Monthly Archives: May 2022

Long-term cannabidiol treatment for seizures in patients with tuberous sclerosis complex: An open-label extension trial

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“Objective: To evaluate the long-term safety and efficacy of add-on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open-label extension (OLE) of the randomized, placebo-controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February 2019 data cut) analysis are reported.

Methods: Patients who completed the randomized trial enrolled to receive CBD (Epidiolex® in the United States; Epidyolex® in the EU; 100 mg/mL oral solution). The initial target dose was 25 mg/kg/day, which, based on response and tolerability, could be decreased or increased up to 50 mg/kg/day. The primary end point was safety. Key secondary end points included percentage reduction in TSC-associated (countable focal and generalized) seizures, responder rates, and Subject/Caregiver Global Impression of Change (S/CGIC).

Results: Of 201 patients who completed the randomized phase, 199 (99%) entered the OLE. Mean age was 13 years (range, 1-57). At the time of analysis, 5% of patients had completed treatment, 20% had withdrawn, and 75% were ongoing. One-year retention rate was 79%. Median treatment time was 267 days (range, 18-910) at a 27 mg/kg/day mean modal dose. Most patients (92%) had an adverse event (AE). Most common AEs were diarrhea (42%), seizure (22%), and decreased appetite (20%). AEs led to permanent discontinuation in 6% of patients. There was one death that was deemed treatment unrelated by the investigator. Elevated liver transaminases occurred in 17 patients (9%) patients; 12 were taking valproate. Median percentage reductions in seizure frequency (12-week windows across 48 weeks) were 54%-68%. Seizure responder rates (≥50%, ≥75%, 100% reduction) were 53%-61%, 29%-45%, and 6%-11% across 12-week windows for 48 weeks. Improvement on the S/CGIC scale was reported by 87% of patients/caregivers at 26 weeks.

Significance: In patients with TSC, long-term add-on CBD treatment was well tolerated and sustainably reduced seizures through 48 weeks, with most patients/caregivers reporting global improvement.”

https://pubmed.ncbi.nlm.nih.gov/34957550/

“The results of our study show that add-on CBD can be an efficacious long-term treatment for TSC-associated seizures with manageable side effects and has been approved in patients as young as 1 year of age in the United States.”

https://onlinelibrary.wiley.com/doi/10.1111/epi.17150

Antiseizure Effects of Fully Characterized Non-Psychoactive Cannabis sativa L. Extracts in the Repeated 6-Hz Corneal Stimulation Test

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“Compounds present in Cannabis sativa L. preparations have recently attracted much attention in the treatment of drug-resistant epilepsy. Here, we screened two olive oil extracts from a non-psychoactive C. sativa variety, fully characterized by high-performance liquid chromatography and gas chromatography. Particularly, hemp oils with different concentrations of terpenes were administered at the same dose of cannabidiol (25 mg/kg/day orally), 1 h before the 6-Hz corneal stimulation test (44 mA). Mice were stimulated once a day for 5 days and evaluated by video-electrocorticographic recordings and behavioral analysis. Neuronal activation was assessed by FosB/ΔFosB immunoreactivity. Both oils significantly reduced the percentage of mice experiencing convulsive seizures in comparison to olive oil-treated mice (p < 0.050; Fisher’s exact test), but only the oil enriched with terpenes (K2) significantly accelerated full recovery from the seizure. These effects occurred in the presence of reduced power of delta rhythm, and, instead, increased power of theta rhythm, along with a lower FosB/ΔFosB expression in the subiculum (p < 0.050; Duncan’s method). The overall findings suggest that both cannabinoids and terpenes in oil extracts should be considered as potential therapeutic agents against epileptic seizures and epilepsy.”

https://pubmed.ncbi.nlm.nih.gov/34959660/

https://www.mdpi.com/1424-8247/14/12/1259


Cannabis sativa extracts protect LDL from Cu 2+-mediated oxidation

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“Background: Multiple therapeutic properties have been attributed to Cannabis sativa. However, further research is required to unveil the medicinal potential of Cannabis and the relationship between biological activity and chemical profile.

Objectives: The primary objective of this study was to characterize the chemical profile and antioxidant properties of three varieties of Cannabis sativa available in Uruguay during progressive stages of maturation.

Methods: Fresh samples of female inflorescences from three stable Cannabis sativa phenotypes, collected at different time points during the end of the flowering period were analyzed. Chemical characterization of chloroform extracts was performed by 1H-NMR. The antioxidant properties of the cannabis sativa extracts, and pure cannabinoids, were measured in a Cu2+-induced LDL oxidation assay.

Results: The main cannabinoids in the youngest inflorescences were tetrahydrocannabinolic acid (THC-A, 242 ± 62 mg/g) and tetrahydrocannabinol (THC, 7.3 ± 6.5 mg/g). Cannabinoid levels increased more than twice in two of the mature samples. A third sample showed a lower and constant concentration of THC-A and THC (177 ± 25 and 1 ± 1, respectively). The THC-A/THC rich cannabis extracts increased the latency phase of LDL oxidation by a factor of 1.2-3.5 per μg, and slowed down the propagation phase of lipoperoxidation (IC50 1.7-4.6 μg/mL). Hemp, a cannabidiol (CBD, 198 mg/g) and cannabidiolic acid (CBD-A, 92 mg/g) rich variety, also prevented the formation of conjugated dienes during LDL oxidation. In fact, 1 μg of extract was able to stretch the latency phase 3.7 times and also to significantly reduce the steepness of the propagation phase (IC50 of 8 μg/mL). Synthetic THC lengthened the duration of the lag phase by a factor of 21 per μg, while for the propagation phase showed an IC50 ≤ 1 μg/mL. Conversely, THC-A was unable to improve any parameter. Meanwhile, the presence of 1 μg of pure CBD and CBD-A increased the initial latency phase 4.8 and 9.4 times, respectively, but did not have an effect on the propagation phase.

Conclusion: Cannabis whole extracts acted on both phases of lipid oxidation in copper challenged LDL. Those effects were just partially related with the content of cannabinoids and partially recapitulated by isolated pure cannabinoids. Our results support the potentially beneficial effects of cannabis sativa whole extracts on the initial phase of atherosclerosis.”

https://pubmed.ncbi.nlm.nih.gov/33123676/

“Our findings support the beneficial effects of Cannabis sativa extracts on the initial phase of atherosclerosis. Since isolated cannabinoids were less effective preventing the oxidation of LDL, a synergistic effect between the diverse arrange of phytochemicals present in complex extracts is supported, reinforcing the entourage hypothesis and the use of whole medicinal cannabis extracts for therapeutic purposes.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-020-00042-0

Tetrahydrocannabinol-Rich Extracts From Cannabis Sativa L. Improve Glucose Consumption and Modulate Metabolic Complications Linked to Neurodegenerative Diseases in Isolated Rat Brains

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“Reduced brain glucose consumption arising from impaired glucose uptake and utilization has been linked to the pathogenesis and complications of neurodegenerative diseases. The ability of Cannabis sativa L. tetrahydrocannabinol (THC)-rich extracts to stimulate brain glucose uptake and utilization as well as its modulatory effect on gluconeogenesis, antioxidative, purinergic and cholinergic activities were investigated in isolated rats’ brains. C. sativa leaves were sequentially extracted to yield the hexane and dichloromethane extracts. The extracts were incubated at 37°C with freshly harvested brains in the presence of glucose for 2 h. The control consisted of incubation without the extracts, while brains without the extracts and glucose served as the normal control. Metformin was used as the standard drug. C. sativa extracts caused a significant (p < 0.05) increase in brain glucose uptake, with concomitant elevation of glutathione level, superoxide dismutase, catalase, and ecto-nucleoside triphosphate diphosphohydrolase activities compared to the controls. Incubation with C. sativa extracts also led to depletion in malondialdehyde and nitric oxide levels, acetylcholinesterase, butyrylcholinesterase, glucose 6-phosphatase and fructose-1,6-biphosphatase activities. GC-MS analysis of the extracts revealed the presence of THC. In silico analysis predicted THC to be permeable across the blood-brain-barrier. THC was also predicted to have an oral LD50 and toxicity class values of 482 mg/kg and 4 respectively. These results indicate that C. sativa improves glucose consumption with concomitant suppression of oxidative stress and cholinergic dysfunction, and modulation of purinergic and gluconeogenic activities in brain tissues.”

https://pubmed.ncbi.nlm.nih.gov/33390972/

“As portrayed by these results, C. sativa improves glucose consumption with concomitant suppression of oxidative stress and cholinergic dysfunction, and modulation of purinergic and gluconeogenic activities in brain tissues. Further studies are recommended to decipher the molecular mechanisms that may be involved in these neuroprotective activities in in vivo studies.”

https://www.frontiersin.org/articles/10.3389/fphar.2020.592981/full

Cannabis sativa L. (var. indica) Exhibits Hepatoprotective Effects by Modulating Hepatic Lipid Profile and Mitigating Gluconeogenesis and Cholinergic Dysfunction in Oxidative Hepatic Injury

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“Cannabis sativa L. is a crop utilized globally for recreational, therapeutic, and religious purposes. Although considered as an illicit drug in most countries, C. sativa until recently started gaining attention for its medicinal application. This study sought to investigate the hepatoprotective effect of C. sativa on iron-mediated oxidative hepatic injury. Hepatic injury was induced ex vivo by incubating hepatic tissues with Fe2+, which led to depleted levels of reduced glutathione, superoxide dismutase, catalase and ENTPDase activities, triglyceride, and high-density lipoprotein-cholesterol (HDL-C). Induction of hepatic injury also caused significant elevation of malondialdehyde, nitric oxide, cholesterol, and low-density lipoprotein-cholesterol (LDL-C) levels while concomitantly elevating the activities of ATPase, glycogen phosphorylase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, amylase, and lipase. Treatment with the hexane, dichloromethane (DCM), and ethanol extracts of C. sativa leaves significantly (p < 0.05) reversed these levels and activities to almost near normal. However, there was no significant effect on the HDL-C level. The extracts also improved the utilization of glucose in Chang liver cells. High-performance liquid chromatography (HPLC) analysis showed the presence of phenolics in all extracts, with the ethanol extract having the highest constituents. Cannabidiol (CBD) was identified in all the extracts, while Δ-9-tetrahydrocannabinol (Δ-9-THC) was identified in the hexane and DCM extracts only. Molecular docking studies revealed strong interactions between CBD and Δ-9-THC with the β2 adrenergic receptor of the adrenergic system. The results demonstrate the potential of C. sativa to protect against oxidative-mediated hepatic injury by stalling oxidative stress, gluconeogenesis, and hepatic lipid accumulation while modulating cholinergic and purinergic activities. These activities may be associated with the synergistic effect of the compounds identified and possible interactions with the adrenergic system.”

https://pubmed.ncbi.nlm.nih.gov/34992528/

“The data obtained in this study indicate the ability of C. sativa to protect against oxidative-mediated hepatic injury by stalling oxidative stress, gluconeogenesis, and hepatic lipid accumulation while modulating cholinergic and purinergic activities. These activities may be associated with the synergistic effect of the identified phenolics, CBD, and Δ-9-THC and possible interactions with the adrenergic system.”

https://www.frontiersin.org/articles/10.3389/fphar.2021.705402/full

Long-term use of cannabidiol-enriched medical cannabis in a prospective cohort of children with drug-resistant developmental and epileptic encephalopathy

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“Objective: We report our findings regarding effectiveness, safety, and tolerability of cannabidiol (CBD)-enriched medical cannabis as add-on therapy in children with drug-resistant epileptic encephalopathies (DEEs) after a median follow-up of 20 months.

Methods: A prospective cohort study was conducted to assess effectiveness, safety, and tolerability of CBD-enriched medical cannabis oil added to standard antiseizure medications in children with drug-resistant DEE seen at a single center.

Results: Between October 2018 and March 2020, 59 patients were enrolled. Mean age at enrollment was 10.5 years (range, 2-17 years). Median treatment duration was 20 months (range, 12-32). Median age at first seizure was 8 months (range, 1 day – 10 years). At the end of follow-up, 78% of the children had a ≥ 50% decrease in seizure frequency and 47.5% had a > 75% decrease. Seven patients (11.9%) were seizure free. The number of seizures was reduced from a median of 305/month to 90/month, amounting to a mean reduction of 57% and a median reduction of 71% (p < 0.0001). Adverse effects were mostly mild or moderate. CBD was discontinued in 17 patients (28.8%) due to lack of response to treatment, increased seizure frequency, intolerance to the drug, or poor compliance.

Conclusion: In children with drug-resistant DEEs, long-term treatment of CBD-enriched medical cannabis as an adjuvant therapy to antiseizure therapy was found to be safe, well tolerated, and effective. Sustained reductions in seizure frequency and improvement of aspects of daily living were observed compared to our preliminary findings.”

https://pubmed.ncbi.nlm.nih.gov/34999381/

  • “•Long-term use of CBD-enriched medical cannabis as add-on treatment seems safe and effective in DEE.
  • •The drug was well tolerated and had a positive impact on aspects of daily living.
  • •Good results were found in patients with LGS and DS, as well as those with DEEs other than LGS and DS.
  • •No tolerance to CBD-enriched medical cannabis was observed in any of the children.”

https://www.seizure-journal.com/article/S1059-1311(22)00001-2/fulltext

Healing of a Chronic Pressure Injury in a Patient Treated With Medical Cannabis for Pain and Sleep Improvement: A Case Report

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“Background: A small body of evidence suggests medical cannabis may facilitate wound healing, but the exact mechanism of this effect is unclear.

Purpose: This case report describes a patient with a pressure injury (PI) who received cannabis oil treatment for pain management and sleep improvement.

Methods: A 37-year-old woman with multiminicore disease, scoliosis, short-chain acyl-CoA dehydrogenase deficiency, and epilepsy presented to the Neurology Centre of Toronto with chronic pain and sleep disturbance, including difficulty initiating and maintaining sleep. She also had a 5-year history of a PI between her right iliac crest and right rib cage that had progressively worsened. The patient received a medical cannabis oil protocol that used a combination of cannabidiol and tetrahydrocannabinol.

Results: Cannabis oil was effective in treating pain and sleep difficulties. Unexpectedly, during the first 2 weeks of treatment, the PI started to heal and was almost completely closed at the 2-month follow-up.

Conclusion: Although it is unknown if the observed healing of this refractory PI was indirectly or directly related to the cannabidiol and tetrahydrocannabinol treatment, the potential relationships among pain, sleep disturbance, cannabis treatment, and healing should be explored.”

https://pubmed.ncbi.nlm.nih.gov/35030093/

“This case report provides an account of a patient who began using orally administered medical cannabis oil for sleep disturbances and pain management and subsequently experienced rapid healing of a chronic PI.”

https://www.hmpgloballearningnetwork.com/site/wmp/case-report/healing-chronic-pressure-injury-patient-treated-medical-cannabis-pain-and

Adherence, Safety, and Effectiveness of Medical Cannabis and Epidemiological Characteristics of the Patient Population: A Prospective Study

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“Background: Despite the absence of rigorous prospective studies, there has been an increase in the use of cannabis-based medicinal products. During the study period, the use of medical cannabis in Israel was tightly regulated by national policy. Through a prospective study of approximately 10,000 patients, we aimed to characterize the medical cannabis patient population as well as to identify treatment adherence, safety, and effectiveness.

Methods and findings: In this study of prescribed medical cannabis patients, adherence, safety, and effectiveness were assessed at 6 months. Treatment adherence was assessed by the proportion of patients purchasing the medication out of the total number of patients (excluding deceased cases and patients transferred to another cannabis clinic). Safety was assessed by the frequency of the side-effects, while effectiveness was defined as at least moderate improvement in the patient condition without treatment cessation or serious side-effects. The most frequent primary indications requiring therapy were cancer (49.1%), followed by non-specific pain (29.3%). The average age was 54.6 ± 20.9 years, 51.1% males; 30.2% of the patients reported prior experience with cannabis. During the study follow-up, 1,938 patients died (19.4%) and 1,735 stopped treatment (17.3%). Common side-effects, reported by 1,675 patients (34.2%), were: dizziness (8.2%), dry mouth (6.7%), increased appetite (4.7%), sleepiness (4.4%), and psychoactive effect (4.3%). Overall, 70.6% patients had treatment success at 6 months. Multivariable logistic regression analysis revealed that the following factors were associated with treatment success: cigarette smoking, prior experience with cannabis, active driving, working, and a young age. The main limitation of this study was the lack of data on safety and effectiveness of the treatment for patients who refused to undergo medical assessment even at baseline or died within the first 6 months.

Conclusions: We observed that supervised medical-cannabis treatment is associated with high adherence, improvement in quality of life, and a decrease in pain level with a low incidence of serious adverse events.”

https://pubmed.ncbi.nlm.nih.gov/35223923/


“This is a large study describing certain characteristics of medical cannabis users in a tightly regulated environment. The treatment appears to be safe and efficacious.”

https://www.frontiersin.org/articles/10.3389/fmed.2022.827849/full

Medical Cannabis for Gilles de la Tourette Syndrome: An Open-Label Prospective Study

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“Objectives: Assessing the effectiveness and tolerability of medical cannabis (MC) treatment on Gilles de la Tourette syndrome (GTS) patients.

Methods: We report on an open-label, prospective study on the effect of MC on adult GTS patients. MC mode of use was decided by the treating neurologist and the patient. Δ9-Tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) content within MC product and monthly dose were titrated during the study. Following treatment initiation, patients were assessed after 4 and 12 weeks for efficacy, tolerability, and side effects.

Results: Eighteen patients entered the study. Baseline Yale Global Tic Severity Scale- (YGTSS) Total (range 0-100) was 60.3 ± 17.1. Three patients did not reach the end of follow-up period. The most common mode of administration was smoking (80%). Following twelve weeks of treatment, a significant 38% average reduction (p = 0.002) of YGTSS-Total and a 20% reduction (p = 0.043) of Premonitory Urge for Tic Scale (PUTS) were observed. Common side effects were dry mouth (66.7%), fatigue (53.3%), and dizziness (46.7%). Three patients suffered from psychiatric side effects including worsening of obsessive compulsive disorder (stopped treatment), panic attack, and anxiety (resolved with treatment modification). Six patients (40%) reported cognitive side effects regarding time perception, visuospatial disorientation, confusion, slow processing speed, and attention.

Conclusions: MC treatment demonstrates good efficacy and tolerability in adult GTS patients. Predilection for smoking rather than using oil drops requires further comparative studies to evaluate the efficacy of each. Cognitive and psychiatric side effects have to be monitored and addressed.”

https://pubmed.ncbi.nlm.nih.gov/35310886/

“Our results are in line with a number of other studies suggesting that MC is effective and well tolerated in adults with GTS. From our data, it is suggested that MC might be a treatment option for resistant TS patients, and MC has a significant effect on tics, premonitory urges, and patients’ overall quality of life. In our sample, patients favored THC-rich cannabis strands and smoking/inhaling MC over sublingual oil.”

https://www.hindawi.com/journals/bn/2022/5141773/

Nutraceutical potential of industrial hemp ( Cannabis sativa L.) extracts: physicochemical stability and bioaccessibility of cannabidiol (CBD) nanoemulsions

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“Cannabidiol (CBD) is one of the most promising functional food ingredients, which displays a number of health benefits. However, its low solubility and bioavailability impede its applications in functional foods. Herein, we developed a food-grade CBD nanoemulsion system using medium chain triacylglycerides (MCT), canola oil (CO), or hemp seed oil (HSO) as the carrier oil to compare the physicochemical stability and bioaccessibility of CBD. Encouragingly, all formulations were well maintained for 90 days under the tested temperatures (4, 25 and 37 °C) and pH values (3.5 and 7.0). Quantitative analysis of CBD during storage using high performance liquid chromatography revealed that the light exposure and acidity of the solution are two important factors affecting the chemical stability of CBD. Moreover, improved bioaccessibility of CBD in all three nanoemulsion formulations compared to that of bulk oil forms was confirmed, and the long chain triacylglyceride (LCT)-based nanoemulsion was superior to the MCT-based counterpart.”

https://pubmed.ncbi.nlm.nih.gov/35348145/

https://pubs.rsc.org/en/content/articlelanding/2022/FO/D1FO04433H