Animal evidence considered in determination of cannabis smoke and Δ⁹‐tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint); Part I. Somatic development

Abstract

Objectives: On December 11, 2019, California's Developmental and Reproductive Toxicant Identification Committee (DARTIC) met to consider the addition of cannabis smoke and Δ 9 -THC to the Proposition 65 list as causing reproductive toxicity (developmental endpoint). As the lead state agency for implementing Proposition 65, the Office of Environmental Health Hazard Assessment (OEHHA) reviewed and summarized the relevant scientific literature in the form of a hazard identification document (HID). Here we provide reviews based on the HID: shortened, revised, and reformatted for a larger audience.Methods: While the HID included both human and animal data, this set of three reviews will highlight the animal-derived data pertaining to somatic development (Part I), neurodevelopmental effects (Part II), and proposed neurodevelopmental mechanisms of action (Part III).Results: Endogenous cannabinoids (eCBs) and their receptors serve many critical functions in normal development. Δ 9 -THC can interfere with these functions. Mechanistic studies employed techniques including: blocking Δ 9 -THC binding to endocannabinoid (EC) receptors, inhibiting Δ 9 -THC metabolism, and/or using animals expressing knockout mutations of EC receptors.Apical somatic effects of cannabis smoke or Δ 9 -THC reported in whole animal studies included decreases in offspring viability and growth. Mechanistic studies discussed in Part I focused on Δ 9 -THC effects on early embryos and implantation, immune development, and bone growth. Conclusions: In reaching its decision to list cannabis and Δ 9 -THC as a developmental toxicant under California's Proposition 65, the DARTIC considered biological plausibility and the consistency of mechanistic information with effects reported in human and whole animal studies.

The Development of Cannabinoids as Therapeutic Agents in the United States

“…Reproductive and developmental toxicology findings in ∆9-THC-treated animals have been discussed in FDAapproved product labels and the published literature (for review see (Campbell et al, 2022;Iyer et al, 2022;Niknam et al, 2022), According to the package insert for the Marinol product, data from embryo-fetal toxicology studies in mice (15 to 450 mg/m 2 ) and rats (74 to 295 mg/m 2 ) demonstrated that teratogenic effects were not produced up to maternally toxic doses and embryo-and fetal-lethal doses (Marinol). Pregnant rodents treated with ∆9-THC were observed with decreased weight gain values.…”

Prenatal Exposure to Tobacco and Cannabis in Six Race/Ethnicity Groups during the First Three Years after Legalization of Cannabis for Recreational Use in California

“…Cannabis use during pregnancy can also harm fetal and long-term development [8]. Babies exposed to cannabis prenatally are more likely to have restricted growth in utero, lower birth weight, and smaller head circumference [9,10]. In addition, emotional processing, sleep, aggressive behavior, and the ability to pay attention may be affected in infants [11,12].…”

“…Prenatal cannabis exposure also lowers immune response to viruses and causes ventricular septal defects [13,14]. Children exposed to cannabis in utero are at a greater risk for delinquent behavior, lower IQ, decreased attention span, and using cannabis and nicotine products themselves [9,10]. While many of the same toxic chemicals in tobacco smoke such as heavy metals, carbon monoxide, benzene, and formaldehyde are found in cannabis smoke, some are unique cannabinoid compounds found specifically in cannabis smoke such as tetrahydrocannabinol (THC), the psychoactive chemical in cannabis [15].…”