Isolation, Purification, and Antimicrobial Characterization of Cannabidiolic Acid and Cannabidiol From Cannabis sativa L

biomolecules-logo“The emergence of multi-drug resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) causes a major threat to public health due to its limited therapeutic options.

There is an urgent need for the development of new effective antimicrobial agents and alternative strategies that are effective against resistant bacteria.

The parallel legalization of cannabis and its products has fueled research into its many therapeutic avenues in many countries around the world.

This study aimed at the development of a reliable method for the extraction, purification, characterization, and quantification of cannabidiolic acid (CBDA) and its decarboxylated form cannabidiol (CBD) present in the fiber type Cannabis sativa L.

Overall, CBD exhibited a strong antimicrobial effect against Gram-positive strains and could serve as an alternative drug for tackling MRSA.”

https://pubmed.ncbi.nlm.nih.gov/32545687/

https://www.mdpi.com/2218-273X/10/6/900

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(‒)-Cannabidiolic Acid, a Still Overlooked Bioactive Compound: An Introductory Review and Preliminary Research

molecules-logo“Cannabidiolic acid (CBDA) is the main phytocannabinoid in fiber and seed-oil hemp (Cannabis sativa L.) plants, but its potential health-related capabilities have been masked for years by a greater scientific interest towards its neutral derivative cannabidiol (CBD). This review aims to collect from the literature and critically discuss all the information about this molecule, starting from its biosynthesis, and focusing on its bioactivity, as an anti-inflammatory, anti-emetic, anti-convulsant, and anti-cancerogenic drug. Furthermore, in the awareness that, despite its multiple bioactive effects, currently poor efforts have been made to achieve its reliable purification, herein, we propose a relatively simple, fast, and inexpensive procedure for its recovery from pollen of industrial hemp cultivars. Spectroscopic and spectrometric techniques allowed us to unequivocally identify pure isolated CBDA and to distinguish it from the constitutional isomer tetrahydrocannabinolic acid (THCA-A).”

https://pubmed.ncbi.nlm.nih.gov/32517131/

https://www.mdpi.com/1420-3049/25/11/2638

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Evaluation of Repeated or Acute Treatment With Cannabidiol (CBD), Cannabidiolic Acid (CBDA) or CBDA Methyl Ester (HU-580) on Nausea and/or Vomiting in Rats and Shrews

 SpringerLink“Rationale: When acutely administered intraperitoneally, the non-psychoactive cannabinoid cannabidiol (CBD), its acidic precursor cannabidiolic acid (CBDA) and a stable methyl ester of CBDA (HU-580) reduce lithium chloride (LiCl)-induced conditioned gaping in male rats (a selective preclinical model of acute nausea) via activation of the serotonin 1A (5-HT1A) receptor.

Objectives: To utilise these compounds to manage nausea in the clinic, we must determine if their effectiveness is maintained when injected subcutaneously (s.c) and when repeatedly administered. First, we compared the effectiveness of each of these compounds to reduce conditioned gaping following repeated (7-day) and acute (1-day) pretreatments and whether these anti-nausea effects were mediated by the 5-HT1A receptor. Next, we assessed whether the effectiveness of these compounds can be maintained when administered prior to each of 4 conditioning trials (once per week). We also evaluated the ability of repeated CBD (7 days) to reduce LiCl-induced vomiting in Suncus murinus. Finally, we examined whether acute CBD was equally effective in male and female rats.

Results: Both acute and repeated (7 day) s.c. administrations of CBD (5 mg/kg), CBDA (1 μg/kg) and HU-580 (1 μg/kg) similarly reduced LiCl-induced conditioned gaping, and these effects were blocked by 5HT1A receptor antagonism. When administered over 4 weekly conditioning trials, the anti-nausea effectiveness of each of these compounds was also maintained. Repeated CBD (5 mg/kg, s.c.) maintained its anti-emetic efficacy in S. murinus. Acute CBD (5 and 20 mg/kg, s.c.) administration reduced LiCl-induced conditioned gaping similarly in male and female rats.

Conclusion: When administered repeatedly (7 days), CBD, CBDA and HU-580 did not lose efficacy in reducing nausea and continued to act via agonism of the 5-HT1A receptor. When administered across 4 weekly conditioning trials, they maintained their effectiveness in reducing LiCl-induced nausea. Repeated CBD also reduced vomiting in shrews. Finally, CBD’s anti-nausea effects were similar in male and female rats. This suggests that these cannabinoids may be useful anti-nausea and anti-emetic treatments for chronic conditions, without the development of tolerance.”

https://pubmed.ncbi.nlm.nih.gov/32488349/

https://link.springer.com/article/10.1007%2Fs00213-020-05559-z

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Cannabidiol Disrupts Conditioned Fear Expression and Cannabidiolic Acid Reduces Trauma-Induced Anxiety-Related Behaviour in Mice

Behavioural Pharmacology (journal) - Wikipedia“The major phytocannabinoid cannabidiol (CBD) has anxiolytic properties and lacks tetrahydrocannabinol-like psychoactivity. Cannabidiolic acid (CBDA) is the acidic precursor to CBD, and this compound appears more potent than CBD in animal models of emesis, pain and epilepsy. In this short report, we aimed to examine whether CBDA is more potent than CBD in disrupting expression of conditioned fear and generalised anxiety-related behaviour induced by Pavlovian fear conditioning. Mice underwent fear conditioning and 24 h later were administered CBD and CBDA before testing for fear expression and generalized anxiety-like behaviour. We found that CBD and CBDA had dissociable effects; while CBD but not CBDA disrupted cued fear memory expression, CBDA but not CBD normalized trauma-induced generalized anxiety-related behaviour. Neither phytocannabinoid affected contextual fear expression. Our findings form the basis for future experiments examining whether phytocannabinoids, alone and in combination, are effective in these mouse models of fear and anxiety.”

https://pubmed.ncbi.nlm.nih.gov/32483052/

https://journals.lww.com/behaviouralpharm/Abstract/9000/Cannabidiol_disrupts_conditioned_fear_expression.99176.aspx

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Cannabidiolic acid dampens the expression of cyclooxygenase-2 in MDA-MB-231 breast cancer cells: Possible implication of the peroxisome proliferator-activated receptor β/δ abrogation.

The Journal of Toxicological Sciences “A growing body of experimental evidence strongly suggests that cannabidiolic acid (CBDA), a major component of the fiber-type cannabis plant, exerts a variety of biological activities.

We have reported that CBDA can abrogate cyclooxygenase-2 (COX-2) expression and its enzymatic activity. It is established that aberrant expression of COX-2 correlates with the degree of malignancy in breast cancer.

Although the reduction of COX-2 expression by CBDA offers an attractive medicinal application, the molecular mechanisms underlying these effects have not fully been established.

It has been reported that COX-2 expression is positively controlled by peroxisome proliferator-activated receptor β/δ (PPARβ/δ) in some cancerous cells, although there is “no” modulatory element for PPARβ/δ on the COX-2 promoter. No previous studies have examined whether an interaction between PPARβ/δ-mediated signaling and COX-2 expression exists in MDA-MB-231 cells.

We confirmed, for the first time, that COX-2 expression is positively modulated by PPARβ/δ-mediated signaling in MDA-MB-231 cells. CBDA inhibits PPARβ/δ-mediated transcriptional activation stimulated by the PPARβ/δ-specific agonist, GW501516. Furthermore, the disappearance of cellular actin stress fibers, a hallmark of PPARβ/δ and COX-2 pathway activation, as evoked by the GW501516, was effectively reversed by CBDA. Activator protein-1 (AP-1)-driven transcriptional activity directly involved in the regulation of COX-2 was abrogated by the PPARβ/δ-specific inverse agonists (GSK0660/ST-247). Thus, it is implicated that there is positive interaction between PPARβ/δ and AP-1 in regulation of COX-2.

These data support the concept that CBDA is a functional down-regulator of COX-2 through the abrogation of PPARβ/δ-related signaling, at least in part, in MDA-MB-231 cells.”

https://www.ncbi.nlm.nih.gov/pubmed/32238697

https://www.jstage.jst.go.jp/article/jts/45/4/45_227/_article

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Phytocannabinoids promote viability and functional adipogenesis of bone marrow-derived mesenchymal stem cells through different molecular targets.

Biochemical Pharmacology“The cellular microenvironment plays a critical role in the maintenance of bone marrow-derived mesenchymal stem cells (BM-MSCs) and their subsequent cell lineage differentiation. Recent studies suggested that individuals with adipocyte-related metabolic disorders have altered function and adipogenic potential of adipose stem cell subpopulations, primarily BM-MSCs, increasing the risk of heart attack, stroke or diabetes.

In this study, we explored the potential therapeutic effect of some of the most abundant non-euphoric compounds derived from the Cannabis sativa plant (or phytocannabinoids) including tetrahydrocannabivarin (THCV), cannabidiol (CBD), cannabigerol (CBG), cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA), by analysing their pharmacological activity on the viability of endogenous BM-MSCs as well as their ability to alter BM-MSC proliferation and differentiation into mature adipocytes.

We provide evidence that CBD, CBDA, CBGA and THCV (5 µM) increase the number of viable BM-MSCs; whereas only CBG (5 µM) and CBD (5 µM) alone or in their combination promote their maturation into adipocytes via distinct molecular mechanisms. These effects were revealed both in vitro and in vivo. In addition, phytocannabinoids prevented the insulin signalling impairment induced by palmitate in adipocytes differentiated from BM-MSCs.

Our study highlights phytocannabinoids as a potential novel pharmacological tool to regain control of functional adipose tissue in unregulated energy homeostasis often occurring in metabolic disorders including type 2 diabetes mellitus (T2DM), aging and lipodystrophy.”

https://www.ncbi.nlm.nih.gov/pubmed/32061773

“The promiscuous pharmacology of phytocannabinoids makes them viable candidates for new medicines for the treatment of metabolic syndromes through the simultaneous resolution of collective complications due to impaired development, maintenance, activity and function of the adipose tissue. Furthermore, phytocannabinoids are generally well tolerated in comparison to potent synthetic PPAR agonists, and combination treatments may further improve their efficacy at lower doses.”

https://www.sciencedirect.com/science/article/pii/S0006295220300873?via%3Dihub

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Effect of combined doses of Δ9-tetrahydrocannabinol and cannabidiol or tetrahydrocannabinolic acid and cannabidiolic acid on acute nausea in male Sprague-Dawley rats.

 “This study evaluated the potential of combined cannabis constituents to reduce nausea.

CONCLUSION:

Combinations of very low doses of CBD + THC or CBDA + THCA robustly reduce LiCl-induced conditioned gaping. Clinical trials are necessary to determine the efficacy of using single or combined cannabinoids as adjunct treatments with existing anti-emetic regimens to manage chemotherapy-induced nausea.”

https://www.ncbi.nlm.nih.gov/pubmed/31897571

https://link.springer.com/article/10.1007%2Fs00213-019-05428-4

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Sleep and Neurochemical Modulation by Cannabidiolic Acid Methyl Ester in Rats.

Brain Research Bulletin“Cannabidiolic acid methyl ester (HU-580) is a more stable compound than cannabidiolic acid (CBDA) which has been shown to be effective in reducing nausea, anxiety, depression behaviors in animal models.

Here we extend the investigation of this compound to determine its effect on the sleep-wake cycle in male Wistar rats.

HU-580 dose-dependently (0.1, 1.0 or 100 µg/Kg, i.p.) prolonged wakefulness (W) and decreased slow wave sleep (SWS) duration whereas rapid eye movement sleep (REMS) showed no statistical change. In addition, the brain microdialysis probes either placed at nucleus accumbens (NAc) or into the basal forebrain in freely moving animals were used to evaluate the effects of HU-580 treatment on neurotransmitters related to the sleep-wake cycle modulation. HU-580 enhanced extracellular levels of dopamine, serotonin collected from NAc while adenosine and acetylcholine were increased in basal forebrain.

In summary, HU-580 seems to possess wake-promoting pharmacological properties and enhances the levels of wake-related neurochemicals. This is the first report of effects of HU-580 on sleep modulation expanding the very limited existent data on the neurobiological effects of HU-580 on rats.”

https://www.ncbi.nlm.nih.gov/pubmed/31838151

https://www.sciencedirect.com/science/article/abs/pii/S0361923019306306?via%3Dihub

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Pharmacokinetics of Phytocannabinoid Acids and Anticonvulsant Effect of Cannabidiolic Acid in a Mouse Model of Dravet Syndrome.

 Go to Volume 0, Issue 0“Cannabis sativa produces a complex mixture of many bioactive molecules including terpenophenolic compounds known as phytocannabinoids. Phytocannabinoids come in neutral forms (e.g., Δ9-tetrahydrocannabinol, THC; cannabidiol, CBD; etc.) or as acid precursors, which are dominant in the plant (e.g., Δ9-tetrahydrocannabinolic acid, THCA; cannabidiolic acid, CBDA; etc.).

There is increasing interest in unlocking the therapeutic applications of the phytocannabinoid acids; however, the present understanding of the basic pharmacology of phytocannabinoid acids is limited. Herein the brain and plasma pharmacokinetic profiles of CBDA, THCA, cannabichromenic acid (CBCA), cannabidivarinic acid (CBDVA), cannabigerolic acid (CBGA), and cannabigerovarinic acid (CBGVA) were examined following intraperitoneal administration in mice.

Next it was examined whether CBDA was anticonvulsant in a mouse model of Dravet syndrome (Scn1aRX/+ mice). All the phytocannabinoid acids investigated were rapidly absorbed with plasma tmax values of between 15 and 45 min and had relatively short half-lives (<4 h). The brain-plasma ratios for the acids were very low at ≤0.04. However, when CBDA was administered in an alternate Tween 80-based vehicle, it exhibited a brain-plasma ratio of 1.9. The anticonvulsant potential of CBDA was examined using this vehicle, and it was found that CBDA significantly increased the temperature threshold at which the Scn1aRX/+ mice had a generalized tonic-clonic seizure.”

https://www.ncbi.nlm.nih.gov/pubmed/31686510

https://pubs.acs.org/doi/abs/10.1021/acs.jnatprod.9b00600

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Cannabidiolic Acid-Mediated Interference with AP-1 Transcriptional Activity in MDA-MB-231 Breast Cancer Cells.

 Image result for Nat Prod Commun journal

“We reported that cannabidiolic acid (CBDA), a non-psychotropic constituent of fiber-type cannabis plants, down-regulates the mRNA expression of cyclooxygenase-2 (COX-2) in highly aggressive MDA-MB-231 human breast cancer cells. However, the molecular mechanism(s) underlying the CBDA suppression of COX-2 have not yet been elucidated in detail. In MDA-MB-231 cells, COX-2 expression is known to be tightly regulated by the transcriptional activity of activator protein-I (AP-1), which is composed of a heterodimer of c-Fos and c-Jun. AP-1-mediated transcriptional activity was inhibited by CBDA in a dose-dependent manner. The expression of c-fos was maintained at markedly lower levels (0.035) than basal c-jun expression levels (1.0), implicating c- fos as a limiting factor in the regulation of COX-2. Analyses indicated that CBDA abrogated the expression of c-fos mRNA without affecting c-jun. Collectively, these results suggest that CBDA abolishes the expression of COX-2 by interfering with AP-I activity in MDA-MB3-231 cells.”

https://www.ncbi.nlm.nih.gov/pubmed/30496661

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