Authors: Cyntia Duval, Brandon A. Wyse, Noga Fuchs Weizman, Iryna Kuznyetsova, Svetlana Madjunkova & Clifford L. Librach

Published by: Nature Communications

Published: 09 September 2025

Abstract

Cannabis consumption and legalization is increasing globally, raising concerns about its impact on fertility. In humans, we previously demonstrated that tetrahydrocannabinol (THC) and its metabolites reach the ovarian follicle. An extensive body of literature describes THC’s impact on sperm, however no such studies have determined its effects on the oocyte. Herein, we investigate the impact of THC on human female fertility through both a clinical and in vitro analysis. In a case-control study, we show that follicular fluid THC concentration is positively correlated with oocyte maturation and THC-positive patients exhibit significantly lower embryo euploid rates than their matched controls. In vitro, we observe a similar, but non-significant, increased oocyte maturation rate following THC exposure and altered expression of key genes implicated in extracellular matrix remodeling, inflammation, and chromosome segregation. Furthermore, THC induces oocyte chromosome segregation errors and increases abnormal spindle morphology. Finally, this study highlights potential risks associated with cannabis use for female fertility.

Introduction

Cannabis consumption for both medicinal and recreational use and legalization have been rising globally1. Cannabis contains several classes of chemicals with cannabinoids being the most prominent; among these, tetrahydrocannabinol (THC) is the primary psychoactive compound and the most studied2. Notably, the concentration of THC in cannabis products has increased significantly, from an average of 3% (by weight) in the 1980s to around 15% in 2020, with some strains reaching 30% of THC2. The increase in frequency, ease of availability, and escalation in potency raises concerns about broader impacts on global human health, including reproductive health. Indeed, the main apprehension regarding THC and reproductive health stems from the importance of the endocannabinoid system in human reproduction3. Endocannabinoids, including N-arachidonoylethanolamide and 2-arachidonoylglycerol, are endogenous cannabinoids that play a central role in both male and female reproduction3, whereas THC is an exogenous cannabinoid. Extensive research has documented the effects of THC on male reproduction, highlighting an impact on sperm deoxyribonucleic acid (DNA) methylation  4^,5^,6^,7 and sperm parameters8 including sperm concentration  9^,10^,11, morphology  12^,13^,14 and motility14. As for female health, literature reports the impact of cannabis use during pregnancy on pregnancy outcomes  15^,16^,17^,18, placental development  18^,19^,20 and offspring health  18^,20^,21^,22. However, to our knowledge, no studies have investigated the impact of cannabis on the human female gamete, the oocyte, a gap partly due to the challenge associated with obtaining these samples.

During in vitro fertilization (IVF) treatment, exogenous gonadotropins are administered in a process called “controlled ovarian hyperstimulation” which recruits multiple follicles and induces follicle growth. These recruited follicles, each containing an oocyte, are then collected by a physician in a procedure called oocyte retrieval. Oocytes are collected along with their surrounding microenvironment, including follicular fluid (FF) and supportive somatic cells (granulosa cells). The oocytes are isolated, and mature oocytes are used for subsequent in vitro fertilization. Using FF, our group has previously quantified Δ9-THC and its metabolites, 11-OH-THC and 11-COOH-THC  23^,24, demonstrating that these compounds could reach the follicular niche. This is significant as it suggests that THC may directly alter the microenvironment where the oocyte matures. Furthermore, our group has shown that THC exposure altered human granulosa cell methylation in a concentration dependent manner23, and in vitro exposure modulated cannabinoid receptor dynamics in granulosa cells24. However, no human studies and only a few animal model studies have investigated the impact of cannabis directly on oocyte development with conflicting results  25^,26^,27^,28^,29.

Maturation of the oocyte is a unique and highly specialized process beginning in utero during fetal development. It is widely accepted that female neonates are born with a finite number of oocytes, which, following menarche, are recruited to mature in cohorts with each menstrual cycle30. Although oocytes are protected in the ovary by the blood-follicle-barrier, they remain highly sensitive to environmental factors31. Given their essential role in reproduction, any perturbations in their development and maturation could have profound effects on fertility and on future generations. Thus, understanding the impact of THC on oocyte health is critical for providing informed guidance and counseling to patients of the potential risks to their fertility and future offspring.

In this study, we determine the impact of physiologically relevant concentrations of THC on oocyte maturation, elucidate the transcriptomic changes induced by THC exposure and its effect on chromosome segregation, and compare our findings with a retrospective cohort study. Our investigation will aid in bridging the knowledge gap in our understanding of the sex-specific reproductive consequences of cannabis use and contribute to more effective and evidence-based patient counseling.

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Source:  https://www.nature.com/articles/s41467-025-63011-2