Molecular Modeling Targeting the ACE2 Receptor with Cannabis sativa’s Active Ingredients for Antiviral Drug Discovery against SARS-CoV-2 Infections

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“The emergence of a novel coronavirus that later on rendered a global pandemic, caused desperation within the communities and drove increased interest in exploring medicinal plant-based therapeutics to treat and prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infections.

Many medicinal plants have been reported to have antiviral, anti-inflammatory, and immunomodulatory effects that hinder, cure, or ease the symptoms of COVID-19 infection.

This exploratory study seeks to dock the active components of Cannabis sativa, a natural plant with several pharmacological and biological properties, with the angiotensin-converting enzyme II (ACE2) receptor. A total of 3 C. sativa active components have been found to bind to the ACE2 protein active site and could inhibit spike binding, although they do not compete directly with the receptor-binding domain (RBD) of SARS-CoV-2. 6-Prenylapigenin, cannabivarin (CBN-C3), and Δ8-tetrahydrocannabinolic acid-A (Δ8-THCA) have a greater affinity (-8.3, -8.3, and -8.0 kcal/mol, respectively) and satisfactory interaction with ACE2 than its inhibitor MLN-4760 (-7.1 kcal/mol).

These potential drugs with higher affinity for the ACE2 receptor and adequate absorption, distribution, metabolism, excretion, and toxicity (ADMET) values are candidates for treating or preventing SARS-CoV-2 infections. In vitro and in vivo investigations are needed to evaluate further the efficacy and toxicity of these hit compounds.”

“Our research reveals that 6-prenylapigenin, CBN-C3, and 8-THCA are 3 compounds that have shown promising binding and drug-likeness outcomes, which should be evaluated further for pharmaceutical development research.”

Substance abuse and the risk of severe COVID-19: Mendelian randomization confirms the causal role of opioids but hints a negative causal effect for cannabinoids

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“Since the start of the COVID-19 global pandemic, our understanding of the underlying disease mechanism and factors associated with the disease severity has dramatically increased. A recent study investigated the relationship between substance use disorders (SUD) and the risk of severe COVID-19 in the United States and concluded that the risk of hospitalization and death due to COVID-19 is directly correlated with substance abuse, including opioid use disorder (OUD) and cannabis use disorder (CUD). While we found this analysis fascinating, we believe this observation may be biased due to comorbidities (such as hypertension, diabetes, and cardiovascular disease) confounding the direct effect of SUD on severe COVID-19 illness. To answer this question, we sought to investigate the causal relationship between substance abuse and medication-taking history (as a proxy trait for comorbidities) with the risk of COVID-19 adverse outcomes.

Our Mendelian randomization analysis confirms the causal relationship between OUD and severe COVID-19 illness but suggests an inverse causal effect for cannabinoids.

Considering that COVID-19 mortality is largely attributed to disturbed immune regulation, the possible modulatory impact of cannabinoids in alleviating cytokine storms merits further investigation.”

“In conclusion, our MR analysis confirms the causal relationship between opioids and severe COVID-19 illness. However, our MR analysis questions the validity of the causal relationship between CUD and COVID-19 severe illness. A recent study showed that treatment with cannabis compounds significantly reduces cytokine secretion in lung epithelial cells and, therefore, may be useful in alleviating severe symptoms in COVID-19 patients. The fact that a great deal of COVID-19 mortality is attributed to immune dysregulation and cytokine storm, the possible modulatory impact of cannabinoids merits further investigation. Besides, it is shown that cannabidiol (CBD) blocks viral replication in lung epithelial cells through the up-regulation of endoplasmic reticulum (ER) stress response and interferon signaling pathways. Intriguingly, medical history of oral CBD use was associated with a reduced COVID-19 test-positivity rate.”

Cannabidivarin alleviates α-synuclein aggregation via DAF-16 in Caenorhabditis elegans

“Cannabidivarin (CBDV), a structural analog of cannabidiol (CBD), has received attention in recent years owing to its anticonvulsant property and potential for treating autism spectrum disorder. However, the function and mechanism of CBDV involved in the progression of Parkinson’s disease (PD) remain unclear. In this work, we found that CBDV inhibited α-synuclein (α-syn) aggregation in an established transgenetic Caenorhabditis elegans (C. elegans). The phenolic hydroxyl groups of CBDV are critical for scavenging reactive oxygen species (ROS), reducing the in vivo aggregation of α-syn and preventing DAergic neurons from 6-hydroxydopamine (6-OHDA)-induced injury and degeneration. By combining multiple biophysical approaches, including nuclear magnetic resonance spectrometry, transmission electron microscopy and fibrillation kinetics assays, we confirmed that CBDV does not directly interact with α-syn or inhibit the formation of α-syn fibrils in vitro. Further cellular signaling investigation showed that the ability of CBDV to prevent oxidative stress, the accumulation of α-syn and the degeneration of DAergic neurons was mediated by DAF-16 in the worms. This study demonstrates that CBDV alleviates the aggregation of α-syn in vivo and reveals that the phenolic hydroxyl groups of CBDV are critical for this activity, providing a potential for the development of CBDV as a drug candidate for PD therapeutics.”

Cannabidiol-rich non-psychotropic Cannabis sativa L. oils attenuate peripheral neuropathy symptoms by regulation of CB2-mediated microglial neuroinflammation

“Neuropathic pain (NP) is a chronic disease that affects the normal quality of life of patients. To date, the therapies available are only symptomatic and they are unable to reduce the progression of the disease. Many studies reported the efficacy of Cannabis sativa L. (C. sativa) on NP, but no Δ9 -tetrahydrocannabinol (Δ9 -THC)-free extracts have been investigated in detail for this activity so far. The principal aim of this work is to investigate the potential pain-relieving effect of innovative cannabidiol-rich non-psychotropic C. sativa oils, with a high content of terpenes (K2), compared to the same extract devoid of terpenes (K1). Oral administration of K2 (25 mg kg-1 ) induced a rapid and long-lasting relief of pain hypersensitivity in a mice model of peripheral neuropathy. In spinal cord samples, K2 reduced mitogen-activated protein kinase (MAPKs) levels and neuroinflammatory factors. These effects were reverted by the administration of a CB2 antagonist (AM630), but not by a CB1 antagonist (AM251). Conversely, K1 showed a lower efficacy in the absence of CB1/CB2-mediated mechanisms. In LPS-stimulated murine microglial cells (BV2), K2 reduced microglia pro-inflammatory phenotype through the downregulation of histone deacetylase 1 (HDAC-1) and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (IKBα) and increased interleukin-10 (IL-10) expression, an important antiinflammatory cytokine. In conclusion, these results suggested that K2 oral administration attenuated NP symptoms by reducing spinal neuroinflammation and underline the important role of the synergism between cannabinoids and terpenes.”

Antidiabetic actions of GPR55 agonist Abn-CBD and sitagliptin in obese-diabetic high fat fed mice

Biochemical Pharmacology

“GPR55 has been recognized as a novel anti-diabetic target exerting positive effects on beta cell function and mass. This study evaluated the metabolic actions and therapeutic efficacy of GPR55 agonist abnormal cannabidiol (Abn-CBD) administered alone and in combination with sitagliptin in diet-induced obese-diabetic mice. Chronic effects of 21-day oral administration of Abn-CBD (0.1µmol/kg BW) monotherapy and in combination with sitagliptin (50mg/kg BW) were assessed in obese-diabetic HFF mice (n=8). Assessments of plasma glucose, circulating insulin, DPP-IV activity, CRP, amylase, lipids, body weight and food intake were undertaken. Glucose tolerance, insulin sensitivity, DEXA scanning and islet morphology analysis were performed at 21-days. Sitagliptin, Abn-CBD alone and in combination with sitagliptin attenuated plasma glucose by 37-53% (p<0.01 – p<0.001) and enhanced circulating insulin concentrations by 23-31% (p<0.001). Abn-CBD alone and with sitagliptin reduced bodyweight by 9-10% (p<0.05). After 21-days, Abn-CBD in combination with sitagliptin (44%; p<0.01) improved glucose tolerance, whilst enhancing insulin sensitivity by 79% (p<0.01). Abn-CBD increased islet area (86%; p<0.05), beta cell mass (p<0.05) and beta cell proliferation (164%; p<0.001), whilst in combination with sitagliptin islet area was decreased (50%; p<0.01). Abn-CBD alone, in combination with sitagliptin or sitagliptin alone decreased triglycerides by 34-65% (p<0.001) and total cholesterol concentrations by 15-25% (p<0.001). In addition, Abn-CBD in combination with sitagliptin reduced fat mass by 19% (p<0.05) and reduced CRP concentrations (39%; p<0.05). These findings advocate Abn-CBD monotherapy and in combination with sitagliptin as a novel and effective approach for bodyweight control and the treatment of glucose intolerance and dyslipidaemia in type-2-diabetes.”

Cannabidiol Reduced the Severity of Gastrointestinal Symptoms of Opioid Withdrawal in Male and Female Mice

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“Introduction: Opioid withdrawal is a powerful driver of drug-seeking behavior as relief from this aversive state through drug-taking is a strong negative reinforcer. There are currently limited treatment options available for opioid withdrawal and cannabidiol (CBD) has been identified as a potential novel therapeutic. This study explored the efficacy and dose dependency of CBD for reducing the severity of naloxone-precipitated and spontaneous oxycodone withdrawal (PW and SW, respectively) in male and female mice. 

Methods: Mice were administered saline or escalating doses of oxycodone, whereby 9, 17.8, 23.7, and 33 mg/kg oxycodone IP was administered twice daily on days 1-2, 3-4, 5-6, and 7-8, respectively. On the 9th day, a single 33 mg/kg dose of oxycodone (or saline) was administered. To precipitate withdrawal, on day 9, mice in the withdrawal conditions were administered an IP injection of 10 mg/kg naloxone 2 h after the final oxycodone injection and immediately before withdrawal testing. To elicit SW, a separate group of mice underwent withdrawal testing 24 h after their final oxycodone injection. Mice were treated with an IP injection of 0, 10, 30 or 100 mg/kg of CBD 60 min before testing. Withdrawal symptoms examined included gastrointestinal symptoms (fecal boli, diarrhea, and body weight loss), somatic symptoms (paw tremors), and negative affect (jumping). 

Results: A robust PW syndrome was observed in both male and female mice, whereas only male mice displayed an SW syndrome. CBD dose dependently reduced gastrointestinal symptoms during both PW and SW in male mice and during PW in female mice. CBD had no effect on PW- or SW-induced jumping in male mice. However, in female mice, the PW-induced increase in jumps was less pronounced in CBD-treated mice. The highest dose of CBD inhibited paw tremors during PW, but not SW, in male mice. Neither PW- nor SW-induced paw tremors were observed in female mice. 

Conclusions: The magnitude of effects on the gastrointestinal symptoms, their consistency across PW and SW, and both sexes, alongside the availability of CBD for clinical use, suggest further exploration of the potential for CBD to treat these symptoms could be justified.”

A Case Report of Treatment-Resistant Agitation in Dementia with Lewy Bodies: Medical Marijuana as an Alternative to Antipsychotics

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“Palliative care teams are often consulted to assist in treating persistent dementia-related behavioral issues. Delta-9-tetrahydrocannabinol (THC) offers an alternative to traditional antipsychotic drugs in the long-term management of dementia with behavioral change. We present the case of an 85-year-old man with dementia with Lewy bodies with worsening aggression refractory to antipsychotic management. Multiple regimens of antipsychotics failed both in the outpatient and inpatient settings. After exhausting other options and in the setting of worsening agitation, a tincture of THC was prescribed. After starting THC tincture, the patient’s behavior rapidly improved, and he was discharged home to the care of his spouse. The challenges of prescribing and obtaining THC are discussed.”

Cannabis Use Among Lower-Extremity Arthroplasty Patients Does Not Lead to Worse Postoperative Outcomes

“Introduction: Smoking and general categorizations of substance use are linked with increased postoperative complications following total knee arthroplasty (TKA) and total hip arthroplasty (THA). There is a lack of similar evidence on how cannabis use may affect outcomes after arthroplasty. The present study aims to compare postoperative outcomes in cannabis users versus non-cannabis users who underwent THA/TKA. We hypothesize that cannabis users will have no difference in primarily the complication rate, revision rate, and secondarily post-operative Patient-Reported Outcomes Information System (PROMIS) scores, hospital stay, or pain compared to matched controls.

Methods: Billing codes were used to generate lists of hip/knee arthroplasty patients from 2013 to 2019 at our institution. In the case group, cannabis use was confirmed via chart review. Cannabis-using patients were matched appropriately with non-users by (1) the same arthroplasty procedure; (2) BMI ± 3.5; (3) age ± 3 years; (4) sex. Data on postoperative outcomes were collected from charts and compared between groups using either a Chi-square test for qualitative variables or a paired t-test for quantitative variables.

Results: A total of 24 patients with an average age of 57.1 and a BMI of 30.6 were confirmed to have isolated cannabis use. They were matched to 24 patients with an average age of 57.6 and a BMI of 31.4. There were no significant differences in the complication rate (4.2% vs 4.2%, p=1.00), the revision rate (0% vs 4.2%, p=0.31), days of hospital stay (2.7 vs 3.3, p=0.22), or postoperative pain (4.7 vs 4.9, p=0.86). Similarly, there were no significant differences in all PROMIS score measures.

Discussion/conclusions: Current research shows that cannabis use may lead to increased revision arthroplasty and decreased mortality, with mixed findings regarding post-surgical complications. The present study suggests that cannabis-using patients have no difference in postoperative complication rate, revision rate, PROMIS scores, hospital stay, or pain compared to matched controls.”

Drug-Drug Interaction Between Orally Administered Hydrocodone-Acetaminophen and Inhalation of Cannabis Smoke: A Case Report

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“Objective: To determine if a 2-day protocol measuring pharmacokinetic and pharmacodynamic characteristics can demonstrate drug-drug interactions when smoked cannabis is added to orally administered hydrocodone/acetaminophen combination products.

Case summary: A 51-year-old non-Hispanic white male with chronic pain diagnoses participated in a 2-day pilot protocol. The participant attended two 7-hour in-lab days where he received 10 blood draws each day and completed self-administered pain and anxiety surveys. For both days, the participant took his prescribed dose of hydrocodone/acetaminophen (1/2 tablet of 7.5 mg/325 mg combination product) with the addition of 1 smoked pre-rolled marijuana cigarette (labeled as 0.5 g; 22.17% Δ9-tetrahydrocannabinol; 0.12% cannabidiol) on Day 2. Blood specimens were analyzed using mass spectrometry to quantify the difference of plasma hydrocodone levels between Day 1 and Day 2.

Results: Compared to Day 1, lower levels of pain and anxiety were reported during Day 2 with the addition of cannabis to oral hydrocodone/acetaminophen. Day 2 pharmacokinetic analysis also revealed more rapid absorption and overall lower levels of hydrocodone in plasma.

Discussion: Lower hydrocodone plasma levels in Day 2 may indicate cannabis’s effect on metabolism and reduce the risk of opioid toxicity. The quicker absorption rate of hydrocodone could explain lower pain and anxiety scores reported on the second day.

Conclusion and relevance: A 2-day protocol was able to capture differences across time in pharmacokinetic and pharmacodynamic measurements. Larger studies can be designed to better characterize the potential drug-drug interaction of cannabis and opioids.”

The Quebec Cannabis Registry: Investigating the Safety and Effectiveness of Medical Cannabis

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“Objective: To investigate the safety and effectiveness of medical cannabis (MC) in the real-world clinical practice setting. 

Design: A 4-year prospective noncomparative registry of adult patients who initiated MC for a variety of indications. This paper reports on patients followed for up to 12 months, with interim visits at 3, 6, and 9 months after enrollment. 

Setting: Public or private outpatient clinics certified to authorize MC in the province of Quebec, Canada. 

Participants: Overall, 2991 adult (age ≥18 years) patients (mean age 51 years; 50.2% women) were enrolled between May 2015 and October 2018, with the last follow-up ending in May 2019. 

Interventions/Exposures: Cannabis products (dried, oil, or other) purchased from a Canadian licensed cannabis producer as authorized by physicians. 

Main Outcome Measures: The primary outcomes were self-reported pain severity, interference and relief (Brief Pain Inventory [BPI]), symptoms using the Revised Edmonton Symptom Assessment System (ESAS-r) and health-related quality of life dimensions (EQ-5D-5L) at baseline and each follow-up visit. The secondary outcomes were self-reported adverse events (AEs) and characteristics of cannabis treatment. 

Results: All patient-reported outcomes (BPI, ESAS-r, and EQ-5D-5L) showed a statistically significant improvement at 3 months (all p<0.01), which was maintained or further improved (for pain interference, tiredness, and well-being) over the remainder of the 12-month follow-up. Results also revealed clinically significant improvements in pain interference and tiredness, anxiety, and well-being from baseline. There were 79 AE reports (77 patients), 16 met the regulatory definition of seriousness, in which only 8 AEs were certainly or probably related to MC. 

Conclusions: MC directed by physicians appears to be safe and effective within 3 months of initiation for a variety of medical indications.”