Cannabis use may harm reproductive health and reduce healthy embryos in IVF

CReATe Fertility Center in Toronto reports that tetrahydrocannabinol (THC) reaches the ovarian follicle, aligns with higher oocyte maturation, and associates with lower embryo euploid rates in IVF, with in vitro exposure linked to chromosome segregation errors and abnormal meiotic spindles.

Cannabis use and legalization are rising globally. Potency of THC in consumer products has climbed from about 3% in the 1980s to roughly 15% by 2020, with some strains near 30%.

Endocannabinoids such as N-arachidonoylethanolamide and 2-arachidonoylglycerol play a central role in male and female reproduction and are present at all stages of oocyte maturation. THC is not part of the body’s normal cannabinoid repertoire, though it can bind to cannabinoid receptors normally bound by native cannabinoids. Concern stems from the potential to disrupt the endocannabinoid system in human reproduction.

Extensive research describes effects on sperm, including DNA methylation and changes in concentration, morphology, and motility. Direct study of THC’s impact on the human oocyte has been missing, largely due to challenges in obtaining samples.

Oocytes remain sensitive to environmental factors and any perturbation could shape fertility and outcomes for future generations. Clear evidence on oocyte health is needed for counseling patients considering or undergoing fertility care.

In the study, “Cannabis impacts female fertility as evidenced by an in vitro investigation and a case-control study,” published in Nature Communications, researchers combined a retrospective case-control analysis with in vitro experiments to determine THC’s impact on human oocyte maturation, transcriptome, spindle architecture, and chromosome segregation, and to relate those findings to in vitro fertilization (IVF) outcomes.

Retrospective measurements covered 1,059 follicular fluid (FF) samples from patients undergoing IVF at CReATe Fertility Center, with 62 positives for THC (6%). Among THC-positive patients, 73% did not disclose cannabis use on intake forms.

Case-control matching paired each positive with two negatives, yielding 51 THC-positive and 101 THC-negative cases for embryo euploidy analysis. In vitro work used immature germinal vesicle oocytes from 24 patients.

Mass spectrometry of follicular fluid from 1,059 IVF patients found THC metabolites in 62 samples (6%). Positivity meant detection of 11-COOH-THC. Among positives, 13% had 11-COOH-THC alone, 37% had co-detected Δ9-THC, 2% had co-detected 11-OH-THC, and 48% had all three.

Non-disclosure on intake forms occurred in 73% of positives. Mean concentrations in follicular fluid were 28.8 ng/mL for 11-COOH-THC, 7.5 ng/mL for Δ9-THC, and 1.7 ng/mL for 11-OH-THC. Matched follicular fluid and serum showed no concentration differences in a small subset.

Spearman analysis in the THC-positive group linked Δ9-THC, 11-OH-THC, and 11-COOH-THC with higher oocyte maturation rate (Δ9-THC ρ=0.370; 11-OH-THC ρ=0.309; 11-COOH-THC ρ=0.295). Δ9-THC levels showed an inverse association with body mass index.

Germinal vesicle oocytes matured for 24 hours showed a non-significant increase in reaching metaphase II with THC exposure: 46% in control, 52% with THC1, and 58% with THC2. Oocyte diameter before and after culture did not differ across groups. Timings for germinal vesicle breakdown and first polar body extrusion were unchanged by THC exposure.

Single-oocyte RNA sequencing on 86 metaphase II oocytes from 24 patients recorded many gene changes. THC1 vs. control showed 89 up-regulated and 227 down-regulated genes (|log₂FC|>1), including shifts in pathways for nerve-signal processes, axonemal dynein complex assembly, glutamate receptor signaling, protein synthesis, regulation of SLITS and ROBOS, and inflammatory processes.

THC2 vs. control showed 402 up-regulated and 62 down-regulated genes with enrichment in immune and apoptotic pathways and a decrease in the attachment of spindle microtubules to kinetochores. A shared set of 50 protein-coding genes included higher RGS5, RGS18, and SLC1A3 and lower MMP9, IFNG, and IL33.

Polar body sequencing and confocal imaging assessed chromosome copy number and spindle shape. Aneuploidy rose by 9% in THC-exposed oocytes relative to control (control 39% vs. THC1 48% and THC2 48%) though the result was not significant (p=0.1029).

Complex aneuploidy, defined as gain or loss of ≥3 chromosomes, appeared more often after THC exposure (control 0% vs. THC groups 42%). Abnormal spindle morphology increased across THC conditions and reached 92% in THC2 vs. 42% in control, a pattern consistent with a higher risk of producing embryos with the wrong number of chromosomes.

Pairwise, case-control matching associated THC positivity with a lower rate of chromosomally normal embryos. Euploidy measured 60.0% in THC-positive patients (n=51) and 67.0% in THC-negative controls (n=101). Maturation, fertilization, and blastocyst rates showed no significant group differences.

Authors conclude that THC exposure affects oocyte maturation, ooplasm transcript abundance, spindle organization, and chromosome segregation, suggesting that cannabis consumption may negatively impact female fertility. Results offer evidence-based guidance for patients, particularly those pursuing fertility treatment, and potential recommendations during IVF.

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