Dosage Related Efficacy and Tolerability of Cannabidiol in Children With Treatment-Resistant Epileptic Encephalopathy: Preliminary Results of the CARE-E Study

Huntsman, Richard J.; Tang-Wai, Richard; Alcorn, Jane; Vuong, Stephanie; Acton, Bryan; Corley, Scott; Laprairie, Robert B.; Lyon, Andrew W.; Meier, Simona; Mousseau, Darrell D.; Newmeyer, Doris; Prosser-Loose, Erin J.; Seifert, B; Téllez‐Zenteno, José F.; Huh, Linda; Leung, Edward; Major, Philippe

doi:10.3389/fneur.2019.00716

Cited by 43 publications

(42 citation statements)

References 28 publications

(28 reference statements)

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“…The CBD C max , and AUC 0−12h values for both THC and CBD also show a clear (if not statistically significant) trend toward disproportionally greater cannabinoid exposures relative to the dose increase. Similar results were observed in another dog trial using 2–8 mg CBD/kg bw dose range ( 1 ) and in one out of seven pediatric human patient administered similar doses of a comparable 1:20 THC:CBD CHE product as used in this study ( 3 ). Conversely, non-linear kinetics were not apparent in a different canine study using higher (roughly 10–20 mg/kg bw) CBD doses ( 12 ) or in model simulations based on data from trials using various CBD formulations in humans ( 21 ).…”

Section: Discussionsupporting

confidence: 88%

“…Possible physiological explanations for potential non-linear kinetics may be enzyme (cytochrome P450) saturation at higher cannabinoid doses. Saturation of P450 enzymes in the intestinal mucosa or hepatocytes could lead to increased oral bioavailability ( 3 , 19 ). Because of the increased risk of adverse events at higher doses (especially if exhibiting non-linear kinetics), veterinarians should caution clients who choose to increase CHE doses administered to their pets, as for many unapproved CHE formulations dosing is performed via “trial and error” approaches ( 7 , 9 ).…”

Section: Discussionmentioning

confidence: 99%

“…Cannabis -derived herbal extracts (CHEs) are increasingly popular for both human and animal use, with recent legalization of such products in Canada and some European countries and American states. There is significant interest in evaluating CHE products for a variety of applications in both human and animal health, including chronic osteoarthritis ( 1 , 2 ), epilepsy ( 3 , 4 ), neuropathic pain ( 5 ), and nausea/emesis ( 6 ). Substantial differences can exist between CHE formulations produced by licensed vs. unlicensed producers, with wide variations in cannabinoid composition and label accuracy ( 7 , 8 ).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic and Safety Evaluation of Various Oral Doses of a Novel 1:20 THC:CBD Cannabis Herbal Extract in Dogs

et al. 2020

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Objective: To determine the pharmacokinetics (PK) and safety of various oral doses of a Cannabis herbal extract (CHE) containing a 1:20 ratio of Δ9-tetrahydrocannabinol (THC):cannabidiol (CBD) in 13 healthy Beagle-cross dogs. Methods: Single-dose PK was assessed after oral administration of CHE at low, medium, or high doses [2, 5, or 10 mg CBD and 0.1, 0.25, or 0.5 mg THC per kg of body weight (bw), respectively; n = 6 per group]. Dogs were monitored for adverse events for up to 48 h post-dose. Evaluations of neurological signs, clinical laboratory abnormalities, and other adverse events were performed in two separate study phases: a multiple-dose phase with 12 dogs receiving five medium doses (5 mg CBD/kg bw) at 12 h intervals, and a single low-dose (2 mg CBD/kg bw), randomized, blinded, negative controlled study with 13 dogs. Results: Cannabinoids CBD, THC, CBC, and metabolites 6-OH-CBD, 7-OH-CBD, 11-OH-THC, and THC-COOH were quantified in plasma. CBD and THC were rapidly absorbed (mean T max of 1.9–2.3 h) and initially depleted rapidly (mean CBD T 1/2β of 2.3–2.6 h). A prolonged elimination phase (mean CBD T 1/2λ of 13.3–24.4 h) was observed. CBD and THC concentrations increased in a dose-dependent (non-linear) manner, with disproportionally greater cannabinoid exposure relative to the dose increase. Neurological signs (hyperesthesia or proprioceptive deficits) were noted in five of six dogs in the high-dose group, but only occasionally or rarely in the medium- and low-dose groups, respectively. Presence and severity of clinical signs correlated with plasma cannabinoid concentrations. Dogs appeared to develop a tolerance to cannabinoid effects after multiple CHE doses, with fewer neurological signs noted after the final (fifth) vs. first dose. No clinically meaningful changes in blood count or chemistry values occurred after multiple CHE doses. Clinical Significance: Dogs tolerated the 1:20 THC:CBD formulation well at low and medium doses, but clinically meaningful neurological signs were observed at high doses. Because of non-proportional increases in plasma cannabinoid concentrations with increasing doses, as well as potential differences in CHE product composition and bioavailability, the possibility of adverse events and dose regimen consistency should be discussed with dog owners.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic and Safety Evaluation of Various Oral Doses of a Novel 1:20 THC:CBD Cannabis Herbal Extract in Dogs

et al. 2020

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“…Terpenes may have some therapeutic advantages since it has been observed that whole plant extracts can be superior to single molecule constituents, which is known as the "entourage effect". [30][31][32][33] In general, the milligram quantity of total terpenes across products ranges from 0.015-6.7 mg/ mL or gram with only 6 products with over 1 mg/mL or gram of total terpenes. Further examination for any single terpene at concentrations higher than 1 mg/mL leaves only three products (#18, 19,25) that have a single terpene at that level.…”

Section: Discussionmentioning

confidence: 99%

<p>Cannabinoid, Terpene, and Heavy Metal Analysis of 29 Over-the-Counter Commercial Veterinary Hemp Supplements</p>

Wakshlag¹,

Cital²,

Eaton³

et al. 2020

VMRR

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Purpose: The use of veterinary low tetrahydrocannabinol (THC) Cannabis sativa (ie, hemp) products has increased in popularity for a variety of pet ailments. Low-THC Cannabis sativa is federally legal for sale and distribution in the USA, and the rise in internet commerce has provided access to interested consumers, with minimal quality control. Materials and Methods: We performed an internet word search of "hemp extract and dog" or "CBD product and dog" and analyzed 29 products that were using low-THC Cannabis sativa extracts in their production of supplements. All products were tested for major cannabinoids including cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC), cannabigerol (CBG), and other minor cannabinoids, as well as their carboxylic acid derivatives (CBDA, THCA, CBGA) using an ISO/IEC 17025 certified laboratory. Products were also tested for major terpenes and heavy metals to understand constituents in the hemp plants being extracted and distributed. Results: All products were below the federal limit of 0.3% THC with variable amounts of CBD (0-88 mg/mL or g). Only two products did not supply a CBD or total cannabinoid concentration on their packaging or website, while 22/29 could supply a certificate of analysis (COA) from a third-party laboratory. Ten of the 27 products were within 10% of the total cannabinoid concentrations of their label claim with a median concentration of 93% of claims (0-154%). Heavy metal contamination was found in 4/29 products, with lead being the most prevalent contaminant (3/29). Conclusion: The products analyzed had highly variable concentrations of CBD or total cannabinoids with only 18 of 29 being appropriately labeled according to current FDA nonmedication, non-dietary supplement or non-food guidelines. Owners and veterinarians wanting to utilize CBD-rich Cannabis sativa products should be aware of low-concentration products and should obtain a COA enabling them to fully discuss the implications of use and calculated dosing before administering to pets.

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“…In addition, the serum concentration of CBD follows dose-independent linear pharmacokinetics for most participants, although non-linear pharmacokinetics might occur but requires confirmation. Continued improvement in seizure frequency and QOLCE following the discontinuation of CHE suggest a possible enduring anticonvulsant effect [65].…”

Section: The Artisanal and Cbd Oil Extractsmentioning

confidence: 99%

Cannabis for Pediatric and Adult Epilepsy

Huntsman¹,

Tang-Wai²,

Zenteno³

2019

Recent Advances in Cannabinoid Research

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Epilepsy is a chronic disease of the central nervous system characterized by recurrent unprovoked seizures. Up to 30% of patients continue to have seizures despite treatment with appropriate anticonvulsant medications. The presence of abnormal oscillatory events within neural networks is a major feature of epileptogenesis. The endocannabinoid system can modulate these oscillatory events and alter neuronal activity making the phytocannabinoids found in Cannabis a potential therapeutic option for patients with treatment resistant epilepsy. Many in vitro and in vivo studies have demonstrated the anticonvulsant effects of several phytocannabinoids including Δ 9-tetrahydrocannabinol (Δ 9-THC) and Cannabidiol (CBD). Several small observational studies demonstrated a favorable response to cannabis herbal extracts (CHE) containing high concentrations of CBD in children with treatment resistant epilepsy. Two large double blinded clinical trials assessing the efficacy of pharmaceutical grade CBD have also been performed in children with treatment resistant seizures in Dravet syndrome and Lennox-Gastaut syndrome. Both studies demonstrated an improvement in seizure reduction in children taking CBD as compared to the placebo groups. To date there is very limited data regarding the use of cannabis based products to treat adult patients with treatment resistant epilepsy with only one randomized double blinded placebo controlled clinical trial underway.

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Dosage Related Efficacy and Tolerability of Cannabidiol in Children With Treatment-Resistant Epileptic Encephalopathy: Preliminary Results of the CARE-E Study

Cited by 43 publications

References 28 publications

Pharmacokinetic and Safety Evaluation of Various Oral Doses of a Novel 1:20 THC:CBD Cannabis Herbal Extract in Dogs

Pharmacokinetic and Safety Evaluation of Various Oral Doses of a Novel 1:20 THC:CBD Cannabis Herbal Extract in Dogs

<p>Cannabinoid, Terpene, and Heavy Metal Analysis of 29 Over-the-Counter Commercial Veterinary Hemp Supplements</p>

Cannabis for Pediatric and Adult Epilepsy

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