Author Archives: David Worrell

Endocannabinoid modulation of inflammatory hyperalgesia in the IFN-α mouse model of depression.

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Brain, Behavior, and Immunity“Depression is a well-recognised effect of long-term treatment with interferon-alpha (IFN-α), a widely used treatment for chronic viral hepatitis and malignancy. In addition to the emotional disturbances, high incidences of painful symptoms such as headache and joint pain have also been reported following IFN-α treatment.

The endocannabinoid system plays an important role in emotional and nociceptive processing, however it is unknown whether repeated IFN-α administration induces alterations in this system.

The present study investigated nociceptive responding in the IFN-α-induced mouse model of depression and associated changes in the endocannabinoid system. Furthermore, the effects of modulating peripheral endocannabinoid tone on inflammatory pain-related behaviour in the IFN-α model was examined.

In summary, increasing peripheral endocannabinoid tone attenuates inflammatory hyperalgesia induced following repeated IFN-α administration. These data provide support for the endocannabinoid system in mediating and modulating heightened pain responding associated with IFNα-induced depression.”

https://www.ncbi.nlm.nih.gov/pubmed/31505257

“Inflammatory hyperalgesia is associated with altered endocannabinoid levels. Enhancing peripheral endocannabinoid tone attenuates IFN-α related hyperalgesia.”

https://www.sciencedirect.com/science/article/pii/S0889159119306063?via%3Dihub

Medical Cannabis in Treatment of Resistant Familial Mediterranean Fever.

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 Logo“Colchicine-resistant familial Mediterranean fever can be treated by anti-IL-1 biologic therapy; however, such treatment needs approval by the health insurance company, and many patients are denied such treatment or do not respond to it.

CASE REPORT Two familial Mediterranean fever (FMF) patients, both homozygous for M694V mutation and resistant to colchicine treatment, were treated with medical cannabis. Prior to that, 1 patient was denied biologic treatment and the other had no significant response to anakinra.

Under medical cannabis treatment, both patients had remarkable improvement in the severity of the attacks and also a decrease in the frequency of the attacks, from once every 2 weeks to 1 attack every month in 1 patient; this patient had also a remarkable reduction in the C-reactive protein level during the attacks.

CONCLUSIONS Cannabis is a therapeutic option for treating the most complex patients with FMF.”

https://www.ncbi.nlm.nih.gov/pubmed/31501406

https://www.amjcaserep.com/abstract/index/idArt/917180

Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model mice.

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 Image result for J Clin Invest.“Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, lack of speech, ataxia, EEG abnormalities, and epilepsy. Seizures in AS individuals are common, debilitating, and often drug-resistant. Therefore, there is an unmet need for better treatment options.

Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, has antiseizure activity and behavioral benefits in preclinical and clinical studies for some disorders associated with epilepsy, suggesting that the same could be true for AS.

Here we show that acute CBD (100 mg/kg) attenuated hyperthermia- and acoustically-induced seizures in a mouse model of AS. However, neither acute CBD nor a two-weeklong course of CBD administered immediately after a kindling protocol could halt the pro-epileptogenic plasticity observed in AS model mice.

CBD had a dose-dependent sedative effect, but did not have an impact on motor performance. CBD abrogated the enhanced intracortical local field potential power, including delta and theta rhythms observed in AS model mice, indicating that CBD administration could also help normalize the EEG deficits observed in individuals with AS.

Our results provide critical preclinical evidence supporting CBD treatment of seizures and alleviation of EEG abnormalities in AS, and will thus help guide the rational development of CBD as an AS treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/31503547

https://www.jci.org/articles/view/130419

“CBD Could Help Treat Angelman Syndrome, Says Study”   https://www.analyticalcannabis.com/articles/cbd-could-help-treat-angelman-syndrome-says-study-311798

“Medical marijuana saved the life of 8 year old boy with Angelman Syndrome”   http://www.chicagonow.com/soapbox-momma/2016/05/medical-marijuana-saved-the-life-of-8-year-old-boy-with-angelman-syndrome/

State marijuana laws and opioid overdose mortality.

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Image result for Injury Epidemiology “The opioid epidemic in the United States is a national public health crisis.

In recent years, marijuana legalization has been increasingly adopted by state governments as a policy intervention to control the opioid epidemic under the premise that marijuana and opioids are substitutive substances.

The purpose of this systematic review is to synthesize the empirical evidence regarding the impact of state marijuana laws on opioid overdose mortality and other opioid-related health outcomes.

RESULTS:

Of the 16 eligible studies, 4 assessed the association of state marijuana law status with opioid overdose mortality, 7 with prescription opioids dispensed, and the remaining with nonmedical use and opioid-related hospitalizations. Random effects modeling based on pooled data revealed that legalizing marijuana for medical use was associated with a statistically non-significant 8% reduction in opioid overdose mortality (95% confidence interval: - 0.21 to 0.04; p = 0.201) and a 7% reduction in prescription opioids dispensed (95% confidence interval: - 0.13 to - 0.01; p = 0.017). Legalizing marijuana for recreational use was associated with an additional 7% reduction in opioid overdose mortality in Colorado and 6% reduction in opioid prescriptions among fee-for-service Medicaid and managed care enrollees.

CONCLUSIONS:

Legalizing marijuana might contribute to a modest reduction in opioid prescriptions. Evidence about the effect of marijuana legalization on opioid overdose mortality is inconsistent and inconclusive. If any, the effectiveness of state marijuana laws in reducing opioid overdose mortality appears to be rather small and limited to states with operational marijuana dispensaries. It remains unclear whether the presumed benefit of legalizing marijuana in reducing opioid-related harms outweighs the policy’s externalities, such as its impact on mental health and traffic safety.”

https://www.ncbi.nlm.nih.gov/pubmed/31497489

“Legalizing marijuana might contribute to a modest reduction in opioid prescriptions.”

https://injepijournal.biomedcentral.com/articles/10.1186/s40621-019-0213-z

Cannabidiol improves metabolic dysfunction in middle-aged diabetic rats submitted to a chronic cerebral hypoperfusion.

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Chemico-Biological Interactions“Cannabidiol (CBD), a compound obtained from Cannabis sativa, has wide range of therapeutic properties, including mitigation of diabetes and neurodegeneration.

Cerebral ischemia and consequent learning disabilities are aggravated in elderly diabetic subjects. However, there are no studies showing the effect of CBD treatment in elderly diabetes patients suffering cerebral ischemia.

The present work tested the hypothesis that CBD treatment improves metabolic dysfunctions in middle-aged diabetic rats submitted to chronic cerebral hypoperfusion.

CBD may be used as therapeutic tool to protect metabolism against injuries from diabetes aggravated by cerebral ischemia.”

https://www.ncbi.nlm.nih.gov/pubmed/31499052

“CBD reduced hyperglycemia of middle-aged diabetic rats with CCH. CBD increased insulin secretion and decreased AGEs levels. CBD reduced fructosamine, LDL, HDL, triglycerides and total cholesterol levels. CBD presented hepatoprotective effect. CBD could mitigate neurodegeneration caused by DM associated to cerebral ischemia.”

https://www.sciencedirect.com/science/article/abs/pii/S000927971930701X?via%3Dihub

The effects of cannabis, cannabinoids, and their administration routes on pain control efficacy and safety: A systematic review and network meta-analysis.

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“To determine the effects of cannabis, cannabinoids, and their administration routes on pain and adverse euphoria events.

Randomized controlled trials investigating the effects of cannabis or cannabinoids on pain reduction.

RESULTS:

A total of 25 studies involving 2270 patients were included. We found that delta-9-tetrahydrocannabinol/cannabidiol (THC/CBD) (oromucosal route), THC (oromucosal route), and standardized dried cannabis (with THC; SCT; inhalation route) could reduce neuropathic pain score (SMD -0.41, 95% CI -0.7 to -0.1; -0.61, 95% CI -1.2 to -0.02; and -0.77, 95% CI -1.4 to -0.2; respectively). For nociceptive pain, only standardized cannabis extract (with THC; SCET) via oral route could reduce pain score (SMD -1.8, 95% C; -2.4 to -1.2). In cancer pain, THC/CBD via oromucosal route and THC via oral or oromucosal route could reduce pain score (SMD -0.7, 95% CI -1.2 to -0.2; and -2.1, 95% CI -2.8 to -1.4; respectively). No study was observed for THC/CBD via oral route or inhalation or THC via inhalation for cancer and nociceptive pain, SCET via oromucosal route or inhalation for neuropathic and cancer pain, THC via oromucosal route for nociceptive pain, and SCT via oromucosal or oral route for neuropathic, cancer, and nociceptive pain. Statistically significant increased risks of euphoria were observed in THC/CBD (oromucosal), THC (oromucosal), and SCT (inhalation).

CONCLUSION:

The use of cannabis and cannabinoids via certain administration routes could reduce different types of pain. Product developers could consider our findings as part of their product design so that the effective route of cannabis and cannabinoids for pain control can be achieved.”

https://www.ncbi.nlm.nih.gov/pubmed/31495691

https://www.japha.org/article/S1544-3191(19)30353-X/fulltext

Combination of Cannabinoids, Δ9- Tetrahydrocannabinol and Cannabidiol, Ameliorates Experimental Multiple Sclerosis by Suppressing Neuroinflammation Through Regulation of miRNA-Mediated Signaling Pathways.

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 Image result for frontiers in immunology“Multiple sclerosis (MS) is a chronic and disabling disorder of the central nervous system (CNS) characterized by neuroinflammation leading to demyelination.

Recently a combination of Δ9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) extracted from Cannabis has been approved in many parts of the world to treat MS-related spasticity. THC+CBD combination was also shown to suppresses neuroinflammation, although the mechanisms remain to be further elucidated.

In the current study, we demonstrate that THC+CBD combination therapy (10 mg/kg each) but not THC or CBD alone, attenuates murine experimental autoimmune encephalomyelitis (EAE) by reducing neuroinflammation and suppression of Th17 and Th1 cells.

Collectively, this study suggests that combination of THC+CBD suppresses neuroinflammation and attenuates clinical EAE development and that this effect is associated with changes in miRNA profile in brain-infiltrating cells.”

https://www.ncbi.nlm.nih.gov/pubmed/31497013

“Combination of THC+CBD has been used to treat human MS. This treatment is known to decrease not only muscle spasticity but also suppress neuroinflammation.”

https://www.frontiersin.org/articles/10.3389/fimmu.2019.01921/full

Cannabis use and risk of Clostridioides difficile infection: Analysis of 59,824 hospitalizations.

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Anaerobe“The prevalence of Clostridioides difficile Infection (CDI), the most notorious hospital acquired disease, and of excessive cannabis use (cannabis use disorder (CUD)) have both been steadily rising.

Although cannabidiol, an active ingredient of cannabis, maintains gut integrity and suppresses entero-toxins from Clostridioides difficile, the relationship between CUD and CDI has not been studied.

RESULTS:

Among the matched hospitalizations (n = 59,824), cannabis usage was associated with a reduced prevalence of CDI (prevalence: 455.5 [95% CI: 385.1-538.8] vs. 636.4 [95% CI: 549.9-736.5] per 100,000 hospitalizations), resulting in a 28% reduced risk of CDI (relative risk: 0.72 [95% CI: 0.58-0.88]; p = 0002). Non-dependent and dependent CUD respectively had 23% and 80% reduced likelihood of CDI when compared to non-cannabis users (0.77 [95% CI: 0.60-0.95] and 0.20 [95% CI: 0.06-0.54]; p < 0.05). Furthermore, dependent users had less risk of CDI compared to non-dependent users (0.26 [95% CI: 0.08-0.88]; p = 0.01).

CONCLUSIONS:

CUD was associated with a decreased risk of CDI amongst hospitalized patients. Prospective and molecular mechanistic studies are required to elucidate how cannabis and its contents impacts CDI.”

https://www.ncbi.nlm.nih.gov/pubmed/31493498

“Cannabis use was associated with diminished risk of Clostridioides difficile (CDI) amongst hospitalized individuals. Dependent Cannabis users seemed to be the most protected from CDI.”  https://www.sciencedirect.com/science/article/pii/S1075996419301556?via%3Dihub

Real world experience of patients with amyotrophic lateral sclerosis (ALS) in the treatment of spasticity using tetrahydrocannabinol:cannabidiol (THC:CBD).

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Image result for bmc neurology“Treatment of spasticity poses a major challenge in amyotrophic lateral sclerosis (ALS) patient management.

Delta-9-tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (THC:CBD), approved for the treatment of spasticity in multiple sclerosis, serves as a complementary off-label treatment option in ALS-related spasticity.

The mean dose THC:CBD were 5.5 daily actuations (range < 1 to 20). Three subgroups of patients were identified: 1) high-dose daily use (≥ 7 daily actuations, 34%, n = 11), 2) low-dose daily use (< 7 daily actuations, 50%, n = 16), 3) infrequent use (< 1 daily actuation, 16%, n = 5). Overall NPS was + 4.9 (values above 0 express a positive recommendation to fellow patients). Remarkably, patients with moderate to severe spasticity (NRS ≥ 4) reported a high recommendation rate (NPS: + 29) in contrast to patients with mild spasticity (NRS < 4; NPS: - 44). For the three main domains of TSQM-9 high mean satisfaction levels were found (maximum value 100): effectiveness 70.5 (±22.3), convenience 76.6 (±23.3) and global satisfaction 75.0 (±24.7).

CONCLUSION:

THC:CBD is used in a wide dose range suggesting that the drug was applied on the basis of individual patients’ needs and preferences. Contributing to this notion, moderate to severe spasticity was associated with an elevated number of daily THC:CBD actuations and stronger recommendation rate (NPS) as compared to patients with mild spasticity. Overall, treatment satisfaction (TSQM-9) was high. The results suggest that THC:CBD may serve as a valuable addition in the spectrum of symptomatic therapy in ALS. However, prospective studies and head-to-head comparisons to other spasticity medications are of interest to further explore the effectiveness of THC:CBD in the management of spasticity, and other ALS-related symptoms.”

 https://www.ncbi.nlm.nih.gov/pubmed/31493784
“Overall, patients reported outcomes as assessed by TSQM-9 revealed a high treatment satisfaction with THC:CBD. The results of our study suggest that THC:CBD may serve as an important addition to the spectrum of treatment options of spasticity in ALS.”
https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-019-1443-y

The “entourage effect”: Terpenes coupled with cannabinoids for the treatment of mood disorders and anxiety disorders.

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“Mood disorders are the most prevalent mental conditions encountered in psychiatric practice. Numerous patients suffering from mood disorders present with treatment-resistant forms of depression, co-morbid anxiety, other psychiatric disorders and bipolar disorders.

Standardized essential oils (such as that of Lavender officinalis) have been shown to exert clinical efficacy in treating anxiety disorders. As endocannabinoids are suggested to play an important role in major depression, generalized anxiety and bipolar disorders, Cannabis sativa, was suggested for their treatment.

The endocannabinoid system is widely distributed throughout the body including the brain, modulating many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids.

CB1 and CB2 receptors primarily serve as the binding sites for endocannabinoids as well as for phytocannabinoids, produced by cannabis inflorescences. However, ‘cannabis’ is not a single compound product but is known for its complicated molecular profile, producing a plethora of phytocannabinoids alongside a vast array of terpenes.

Thus, the “entourage effect” is the suggested positive contribution derived from the addition of terpenes to cannabinoids. Here we review the literature on the effects of cannabinoids and discuss the possibility of enhancing cannabinoid activity on psychiatric symptoms by the addition of terpenes and terpenoids.

Possible underlying mechanisms for the anti-depressant and anxiolytic effects are reviewed. These natural products may be an important potential source for new medications for the treatment of mood and anxiety disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31481004

http://www.eurekaselect.com/174648/article