Author Archives: David Worrell

Buccally Absorbed Cannabidiol Shows Significantly Superior Pain Control and Improved Satisfaction Immediately After Arthroscopic Rotator Cuff Repair: A Placebo-Controlled, Double-Blinded, Randomized Trial

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SAGE Journals

“Background: Despite the widespread use and sales of cannabidiol (CBD) products in the United States, there is a paucity of literature to evaluate its effectiveness, safety, or ideal route of administration for postoperative pain.

Purpose: To evaluate the potential analgesic effects of buccally absorbed CBD in patients who have undergone arthroscopic rotator cuff repair (ARCR).

Study design: Randomized controlled trial; Level of evidence, 1.

Methods: This was a US Food and Drug Administration-sanctioned, multicenter, placebo-controlled, randomized, double-blinded trial conducted in patients undergoing ARCR. Patients aged from 18 to 75 years undergoing ARCR were prospectively enrolled and randomized to the control and experimental groups. The experimental group received an oral, buccally absorbed tablet containing 25 mg of CBD 3 times a day if <80 kg, or 50 mg of CBD 3 times a day if >80 kg, for 14 days postoperatively, while the control group received an identical placebo. Patients were followed up on days 1, 2, 7, and 14, and visual analog scale (VAS) for pain scores, opioid consumption, and satisfaction with pain control were recorded. Additionally, liver function tests were conducted on days 7 and 14 to assess safety, and nausea was monitored. P < .05 was considered to be statistically significant.

Results: Overall, 100 patients were recruited, with 1 patient being excluded, for a total of 99 patients. There were no significant differences in patient demographics between the 2 groups. On day 1, the VAS pain score was significantly lower in the CBD group than in the control group (4.4 ± 3.1 vs 5.7 ± 3.2, respectively; P = .04), although this difference was no longer present on day 2 (4.7 ± 2.8 vs 5.3 ± 2.6, respectively; P = .32). On both days 1 and 2, patient satisfaction with pain control was significantly higher in the CBD group than in the control group (day 1: 7.0 ± 3.0 vs 5.6 ± 3.7, respectively [P = .04]; day 2: 7.3 ± 2.5 vs 6.0 ± 3.3, respectively [P = .03]). The quantity of opioids consumed was low in both groups, and there were no statistically significant differences in opioid consumption (P > .05). On days 7 and 14, there were no statistically significant differences in VAS scores, opioid consumption, or patient satisfaction with pain control between the CBD and control groups (P > .05 for all). There were no significant differences in liver function test results postoperatively (P > .05).

Conclusion: Buccally absorbed CBD demonstrated an acceptable safety profile and showed significant promise in the reduction of pain in the immediate perioperative period after ARCR compared with the control. Further studies are currently ongoing to confirm dosing and effectiveness in other orthopaedic conditions.”

https://pubmed.ncbi.nlm.nih.gov/35905305/

https://journals.sagepub.com/doi/10.1177/03635465221109573

Estimating the effects of legalizing recreational cannabis on newly incident cannabis use

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Plos One | Publons

“Liberalized state-level recreational cannabis policies in the United States (US) fostered important policy evaluations with a focus on epidemiological parameters such as proportions [e.g., active cannabis use prevalence; cannabis use disorder (CUD) prevalence].

This cannabis policy evaluation project adds novel evidence on a neglected parameter-namely, estimated occurrence of newly incident cannabis use for underage (<21 years) versus older adults. The project’s study populations were specified to yield nationally representative estimates for all 51 major US jurisdictions, with probability sample totals of 819,543 non-institutionalized US civilian residents between 2008 and 2019. Standardized items to measure cannabis onsets are from audio computer-assisted self-interviews. Policy effect estimates are from event study difference-in-difference (DiD) models that allow for causal inference when policy implementation is staggered.

The evidence indicates no policy-associated changes in the occurrence of newly incident cannabis onsets for underage persons, but an increased occurrence of newly onset cannabis use among older adults (i.e., >21 years). We offer a tentative conclusion of public health importance: Legalized cannabis retail sales might be followed by the increased occurrence of cannabis onsets for older adults, but not for underage persons who cannot buy cannabis products in a retail outlet.

Cannabis policy research does not yet qualify as a mature science. We argue that modeling newly incident cannabis use might be more informative than the modeling of prevalences when evaluating policy effects and provide evidence of the advantages of the event study model over regression methods that seek to adjust for confounding factors.”

https://pubmed.ncbi.nlm.nih.gov/35862417/

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0271720


Cannabigerol (CBG) attenuates mechanical hypersensitivity elicited by chemotherapy-induced peripheral neuropathy

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“Background: Cannabigerol (CBG) is a non-psychoactive phytocannabinoid produced by the plant Cannabis sativa with affinity to various receptors involved in nociception. As a result, CBG is marketed as an over-the-counter treatment for many forms of pain. However, there is very little research-based evidence for the efficacy of CBG as an anti-nociceptive agent.

Methods: To begin to fill this knowledge gap, we assessed the anti-nociceptive effects of CBG in C57BL/6 mice using three different models of pain; cisplatin-induced peripheral neuropathy, the formalin test, and the tail-flick assay.

Results: Using the von Frey test, we found that CBG attenuated mechanical hypersensitivity evoked by cisplatin-induced peripheral neuropathy in both male and female mice. Additionally, we observed that this CBG-induced reduction in mechanical hypersensitivity was attenuated by the α2 -adrenergic receptor antagonist atipamezole (3 mg/kg, i.p.) and the CB1 R antagonist, AM4113 (3 mg/kg, i.p.), and blocked by the CB2 R antagonist/inverse agonist, SR144528 (10 mg/kg, i.p.). We found that the TRPV1 antagonist, SB705498 (20 mg/kg, i.p.) was unable to prevent CBG actions. Furthermore, we show that CBG:CBD oil (10 mg/kg, i.p.) was more effective than pure CBG (10 mg/kg) at reducing mechanical hypersensitivity in neuropathic mice. Lastly, we show that pure CBG and CBG:CBD oil were ineffective at reducing nociception in other models of pain, including the formalin and tail flick assays.

Conclusions: Our findings support the role of CBG in alleviating mechanical hypersensitivity evoked by cisplatin-induced peripheral neuropathy, but highlight that these effects may be limited to specific types of pain.”

https://pubmed.ncbi.nlm.nih.gov/35899583/

https://onlinelibrary.wiley.com/doi/10.1002/ejp.2016

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

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SAGE Journals

“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.”

https://pubmed.ncbi.nlm.nih.gov/35898257/

https://journals.sagepub.com/doi/10.1177/00185787211061374

Antiviral activity of medicinal plant-derived products against SARS-CoV-2

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SAGE Journals

“This review presents information from several studies that have demonstrated the antiviral activity of extracts (Andrographis paniculata, Artemisia annua, Artemisia afra, Cannabis sativa, Curcuma longa, Echinacea purpurea, Olea europaea, Piper nigrum, and Punica granatum) and phytocompounds derived from medicinal plants (artemisinins, glycyrrhizin, and phenolic compounds) against SARS-CoV-2.

A brief background of the plant products studied, the methodology used to evaluate the antiviral activity, the main findings from the research, and the possible mechanisms of action are presented.

These plant products have been shown to impede the adsorption of SARS-CoV-2 to the host cell, and prevent multiplication of the virus post its entry into the host cell. In addition to antiviral activity, the plant products have also been demonstrated to exert an immunomodulatory effect by controlling the excessive release of cytokines, which is commonly associated with SARS-CoV-2 infections.”

https://pubmed.ncbi.nlm.nih.gov/35894129/

https://journals.sagepub.com/doi/10.1177/15353702221108915

“Antimicrobial and Antiviral (SARS-CoV-2) Potential of Cannabinoids and Cannabis sativa: A Comprehensive Review”

https://pubmed.ncbi.nlm.nih.gov/34885798/

“Anti-Inflammatory and Antiviral Effects of Cannabinoids in Inhibiting and Preventing SARS-CoV-2 Infection”

https://pubmed.ncbi.nlm.nih.gov/35456990/

“Cannabinoids Block Cellular Entry of SARS-CoV-2 and the Emerging Variants”

https://pubmed.ncbi.nlm.nih.gov/35007072/

Anti-Tumorigenic Effect of a Novel Derivative of 2-Hydroxyoleic Acid and the Endocannabinoid Anandamide on Neuroblastoma Cells

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biomedicines-logo

“Modulation of the endogenous cannabinoid system has been suggested as a potential anticancer strategy.

In the search for novel and less toxic therapeutic options, structural modifications of the endocannabinoid anandamide and the synthetic derivative of oleic acid, Minerval (HU-600), were done to obtain 2-hydroxy oleic acid ethanolamide (HU-585), which is an HU-600 derivative with the anandamide side chain.

We showed that treatment of SK-N-SH neuroblastoma cells with HU-585 induced a better anti-tumorigenic effect in comparison to HU-600 as evidenced by 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide assay, colony-forming assay, and migration assay. Moreover, HU-585 demonstrated pro-apoptotic properties shown by increased levels of activated caspase-3 following treatment and a better senescence induction effect in comparison to HU-600, as demonstrated by increased activity of lysosomal β-galactosidase. Finally, we observed that combined treatment of HU-585 with the senolytic drugs ABT-263 in vitro, and ABT-737 in vivo resulted in enhanced anti-proliferative effects and reduced neuroblastoma xenograft growth in comparison to treatment with HU-585 alone.

Based on these results, we suggest that HU-585 is a pro-apoptotic and senescence-inducing compound, better than HU-600. Hence, it may be a beneficial option for the treatment of resistant neuroblastoma especially when combined with senolytic drugs that enhance its anti-tumorigenic effects.”

https://pubmed.ncbi.nlm.nih.gov/35884854/

“The cannabinoids are a group of more than 100 chemically related compounds found in the marijuana plant Cannabis sativa, that have been found to possess diverse pharmacological activities in cancer, including cytostatic, apoptotic, and antiangiogenic effects. Tetrahydrocannabinol (THC), the main psychoactive constituent in Cannabis sativa, acts mainly through the activation of specific cannabinoid receptors CB1 and CB2 and thus mimics the binding of the animal endogenous cannabinoids (named endocannabinoids).”

https://www.mdpi.com/2227-9059/10/7/1552/htm

Activation of Peripheral Cannabinoid Receptors Synergizes the Effect of Systemic Ibuprofen in a Pain Model in Rat

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pharmaceuticals-logo

“Pharmacological synergism is a current strategy for the treatment of pain. However, few studies have been explored to provide evidence of the possible synergism between a non-steroidal anti-inflammatory drug (NSAID) and a cannabinoid agonist, in order to establish which combinations might be effective to manage pain.

The aim of this study was to explore the synergism between ibuprofen (IBU) and the synthetic cannabinoid WIN 55,212-2 (WIN) to improve pain relief by analyzing the degree of participation of the CB1 and CB2 cannabinoid receptors in the possible antinociceptive synergism using an experimental model of pain in Wistar rats.

First, the effective dose thirty (ED30) of IBU (10, 40, 80, and 160 mg/kg, subcutaneous) and WIN (3, 10, and 30 µg/p, intraplantar) were evaluated in the formalin test. Then, the constant ratio method was used to calculate the doses of IBU and WIN to be administered in combination (COMB) to determine the possible synergism using the isobolographic method. The participation of the CB1 and CB2 receptors was explored in the presence of the antagonists AM281 and AM630, respectively.

The combination of these drugs produced a supra-additive response with an interaction index of 0.13. In addition, AM281 and AM630 antagonists reversed the synergistic effect in 45% and 76%, respectively, suggesting that both cannabinoid receptors are involved in this synergism, with peripheral receptors playing a relevant role.

In conclusion, the combination of IBU + WIN synergism is mainly mediated by the participation of the CB2 receptor, which can be a good option for the better management of pain relief.”

https://pubmed.ncbi.nlm.nih.gov/35893735/

https://www.mdpi.com/1424-8247/15/8/910

Differential Effects of D9 Tetrahydrocannabinol (THC)- and Cannabidiol (CBD)-Based Cannabinoid Treatments on Macrophage Immune Function In Vitro and on Gastrointestinal Inflammation in a Murine Model

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biomedicines-logo

“Phytocannabinoids possess a wide range of immune regulatory properties, mediated by the endocannabinoid system.

Monocyte/macrophage innate immune cells express endocannabinoid receptors. Dysregulation of macrophage function is involved in the pathogenesis of different inflammatory diseases, including inflammatory bowel disease.

In our research, we aimed to evaluate the effects of the phytocannabinoids D9 tetrahydrocannabinol (THC) and cannabidiol (CBD) on macrophage activation.

Macrophages from young and aged C57BL/6 mice were activated in vitro in the presence of pure cannabinoids or cannabis extracts. The phenotype of the cells, nitric oxide (NO•) secretion, and cytokine secretion were examined. In addition, these treatments were administered to murine colitis model. The clinical statuses of mice, levels of colon infiltrating macrophages, and inflammatory cytokines in the blood, were evaluated.

We demonstrated inhibition of macrophage NO• and cytokine secretion and significant effects on expression of cell surface molecules. In the murine model, clinical scores were improved and macrophage colon infiltration reduced following treatment. We identified higher activity of cannabis extracts as compared with pure cannabinoids. Each treatment had a unique effect on cytokine composition.

Overall, our results establish that the effects of cannabinoid treatments differ. A better understanding of the reciprocal relationship between cannabinoids and immunity is essential to design targeted treatment strategies.”

https://pubmed.ncbi.nlm.nih.gov/35892693/

“Overall, our results indicate both similarities and differences between the impact of CBD- and THC-based drugs. Although all the tested treatments had an anti-inflammatory effect, their specific effects (for example, on phenotype of the cells and on cytokine production) differed. These differences may influence the clinical outcome of the treatment. We were surprised to find very similar anti-inflammatory results for the two cannabis extracts, which had diverse content of THC and CBD. This could suggest that THC/CBD content may not be the best indicator for anti-inflammatory properties of a cannabis-based drug. These results highlight the need to expand the research on the interplay between cannabinoids and other phytochemicals in the cannabis extracts. A better understanding of the effects of each molecule and the synergism between these molecules on the immune response will assist physicians to provide the best possible individually targeted treatment for their patients and will allow the design of new treatments.”

https://www.mdpi.com/2227-9059/10/8/1793/htm

Improved Therapeutic Efficacy of CBD with Good Tolerance in the Treatment of Breast Cancer through Nanoencapsulation and in Combination with 20(S)-Protopanaxadiol (PPD)

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“Cannabidiol (CBD), a nonpsychoactive major component derived from Cannabis sativa, widely used in neurodegenerative diseases, has now been proven to have growth inhibitory effects on many tumor cell lines, including breast tumors. Meanwhile CBD can effectively alleviate cancer-associated pain, anxiety, and depression, especially tumor cachexia, thus it is very promising as an anti-tumor drug with unique advantages.

20(S)-Protopanaxadiol (PPD) derived from the best-known tonic Chinese herbal medicine Ginseng was designed to be co-loaded with CBD into liposomes to examine their synergistic tumor-inhibitory effect. The CBD-PPD co-loading liposomes (CP-liposomes) presented a mean particle size of 138.8 nm. Further glycosyl-modified CP-liposomes (GMCP-liposomes) were prepared by the incorporation of n-Dodecyl β-D-maltoside (Mal) into the liposomal bilayer with glucose residue anchored on the surface to act as a ligand targeting the GLUT1 receptor highly expressed on tumor cells.

In vivo studies on murine breast tumor (4T1 cells)-bearing BALB/c mice demonstrated good dose dependent anti-tumor efficacy of CP-liposomes. A high tumor inhibition rate (TIR) of 82.2% was achieved with good tolerance. However, glycosylation modification failed to significantly enhance TIR of CP-liposomes.

In summary, combined therapy with PPD proved to be a promising strategy for CBD to be developed into a novel antitumor drug, with characteristics of effectiveness, good tolerance, and the potential to overcome tumor cachexia.”

https://pubmed.ncbi.nlm.nih.gov/35893789/

https://www.mdpi.com/1999-4923/14/8/1533/htm

Cannabidiol Regulates PPARγ-Dependent Vesicle Formation as well as Cell Death in A549 Human Lung Cancer Cells

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“Extracts of phytocannabinoids from Cannabis sativa have been studied for therapeutic purposes. Although nonpsychoactive CBD has been studied as a promising anticancer drug because it induces apoptosis in many cancer cells, it is also known to induce several physiological changes.

In this study, we clarify the functional role it plays in the morphological characteristics of intracellular vesicle formation as well as apoptosis in A549 human lung cancer cells.

CBD treatment shows growth inhibition at concentrations above 20 μM, but FACS analysis shows low efficacy in terms of cell death. Microscopic observations suggest that multiple vesicles were detected in the cytoplasmic region of CBD-treated A549 cells.

CBD treatment upregulates apoptosis-related proteins, such as p53, PARP, RIP1, RIP3, Atg12, and Beclin, indicating that CBD regulates several types of cell death. CBD treatment also induced E-cadherin, PPARγ, clathrin, β-adaptin, and Tsg101, also known to be cellular-differentiation inducers or vesicle-formation components.

Treatment combining CBD with GW9662, a PPARγ inhibitor, reduced CBD-induced cytoplasmic vesicle formation. This indicates that PPARγ regulates the vesicle-formation mechanism. However, CBD-treated E-cad KO clones did not show this regulatory mechanism.

These results elucidate the pharmacological and molecular networks associated with CBD in PPARγ-dependent vesicle formation and the induction of apoptosis.”

https://pubmed.ncbi.nlm.nih.gov/35890134/

“Recently, the pharmacological efficacy of CBD has been focused on in many types of disease models. In this study, we have shown that CBD treatment upregulated cell death proteins, such as p53, PARP, RIP1, RIP3, Atg12, and Beclin. In addition, CBD treatment also induced E-cadherin, PPARγ, clathrin, β-adaptin, and Tsg101, also known to be cellular-differentiation inducers or vesicle-formation components.

We have also shown that PPARγ regulates the vesicle-formation mechanism. Therefore, not only have we confirmed cell death induction by CBD, we have also confirmed the regulation of vesicle formation by PPARγ in various cancer models.

Detailed molecuclar insights would enhance the therapeutic utilization of CBD without side effects. Cellular proliferation and death could be determined by a variety of molecular regulations in cellular networks composed of a variety of proteins. Moreover, the physiological changes in cells will be closely related to functional changes in intracellular organelles.

We suggest that an understanding of the complex intracellular network system is necessary to optimize the pharmacological efficacy of CBD. These steady research efforts will make significant progress in increasing the utilization of CBD, which has been restricted by legal regulations in some countries.”

https://www.mdpi.com/1424-8247/15/7/836/htm