The impact of pregnancy and associated hormones on the pharmacokinetics of Δ⁹-tetrahydrocannabinol

ABSTRACT

Introduction

(-)-Δ⁹-tetrahydrocannabinol (THC) is the main psychoactive component of cannabis. Cannabis is the most widely used drug of abuse by pregnant individuals, but its maternal-fetal safety is still unclear. The changes in THC disposition during pregnancy may affect THC safety and pharmacology.

Areas covered

This review summarizes the current literature on THC metabolism and pharmacokinetics in humans. It provides an analysis of how hormonal changes during pregnancy may alter the expression of cannabinoid metabolizing enzymes and THC and its metabolite pharmacokinetics. THC is predominately (>70%) cleared by hepatic metabolism to its psychoactive active metabolite, 11-OH-THC by cytochrome P450 (CYP) 2C9 and to other metabolites (<30%) by CYP3A4. Other physiological processes that change during pregnancy and may alter cannabinoid disposition are also reviewed.

Expert Opinion

THC and its metabolites disposition likely change during pregnancy. Hepatic CYP2C9 and CYP3A4 are induced in pregnant individuals and in vitro by pregnancy hormones. This induction of CYP2C9 and CYP3A4 is predicted to lead to altered THC and 11-OH-THC disposition and pharmacodynamic effects. More in vitro studies of THC metabolism and induction of the enzymes metabolizing cannabinoids are necessary to improve the prediction of THC pharmacokinetics in pregnant individuals.

KEYWORDS:

• (-)-Δ⁹-tetrahydrocannabinol
• cannabis
• pregnancy
• hormonal regulation
• Cytochrome P450
• pharmacokinetics
• clearance
• volume of distribution

Article highlights

• (-)-Δ⁹-tetrahydrocannabinol (THC) clearance and distribution processes are likely to be altered during pregnancy.

• Pregnancy alters the disposition of drugs and these changes are associated with altered hormone disposition.

• To improve prediction of THC metabolism in pregnant individuals, more detailed in vitro studies of THC metabolism and induction of enzymes clearing THC are needed.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Two reviewers were recruited by Research Square. Reviewers with declared or apparent competing interests are not utilized for these reviews. This reviewer was paid a small honorarium for completing the review within a specified timeframe. Honoraria for reviews such as this are paid regardless of the reviewer recommendation. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.

Author contributions

A Authement: contributed significantly to conception, drafted and revised written article, agreed to journal submission, reviewed and agreed on all versions of the article, and agreed to take responsibility and accountability for the contents of the manuscript. N Isoherranen: contributed significantly to conception, drafted and revised written article, agreed to journal submission, reviewed and agreed on all versions of the article, and agreed to take responsibility and accountability for the contents of the manuscript.

Additional information

Funding

This work was funded in part by the National Institutes of Health [Grant P01 DA032507 to NI]. AKA is supported in part by the National Institute of General Medical Sciences of the National Institutes of Health under award [T32GM007750].