Comparative Pharmacokinetics of Δ<sup>9</sup>-Tetrahydrocannabinol in Adolescent and Adult Male and Female Rats

Torrens, Alexa; Roy, Pritam; Lin, Lin; Vu, Cindy; Grimes, Dakota; Inshishian, Victoria; Montesinos, J. Seguí; Ahmed, Faizy; Mahler, Stephen V.; Huestis, Marylin A.; Das, Aditi; Piomelli, Daniele

doi:10.1089/can.2021.0205

Cited by 12 publications

(18 citation statements)

References 40 publications

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“…Our ranges of THC levels in plasma are comparable to what has been shown after IP injection of low doses of THC 0.5-3 mg/kg (~25-75 ng/ml) [28][29][30] , after passive THC vapor exposure ng/ml) 17,28,31 , and in rats self-administering THC vapor puffs (~10-40 ng/ml) 32,33 . Blood levels of THC following vapor exposure peak rapidly, within 5-10 minutes after exposure 28,31 .…”

Section: Discussionsupporting

confidence: 86%

Δ⁹-Tetrahydrocannabinol Vapor Exposure Produces Conditioned Place Preference in Male and Female Rats

Moore

Davis

Sempio

et al. 2024

Cannabis and Cannabinoid Research

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Background: The use of place conditioning procedures and drug vapor exposure models can increase our understanding of the rewarding and aversive effects of vaped cannabis products.Currently there are limited data on the conditioned rewarding effects of vaporized Δ 9tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis in rats, and no studies to date examining sex differences.Methods: Male and female Sprague-Dawley rats (N=96; 12 per sex/group) underwent place conditioning sessions immediately after exposure to THC or vehicle (propylene glycol, PG) vapor. Locomotor activity was measured by beam breaks during conditioning sessions. THC vapor-conditioned rats received one of three THC vapor exposure amounts (low: 5 puffs of 100 mg/ml THC, medium: 5 puffs of 200 mg/ml THC, or high: 10 puffs of 200 mg/ml THC) and matched vehicle vapor (PG) exposure on alternate days for 16 daily sessions. A 'no THC' control group of vehicle-conditioned rats received only PG vapor exposure each day. After the 8th and 16th conditioning sessions, untreated rats were tested for conditioned place preference (CPP) or avoidance (CPA). Next, extinction tests and a THC vapor-primed reinstatement test were conducted.Results: THC vapor produced CPP and locomotor effects in an exposure dependent manner, and some sex differences were observed. Low THC vapor exposure did not produce CPP in males or females. Medium THC vapor exposure produced CPP in males, but not females. High THC vapor exposure produced CPP in both males and females. Medium and high THC vapor exposure amounts produced hyperactivity in female rats, but not male rats. CPP was more resistant to extinction in females than males. THC vapor re-exposure (i.e., drug-prime) after extinction did not result in reinstatement of CPP for either sex. Conclusion:This study demonstrates conditioned rewarding effects of THC vapor in both male and female rats and provides evidence for sex differences in amounts of THC vapor that produce CPP and in time to extinction. CPA was not observed at any of the THC vapor

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Section: Discussionsupporting

confidence: 86%

Δ⁹-Tetrahydrocannabinol Vapor Exposure Produces Conditioned Place Preference in Male and Female Rats

Moore

Davis

Sempio

et al. 2024

Cannabis and Cannabinoid Research

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“…Overall evaluation of CB metabolites has shown that females accumulate higher levels of 11-OH-THC than males 1,8,10,24 . Here, 2-hours post-treatment, females had higher 11-OH-THC levels only when THC was delivered in combination with CBD.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, sex differences in CYPs might explain the differences in metabolism seen here. Indeed, metabolism of THC to 11-OH-THC in microsomal preparations derived from females occurs at 3 times the rate of the metabolism in cells derived from males 1 .…”

Section: Discussionmentioning

confidence: 99%

“…One explanation for these sex differences may stem from the fact that CBs are metabolized differently in male and female animals and that these metabolites drive different signaling efficacy. Adult female rats have higher peak plasma levels of 11-OH-THC after acute injection with 5 mg/kg of THC compared to males 1 , and adult female-derived microsomes convert THC to 11-OH-THC at 3 times the rate of male microsomes, while conversion to 11-COOH-THC is similar between sexes 1 . After a 2.5 mg/kg injection of THC, female rats have higher plasma levels of 11-OH-THC and 11-COOH-THC than males, but males have higher levels of THC 10 .…”

Section: Introductionmentioning

confidence: 93%

“…Multiple lines of evidence have established sex differences in cannabinoid (CB) behavioral and molecular pharmacology [1][2][3][4][5] . ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have different time and dose-response courses for male and female rats on mechanical pain (von Frey test), and temperature 6 .…”

Section: Introductionmentioning

confidence: 99%

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Plasma and Liver Lipids are Differentially Regulated After Cannabinoid Treatments in Male and Female Mice

Johnson

Bosquez-Berger

Bentz

et al. 2023

Preprint

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Cannabinoids (CBs) have sex-dependent behavioral and physiological effects and modulate lipids across the body. To understand how some of these sex differences may be due to differences how both phyto- and endocannabinoids are regulated in the liver and plasma, male and female CD1 mice were administered 10 mg/kg i.p. of cannabidiol (CBD), ∆9-tetrahydrocannabinol (THC), or THC+CBD then core blood and liver tissue were collected after 2 hours. Lipids were extracted from both liver and plasma, and samples were screened via HPLC/MS/MS for ∆9-tetrahydrocannabinol (THC), metabolites 11-OH-THC and 11-COOH-THC, cannabidiol (CBD), metabolites 7-OH-CBD and 7-COOH-CBD, ~70 endolipids including the endocannabinoids, N-arachidonoyl ethanolamine (Anandamide; AEA) and 2-sn-arachidonoyl glycerol (2-AG). Structural analogs to AEA (e.g. lipoamino acids, lipoamines) and 2-acyl glycerols) as well as free fatty acids and prostaglandins were also evaluated. Results show that at 2 hours post injection levels of CBs demonstrate key differences between males and females in both plasma and liver, and that these differences vary when co-administered as opposed to administered alone. Illustrating a link between liver and plasma, directionality of CB differences are similar between the two tissue types as a function of both sex and CB treatment. By contrast, endolipids had very different profiles as a function of sex, CB administration, and tissue type. Importantly, there are baseline differences between male and female mice in endocannabinoids and related lipids, which likely impact how CB administration modulates these endolipids. These data illustrate the complexity of outcomes of CB treatment between males and females on circulating CBs and endolipids and highlight the need to consider these factors when evaluating efficacy of CB drug treatments or usage.

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Sex and Gender Differences in Simultaneous Alcohol and Cannabis Use: a Narrative Review

Tomko,

Gex,

Davis

et al. 2023

Curr Addict Rep

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Comparative Pharmacokinetics of Δ⁹-Tetrahydrocannabinol in Adolescent and Adult Male and Female Rats

Cited by 12 publications

References 40 publications

Δ⁹-Tetrahydrocannabinol Vapor Exposure Produces Conditioned Place Preference in Male and Female Rats

Δ⁹-Tetrahydrocannabinol Vapor Exposure Produces Conditioned Place Preference in Male and Female Rats

Plasma and Liver Lipids are Differentially Regulated After Cannabinoid Treatments in Male and Female Mice

Sex and Gender Differences in Simultaneous Alcohol and Cannabis Use: a Narrative Review

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Comparative Pharmacokinetics of Δ9-Tetrahydrocannabinol in Adolescent and Adult Male and Female Rats

Cited by 12 publications

References 40 publications

Δ9-Tetrahydrocannabinol Vapor Exposure Produces Conditioned Place Preference in Male and Female Rats

Δ9-Tetrahydrocannabinol Vapor Exposure Produces Conditioned Place Preference in Male and Female Rats

Plasma and Liver Lipids are Differentially Regulated After Cannabinoid Treatments in Male and Female Mice

Sex and Gender Differences in Simultaneous Alcohol and Cannabis Use: a Narrative Review

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Product

Resources

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Comparative Pharmacokinetics of Δ⁹-Tetrahydrocannabinol in Adolescent and Adult Male and Female Rats

Δ⁹-Tetrahydrocannabinol Vapor Exposure Produces Conditioned Place Preference in Male and Female Rats

Δ⁹-Tetrahydrocannabinol Vapor Exposure Produces Conditioned Place Preference in Male and Female Rats