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Paradoxical Patterns of Sinusoidal Obstruction Syndrome-Like Liver Injury in Aged Female CD-1 Mice Triggered by Cannabidiol-Rich Cannabis Extract and Acetaminophen Co-Administration

The goal of this study was to investigate the potential for a cannabidiol-rich cannabis extract (CRCE) to interact with the most common over-the-counter drug and the major known cause of drug-induced liver injury-acetaminophen (APAP)-in aged female CD-1 mice. Gavaging mice with 116 mg/kg of cannabidiol (CBD) [mouse equivalent dose (MED) of 10 mg/kg of CBD] in CRCE delivered with sesame oil for three consecutive days followed by intraperitoneally (i.p.) acetaminophen (APAP) administration (400…

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. 2019 Jun 17;24(12):2256.

doi: 10.3390/molecules24122256.

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Laura E Ewing et al. Molecules. .

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Abstract

The goal of this study was to investigate the potential for a cannabidiol-rich cannabis extract (CRCE) to interact with the most common over-the-counter drug and the major known cause of drug-induced liver injury-acetaminophen (APAP)-in aged female CD-1 mice. Gavaging mice with 116 mg/kg of cannabidiol (CBD) [mouse equivalent dose (MED) of 10 mg/kg of CBD] in CRCE delivered with sesame oil for three consecutive days followed by intraperitoneally (i.p.) acetaminophen (APAP) administration (400 mg/kg) on day 4 resulted in overt toxicity with 37.5% mortality. No mortality was observed in mice treated with 290 mg/kg of CBD+APAP (MED of 25 mg/kg of CBD) or APAP alone. Following CRCE/APAP co-administration, microscopic examination revealed a sinusoidal obstruction syndrome-like liver injury-the severity of which correlated with the degree of alterations in physiological and clinical biochemistry end points. Mechanistically, glutathione depletion and oxidative stress were observed between the APAP-only and co-administration groups, but co-administration resulted in much greater activation of c-Jun N-terminal kinase (JNK). Strikingly, these effects were not observed in mice gavaged with 290 mg/kg CBD in CRCE followed by APAP administration. These findings highlight the potential for CBD/drug interactions, and reveal an interesting paradoxical effect of CBD/APAP-induced hepatotoxicity.

Keywords: acetaminophen; cannabidiol; liver injury; natural products; phytochemical; sinusoidal obstruction syndrome.

Conflict of interest statement

Quick serves as a scientific consultant for Allergan. James is a co-owner of Acetaminophen Toxicity Diagnostics, LLC. No conflicts of interest are declared by the other authors.

Figures

Figure 1

Figure 1

Co-administration of cannabidiol-rich cannabis extract (CRCE) and APAP results in sinusoid obstructive syndrome-like histomorphological alterations in the livers of aged female CD-1 mice. H&E stained liver sections from (A) vehicle-gavaged mice (sesame oil), (B) 116 mg/kg CBD, (C) 290 mg/kg CBD, (D) APAP (400 mg/kg), (E) 116 mg/kg CBD+APAP, (F) 290 mg/kg CBD+APAP. Black brackets indicate areas of clear cell changes (D), yellow brackets (E) and arrows (F) indicate areas of sinusoidal dilation with vascular congestion, and blue arrows (E) indicate areas of hepatic plate atrophy. CRCE—cannabidiol-rich cannabis extract; APAP—acetaminophen. Magnification: X10.

Figure 2

Figure 2

Effects of CRCE/APAP co-administration on commonly assessed clinical chemistry parameters for liver injury. Blood was collected at the time of sacrifice, and the serum was subsequently separated and removed for analysis. Veh (n = 7); Veh + APAP (n = 7); 116 mg/kg CBD (n = 7); 116 mg/kg CBD+APAP (n = 5); 290 mg/kg CBD (n = 7); 290 mg/kg CBD + APAP (n = 6). Data are presented as mean ± SEM (* p < 0.05). ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase; GGT: gamma-glutamyl transferase.

Figure 3

Figure 3

Effects of CRCE/APAP co-administration on intrahepatic expression of cytochrome P450s and UDP-glucuronosyltransferases. Livers were collected 5 h after APAP administration and gene expression was measured using the quantitative real-time (qRT) PCR. Veh (n = 7); Veh + APAP (n = 7); 116 mg/kg CBD (n = 7); 116 mg/kg CBD + APAP (n = 7); 290 mg/kg CBD (n = 8); 290 mg/kg CBD + APAP (n = 8). Data presented as mean ± SEM fold changed from vehicle (* p < 0.05; ** p < 0.01; *** p < 0.001; and **** p < 0.0001). The following genes were changed significantly with either CBD or APAP, but the two-way ANOVA did not yield any significant comparisons: Cyp2d22 (APAP, p = 0.0016), Ugt1a1 (CBD, p = 0.0186; APAP, p = 0.0255), Ugt1a6 (CBD, p = 0.0222), and Ugt1a9 (APAP, p = 0.0026).

Figure 4

Figure 4

Mechanisms of CRCE/APAP-induced liver injury. (A) APAP-Cys protein adducts; levels of (B) GSH, and (C) GSSG/GSH; (D) mRNA levels of Gclm as measured by quantitative real-time (qRT) PCR; E) protein levels of Jnk and pJNK as measured by Western blot; and F) representative blot. Veh (n = 7); Veh + APAP (n = 7); 116 mg/kg CBD (n = 7); 116 mg/kg CBD + APAP (n = 7); 290 mg/kg CBD (n = 8); 290 mg/kg CBD + APAP (n = 8). Data presented as mean ± SEM fold changed from vehicle (* p < 0.05; ** p < 0.01; and **** p < 0.0001). GSSG levels were significantly affected by APAP (p = 0.0151), but there are no significant comparisons.

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References

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    1. Thiele E.A., Marsh E.D., French J.A., Mazurkiewicz-Beldzinska M., Benbadis S.R., Joshi C., Lyons P.D., Taylor A., Roberts C., Sommerville K., et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391:1085–1096. doi: 10.1016/S0140-6736(18)30136-3. – DOI PubMed
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Thinking about ordering some CBD online from a reputable source, but the lab results say it has .20% THC? Can I have this shipped?

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I’m in Michigan. Really want to try this but I’m worried about shipping it to my apartment and having it get seized or getting in trouble or something.

I want to put the link to the website but I’m not sure if I can source so I’ll just say the brand is pretty reputable I just don’t know if I could get in trouble for this and what the likelihood of that would be.

Like I said it’s CBD flower but it still has larger amounts of CBD unlike most CBD in Michigan which has .3% or less (legal limit.)

Anyone think I’d be fine to order it?

Source: https://www.reddit.com/r/CBD/comments/lsgs4p/thinking_about_ordering_some_cbd_online_from_a/

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Lifter 💚 21.6% CBDa

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Visit our community site for vetted suppliers at http://theCBD.place. It’s time that this subject was given more internet exposure. We are here to discuss topics related to medical marijuana and our experiences using CBD. Please do not assume that anyone here is a medical professional.

Source: https://www.reddit.com/r/CBD/comments/lsgpsn/lifter_216_cbda/

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I believe I was scammed by Peace CBD. Has anyone heard of this brand? HELP!

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Hi, thank you for your time!

My grandparents are avid CBD users, and always order from the same brand. Around 3 months ago they received a package with a bottle of Peace CBD oil in it which they had not ordered, but they had lots of family staying at their house for Christmas and thought it must have been an order placed by somebody else. But they received another in late January, and now they realized they have been charged $100 a month, all by different billing companies across the USA, and they believe it is for these bottles of CBD. They have obviously not opened or used them, and I have had little success tracking down any information about this company online. The only posts on Reddit I was able to find under “Peace CBD” all seemed weird and scam-like, and contained the following two weird scam-like links. I was hoping someone has heard of this company or a similar scam.

(My grandparents think these scammers could have possibly gotten their information from a CBD trial they had signed up for about a year ago when they were finding a brand of CBD they liked.)

Any help or information is much appreciated!

https://sites.google.com/view/peace-cbd-oil-benefits/

https://apnews.com/press-release/newmediawire/lifestyle-business-stress-anxiety-mental-health-95498ba8a73a4c10676ba086875744b5

This last link is what comes up if you click on the attached link to “Buy Peace CBD today” on the ap article. It is not even the actual bottle of peace cbd.

https://buycannagenix.com/m/index?ts=64AAF081&s1=2503&s2=4464-8958&clickid=167390707

Thank you so much!

Source: https://www.reddit.com/r/CBD/comments/lsg4si/i_believe_i_was_scammed_by_peace_cbd_has_anyone/

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