Efficacy of cannabis and its constituents in disease management: Insights from clinical studies

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“There is a long history of informal use of Cannabis sativa (commonly called cannabis) for many purposes, including treating various ailments worldwide. However, the legalization of cannabis in multiple countries, specifically for medical purposes, has grabbed the researchers’ attention to discover the scientific evidence of cannabis’s beneficial effects. Among over 500 identified compounds (cannabinoids), Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two major active cannabinoids derived from cannabis. Cannabinoids exert their effects through cannabinoid receptors (CB1R and CB2R). In the recent past, clinical trials have shown the efficacy of cannabis and cannabinoids for various human ailments such as cancer, neurological disorders, inflammatory bowel disease, chronic pain, and metabolic disorders. The commonly used constituents and derivatives of cannabis include CBD, THC, THCV, dronabinol, nabilone, and nabiximol. The cannabis constituents have also been used in combination with other agents such as megestrol acetate in some clinical trials. The common routes for the administration of cannabis are oral, sublingual, or topical. Cannabis has also been consumed through smoking, inhalation, or with food and tea. As high as 572 patients and as low as nine patients have participated in a single clinical trial. Cannabis is legalized in some countries with restrictions, such as Belize, Canada, Colombia, Costa Rica, The Czech Republic, Jamaica, Netherlands, South Africa, Spain, and Uruguay. This article provides a compilation of published studies focusing on clinal trials on the therapeutic effects of cannabis. The adverse effects of cannabis and its constituents are also discussed.”

https://pubmed.ncbi.nlm.nih.gov/35619266/

https://www.eurekaselect.com/article/123960

Medical Cannabis Activity Against Inflammation: Active Compounds and Modes of Action

Frontiers in Pharmacology welcomes new Field Chief Editor – Science &  research news | Frontiers

“Inflammation often develops from acute, chronic, or auto-inflammatory disorders that can lead to compromised organ function. Cannabis (Cannabis sativa) has been used to treat inflammation for millennia, but its use in modern medicine is hampered by a lack of scientific knowledge. Previous studies report that cannabis extracts and inflorescence inhibit inflammatory responses in vitro and in pre-clinical and clinical trials. The endocannabinoid system (ECS) is a modulator of immune system activity, and dysregulation of this system is involved in various chronic inflammations. This system includes cannabinoid receptor types 1 and 2 (CB1 and CB2), arachidonic acid-derived endocannabinoids, and enzymes involved in endocannabinoid metabolism. Cannabis produces a large number of phytocannabinoids and numerous other biomolecules such as terpenes and flavonoids. In multiple experimental models, both in vitro and in vivo, several phytocannabinoids, including Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabigerol (CBG), exhibit activity against inflammation. These phytocannabinoids may bind to ECS and/or other receptors and ameliorate various inflammatory-related diseases by activating several signaling pathways. Synergy between phytocannabinoids, as well as between phytocannabinoids and terpenes, has been demonstrated. Cannabis activity can be improved by selecting the most active plant ingredients (API) while eliminating parts of the whole extract. Moreover, in the future cannabis components might be combined with pharmaceutical drugs to reduce inflammation.”

https://pubmed.ncbi.nlm.nih.gov/35614947/

“Cannabis compounds, in some cases via the endocannabinoids system, were shown to affect some of the cornerstones of chronic inflammation. However, in light of the large number of active molecules produced by cannabis and their sometimes-synergistic interactions, there is a need to better specify cannabis-based treatments and the active compounds, while utilizing the synergy identified between cannabis phytomolecules. Thus, even if CBD or THC are considered potentially leading molecules, additional cannabis-derived compounds may be selected for improved activity.

Future approaches for improved usage of cannabis demand the development, transformation and formulation of full-spectrum cannabis extracts into active plant ingredients (APIs) to achieve higher effectivity.

Importantly, once the mode of action of phytocannabinoids and that of their combination is known, APIs might be targeted towards specific mechanisms involved with inflammation.

Moreover, it might be that cannabis components can be combined with other pharmaceutical drugs to reduce inflammation. “

https://www.frontiersin.org/articles/10.3389/fphar.2022.908198/full


Tobacco, but Neither Cannabis Smoking Nor Co-Drug Use, Is Associated With Hearing Loss in the National Health and Nutrition Examination Survey, 2011 to 2012 and 2015 to 2016

Ear and Hearing - Home | Facebook


“Introduction:
A relationship between tobacco smoking and hearing loss has been reported; associations with cannabis smoking are unknown. In this cross-sectional population-based study, we examined relationships between hearing loss and smoking (tobacco, cannabis, or co-drug use).

Methods: We explored the relationship between hearing loss and smoking among 2705 participants [mean age = 39.41 (SE: 0.36) years] in the National Health and Nutrition Examination Survey (2011 to 12; 2015 to 16). Smoking status was obtained via questionnaire; four mutually exclusive groups were defined: nonsmokers, current regular cannabis smokers, current regular tobacco smokers, and co-drug users. Hearing sensitivity (0.5 to 8 kHz) was assessed, and two puretone averages (PTAs) computed: low- (PTA0.5,1,2) and high-frequency (PTA3,4,6,8). We defined hearing loss as threshold >15 dB HL. Multivariable logistic regression was used to examine sex-specific associations between smoking and hearing loss in the poorer ear (selected based on PTA0.5,1,2) adjusting for age, sex, race/ethnicity, hypertension, diabetes, education, and noise exposure with sample weights applied.

Results: In the age-sex adjusted model, tobacco smokers had increased odds of low- and high-frequency hearing loss compared with non-smokers [odds ratio (OR) = 1.58, 95% confidence ratio (CI): 1.05 to 2.37 and OR = 1.97, 95% CI: 1.58 to 2.45, respectively]. Co-drug users also had greater odds of low- and high-frequency hearing loss [OR = 2.07, 95% CI: 1.10 to 3.91 and OR = 2.24, 95% CI: 1.27 to 3.96, respectively]. In the fully adjusted multivariable model, compared with non-smokers, tobacco smokers had greater odds of high-frequency hearing loss [multivariable adjusted odds ratio = 1.64, 95% CI: 1.28-2.09]. However, in the fully adjusted model, there were no statistically significant relationships between hearing loss (PTA0.5,1,2 or PTA3,4,6,8) and cannabis smoking or co-drug use.

Discussion: Cannabis smoking without concomitant tobacco consumption is not associated with hearing loss. However, sole use of cannabis was relatively rare and the prevalence of hearing loss in this population was low, limiting generalizability of the results. This study suggests that tobacco smoking may be a risk factor for hearing loss but does not support an association between hearing loss and cannabis smoking. More definitive evidence could be derived using physiological measures of auditory function in smokers and from longitudinal studies.”

https://pubmed.ncbi.nlm.nih.gov/35383601/

https://journals.lww.com/ear-hearing/Abstract/9900/Tobacco,_but_Neither_Cannabis_Smoking_Nor_Co_Drug.3.aspx

Management of chronic pain with Jalaprakshalana (water-wash) Shodhita (processed) Bhanga ( Cannabis sativa L.) in cancer patients with deprived quality of life: An open-label single arm clinical trial

“Introduction: Pain is a common and complex symptom of cancer having physical, social, spiritual and psychological aspects. Approximately 70%-80% of cancer patients experiences pain, as reported in India. Ayurveda recommends use of Shodhita (Processed) Bhanga (Cannabis) for the management of pain but no research yet carried out on its clinical effectiveness.

Objective: To assess the analgesic potential of Jala-Prakshalana (Water-wash) processed Cannabis sativa L. leaves powder in cancer patients with deprived quality of life (QOL) through openlabel single arm clinical trial.

Materials and methods: Waterwash processed Cannabis leaves powder filled in capsule, was administered in 24 cancer patients with deprived QOL presenting complaints of pain, anxiety or depression; for a period of 4 weeks; in a dose of 250 mg thrice a day; along with 50 ml of cow’s milk and 4 g of crystal sugar. Primary outcome i.e. pain was measured by Wong-Bakers FACES Pain Scale (FACES), Objective Pain Assessment (OPA) scale and Neuropathic Pain Scale (NPS). Secondary outcome namely anxiety was quantified by Hospital Anxiety and Depression Scale (HADS), QOL by FACT-G scale, performance score by Eastern Cooperative Oncology Group (ECOG) and Karnofsky score.

Results: Significant reduction in pain was found on FACES Pain Scale (P < 0.05), OPA (P < 0.05), NPS (P < 0.001), HADS (P < 0.001), FACT-G scale (P < 0.001), performance status score like ECOG (P < 0.05) and Karnofsky score (P < 0.01).

Conclusion: Jalaprakshalana Shodhita Bhanga powder in a dose of 250 mg thrice per day; relieves cancerinduced pain, anxiety and depression significantly and does not cause any major adverse effect and withdrawal symptoms during trial period.”

https://pubmed.ncbi.nlm.nih.gov/31831967/

“Administration of Jalaprakshalana Shodhita Bhanga (water-wash processed Cannabis) leaves powder in dose of 250 mg thrice a day with 50 ml of cow’s milk and 4 g sugar as an adjuvant, for a period of 1 month; significantly relieves pain, anxiety and depression of cancer patients without creating any major side effects, dependency and withdrawal symptoms. Processed Cannabis is significantly effective for improvement in QOL of a cancer patient.”

https://www.ayujournal.org/article.asp?issn=0974-8520;year=2019;volume=40;issue=1;spage=34;epage=43;aulast=Tavhare

Heavy and Chronic Cannabis Addiction does not Impact Motor Function: BOLD-fMRI Study

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“Objective: The aim of this paper is to demonstrate the impact of heavy and chronic cannabis use on brain potential functional control, reorganization, and plasticity in the cortical area.

Methods: 23 cannabis users were convened in 3 user’s groups. The first group included 11 volunteers with an average of 15 joins/day; the second group included 6 volunteers with an average of 1.5 joins/day; the third group included 6 volunteers with an average of 2.8 joins/week. Besides, a 6 healthy volunteers (control group). All healthy and cannabis users underwent identical brain BOLD-fMRI assessment of the motor function. Besides, neuropsychological and full biological assessments were achieved.

Results: BOLD-fMRI maps of motor areas were obtained, including quantitative evaluation of the activations in the motor area. Besides, statistical analysis of various groups was achieved.

Conclusion: Chronic cannabis addiction of varying use strength by groups of heavy, moderate, low dose, and zero doses are shown to have systematically equivalent effects on the control of brain motor function. Indeed, the BOLD-fMRI shows a remarkable sensitivity to minimal brain plasticity and reorganization of the functional motor control of the studied cortical area, and such varionation was not shown. Specific elucidation of the cannabis effect mechanisms in this unique function should clarify further protective pharmacological effects. This might illuminate the use of neuronal resources to prepare processes for pharmacological use and pharmaceutical forms. This suggests exploring any potential cannabis pharmaceutical form in diseases involving motor impairments.”

https://pubmed.ncbi.nlm.nih.gov/35578884/

https://www.eurekaselect.com/article/123583

Indeterminacy of cannabis impairment and ∆ 9-tetrahydrocannabinol (∆ 9-THC) levels in blood and breath

Scientific Reports

“Previous investigators have found no clear relationship between specific blood concentrations of ∆9-tetrahydrocannabinol (∆9-THC) and impairment, and thus no scientific justification for use of legal “per se” ∆9-THC blood concentration limits. Analyzing blood from 30 subjects showed ∆9-THC concentrations that exceeded 5 ng/mL in 16 of the 30 subjects following a 12-h period of abstinence in the absence of any impairment. In blood and exhaled breath samples collected from a group of 34 subjects at baseline prior to smoking, increasing breath ∆9-THC levels were correlated with increasing blood levels (P < 0.0001) in the absence of impairment, suggesting that single measurements of ∆9-THC in breath, as in blood, are not related to impairment. When post-smoking duration of impairment was compared to baseline ∆9-THC blood concentrations, subjects with the highest baseline ∆9-THC levels tended to have the shortest duration of impairment. It was further shown that subjects with the shortest duration of impairment also had the lowest incidence of horizontal gaze nystagmus at 3 h post-smoking compared to subjects with the longest duration of impairment (P < 0.05). Finally, analysis of breath samples from a group of 44 subjects revealed the presence of transient cannabinoids such as cannabigerol, cannabichromene, and ∆9-tetrahydrocannabivarin during the peak impairment window, suggesting that these compounds may be key indicators of recent cannabis use through inhalation. In conclusion, these results provide further evidence that single measurements of ∆9-THC in blood, and now in exhaled breath, do not correlate with impairment following inhalation, and that other cannabinoids may be key indicators of recent cannabis inhalation.”

https://pubmed.ncbi.nlm.nih.gov/35585089/

“In conclusion, we present further evidence that single measurements of ∆9-THC in blood cannot establish impairment, that single measurements of ∆9-THC in exhaled breath likewise do not correlate with impairment, and that ∆9-THCV and CBC may be key indicators of recent cannabis use through inhalation within the impairment window.”

https://www.nature.com/articles/s41598-022-11481-5

Comparative study of CNR1 and CNR2 cannabinoid receptors expression levels in COVID-19 patients with and without diabetes mellitus: Recommendations for future research targets

Diabetes & Metabolic Syndrome: Clinical Research & Reviews

“Background and aims: The COVID-19 pandemic has prompted researchers to look for effective therapeutic targets. The effect of endocannabinoid system against infectious diseases is investigated for several years. In this study, we evaluated the expression level of CNR1 and CNR2 genes in patients with COVID-19 with and without diabetes to provide new insights regarding these receptors and their potential effect in COVID-19 disease.

Methods: In this study, peripheral blood monocytes cells (PBMCs) were isolated from eight different groups including COVID-19 patients, diabetic patients, and healthy individuals. RNA were extracted to evaluate the expression level of CNR1 and CNR2 genes using real-time PCR. The correlation between the expression levels of these genes in different groups were assessed.

Results: A total of 80 samples were divided into 8 groups, with each group consisting of ten samples. When comparing severe and moderate COVID-19 groups to healthy control group, the expression levels of the CNR1 and CNR2 genes were significantly higher in the severe and moderate COVID-19 groups. There were no significant differences between the mild COVID-19 group and the healthy control group. It was found that the expression levels of these genes in patients with diabetes who were infected with SARS-COV-2 did not differ across COVID-19 groups with varying severity, but they were significantly higher when compared to healthy controls.

Conclusion: Our study suggests the possible role of endocannabinoid system during SARS-COV-2 pathogenicity as the expression of CNR1 and CNR2 were elevated during the disease.”

https://pubmed.ncbi.nlm.nih.gov/35580523/

“In conclusion, the outcomes of this research supports the possible role of endocannabinoid system during SARS-COV-2 pathogenicity as the expression of CNR1 and CNR2 were elevated during the disease. Moreover, despite their limitations due to psychiatric side effects, the regulated use of cannabinoids should be examined by researchers to identify their potential effectiveness as a therapeutic target in COVID-19 disease.”

https://www.sciencedirect.com/science/article/pii/S1871402122001138?via%3Dihub

Cannabinoids Alleviate the LPS-Induced Cytokine Storm via Attenuating NLRP3 Inflammasome Signaling and TYK2-Mediated STAT3 Signaling Pathways In Vitro

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“Cannabinoids, mainly cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), are the most studied group of compounds obtained from Cannabis sativa because of their several pharmaceutical properties. Current evidence suggests a crucial role of cannabinoids as potent anti-inflammatory agents for the treatment of chronic inflammatory diseases; however, the mechanisms remain largely unclear. Cytokine storm, a dysregulated severe inflammatory response by our immune system, is involved in the pathogenesis of numerous chronic inflammatory disorders, including coronavirus disease 2019 (COVID-19), which results in the accumulation of pro-inflammatory cytokines. Therefore, we hypothesized that CBD and THC reduce the levels of pro-inflammatory cytokines by inhibiting key inflammatory signaling pathways. The nucleotide-binding and oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling has been implicated in a variety of chronic inflammatory diseases, which results in the release of pyroptotic cytokines, interleukin-1β (IL-1β) and IL-18. Likewise, the activation of the signal transducer and activator of transcription-3 (STAT3) causes increased expression of pro-inflammatory cytokines. We studied the effects of CBD and THC on lipopolysaccharide (LPS)-induced inflammatory response in human THP-1 macrophages and primary human bronchial epithelial cells (HBECs). Our results revealed that CBD and, for the first time, THC significantly inhibited NLRP3 inflammasome activation following LPS + ATP stimulation, leading to a reduction in the levels of IL-1β in THP-1 macrophages and HBECs. CBD attenuated the phosphorylation of nuclear factor-κB (NF-κB), and both cannabinoids inhibited the generation of oxidative stress post-LPS. Our multiplex ELISA data revealed that CBD and THC significantly diminished the levels of IL-6, IL-8, and tumor necrosis factor-α (TNF-α) after LPS treatment in THP-1 macrophages and HBECs. In addition, the phosphorylation of STAT3 was significantly downregulated by CBD and THC in THP-1 macrophages and HBECs, which was in turn attributed to the reduced phosphorylation of tyrosine kinase-2 (TYK2) by CBD and THC after LPS stimulation in these cells. Overall, CBD and THC were found to be effective in alleviating the LPS-induced cytokine storm in human macrophages and primary HBECs, at least via modulation of NLRP3 inflammasome and STAT3 signaling pathways. The encouraging results from this study warrant further investigation of these cannabinoids in vivo.”

https://pubmed.ncbi.nlm.nih.gov/35563697/

https://www.mdpi.com/2073-4409/11/9/1391


Cannabis for Medical Use: Versatile Plant Rather Than a Single Drug

Frontiers in Pharmacology welcomes new Field Chief Editor – Science &  research news | Frontiers

“Medical Cannabis and its major cannabinoids (-)-trans9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are gaining momentum for various medical purposes as their therapeutic qualities are becoming better established. However, studies regarding their efficacy are oftentimes inconclusive. This is chiefly because Cannabis is a versatile plant rather than a single drug and its effects do not depend only on the amount of THC and CBD. Hundreds of Cannabis cultivars and hybrids exist worldwide, each with a unique and distinct chemical profile. Most studies focus on THC and CBD, but these are just two of over 140 phytocannabinoids found in the plant in addition to a milieu of terpenoids, flavonoids and other compounds with potential therapeutic activities. Different plants contain a very different array of these metabolites in varying relative ratios, and it is the interplay between these molecules from the plant and the endocannabinoid system in the body that determines the ultimate therapeutic response and associated adverse effects. Here, we discuss how phytocannabinoid profiles differ between plants depending on the chemovar types, review the major factors that affect secondary metabolite accumulation in the plant including the genotype, growth conditions, processing, storage and the delivery route; and highlight how these factors make Cannabis treatment highly complex.”

https://pubmed.ncbi.nlm.nih.gov/35548332/

“The use of medical Cannabis is ever increasing in the treatment of numerous conditions as it has been proven to be both effective and safe, but the Cannabis plant contains more than 500 different components, each with potential therapeutic qualities. The components of Cannabis act together, hitting several targets at once and mutually enhancing each other’s activity so that the overall outcome is greater than that of their additive effect.

Cannabis can treat a multitude of very different conditions as it exerts its effects via the ECS, which is involved in many physiological processes. Cannabis treatment can be personalized to both the condition and the person to improve treatment outcomes while also reducing the drug load and minimizing the adverse effects. “

https://www.frontiersin.org/articles/10.3389/fphar.2022.894960/full


Synthesis of A Tetrahydrocannabinol (THC) Analog For Analyzing Cellular Proliferation in Concert With Epigallocatechin Gallate (EGCG) on A Bone-like Cancer Cell Line (UMR 106-01 BSP)

“Cannabinoids have been extensively studied in the field of cancer research. Tetrahydrocannabinol (THC) has shown promising results in influencing cellular proliferation when in association with other cannabinoids. This traditional entourage effect solely focuses on the study of THC with other cannabinoids. However, not many studies have been done to explore the synergistic effect of THC analogs when used with non-cannabinoid compounds. THC in its isolate form for experimentation is very strictly regulated. Therefore, this study was conducted in the pursuit of synthesizing and experimenting with analogs of THC to observe a potential entourage effect with epigallocatechin gallate (EGCG), a compound known for its efficacy to reduce proliferation at higher concentrations in UMR cells. It was hypothesized that active analogs of THC can be synthesized and used in concert with EGCG to potentiate decreased proliferation in the bone-like cancer cell line UMR 106-01 BSP (UMR cells). Briefly, a Knoevenagel condensation and a Diels-Alder reaction using 1,3-cyclohexanediol dissolved in methanol (MeOH) and citronellal with ethylenediamine diacetic acid (EDDA) at a temperature of 60℃ was used to synthesize a novel THC analog, 3,10,10-Trimethyl-1,2,3,4,4a,6,7,8,10,10a-decahydro-9-oxa-5-phenanthrenone (TDP). UMR cells were routinely passaged, counted, plated in six-well culture plates at 480,00 cells/mL, then treated with 10-fold dilutions of TDP. The plates were incubated for 72 hours in a humidified incubator at 37 degrees Celsius with 5% carbon dioxide infusion. At the end of the experiment, the cells were routinely washed with HANKS buffered saline solution (HBSS), then routinely counted using the Luna Automated Cell Counter. In another experiment, designated cells were co-treated with TDP+EGCG, following the protocol above. F test ANOVA was used to compare variances and all values in the results were expressed as means ± SD. The results from the attempted cannabinoid analog synthesis yielded a novel active THC analog, TDP. Serial dilutions treatment of the UMR cells with TDP alone showed its ability to decrease cell count in a concentration dependent manner. However, when coupled with higher concentrations of EGCG, the co-treatment increased cell count rather than potentiating the effect of decreasing cellular proliferation. The F Test ANOVA showed robust statistical significance (p values <0.05) with regard to TDP’s effect of decreasing cell proliferation in UMR cells in a concentration-dependent manner. Overall, the outcomes of this study suggest that active forms of THC analogs can be synthesized and tested in concert with other non-cannabinoid compounds like EGCG. This study opens the door to explore the entourage effect of TDP with other non-cannabinoid compounds that may provide another tool in the therapeutic treatment of bone cancer cells.”

https://pubmed.ncbi.nlm.nih.gov/35555816/

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.2022.36.S1.L8061