Disposition of Cannabidiol Metabolites in Serum and Urine from Healthy Individuals Treated with Pharmaceutical Preparations of Medical Cannabis

Pérez-Acevedo, Ana Pilar; Busardò, Francesco Paolo; Pacifici, Roberta; Mannocchi, Giulio; Gottardi, Massimo; Poyatos, Lourdes; Papaseit, Esther; Pérez‐Mañá, Clara; Martin, Soraya; Trana, Annagiulia Di; Pichini, Simona; Farré, Magı́

doi:10.3390/ph13120459

Cited by 14 publications

(12 citation statements)

References 15 publications

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“…This experiment with vaporized medical cannabis has been the third part of a study on the disposition of THC, CBD, their acidic precursors, and their metabolites following the administration of the three most common formulations of medical cannabis: Decoction, oil, and vaporized flowering tops [7,8]. In this regard, it is worth noticing that:…”

Section: Discussionmentioning

confidence: 99%

“…We recently investigated the disposition of THC, CBD, their precursors, and their principal metabolites in biological matrices of healthy individuals treated with oral decoction and oil, the most used medical cannabis herbal preparations [7,8]. We found that the aqueous preparation was generally better absorbed than the oil, even if it contained a minor amount of THC, THCA-A, and CBD.…”

Section: Introductionmentioning

confidence: 99%

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Disposition of Phytocannabinoids, Their Acidic Precursors and Their Metabolites in Biological Matrices of Healthy Individuals Treated with Vaporized Medical Cannabis

et al. 2021

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Inhalation by vaporization is a useful application mode for medical cannabis. In this study, we present the disposition of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, and their metabolites in serum, oral fluid, and urine together with the acute pharmacological effects in 14 healthy individuals treated with vaporized medical cannabis. THC and CBD peaked firstly in serum and then in oral fluid, with higher concentrations in the first biological matrices and consequent higher area under the curve AUCs. Acidic precursors Δ-9-tetrahydrocannabinolic acid A (THCA) and cannabidiolic acid (CBDA) showed a similar time course profile but lower concentrations due to the fact that vaporization partly decarboxylated these compounds. All THC and CBD metabolites showed a later onset with respect to the parent compounds in the absorption phase and a slower decrease to baseline. In agreement with serum kinetics, THC-COOH-GLUC and 7-COOH-CBD were the significantly most excreted THC and CBD metabolites. The administration of vaporized medical cannabis induced prototypical effects associated with the administration of cannabis or THC in humans, with a kinetic trend overlapping that of parent compounds and metabolites in serum. The pharmacokinetics of cannabinoids, their precursors, and their metabolites in biological fluids of individuals treated with vaporized medical cannabis preparations showed a high interindividual variability as in the case of oral medical cannabis decoction and oil. Inhaled medical cannabis was absorbed into the organism earlier than decoction and oil. Cannabinoids reached higher systemic concentrations, also due to the fact that the acid precursors decarboxylated to parent cannabinoids at high temperatures, and consequently, the physiological and subjective effects occurred earlier and resulted with higher intensity. No serious adverse effects were observed.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Disposition of Phytocannabinoids, Their Acidic Precursors and Their Metabolites in Biological Matrices of Healthy Individuals Treated with Vaporized Medical Cannabis

et al. 2021

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“…9,11 The most common metabolites of CBD are 7-COOH-CBD, the inactive metabolite, 7-OH-CBD, the active metabolite, and the 6-α-OH-CBD and 6-β-OH-CBD minor metabolites. 12 However, CBD metabolism is complex, and over 40 phase I metabolites alone have been identified.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, CBD has the potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, UGT1A9, and UGT2B7 9,11 . The most common metabolites of CBD are 7‐COOH‐CBD, the inactive metabolite, 7‐OH‐CBD, the active metabolite, and the 6‐α‐OH‐CBD and 6‐β‐OH‐CBD minor metabolites 12 . However, CBD metabolism is complex, and over 40 phase I metabolites alone have been identified.…”

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confidence: 99%

Pharmacogenetic Predictors of Cannabidiol Response and Tolerability in Treatment‐Resistant Epilepsy

Davis

Beasley

Amaral

et al. 2021

Clin Pharma and Therapeutics

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In patients with treatment-resistant epilepsy (TRE), cannabidiol (CBD) produces variable improvement in seizure control. Patients in the University of Alabama at Birmingham CBD Expanded Access Program (EAP) were enrolled in the genomic study and genotyped using the Affymetrix Drug Metabolizing Enzymes and Transporters plus array. Associations between variants and CBD response (≥50% seizure reduction) and tolerability (diarrhea, sedation, abnormal liver function) was evaluated under dominant and recessive models. Expression quantitative trait loci (eQTL) influencing potential CBD targets was evaluated in Braineac, and genetic co-expression examined. Of 169 EAP patients, 112 (54.5% pediatric; 50.0% female) were included in the genetic analyses. Patients with AOX1 rs6729738 CC (aldehyde oxidase; OR 6.69, 95%CI 2.19-20.41; p=0.001) or ABP1 rs12539 (diamine oxidase; OR 3.96, 95%CI 1.62-9.73; p=0.002) were more likely to respond. Conversely, patients with SLC15A1 rs1339067 TT had lower odds of response (OR 0.06, 95%CI 0.01-0.56; p=0.001). ABCC5 rs3749442 was associated with lower likelihood of response and abnormal LFTs, and higher likelihood of sedation. EQTL revealed that rs1339067 decreased GPR18 expression (endocannabinoid receptor) in white matter (p=5.6x10 -3 ), and rs3749442 decreased hippocampal HTR3E expression (serotonin 5-HT 3E ; p=8.5x10 -5 ). Furthermore, 75% of genes associated with lower likelihood of response were co-expressed. Pharmacogenetic variation is associated with CBD response and influences expression of CBD targets in TRE. Implicated pathways, including cholesterol metabolism and glutathione conjugation, demonstrate potential interactions between CBD and common medications (e.g. statins, acetaminophen) that may require closer monitoring.These results highlight the role of pharmacogenes in fundamental biologic processes and potential genetic underpinnings of treatment-resistance.

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“…Previous studies have determined the levels of CBD or its metabolites in biological samples after medical cannabis consumption [ 17 , 18 , 19 , 20 , 21 , 22 ]. Although these studies were valuable, no analytical assay exists for the simultaneous determination of CBD and its main metabolites, 7-hydroxycannabidiol (7-OH-CBD), 6-α-hydroxycannabidiol (6-α–OH–CBD) and 6-β-hydroxycannabidiol (6-β–OH–CBD) in serum samples of individuals treated with CBD-based pharmaceuticals or medical cannabis.…”

Section: Introductionmentioning

confidence: 99%

UHPLC-MS/MS Analysis of Cannabidiol and Its Metabolites in Serum of Patients with Resistant Epilepsy Treated with CBD Formulations

Malaca

Gottardi²,

Pigliasco

et al. 2021

Pharmaceuticals

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Cannabidiol (CBD) is a promising therapeutic agent with analgesic, myorelaxant, and anti-epileptic actions. Recently, a purified form of CBD (Epidiolex®) has been approved by the European Medicines Agency (EMA) for the treatment of two highly-refractory childhood-onset epilepsies (Dravet and Lennox-Gastaut syndrome). Given the interindividual response and the relationship between the dose administered and CBD blood levels, therapeutic drug monitoring (TDM) is a valuable support in the clinical management of patients. We herein report for the first time a newly developed and validated method using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC–MS/MS) to evaluate CBD and its metabolites (i.e., cannabidiol-7-oic acid (7-COOH-CBD), 7-hydroxycannabidiol (7-OH-CBD), 6-α-hydroxycannabidiol (6-α–OH–CBD) and 6-β-hydroxycannabidiol (6-β–OH–CBD)) in serum samples. The method reached the sensitivity needed to detect minimal amounts of analytes under investigation with limits of quantification ranging from 0.5 to 20 ng/mL. The validation results indicated in this method were accurate (average inter/intra-day error, <15%), precise (inter/intra-day imprecision, <15%), and fast (8 min run time). The method resulted to be linear in the range of 1–10,000 ng/mL for CBD-COOH, 1–500 ng/mL for 7-OH-CBD and CBD and 1–25 ng/mL for 6-α–OH–CBD and 6-β–OH–CBD. Serum levels of CBD (88.20–396.31 and 13.19–170.63 ng/mL) as well as of 7-OH-CBD (27.11–313.63 and 14.01–77.52 ng/mL) and 7-COOH-CBD (380.32–10,112.23 and 300.57–2851.82 ng/mL) were significantly higher (p < 0.05) in patients treated with GW pharma CBD compared to those of patients treated with galenic preparations. 6-α–OH–CBD and 6-β–OH–CBD were detected in the first group and were undetectable in the second group. 7-COOH-CBD was confirmed as the most abundant metabolite in serum (5–10 fold higher than CBD) followed by 7-OH-CBD. A significant correlation (p < 0.05) between the dose administrated and a higher bioavailability was confirmed in patients treated with a GW pharma CBD preparation.

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Disposition of Cannabidiol Metabolites in Serum and Urine from Healthy Individuals Treated with Pharmaceutical Preparations of Medical Cannabis

Cited by 14 publications

References 15 publications

Disposition of Phytocannabinoids, Their Acidic Precursors and Their Metabolites in Biological Matrices of Healthy Individuals Treated with Vaporized Medical Cannabis

Disposition of Phytocannabinoids, Their Acidic Precursors and Their Metabolites in Biological Matrices of Healthy Individuals Treated with Vaporized Medical Cannabis

Pharmacogenetic Predictors of Cannabidiol Response and Tolerability in Treatment‐Resistant Epilepsy

UHPLC-MS/MS Analysis of Cannabidiol and Its Metabolites in Serum of Patients with Resistant Epilepsy Treated with CBD Formulations

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