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

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.

Safety and Molecular-Toxicological Implications of Cannabidiol-Rich Cannabis Extract and Methylsulfonylmethane Co-Administration

“…At the same time, administration of CRCE or CRCE/MSM caused a significant increase in the liver-to-body weight ratio in mice. This corroborated the findings of other animal studies examining the effects of CBD or CRCE alone [12,13], or in combination with other hepatotoxicants [15]. Xenobiotic-induced increase in liver weight and liver-to-body weight ratio is not a rare finding in rodent models and is not necessarily a prerequisite of liver injury (especially, when other more reliable markers of liver injury are absent) and may be considered an adaptive response.…”

“…CRCE phytochemical characterization results are presented in Table 1. This phytocannabinoid composition is comparable to those of CRCEs used in previous studies, as well as in products currently on the U. S. market [13][14][15]33]. Other measurements were as follows: loss on drying-0.32%; heavy metals: lead, mercury, cadmium, and arsenic-not detected; aflatoxins: AFB 1 , AFB 2 , AGF 1 , and AFG 2 -not detected; Escherichia coli-absent; Salmonella-absent; Total Aerobic Microbial Count (TAMC)-<10 cfu/g; Total Yeast and Mold Count (TYMC)-<10 cfu/g; all of which are below USP acceptable levels for non-sterile oral preparations.…”

“…Accumulating evidence, however, indicates that CBD, when administered at clinically relevant doses, possesses significant potential for hepatotoxicity as well as for interactions with various conventional medications. In our previous studies, we have investigated the hepatotoxic potential of CRCE, either alone or when co-administered with another potent hepatotoxicant-APAP [13,15]. Therefore, the present study was designed to explore the potential interaction between CRCE and MSM-a popular DS on the U. S. market-that, due to their widespread usage, may overlap in the treatment of various ailments.…”

“…Previous studies have demonstrated that high doses of CBD/CRCE can deplete intrahepatic glutathione and its synthesis [13,15]. The latter plays a critical role in protecting cells from oxidative damage and the toxicity of xenobiotic electrophiles by maintaining redox homeostasis.…”

“…For instance, plasma levels of liver aminotransferases were greater than three times the upper limit of normal in patients taking valproate while being treated with Epidiolex ® , a purified CBD-containing drug used to treat some rare forms of pediatric refractory epilepsy [16,17,21]. Recent findings have shown that cannabidiol-rich cannabis extract (CRCE) given concomitantly with acetaminophen (APAP), one of the most common over-the-counter medications, exacerbates CBD hepatotoxicity, leading to sinusoidal obstruction syndrome-like liver injury and mortality in the mouse model [15]. These effects were associated with ingestion of high (therapeutic range) doses of CBD, however, the widespread and relatively indiscriminate distribution of CBD-containing products in the supplement market, and the potential inter-individual variability in response to CBD raises concerns as to co-ingestion of CBD and CBD-containing products with prescription and nonprescription drugs.…”