title: At the Tip of an Iceberg: Prenatal Marijuana and Its Possible Relation to Neuropsychiatric Outcome in the Offspring.
abstract: Endocannabinoids regulate brain development via modulating neural proliferation, migration, and the differentiation of lineage-committed cells. In the fetal nervous system, (endo)cannabinoid-sensing receptors and the enzymatic machinery of endocannabinoid metabolism exhibit a cellular distribution map different from that in the adult, implying distinct functions. Notably, cannabinoid receptors serve as molecular targets for the psychotropic plant-derived cannabis constituent Δ(9)-tetrahydrocannainol, as well as synthetic derivatives (designer drugs). Over 180 million people use cannabis for recreational or medical purposes globally. Recreational cannabis is recognized as a niche drug for adolescents and young adults. This review combines data from human and experimental studies to show that long-term and heavy cannabis use during pregnancy can impair brain maturation and predispose the offspring to neurodevelopmental disorders. By discussing the mechanisms of cannabinoid receptor-mediated signaling events at critical stages of fetal brain development, we organize histopathologic, biochemical, molecular, and behavioral findings into a logical hypothesis predicting neuronal vulnerability to and attenuated adaptation toward environmental challenges (stress, drug exposure, medication) in children affected by in utero cannabinoid exposure. Conversely, we suggest that endocannabinoid signaling can be an appealing druggable target to dampen neuronal activity if pre-existing pathologies associate with circuit hyperexcitability. Yet, we warn that the lack of critical data from longitudinal follow-up studies precludes valid conclusions on possible delayed and adverse side effects. Overall, our conclusion weighs in on the ongoing public debate on cannabis legalization, particularly in medical contexts.
authors.affiliation: MTA-SE NAP B Research Group of Experimental Neuroanatomy and Developmental Biology, Hungarian Academy of Sciences, Budapest, Hungary; Department of Anatomy, Semmelweis University, Budapest, Hungary.
authors.forename: Alán
authors.initials: A
authors.lastname: Alpár
authors.affiliation: Endocannabinoid Research Group, Instituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: Division of Molecular Neurosciences, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria. Electronic address: Tibor.Harkany@meduniwien.ac.at.
authors.forename: Tibor
authors.initials: T
authors.lastname: Harkany
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D063388:Endocannabinoids / Q000378:metabolism*; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D006801:Humans; D013287:Illicit Drugs / Q000009:adverse effects*; D008385:Marijuana Smoking / Q000009:adverse effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D063388:Endocannabinoids; D013287:Illicit Drugs
keywords: Epilepsy; Marijuana; Psychosis; Schizophrenia; Skunk; Stratification