Sex Differences in the Pharmacokinetics of Cannabidiol and Metabolites Following Oral Administration of a Cannabidiol-Dominant Cannabis Oil in Healthy Adults

Kulpa, Justyna; Hill, Melanie L.; Eglit, Graham M.L.; Mosesova, Irina; Bonn‐Miller, Marcel O.; Peters, Erica N.

doi:10.1089/can.2022.0345

Cited by 11 publications

(10 citation statements)

References 32 publications

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“…For 7-COOH-CBD, a 2.25-fold higher C max and 1.97-fold higher AUC for female subjects after normalizing body weight. These results are consistent with recently published clinical research by MacNair et al [ 28 ] on the administration of cannabis oil. The reason for the sex difference in C max and AUC is unclear, but it could be due to sex differences in UGT activity.…”

Section: Discussionsupporting

confidence: 93%

Pharmacokinetic Variability of Oral Cannabidiol and Its Major Metabolites after Short-Term High-Dose Exposure in Healthy Subjects

Zhang,

Melchert,

Markowitz

2024

Med Cannabis Cannabinoids

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Introduction: Cannabidiol (CBD) is a widely utilized nonpsychoactive cannabinoid available as a prescriptive drug treatment and over-the-counter supplement. In humans, CBD is metabolized and forms the major active metabolite 7-hydroxy-cannabidiol (7-OH-CBD), which is further metabolized to 7-carboxy-cannabidiol (7-COOH-CBD). In the current study, plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD were measured, and the potential influences of sex, race, and body mass index (BMI) on the pharmacokinetic variability were assessed. Methods: Blood samples from a previously conducted CBD drug interaction study in healthy volunteers (n = 12) were utilized. The subjects received orally administered CBD (Epiodiolex®), 750 mg twice daily for 3 days and a single dose on the 4th day. Nine plasma samples were collected, and plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD were analyzed by LC-MS/MS. Peak plasma concentration (Cmax), time to Cmax (Tmax), area under the curve (AUC), and metabolite‐to‐parent drug exposure ratios (MPR) were calculated. Statistical analysis was performed to determine the correlations of Cmax, AUC, and MPR of CBD, 7-OH-CBD, and 7-COOH-CBD in different sex, race, BMI, and body weight. Results: For CBD, the mean Cmax was 389.17 ± 153.23 ng/mL, and the mean AUC was 1,542.19 ± 488.04 ng/mL*h. For 7-OH-CBD, the mean Cmax was 81.35 ± 36.64 ng/mL, the mean AUC was 364.70 ± 105.59 ng/mL*h, and the mean MPR was 0.25 ± 0.07. For 7-COOH-CBD, the mean Cmax was 1,717.33 ± 769.22 ng/mL, the mean AUC was 9,888.42 ± 3,961.47 ng/mL*h, and the mean MPR was 7.11 ± 3.48. For 7-COOH-CBD, a 2.25-fold higher Cmax was observed in female subjects (p = 0.0155) and a 1.97-fold higher AUC for female subjects (p = 0.0285) with the normalization of body weight. A significant linearity (p = 0.0135) of 7-OH-CBD AUC with body weight in females was observed. No significant differences were identified in Cmax, AUC, and PMR with race and BMI. Conclusion: Observed differences in sex were in agreement with previously reported findings. A larger population pharmacokinetics study is warranted to validate the observed higher Cmax and AUC in females and significant linearity with body weight in females from the current study.

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Section: Discussionsupporting

confidence: 93%

Pharmacokinetic Variability of Oral Cannabidiol and Its Major Metabolites after Short-Term High-Dose Exposure in Healthy Subjects

Zhang,

Melchert,

Markowitz

2024

Med Cannabis Cannabinoids

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“…Further, FAAH expression levels in the cerebellum were higher for Tat(+) males compared to Tat(+) females and also compared to Tat(−) males, which supports the finding of Tat(+) males displaying high AA levels in the cerebellum, potentially due to increased breakdown of AEA, which however demonstrated no differences in AEA expression based on sex or Tat expression in our study. More research is needed to understand how sex alters the endocannabinoid system in PLWH and how it relates to neuroinflammation and HAND, but vulnerabilities to HAND symptoms ( Levine et al, 2021 ; Arkell et al, 2022 ; Yuan et al, 2022 ; Batinic et al, 2023 ; MacNair et al, 2023 ) and immune activation ( Funderburg and Mehta, 2016 ; Koethe et al, 2020 ) have been reported to be higher in women compared to men. Whereas a recent study did not find sex differences in various metabolites of the AA cascade of gp120 transgenic mice, transcriptomic analysis revealed sexual dimorphism of AA pathway-related genes, and females appear to be more responsive to the lipoxygenase pathway compared to males ( Koethe, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Effects of acute cannabidiol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

Yadav-Samudrala,

Gorman,

Barmada

et al. 2024

Front. Neurosci.

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BackgroundSome evidence suggests that cannabidiol (CBD) has potential to help alleviate HIV symptoms due to its antioxidant and anti-inflammatory properties. Here we examined acute CBD effects on various behaviors and the endocannabinoid system in HIV Tat transgenic mice.MethodsTat transgenic mice (female/male) were injected with CBD (3, 10, 30 mg/kg) and assessed for antinociception, activity, coordination, anxiety-like behavior, and recognition memory. Brains were taken to quantify endocannabinoids, cannabinoid receptors, and cannabinoid catabolic enzymes. Additionally, CBD and metabolite 7-hydroxy-CBD were quantified in the plasma and cortex.ResultsTat decreased supraspinal-related nociception and locomotion. CBD and sex had little to no effects on any of the behavioral measures. For the endocannabinoid system male sex was associated with elevated concentration of the proinflammatory metabolite arachidonic acid in various CNS regions, including the cerebellum that also showed higher FAAH expression levels for Tat(+) males. GPR55 expression levels in the striatum and cerebellum were higher for females compared to males. CBD metabolism was altered by sex and Tat expression.ConclusionFindings indicate that acute CBD effects are not altered by HIV Tat, and acute CBD has no to minimal effects on behavior and the endocannabinoid system.

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“…A major limitation of this study was that it was only performed in male rats. Sex differences have been reported in the pharmacokinetics of cannabidiol [ 45 , 46 ]. In addition, limited clinical data in humans indicated three female participants withdrew from study due to nausea and/or vomiting, which may indicate that females are more sensitive to kratom than males [ 8 , 10 ].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Interaction of Kratom and Cannabidiol in Male Rats

Berthold,

Kamble,

Kanumuri

et al. 2024

Pharmaceutics

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Kratom and cannabidiol products are used to self-treat a variety of conditions, including anxiety and pain, and to elevate mood. Research into the individual pharmacokinetic properties of commercially available kratom and cannabidiol products has been performed, but there are no studies on coadministration of these products. Surveys of individuals with kratom use history indicate that cannabidiol use is one of the strongest predictors of both lifetime and past month kratom use. The purpose of this study was to determine if there are changes in pharmacokinetic properties when commercially available kratom and cannabidiol products are administered concomitantly. It was found that with concomitant administration of cannabidiol, there was a 2.8-fold increase in the exposure of the most abundant kratom alkaloid, mitragynine, and increases in the exposure of other minor alkaloids. The results of this work suggest that with cannabidiol coadministration, the effects of kratom may be both delayed and increased due to a delay in time to reach maximum plasma concentration and higher systemic exposure of the psychoactive alkaloids found in kratom.

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Sex Differences in the Pharmacokinetics of Cannabidiol and Metabolites Following Oral Administration of a Cannabidiol-Dominant Cannabis Oil in Healthy Adults

Cited by 11 publications

References 32 publications

Pharmacokinetic Variability of Oral Cannabidiol and Its Major Metabolites after Short-Term High-Dose Exposure in Healthy Subjects

Pharmacokinetic Variability of Oral Cannabidiol and Its Major Metabolites after Short-Term High-Dose Exposure in Healthy Subjects

Effects of acute cannabidiol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

Pharmacokinetic Interaction of Kratom and Cannabidiol in Male Rats

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