Hepatotoxicity of a Cannabidiol-Rich Cannabis Extract in the Mouse Model

Ewing, Laura; Skinner, Charles M.; Quick, Charles M.; Kennon-McGill, Stefanie; McGill, Mitchell R.; Walker, Larry; ElSohly, Mahmoud A.; Gurley, Bill J.; Koturbash, Igor

doi:10.3390/molecules24091694

Cited by 116 publications

(104 citation statements)

References 38 publications

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“…Reported rodent studies have differing findings on hepatotoxicity when CBD is orally administered in high doses [4,26]. Hepatocellular hypertrophy with a centrilobular pattern was observed in rat livers in the study being reported.…”

Section: Discussionmentioning

confidence: 76%

Safety Assessment of a Hemp Extract using Genotoxicity and Oral Repeat-Dose Toxicity Studies in Sprague-Dawley Rats

Dziwenka¹,

Coppock²,

Alexander³

et al. 2020

Toxicology Reports

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Keywords:Cannabis sativa cannabinoids cannabidiol CBD toxicology olive oil hemp extract CYP liver mutagenicity CW hemp Charlotte's Web, Inc. A B S T R A C TCannabinoids are extracted from Cannabis sativa L. and are used for a variety of medicinal purposes. Recently, there has been a focus on the cannabinoid Cannabidiol (CBD) and its potential benefits. This study investigated the safety of a proprietary extract of C. sativa, consisting of 9% hemp extract (of which 6.27% is CBD) and 91% olive oil. The mutagenic potential of the hemp extract was evaluated with the AMES assay inclusive of a hepatic drug metabolizing mix (S9) rich in CYP enzymes. The test article did not elicit evidence of bacterial mutagenicity. GLP compliant 14-day and a 90-day toxicity study were conducted. Olive oil was used as a control. The 90-day study had a 28-day recovery period. Treatments for the 14-day non-recovery range-finding study were 0, 1000, 2000 and 4000 mg test article/kg body weight (bw)/day for 14 days. There was a non-statistically significant (p > 0.05) decrease in body weights for the male and female rats receiving the test article. Hypoactivity, hyperactivity, reduced food consumption and piloerection were observed in the rats receiving 4000 mg test article/kg bw. Histopathology showed an increase in the size of liver cells (hypertrophy) around the central vein (centrilobular) in Groups 3 (3/10) and 4 (5/10) that correlated with increased liver weights. In the 90-day study, 8 groups of rats were dosed with 0, 200, 400 and 800 mg test article/kg bw/day. Groups 5 to 8 had a 28-day recovery. There were no test article-linked changes in clinical observations, physical examinations, Functional Observation Battery, ophthalmology, Motor Activity Assessment, hematology, clinical chemistries and macropathology (all groups). With the exception of the liver and adrenal gland, no test article-linked pathology was observed. For all rats receiving the test article, histopathology showed hypertrophy of liver cells around the central vein. The increase of liver weight is most likely caused by hypertrophy due to up-regulation of the hepatic drug metabolizing enzymes. The hepatocellular hypertrophy was completely reversed in 28 days and was not considered to be an adverse effect. Vacuolization of the adrenal zona fasciculata was observed in the control and 800 mg test article/kg bw groups. The vacuolization of the zona fasciculata was of the same incidence and severity in treatment and control male rats and correlated with an increased in the weights of the adrenal glands. In addition, a statistically significant increase (p < 0.05) in adrenal-to-body weight ratios was observed for females receiving 800 mg test article/kg bw. This increase in adrenal-to-body weight ratio did not correlate with any of the pathology findings. The NOAEL for the test article is 800 mg/kg bw/day for female and 400 mg/kg bw/day for male Sprague Dawley rats.

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Section: Discussionmentioning

confidence: 76%

Safety Assessment of a Hemp Extract using Genotoxicity and Oral Repeat-Dose Toxicity Studies in Sprague-Dawley Rats

Dziwenka¹,

Coppock²,

Alexander³

et al. 2020

Toxicology Reports

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“…Cross-sectional human studies have shown plasma ALP to be elevated in habitual daily cannabis users (30,31) with hepatomegaly also observed (31). Increases in plasma AST, ALT, and liver-to-body weight ratios were observed in rodents treated with CBD (oral gavage; 615 mg/kg for 10 days) albeit there were unremarkable changes in liver enzymes in lower dose groups (61.5 and 184.5 mg/kg) (32). The potential short-and long-term effects of CBD on liver function in dogs warrant further investigation.…”

Section: Discussionmentioning

confidence: 98%

Preliminary Investigation of the Safety of Escalating Cannabinoid Doses in Healthy Dogs

Vaughn¹,

Kulpa²,

Paulionis³

2020

Front. Vet. Sci.

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Objective: To determine the safety and tolerability of escalating doses of three cannabis oil formulations, containing predominantly CBD, THC, or CBD and THC (1.5:1) vs. placebo in dogs.Design: Randomized, placebo-controlled, blinded, parallel study.Animals: Twenty healthy Beagle dogs (10 males, 10 females).Methods: Dogs were randomly assigned to one of five treatment groups (n = 4 dogs per group balanced by sex): CBD-predominant oil, THC-predominant oil, CBD/THC-predominant oil (1.5:1), sunflower oil placebo, medium-chain triglyceride oil placebo. Up to 10 escalating doses of the oils were planned for administration via oral gavage, with at least 3 days separating doses. Clinical observations, physical examinations, complete blood counts, clinical chemistry, and plasma cannabinoids were used to assess safety, tolerability, and the occurrence of adverse events (AEs). AEs were rated as mild, moderate, or severe/medically significant.Results: Dose escalation of the CBD-predominant oil formulation was shown to be as safe as placebo and safer than dose escalation of oils containing THC (CBD/THC oil or THC oil). The placebo oils were delivered up to 10 escalating volumes, the CBD oil up to the tenth dose (640.5 mg; ∼62 mg/kg), the THC oil up to the tenth dose (597.6 mg; ∼49 mg/kg), and the CBD/THC oil up to the fifth dose (140.8/96.6 mg CBD/THC; ∼12 mg/kg CBD + 8 mg/kg THC). AEs were reported in all dogs across the five groups and the majority (94.9%) were mild. Moderate AEs (4.4% of all AEs) and severe/medically significant AEs (0.8% of all AEs) manifested as constitutional (lethargy, hypothermia) or neurological (ataxia) symptoms and mainly occurred across the two groups receiving oils containing THC (CBD/THC oil or THC oil).Conclusions and clinical significance: Overall, dogs tolerated dose escalation of the CBD oil well, experiencing only mild AEs. The favorable safety profile of 10 escalating doses of a CBD oil containing 18.3-640.5 mg CBD per dose (∼2-62 mg/kg) provides comparative evidence that, at our investigated doses, a CBD-predominant oil formulation was safer and more tolerated in dogs than oil formulations containing higher concentrations of THC.

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“…52 Dosedependent CBD potential for inducing liver toxicity when administered at pharmacological doses is confirmed by pre-clinical experiences in the mouse model. 53 In Epidiolex registrative trials, somnolence and sedation were reported in 34% and 27% of patients consuming 20 versus 10 mg/kg/day, while the risk of suicidal behavior associated with Epidiolex versus placebo was *3.5 fold. 48 Decreased appetite, fatigue, diarrhea, transaminase elevation, rash, sleep disorders, as well as infections, were also reported in > 10% of subjects treated with Epidiolex.…”

Section: Hemp Supplementsmentioning

confidence: 99%

A Review of Hemp as Food and Nutritional Supplement

Pellegrino

Buonerba

Cannazza

et al. 2021

Cannabis and Cannabinoid Research

151

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The term ''hemp'' refers to Cannabis sativa cultivars grown for industrial purposes that are characterized by lower levels of tetrahydrocannabinol (THC), the active principle responsible for Cannabis psychotropic effects. Hemp is an extraordinary crop, with enormous social and economic value, since it can be used to produce food, textiles, clothing, biodegradable plastics, paper, paint, biofuel, and animal feed, as well as lighting oil. Various parts of the hemp plant represent a valuable source of food and ingredients for nutritional supplements. While hemp inflorescence is rich in nonpsychoactive, yet biologically active cannabinoids, such as cannabidiol (CBD), which exerts potent anxiolytic, spasmolytic, as well as anticonvulsant effects, hempseed has a pleasant nutty taste and represents a valuable source of essential amino acids and fatty acids, minerals, vitamins, and fibers. In addition, hempseed oil is a source of healthy polyunsaturated fatty acids, and hemp sprouts are rich in antioxidants. This review article aims to provide a comprehensive outlook from a multidisciplinary perspective on the scientific evidence supporting hemp beneficial properties when consumed as food or supplement. Marketing of hemp-derived products is subjected to diversified and complex regulations worldwide for several reasons, including the fact that CBD is also the active principal of pharmaceutical agents and that regulatory bodies in some cases ban Cannabis inflorescence regardless of its THC content. Some key regulatory aspects of such a complex scenario are also analyzed and discussed in this review article.

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Hepatotoxicity of a Cannabidiol-Rich Cannabis Extract in the Mouse Model

Cited by 116 publications

References 38 publications

Safety Assessment of a Hemp Extract using Genotoxicity and Oral Repeat-Dose Toxicity Studies in Sprague-Dawley Rats

Safety Assessment of a Hemp Extract using Genotoxicity and Oral Repeat-Dose Toxicity Studies in Sprague-Dawley Rats

Preliminary Investigation of the Safety of Escalating Cannabinoid Doses in Healthy Dogs

A Review of Hemp as Food and Nutritional Supplement

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