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Cannabinomics: Application of Metabolomics in Cannabis ( Cannabis sativa L.) Research and Development

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frontiers in plant science – Retraction Watch “Cannabis (Cannabis sativa L.) is a complex, polymorphic plant species, which produces a vast array of bioactive metabolites, the two major chemical groups being cannabinoids and terpenoids. Nonetheless, the psychoactive cannabinoid tetrahydrocannabinol (Δ 9 -THC) and the non-psychoactive cannabidiol (CBD), are the two major cannabinoids that have monopolized the research interest.

Currently, more than 600 Cannabis varieties are commercially available, providing access to a multitude of potent extracts with complex compositions, whose genetics are largely inconclusive. Recently introduced legislation on Cannabis cultivation in many countries represents a great opportunity, but at the same time, a great challenge for Cannabis research and development (R&D) toward applications in the pharmaceutical, food, cosmetics, and agrochemical industries.

Based on its versatility and unique capabilities in the deconvolution of the metabolite composition of complex matrices, metabolomics represents an ideal bioanalytical tool that could greatly assist and accelerate Cannabis R&D. Among others, Cannabis metabolomics or cannabinomics can be applied in the taxonomy of Cannabis varieties in chemovars, the research on the discovery and assessment of new Cannabis-based sources of bioactivity in medicine, the development of new food products, and the optimization of its cultivation, aiming for improvements in yield and potency.

Although Cannabis research is still in its infancy, it is highly foreseen that the employment of advanced metabolomics will provide insights that could assist the sector to face the aforementioned challenges. Within this context, here, the current state-of-the-art and conceptual aspects of cannabinomics are presented.”

https://pubmed.ncbi.nlm.nih.gov/32457786/

https://www.frontiersin.org/articles/10.3389/fpls.2020.00554/full

www.frontiersin.org

Post Marketing Safety of Plus CBD™ Products, a Full Spectrum Hemp Extract: A 2-Year Experience

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 Publication Cover“The market for products featuring hemp extracts is large and growing larger. However, safety concerns have been raised by medical and regulatory agencies. Post marketing surveillance of full spectrum hemp extract (FSHE) products manufactured and distributed by CV Sciences (CVSI) and traded under the brand PlusCBD™ was conducted over a 2-year period (2018-2019). The safety of these products was assessed by analyzing adverse events reports.

From a total of approximately five million product units sold during the 2-year period, 1,429 (0.03%) adverse events (AE) were reported in 1,151 unique customers. Of those, only two were classified as serious AEs. For orally ingested products, the most common types of AEs reported were gastrointestinal (e.g. abdominal discomfort), while for topically applied products, the most reports mentioned dermatological symptoms (e.g. rashes). There has been no evidence of liver toxicity associated with CVSI products.

Based on this longitudinal dataset, the products manufactured using CVSI’s proprietary processes are safe and well tolerated at the recommended doses.”

https://pubmed.ncbi.nlm.nih.gov/32449632/

https://www.tandfonline.com/doi/abs/10.1080/19390211.2020.1767255?journalCode=ijds20

Antioxidant and Neuroprotective Effects Induced by Cannabidiol and Cannabigerol in Rat CTX-TNA2 Astrocytes and Isolated Cortexes

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ijms-logo“Cannabidiol (CBD) and cannabigerol (CBG) are Cannabis sativa terpenophenols.

Although CBD’s effectiveness against neurological diseases has already been demonstrated, nothing is known about CBG. Therefore, a comparison of the effects of these compounds was performed in two experimental models mimicking the oxidative stress and neurotoxicity occurring in neurological diseases.

Rat astrocytes were exposed to hydrogen peroxide and cell viability, reactive oxygen species production and apoptosis occurrence were investigated. Cortexes were exposed to K+ 60 mM depolarizing stimulus and serotonin (5-HT) turnover, 3-hydroxykinurenine and kynurenic acid levels were measured. A proteomic analysis and bioinformatics and docking studies were performed.

Both compounds exerted antioxidant effects in astrocytes and restored the cortex level of 5-HT depleted by neurotoxic stimuli, whereas sole CBD restored the basal levels of 3-hydroxykinurenine and kynurenic acid. CBG was less effective than CBD in restoring the levels of proteins involved in neurotransmitter exocytosis. Docking analyses predicted the inhibitory effects of these compounds towards the neurokinin B receptor.

Conclusion: The results in the in vitro system suggest brain non-neuronal cells as a target in the treatment of oxidative conditions, whereas findings in the ex vivo system and docking analyses imply the potential roles of CBD and CBG as neuroprotective agents.”

https://pubmed.ncbi.nlm.nih.gov/32443623/

https://www.mdpi.com/1422-0067/21/10/3575

The Cannabis Spread Throughout the Continents and Its Therapeutic Use in History

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“Historical relevance: Cannabis sativa L. (C. sativa) is a plant whose use as a therapeutic agent shares its origins with the first Far East’s human societies. Cannabis has been used not only for recreational purposes, but as a food to obtain textile fibers, to produce hemp paper, to treat many physical and mental disorders.

This review aims to provide a complete assessment of the deep knowledge of the cannabis psychoactive effects and medicinal properties in the course of history covering i.) the empirical use of the seeds and the inflorescences to treat many physical ailments by the ancient Oriental physicians ii.) the current use of cannabis as a therapeutic agent after the discovery of its key psychoactive constituent and the human endogenous endocannabinoid system.

Results and conclusion: Through a detailed analysis of the available resources about the origins of C. sativa we found that its use by ancient civilizations as a source of food and textile fibers dates back over 10,000 years, while its therapeutic applications have been improved over the centuries, from the ancient East medicine of the 2nd and 1st millennium B.C. to the more recent introduction in the Western world after the 1st century A.D. In the 20th and 21th centuries, Cannabis and its derivatives have been considered as a menace and banned throughout the world, but nowadays they are still the most widely consumed illicit drugs all over the world. Its legalization in some jurisdictions has been accompanied by new lines of research to investigate its possible applications for medical and therapeutic purposes.”

https://pubmed.ncbi.nlm.nih.gov/32433013/?from_term=cannabinoid&from_sort=date&from_size=200&from_pos=6

http://www.eurekaselect.com/182145/article

Cannabis Phytomolecule ‘Entourage’: From Domestication to Medical Use.

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Trends in Plant Science: Special issue: Specifi...“Cannabis has been used as a medicine for millennia.

Crude extracts of cannabis inflorescence contain numerous phytomolecules, including phytocannabinoids, terpenes, and flavonoids. Combinations of phytomolecules have been recently established as superior to the use of single molecules in medical treatment owing to the ‘entourage effect’.

Two types of entourage effects are defined: ‘intra-entourage’, resulting from interactions among phytocannabinoids or terpenes, and ‘inter-entourage’, attributed to interactions between phytocannabinoids and terpenes. It is suggested that the phytomolecule assemblages found in cannabis chemovars today derive from selective breeding during ancient cultivation.

We propose that the current cannabis chemotaxonomy should be redefined according to chemical content and medicinal activity. In parallel, combinations of phytomolecules that exhibit entourage activity should be explored further for future drug development.”

https://www.ncbi.nlm.nih.gov/pubmed/32417167

“Cannabis has been used for millennia by humanity for social, ritual, and medical purposes. Humans bred and selected for cannabis strains based on their needs.”

https://www.cell.com/trends/plant-science/pdf/S1360-1385(20)30122-9.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1360138520301229%3Fshowall%3Dtrue

Biological potential of varinic-, minor-, and acidic phytocannabinoids.

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Pharmacological Research“While natural Δ9-tetrahidrocannabinol (Δ9THC), cannabidiol (CBD), and their therapeutic potential have been extensively researched, some cannabinoids have not been widely investigated.

The present article compiles data from the literature that highlights research on and the therapeutic possibilities of lesser known phytocannabinoids, which we have divided into varinic, acidic, and “minor” (i.e., cannabinoids that are not present in high quantities in common varieties of Cannabis sativa L).

A growing interest in these compounds, which are enriched in some cannabis varieties, has already resulted in enough preclinical information to show that they are promising therapeutic agents for a variety of diseases.

Each phytocannabinoid has a “preferential” mechanism of action, and often target the cannabinoid receptors CB1 and/or CB2. The recent resolution of the structure of cannabinoid receptors demonstrates the atypical nature of cannabinoid binding, and that different binding modes depend on the agonist or partial agonist/inverse agonist, which allows for differential signaling, even acting on the same cannabinoid receptor. In addition, other players and multiple signaling pathways may be targeted/engaged by phytocannabinoids, thereby expanding the mechanistic possibilities for therapeutic use.”

https://www.ncbi.nlm.nih.gov/pubmed/32416215

https://www.sciencedirect.com/science/article/abs/pii/S1043661820311099?via%3Dihub

A Phase 1, Randomised, Placebo-Controlled, Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of Cannabidiol in Fed Healthy Volunteers.

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SpringerLink“There is increasing interest in the use of purified cannabidiol (CBD) as a treatment for a wide range of conditions due to its reported anti-inflammatory, anxiolytic, antiemetic and anticonvulsant properties.

OBJECTIVE:

The objective of this study was to assess the safety, tolerability and pharmacokinetics of a single ascending dose of a new lipid-based oral formulation of CBD in healthy volunteers after a high-fat meal.

RESULTS:

CBD was well tolerated in the healthy volunteers (mean age: 24.0 years) treated with a single oral dose of CBD. There were no safety concerns with increasing the dose and the safety profiles of the CBD-treated and placebo-treated subjects were similar. The most frequently reported treatment emergent adverse events (TEAEs) were headache (17%) and diarrhoea (8%). There were no reported serious adverse events (SAEs) and no clinical laboratory findings, vital signs, ECGs or physical examination findings that were reported as TEAEs or were of clinical significance during the study. After a high-fat meal, CBD was detected in plasma samples at 15 min postdose; the median time to maximum plasma concentration (Tmax) was 4 h across all three CBD dose cohorts. The CBD plasma exposure [maximum observed plasma concentration (Cmax) and the area under the concentration-time curve (AUC)] increased in a dose-proportional manner and declined to levels approaching the lower level of quantification by day 8. The terminal elimination half-life was approximately 70 h, suggesting that 2-3 weeks are needed to fully eliminate CBD.

CONCLUSIONS:

This new CBD formulation demonstrated a favourable safety and tolerability profile in healthy volunteers that was consistent with the profiles reported for other purified CBD products. No severe or serious AEs were observed in this study and there were no safety concerns.”

https://www.ncbi.nlm.nih.gov/pubmed/32409982

“Cannabidiol (CBD) is a major nonpsychoactive cannabinoid derived from the Cannabis plant that has attracted significant interest due to its anti-inflammatory, anxiolytic, antiemetic and anticonvulsant properties. The findings of this study contribute to the evolving knowledge of cannabidiol pharmacokinetics and indicate that this new oral lipid-based formulation of cannabidiol is generally safe and well tolerated at all doses studied. No severe or serious AEs were observed and there were no safety concerns.”

https://link.springer.com/article/10.1007%2Fs13318-020-00624-6

State Medical Cannabis Laws Associated With Reduction in Opioid Prescriptions by Orthopaedic Surgeons in Medicare Part D Cohort.

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Current Issue Cover Image“Opioid prescriptions and abuse remain a significant national concern.

Cannabinoids offer a potentially attractive nonopioid analgesic option for orthopaedic patients, and 32 US states have passed medical cannabis laws (MCLs), legalizing patient access to cannabinoids.

We examine the association between implementation of state cannabis laws and prescribing patterns for opioids by orthopaedic surgeons in Medicare Part D patients between 2013 and 2017.

RESULTS:

State MCLs were associated with a statistically significant reduction in aggregate opioid prescribing of 144,000 daily doses (19.7% reduction) annually (95% confidence interval [CI], -0.535 to -0.024 million; P < 0.01). States with MCLs allowing access to in-state dispensaries had a statistically significant reduction in total opioid prescriptions of 96,000 daily doses (13.1%) annually (95% CI, -0.165 to -0.026 million; P < 0.01). Specifically, MCLs were associated with a statistically significant reduction of 72,000 daily doses of hydrocodone annually (95% CI, -0.164 to -0.019 million; P < 0.01). No significant association between recreational marijuana legalization and opioid prescribing was found.

CONCLUSION:

Orthopaedic surgeons are among the highest prescribers of opioids, highlighting the importance of providing nonopioid analgesic alternatives in efforts to reduce opioid use in the patient cohort. This study is the first to examine the association between implementation of state cannabis laws and prescribing patterns for opioids by orthopaedic surgeons in Medicare Part D patients.”

https://www.ncbi.nlm.nih.gov/pubmed/32404683

https://journals.lww.com/jaaos/Abstract/9000/State_Medical_Cannabis_Laws_Associated_With.99112.aspx

Nothing Ventured, Nothing Gained: Regulations Cripple Potentially Life-Saving Research of Illicit Substances.

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Go to Volume 0, Issue 0 “Modern day research, in an attempt to determine the potential therapeutic and adverse effects of illicit substances, is a growing field, but one that faces many regulatory challenges. Due to the potential abuse of illicit substances such as Cannabis, 3,4-methylenedioxymethamphetamine (MDMA), lysergic acid diethylamide (LSD) and psilocybin, regulations have been conceived with the intent of preventing harm and addiction. However, these regulations have also become a major barrier for the scientific community as they suffocate attempts of the scientists to acquire illicit substances for research purposes. Therefore, it is imperative to modify the current regulations of drug scheduling, leading to a reclassification of illicit substances that would allow for extensive testing in research settings. This reclassification effort could advance the potentially life-saving research of illicit substances.”

https://www.ncbi.nlm.nih.gov/pubmed/32395981

https://pubs.acs.org/doi/10.1021/acschemneuro.0c00241

Abstract Image

Cannabidiol on 5-FU-induced oral mucositis in mice.

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Oral Diseases

“The aim of this study was to evaluate the clinical, histological, hematological and oxidative stress effects of cannabidiol (CBD) in mice with induced oral mucositis.

RESULTS:

In the clinical evaluation, the groups treated with CBD showed less severity of oral lesions compared with the positive control at both experimental times. The intensity of the inflammatory response was also lower in the groups treated with this drug, but there was no statistically significant difference when compared with the positive control. With regard to erythrocyte, leukocyte and platelet counts and antioxidant enzyme activity, the groups treated with CBD showed better results, but only some of these variables showed statistically significant differences.

CONCLUSIONS:

CBD seems to exert an anti-inflammatory and antioxidant activity favoring a faster resolution of oral mucositis in this animal model.”

https://www.ncbi.nlm.nih.gov/pubmed/32400905

https://onlinelibrary.wiley.com/doi/abs/10.1111/odi.13413