Author Archives: David Worrell

Endocannabinoid system in irritable bowel syndrome and cannabis as a therapy.

Posted on by

Complementary Therapies in Medicine“Irritable bowel syndrome (IBS) global burden is underestimated despite its high prevalence. It’s a gastrointestinal disease having obscure pathophysiology with multiple therapies yet unsatisfactory remedies.

The Endocannabinoid system (ECS) of our body plays a key role in maintaining normal physiology of the gastrointestinal tract as well as involves abnormalities including functional diseases like IBS. This review highlights the importance of the Endocannabinoid system, its connections with the normal gastrointestinal functions and abnormalities like IBS.

It also discusses the role of cannabis as medical therapy in IBS patients.

A literature search for articles related to endocannabinoids in IBS and medical cannabis in PubMed and Google Scholar was conducted. The studies highlighted the significant participation of ECS in IBS. However, the breach in obtaining the promising therapeutic model for IBS needed further investigation in ECS and uncover other treatments for IBS.

This review summarizes ECS, highlights the relationship of ECS with IBS and explores cannabis as a potential therapy to treat IBS.”

https://www.ncbi.nlm.nih.gov/pubmed/31987224

https://www.sciencedirect.com/science/article/pii/S0965229919310179?via%3Dihub

Tetrahydrocannabinol and Cannabidiol Use in an Outpatient Palliative Medicine Population.

Posted on by

Image result for American Journal of Hospice and Palliative Medicine® “Palliative medicine physicians are challenged by lack of guidance regarding effectiveness and dosing of cannabis products in the setting of their emerging popularity.

OBJECTIVE:

The aim of this study was to describe early patterns of tetrahydrocannabinol (THC) and cannabidiol (CBD) use in Florida following passage of the state’s first medical marijuana law. We describe here the perceived benefits, side effects, and beliefs expressed by patients in a single outpatient academic palliative medicine practice.

RESULTS:

In all, 24% (14/58) of respondents reported THC use, with half using THC on a daily basis. Patients reported improvements in pain, appetite, and nausea. In all, 71% (10/14) began using THC after the diagnosis of their chronic illness, and the most common form of usage was vaping. In all, 24% (14/58) of patients reported CBD use. Patients reported improvements in pain, and the most common form of usage was topical application. None of the patients had used CBD prior to the onset of their chronic illness. In all, 21% (3/14) of THC users and 21% (3/14) of CBD users thought that their substance was helping to cure their illness. Individual reported side effects in both groups were minimal.

CONCLUSIONS:

Approximately a quarter of outpatient palliative care patients use THC or CBD, often on a daily basis. Palliative care providers should be aware of the frequency, diverse usage, and beliefs behind cannabis product use in this patient population.”

https://www.ncbi.nlm.nih.gov/pubmed/31986898

https://journals.sagepub.com/doi/10.1177/1049909119900378

An evaluation of the anti-hyperalgesic effects of cannabidiolic acid-methyl ester (CBDA-ME) in a preclinical model of peripheral neuropathic pain.

Posted on by

Publication cover image“Chronic neuropathic pain (NEP) is associated with growing therapeutic cannabis use. To promote quality of life without psychotropic effects, cannabinoids other than Δ9-tetrahydrocannabidiol, including cannabidiol and its precursor cannabidiolic acid (CBDA), are being evaluated. Due to its instability, CBDA has been understudied, particularly as an anti-nociceptive agent. Adding a methyl ester group (CBDA-ME) significantly enhances its stability, facilitating analyses of its analgesic effects in vivo. This study examines early treatment efficacy of CBDA-ME in a rat model of peripherally induced NEP and evaluates sex as a biological variable.

KEY RESULTS:

In males, CBDA-ME elicited a significant concentration-dependent chronic anti-hyperalgesic effect, also influencing both nociceptive and non-nociceptive mechanoreceptors, which were not observed in females at any of the concentrations tested.

CONCLUSION AND IMPLICATIONS:

Initiating treatment of a peripheral nerve injury with CBDA-ME at an early stage post-surgery provides anti-nociception in males, warranting further investigation into potential sexual dimorphisms underlying this response.”

https://www.ncbi.nlm.nih.gov/pubmed/31981216

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14997

The Role of Cannabidiol (CBD) in Chronic Pain Management: An Assessment of Current Evidence.

Posted on by

 “Given the growing challenges in chronic pain management coupled with the ongoing consequences of the opioid epidemic, pain management practitioners are looking into more effective, innovative, and safer alternatives to treat pain.

Cannabis-based medicine had been described for hundreds of years but only recently have we seen the more scientific, evidence-based approach to its use, and ongoing investigations continue to explore its potential medical benefits.

While historically more attention has been paid to the psychoactive component of the cannabis plant Δ9-tetrahydrocannabinol (THC), there have been fewer scientific studies on the medical use of the cannabidiol (CBD) – a non-psychoactive component of the cannabis plant.

RECENT FINDINGS:

By examining recent literature, we investigated the use of CBD and its potential role in pain management. Since there are currently no approved pharmaceutical products that contain CBD alone for the management of pain, this review focused on nabiximols (which is a combined product of THC/CBD in a 1:1 ratio) as the only pharmaceutical product available that contains CBD and is being used for the management of pain.

It is difficult to definitely attribute the therapeutic properties to CBD alone since it is always administered with THC.

Based on the available literature, it is difficult to make a recommendation for the use of CBD in chronic pain management. It is also important to note that there are many CBD products currently available as supplements, but these products are non-pharmaceuticals and lack the appropriate clinical studies to support their efficacy claims.”

https://www.ncbi.nlm.nih.gov/pubmed/31980957 

https://link.springer.com/article/10.1007%2Fs11916-020-0835-4

Abnormal Cannabidiol Affects Production of Pro-Inflammatory Mediators and Astrocyte Wound Closure in Primary Astrocytic-Microglial Cocultures.

Posted on by

molecules-logo “Abnormal cannabidiol (abn-CBD) exerts neuroprotective effects in vivo and in vitro. In the present study, we investigated the impact of abn-CBD on the glial production of proinflammatory mediators and scar formation within in vitro models. Primary astrocytic-microglial cocultures and astrocytic cultures from neonatal C57BL/6 mice and CB2 receptor knockout mice were stimulated with lipopolysaccharide (LPS), and the concentrations of tumor necrosis factor α (TNFα), interleukin-6 (IL-6) and nitrite were determined. Furthermore, we performed a live cell microscopy-based scratch-wound assay. After LPS stimulation, TNFα, IL-6 and nitrite production was more strongly increased in cocultures than in isolated astrocytes. Abn-CBD treatment attenuated the LPS-induced production of TNFα and nitrite in cocultures, while IL-6 production remained unaltered. In isolated astrocytes, only LPS-induced TNFα production was reduced by abn-CBD. Similar effects were observed after abn-CBD application in cocultures of CB2 knockout mice. Interestingly, LPS-induced TNFα and nitrite levels were far lower in CB2 knockout cultures compared to wildtypes, while IL-6 levels did not differ. In the scratch-wound assay, treatment with abn-CBD decelerated wound closure when microglial cells were present. Our data shows a differential role of abn-CBD for modulation of glial inflammation and astrocytic scar formation. These findings provide new explanations for mechanisms behind the neuroprotective potential of abn-CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/31979350

https://www.mdpi.com/1420-3049/25/3/496

Phytocannabinoids in Neurological Diseases: Could They Restore a Physiological GABAergic Transmission?

Posted on by

ijms-logo“γ-Aminobutyric acid type A receptors (GABAARs) are the main inhibitory mediators in the central nervous system (CNS). GABAARs are pentameric ligand gated ion channels, and the main subunit composition is usually 2α2βγ, with various isotypes assembled within a set of 19 different subunits. The inhibitory function is mediated by chloride ion movement across the GABAARs, activated by synaptic GABA release, reducing neuronal excitability in the adult CNS. Several studies highlighted the importance of GABA-mediated transmission during neuro-development, and its involvement in different neurological and neurodevelopmental diseases, from anxiety to epilepsy. However, while it is well known how different classes of drugs are able to modulate the GABAARs function (benzodiazepines, barbiturates, neurosteroids, alcohol), up to now little is known about GABAARs and cannabinoids interaction in the CNS. Endocannabinoids and phytocannabinoids are lately emerging as a new class of promising drugs for a wide range of neurological conditions, but their safety as medication, and their mechanisms of action are still to be fully elucidated. In this review, we will focus our attention on two of the most promising molecules (Δ9-tetrahydrocannabinol; Δ9-THC and cannabidiol; CBD) of this new class of drugs and their possible mechanism of action on GABAARs.”

https://www.ncbi.nlm.nih.gov/pubmed/31979108

https://www.mdpi.com/1422-0067/21/3/723

The Endocannabinoid System: A Target for Cancer Treatment.

Posted on by

ijms-logo“In recent years, the endocannabinoid system has received great interest as a potential therapeutic target in numerous pathological conditions.

Cannabinoids have shown an anticancer potential by modulating several pathways involved in cell growth, differentiation, migration, and angiogenesis.

However, the therapeutic efficacy of cannabinoids is limited to the treatment of chemotherapy-induced symptoms or cancer pain, but their use as anticancer drugs in chemotherapeutic protocols requires further investigation.

In this paper, we reviewed the role of cannabinoids in the modulation of signaling mechanisms implicated in tumor progression.”

https://www.ncbi.nlm.nih.gov/pubmed/31979368

https://www.mdpi.com/1422-0067/21/3/747

“In addition to the symptomatic therapy of cancer patients, the antitumor effects of cannabinoids (whether in monotherapy or in combination with other cancer therapies) have promising potential in the treatment of cancer patients.”   https://www.ncbi.nlm.nih.gov/pubmed/31950844
“In addition to the well-known palliative effects of cannabinoids on some cancer-associated symptoms, a large body of evidence shows that these molecules can decrease tumour growth in animal models of cancer. In addition, cannabinoids inhibit angiogenesis and decrease metastasis in various tumour types in laboratory animals. Thus, numerous studies have provided evidence that thc and other cannabinoids exhibit antitumour effects in a wide array of animal models of cancer.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791144/


“Antitumour actions of cannabinoids.”   https://www.ncbi.nlm.nih.gov/pubmed/30019449 

“The endocannabinoid system as a target for the development of new drugs for cancer therapy” https://www.ncbi.nlm.nih.gov/pubmed/12723496

“Cannabinoids as Anticancer Drugs.”  https://www.ncbi.nlm.nih.gov/pubmed/28826542

http://www.thctotalhealthcare.com/category/cancer/

Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation.

Posted on by

molecules-logo“Cannabinoid receptor 1 (CB1) activation has been reported to reduce transient receptor potential cation channel subfamily V member 1 (TRPV1)-induced inflammatory responses and is anti-nociceptive and anti-inflammatory in corneal injury.

We examined whether allosteric ligands, can modulate CB1 signaling to reduce pain and inflammation in corneal hyperalgesia.

Corneal hyperalgesia was generated by chemical cauterization of cornea in wildtype and CB2 knockout (CB2-/-) mice. The novel racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229 were examined alone or in combination with the orthosteric CB1 agonist Δ8-tetrahydrocannabinol (Δ8-THC). Pain responses were assessed following capsaicin (1 µM) stimulation of injured corneas at 6 h post-cauterization. Corneal neutrophil infiltration was also analyzed. GAT228, but not GAT229 or GAT211, reduced pain scores in response to capsaicin stimulation.

Combination treatments of 0.5% GAT229 or 1% GAT211 with subthreshold Δ8-THC (0.4%) significantly reduced pain scores following capsaicin stimulation. The anti-nociceptive effects of both GAT229 and GAT228 were blocked with CB1 antagonist AM251, but remained unaffected in CB2-/- mice. Two percent GAT228, or the combination of 0.2% Δ8-THC with 0.5% GAT229 also significantly reduced corneal inflammation.

CB1 allosteric ligands could offer a novel approach for treating corneal pain and inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/31968549

https://www.mdpi.com/1420-3049/25/2/417

Microglial Phenotypes and Their Relationship to the Cannabinoid System: Therapeutic Implications for Parkinson’s Disease.

Posted on by

 Image result for molecules journal“Parkinson’s disease is a neurodegenerative disorder, the motor symptoms of which are associated classically with Lewy body formation and nigrostriatal degeneration.

Neuroinflammation has been implicated in the progression of this disease, by which microglia become chronically activated in response to α-synuclein pathology and dying neurons, thereby acquiring dishomeostatic phenotypes that are cytotoxic and can cause further neuronal death.

Microglia have a functional endocannabinoid signaling system, expressing the cannabinoid receptors in addition to being capable of synthesizing and degrading endocannabinoids. Alterations in the cannabinoid system-particularly an upregulation in the immunomodulatory CB2 receptor-have been demonstrated to be related to the microglial activation state and hence the microglial phenotype.

This paper will review studies that examine the relationship between the cannabinoid system and microglial activation, and how this association could be manipulated for therapeutic benefit in Parkinson’s disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31973235

“Microglia activation states and cannabinoid system: Therapeutic implications.  There is accumulating evidence indicating that cannabinoids (CBs) might serve as a promising tool to modify the outcome of inflammation, especially by influencing microglial activity. Microglia has a functional endocannabinoid (eCB) signaling system, composed of cannabinoid receptors and the complete machinery for the synthesis and degradation of eCBs. These actions make CBs a promising therapeutic tool to avoid the detrimental effects of inflammation and possibly paving the way to target microglia in order to generate a reparative milieu in neurodegenerative diseases.” https://www.ncbi.nlm.nih.gov/pubmed/27373505

“These findings imply that a hypofunction or a dysregulation of the endocannabinoid system may be responsible for some of the symptoms of these diseases. Scientific evidence shows that cannabis can provide symptomatic relief in several neurodegenerative diseases.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070159/

“Cannabinoids can have neuroprotective effects, and this can be exploited for therapeutic strategies against neurodegenerative diseases”   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243800/

The effect of orally administered dronabinol on optic nerve head blood flow in healthy subjects- a randomized clinical trial.

Posted on by

Publication cover image“It has been hypothesized that besides its intraocular pressure (IOP) lowering potential, tetrahydrocannabinol (THC) may also improve ocular hemodynamics.

The aim of the present study was to investigate whether single oral administration of dronabinol, a synthetic THC, alters optic nerve head blood flow (ONHBF) and its regulation in healthy subjects.

The study was carried out in a randomized, placebo-controlled, double-masked, two-way crossover design in twenty-four healthy subjects. For each study participant, two study days were scheduled, on which they either received capsules containing 5mg dronabinol or placebo. ONHBF was measured with laser Doppler flowmetry at rest and while the study participants performed isometric exercise for six minutes to increase mean arterial blood pressure (MAP). This was repeated one hour after drug intake. Ocular perfusion pressure (OPP) was calculated as 2/3MAP-IOP.

Dronabinol was well tolerated and no cannabinoid-related psychoactive effects were reported.

Neither administration of dronabinol nor placebo had an effect on IOP, MAP or OPP. In contrast, dronabinol significantly increased ONHBF at rest by 9.5±8.1% whereas placebo did not show a change in ONHBF (0.3±7.4% vs. baseline, p<0.001 between study days). Dronabinol did not alter the autoregulatory response of ONHBF to isometric exercise.

In conclusion, the present data indicate that low dose dronabinol increases ONHBF in healthy subjects without affecting IOP, OPP or inducing psychoactive side effects. In addition, dronabinol does not alter the autoregulatory response of ONHBF to an experimental increase in OPP. Further studies are needed to investigate whether this effect can also be observed in glaucoma patients.”

https://www.ncbi.nlm.nih.gov/pubmed/31977076

https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1002/cpt.1797