Monthly Archives: September 2017

Affinity and Efficacy Studies of Tetrahydrocannabinolic Acid A at Cannabinoid Receptor Types One and Two.

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“Introduction: Cannabis biosynthesizes Δ9-tetrahydrocannabinolic acid (THCA-A), which decarboxylates into Δ9-tetrahydrocannabinol (THC). There is growing interest in the therapeutic use of THCA-A, but its clinical application may be hampered by instability. THCA-A lacks cannabimimetic effects; we hypothesize that it has little binding affinity at cannabinoid receptor 1 (CB1).

Results: The THCA-A reagent contained 2% THC. THCA-A displayed small but measurable binding at both hCB1 and hCB2, equating to approximate Ki values of 3.1μM and 12.5μM, respectively. THC showed 62-fold greater affinity at hCB1 and 125-fold greater affinity at hCB2. In efficacy tests, THCA-A (10μM) slightly inhibited forskolin-stimulated cAMP at hCB1, suggestive of weak agonist activity, and no measurable efficacy at hCB2.

Discussion: The presence of THC in our THCA-A certified standard agrees with decarboxylation kinetics (literature reviewed herein), which indicate contamination with THC is nearly unavoidable. THCA-A binding at 10μM approximated THC binding at 200nM. We therefore suspect some of our THCA-A binding curve was artifact-from its inevitable decarboxylation into THC-and the binding affinity of THCA-A is even weaker than our estimated values. We conclude that THCA-A has little affinity or efficacy at CB1 or CB2.

 https://www.ncbi.nlm.nih.gov/pubmed/28861508
http://online.liebertpub.com/doi/10.1089/can.2016.0032

The Clinical Significance of Endocannabinoids in Endometriosis Pain Management.

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“Patients with endometriosis often suffer from diffuse and poorly localized severe pain. The current pain management strategies include medical and hormonal therapy, as well as surgery. Medical management of pain is often insufficient and is associated with high rate of recurrence. Better pain management is therefore of urgent need.

Methods: Among the various candidates, the endocannabinoid system (ECS) has recently emerged as a relevant pharmacological target for the management of endometriosis-related pain. A computerized literature search was performed to identify relevant studies combining the keywords “endometriosis,” “endocannabinoid,” “cannabinoid receptor,” “THC,” and “pain mechanisms.”

Conclusions: This review describes the multiple and complex pain mechanisms associated with endometriosis. Current data and theories concerning the link between the ECS and pain management for endometriosis patients are presented. Finally, we will discuss which aspects of endometriosis-associated pain can be targeted by modulation of the ECS.”

https://www.ncbi.nlm.nih.gov/pubmed/28861506
http://online.liebertpub.com/doi/10.1089/can.2016.0035

Cannabinoid CB1 and CB2 Receptor Signaling and Bias.

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“An agonist that acts through a single receptor can activate numerous signaling pathways. Recent studies have suggested that different ligands can differentially activate these pathways by stabilizing a limited range of receptor conformations, which in turn preferentially drive different downstream signaling cascades. This concept, termed “biased signaling” represents an exciting therapeutic opportunity to target specific pathways that elicit only desired effects, while avoiding undesired effects mediated by different signaling cascades. The cannabinoid receptors CB1 and CB2 each activate multiple pathways, and evidence is emerging for bias within these pathways. This review will summarize the current evidence for biased signaling through cannabinoid receptor subtypes CB1 and CB2.”

https://www.ncbi.nlm.nih.gov/pubmed/28861504

http://online.liebertpub.com/doi/10.1089/can.2016.0037

Increased Renal 2-Arachidonoylglycerol Level Is Associated with Improved Renal Function in a Mouse Model of Acute Kidney Injury.

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Mary Ann Liebert, Inc. publishers

“Acute kidney injury (AKI) is associated with a significantly increased risk of morbidity and mortality. Ischemia-reperfusion injury (IRI) is a major cause of AKI. In this study, we investigated the role of the endocannabinoid (EC) system in renal IRI using a well-established mouse model.

Results: Renal IRI was associated with significantly increased serum BUN and creatinine, increased tubular damage score, increased expression of renal markers of inflammation and oxidative stress and elevated renal 2-AG content. Pretreatment with JZL184 was associated with a significant increase in renal 2-AG content and there was also improved serum BUN, creatinine and tubular damage score. However, renal expression of inflammation and oxidative stress markers remained unchanged.

Conclusions: This is the first report documenting that renal IRI is associated with an increase in kidney 2-AG content. Further enhancement of 2-AG levels using JZL184 improved indices of renal function and histology, but did not lower renal expression of markers of inflammation and oxidative stress. Further studies are needed to determine the mechanisms responsible for the effects observed and the potential value of 2-AG as a therapeutic target in renal IRI.”

 https://www.ncbi.nlm.nih.gov/pubmed/28861493
http://online.liebertpub.com/doi/10.1089/can.2016.0013

Proximal Tubular Cannabinoid-1 Receptor Regulates Obesity-Induced CKD.

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“Obesity-related structural and functional changes in the kidney develop early in the course of obesity and occur independently of hypertension, diabetes, and dyslipidemia. Activating the renal cannabinoid-1 receptor (CB1R) induces nephropathy, whereas CB1R blockade improves kidney function. Whether these effects are mediated via a specific cell type within the kidney remains unknown. Here, we show that specific deletion of CB1R in the renal proximal tubule cells did not protect the mice from obesity, but markedly attenuated the obesity-induced lipid accumulation in the kidney and renal dysfunction, injury, inflammation, and fibrosis. These effects associated with increased activation of liver kinase B1 and the energy sensor AMP-activated protein kinase, as well as enhanced fatty acid β-oxidation. Collectively, these findings indicate that renal proximal tubule cell CB1R contributes to the pathogenesis of obesity-induced renal lipotoxicity and nephropathy by regulating the liver kinase B1/AMP-activated protein kinase signaling pathway.”

https://www.ncbi.nlm.nih.gov/pubmed/28860163

http://jasn.asnjournals.org/content/early/2017/08/30/ASN.2016101085

Decarboxylation Study of Acidic Cannabinoids: A Novel Approach Using Ultra-High-Performance Supercritical Fluid Chromatography/Photodiode Array-Mass Spectrometry.

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Mary Ann Liebert, Inc. publishers

“Decarboxylation is an important step for efficient production of the major active components in cannabis, for example, Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), and cannabigerol (CBG). These cannabinoids do not occur in significant concentrations in cannabis but can be formed by decarboxylation of their corresponding acids, the predominant cannabinoids in the plant. Study of the kinetics of decarboxylation is of importance for phytocannabinoid isolation and dosage formulation for medical use. Efficient analytical methods are essential for simultaneous detection of both neutral and acidic cannabinoids. Methods:C. sativaextracts were used for the studies. Decarboxylation conditions were examined at 80°C, 95°C, 110°C, 130°C, and 145°C for different times up to 60 min in a vacuum oven. An ultra-high performance supercritical fluid chromatography/photodiode array-mass spectrometry (UHPSFC/PDA-MS) method was used for the analysis of acidic and neutral cannabinoids before and after decarboxylation. Results: Decarboxylation at different temperatures displayed an exponential relationship between concentration and time indicating a first-order or pseudo-first-order reaction. The rate constants for Δ9-tetrahydrocannabinolic acid-A (THCA-A) were twice those of the cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA). Decarboxylation of THCA-A was forthright with no side reactions or by-products. Decarboxylation of CBDA and CBGA was not as straightforward due to the unexplained loss of reactants or products. Conclusion: The reported UHPSFC/PDA-MS method provided consistent and sensitive analysis of phytocannabinoids and their decarboxylation products and degradants. The rate of change of acidic cannabinoid concentrations over time allowed for determination of rate constants. Variations of rate constants with temperature yielded values for reaction energy.”

https://www.ncbi.nlm.nih.gov/pubmed/28861498

http://online.liebertpub.com/doi/10.1089/can.2016.0020

The Name of Cannabis: A Short Guide for Nonbotanists.

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Mary Ann Liebert, Inc. publishers

“The genus Cannabis (Family Cannabaceae) is probably indigenous to wet habitats of Asiatic continent. The long coexistence between mankind and Cannabis led to an early domestication of the plant, which soon showed an amazing spectrum of possible utilizations, as a source of textile fibers, as well as narcotic and psychoactive compounds. Nowadays, the specie(s) belonging to the genus Cannabis are represented by myriads of cultivated varieties, often with unstable taxonomic foundations. The nomenclature of Cannabis has been the object of numerous nomenclatural treatments. Linnaeus in Species Plantarum (1753) described a single species of hemp, Cannabis sativa, whereas Lamarck (1785) proposed two species of Cannabis: C. sativa, the species largely cultivated in Western Continent, and Cannabis indica, a wild species growing in India and neighboring countries. The dilemma about the existence of the species C. indica considered distinct from C. sativa continues up to present days. Due to their prevalent economic interest, the nomenclatural treatment is particularly important as far as it concerns the cultivated varieties of Cannabis. In this context, we propose to avoid the distinction between sativa and indica, suggesting a bimodal approach: when a cultivar has been correctly established. It could be advisable to apply a nomenclature system based on the International Code of Nomenclature for Cultivated Plants (ICNCP): it is not necessary to use the species epithets, sativa or indica, and a combination of the genus name and a cultivar epithet in any language and bounded by single quotation marks define an exclusive name for each Cannabis cultivar. In contrast, Cannabis varieties named with vernacular names by medical patients and recreational users, and lacking an adequate description as required by ICNCP, should be named as Cannabis strain, followed by their popularized name and without single quotation marks, having in mind that their names have no taxonomical validity.”

https://www.ncbi.nlm.nih.gov/pubmed/28861494

http://online.liebertpub.com/doi/10.1089/can.2016.0027

The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain.

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“A great need exists for the development of new medications to treat pain resulting from various disease states and types of injury. Given that the endogenous cannabinoid (ie, endocannabinoid) system modulates neuronal and immune cell function, both of which play key roles in pain, therapeutics targeting this system hold promise as novel analgesics.

Potential therapeutic targets include the cannabinoid receptors, type 1 and 2, as well as biosynthetic and catabolic enzymes of the endocannabinoids N-arachidonoylethanolamine and 2-arachidonoylglycerol. Notably, cannabinoid receptor agonists as well as inhibitors of endocannabinoid-regulating enzymes fatty acid amide hydrolase and monoacylglycerol lipase produce reliable antinociceptive effects, and offer opioid-sparing antinociceptive effects in myriad preclinical inflammatory and neuropathic pain models.

Emerging clinical studies show that ‘medicinal’ cannabis or cannabinoid-based medications relieve pain in human diseases, such as cancer, multiple sclerosis, and fibromyalgia.

Here, we examine the preclinical and clinical evidence of various endocannabinoid system targets as potential therapeutic strategies for inflammatory and neuropathic pain conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/28857069

https://www.nature.com/npp/journal/vaop/naam/abs/npp2017204a.html

Cannabinoids in Parkinson’s Disease.

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Mary Ann Liebert, Inc. publishers

“The endocannabinoid system plays a regulatory role in a number of physiological processes and has been found altered in different pathological conditions, including movement disorders. The interactions between cannabinoids and dopamine in the basal ganglia are remarkably complex and involve both the modulation of other neurotransmitters (γ-aminobutyric acid, glutamate, opioids, peptides) and the activation of different receptors subtypes (cannabinoid receptor type 1 and 2).

In the last years, experimental studies contributed to enrich this scenario reporting interactions between cannabinoids and other receptor systems (transient receptor potential vanilloid type 1 cation channel, adenosine receptors, 5-hydroxytryptamine receptors). The improved knowledge, adding new interpretation on the biochemical interaction between cannabinoids and other signaling pathways, may contribute to develop new pharmacological strategies.

A number of preclinical studies in different experimental Parkinson’s disease (PD) models demonstrated that modulating the cannabinoid system may be useful to treat some motor symptoms. Despite new cannabinoid-based medicines have been proposed for motor and nonmotor symptoms of PD, so far, results from clinical studies are controversial and inconclusive. Further clinical studies involving larger samples of patients, appropriate molecular targets, and specific clinical outcome measures are needed to clarify the effectiveness of cannabinoid-based therapies.”  https://www.ncbi.nlm.nih.gov/pubmed/28861502

“Cannabis is a psychoactive compound widely used along history for recreational and therapeutic purposes. Although many open questions remain, cannabis-based therapies have become increasingly common raising considerable interest in politics as well as in general public for legalization of medical cannabis.”  http://online.liebertpub.com/doi/10.1089/can.2017.0002

The Use of Cannabis for Headache Disorders.

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Mary Ann Liebert, Inc. publishers

“Headache disorders are common, debilitating, and, in many cases, inadequately managed by existing treatments. Although clinical trials of cannabis for neuropathic pain have shown promising results, there has been limited research on its use, specifically for headache disorders. This review considers historical prescription practices, summarizes the existing reports on the use of cannabis for headache, and examines the preclinical literature exploring the role of exogenous and endogenous cannabinoids to alter headache pathophysiology. Currently, there is not enough evidence from well-designed clinical trials to support the use of cannabis for headache, but there are sufficient anecdotal and preliminary results, as well as plausible neurobiological mechanisms, to warrant properly designed clinical trials. Such trials are needed to determine short- and long-term efficacy for specific headache types, compatibility with existing treatments, optimal administration practices, as well as potential risks.” https://www.ncbi.nlm.nih.gov/pubmed/28861505

“Preclinical studies examining the role of the endocannabinoid system in migraine pathogenesis also suggest a potential therapeutic value for cannabis in the treatment of headache. It has been postulated that a general deficiency in endocannabinoid tone could underlie headache disorders.” http://online.liebertpub.com/doi/10.1089/can.2016.0033