical use of cannabis for Parkinson’s disease (PD) has bypassed the traditional drug-approval process, leaving physicians with little evidence with which to guide patients.

OBJECTIVE:

The goal of this study was to gather data on the cannabis-related prescribing practices and views regarding potential risks and benefits of cannabis among experts caring for patients with PD.

METHODS:

An anonymous, 73-item online survey was conducted through an online service (SurveyMonkey) and included neurologists at all National Parkinson Foundation Centers of Excellence.

RESULTS:

Fifty-six responders represented centers across 5 countries and 14 states. 23% reported some formal education on cannabis. Eighty percent of responders had patients with PD who used cannabis, and 95% were asked to prescribe it. Fifty-two percent took a neutral position on cannabis use with their patients, 9% discouraged use, and 39% encouraged it. Most believed that the literature supported use of cannabis for nausea (87%; n = 48), anxiety (60%; n = 33), and pain (86%; n = 47), but responses were divided with regard to motor symptoms. Most respondents expected that cannabis would worsen motivation (59%; n = 32), sleepiness (60%; n = 31), and hallucinations (69%; n = 37). In addition, most feared negative effects on short-term memory (75%; n = 42), long-term memory (55%; n = 31), executive functioning (79%; n = 44), and driving (96%; n = 54). Although many did not believe that cannabis should be recreational (50%; n = 28), most believed that it should be legalized for medicinal purposes (69.6%; n = 39).

CONCLUSIONS:

This study provides data on the cannabis-related practices, beliefs, and attitudes of expert PD physicians. There is a lack of consensus that likely reflects a general knowledge gap and paucity of data to guide clinical practice.”

https://www.ncbi.nlm.nih.gov/pubmed/30713951

https://onlinelibrary.wiley.com/doi/full/10.1002/mdc3.12359

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Cannabinoids: the lows and the highs of chemotherapy-induced nausea and vomiting.

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“Despite remaining one of the most widely abused drugs worldwide, Cannabis sativa exhibits remarkable medicinal properties. The phytocannabinoids, cannabidiol and Δ-9-tetrahydrocannabinol, reduce nausea and vomiting, particularly during chemotherapy. This is attributed to their ability to reduce the release of serotonin from enterochromaffin cells in the small intestine, which would otherwise orchestrate the vomiting reflex. Although there are many preclinical and clinical studies on the effects of Δ-9-tetrahydrocannabinol during nausea and vomiting, little is known about the role that cannabidiol plays in this scenario. Since cannabidiol does not induce psychotropic effects, in contrast to other cannabinoids, its use as an anti-emetic is of great interest. This review aims to summarize the available literature on cannabinoid use, with a specific focus on the nonpsychotropic drug cannabidiol, as well as the roles that cannabinoids play in preventing several other adverse side effects of chemotherapy including organ toxicity, pain and loss of appetite.”

https://www.ncbi.nlm.nih.gov/pubmed/30720344

https://www.futuremedicine.com/doi/10.2217/fon-2018-0530

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Impact of Medical Marijuana Legalization on Opioid Use, Chronic Opioid Use, and High-risk Opioid Use.

“Medical marijuana legalization was found to be associated with a lower odds of any opioid use. In states where marijuana is available through medical channels, a modestly lower rate of opioid and high-risk opioid prescribing was observed. Policy makers could consider medical marijuana legalization as a tool that may modestly reduce chronic and high-risk opioid use.” https://www.ncbi.nlm.nih.gov/pubmed/30684198

https://link.springer.com/article/10.1007%2Fs11606-018-4782-2

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A Cost-Effectiveness Model for Adjunctive Smoked Cannabis in the Treatment of Chronic Neuropathic Pain

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“A recent meta-analysis affirmed the benefit of medicinal cannabis for chronic neuropathic pain, a disabling and difficult-to-treat condition. As medicinal cannabis use is becoming increasingly prevalent among Americans, an exploration of its economic feasibility is warranted. We present this cost-effectiveness analysis of adjunctive cannabis pharmacotherapy for chronic peripheral neuropathy.

A growing body of scientific literature demonstrates reproducible efficacy of cannabis in the treatment of several medical conditions, including chronic neuropathic pain. Clinical trials of oral, smoked, and vaporized cannabis and cannabinoids have all demonstrated analgesic benefit of medicinal cannabis in the treatment of this costly and disabling condition. A recent meta-analysis of individual patient data from five randomized controlled trials of inhaled cannabis demonstrated pain relief comparable to gabapentin. Treatment guidelines for neuropathic pain recommend consideration of cannabinoids as third-line agents.

As recently proposed willingness-to-pay thresholds for the United States health marketplace range from $110,000 to $300,000 per QALY, cannabis appears cost-effective when augmenting second-line treatment for painful neuropathy. Further research is warranted to explore the long-term benefit of smoked cannabis and standardization of its dosing for chronic neuropathic pain.”

https://www.liebertpub.com/doi/10.1089/can.2018.0027

“New study analyzes cost effectiveness of smoked cannabis to treat chronic neuropathic pain” https://www.eurekalert.org/pub_releases/2019-01/mali-nsa012919.php

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