Effects of cannabis tetrahydrocannabinol on endocannabinoid homeostasis in human placenta

Abstract

Cannabis use has become a hot topic in several countries due to the debate about its legalization for medical purposes. However, data are limited regarding adverse events, safety and potential impact on reproductive health. Cannabis consumption during pregnancy has been associated with gestational disorders such as preterm birth, intrauterine growth restriction, low birth weight and increased risk of miscarriage, though the underlying biochemical mechanisms are still unknown. Given that the endocannabinoid system (ECS) is involved in several reproductive processes, we tested the hypothesis that the negative outcomes may result from the impact on the ECS homeostasis caused by the main psychoactive compound of cannabis, Δ 9-tetrahydrocannabinol (THC). We demonstrate that THC (10-40 µM) impairs placental endocannabinoid system by disrupting the endocannabinoid anandamide (AEA) levels and the expression of AEA synthetic and degrading enzymes N-arachidonoylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH), respectively. Although, no alterations in cannabinoid receptors CB1 and CB2 expression were observed. Thus, long-term local AEA levels are associated with a shift in the enzymatic profile to re-establish ECS homeostasis. In chronic cannabis users, high AEA levels in placenta may disturb the delicate balance of trophoblast cells turnover leading to alterations in normal placental development and foetal growth.

Lifestyle and Metabolic Syndrome: Contribution of the Endocannabinoidome

“…Chronic THC administration to rats decreases 2-AG and AEA levels in the striatum, but increases AEA levels in the limbic forebrain [162], and in chronic cannabis users, AEA levels are decreased in cerebrospinal fluid while 2-AG levels are increased in the serum as compared to infrequent users [163]. The mechanism by which eCB levels were altered in these studies are unknown; however, ex vivo treatment of placental explants with THC for long (72 h) but not short (24 h) periods of time increased AEA levels, concomitant with a counterintuitive decrease in NAPE-PLD levels and a trend for increased FAAH levels [164]. In hepatocytes, THC increased both AEA and 2-AG levels, presumably by blocking the activity of fatty acid binding protein 1 (FABP1), which can act as an eCB “chaperone”, allowing eCB enzymatic degradation [165].…”

Mechanisms for the Risk of Acute Coronary Syndrome and Arrhythmia Associated With Phytogenic and Synthetic Cannabinoid Use

“…114,115 Both phytogenic and synthetic cannabinoids with higher potency and CB1 affinity have the potential to overwhelm the endocannabinoid system and disrupt the balance of the autonomic nervous system. 41,113…”

Cannabis “in utero”: the fetus as a compulsive consumer

“…The effects of delta9THC are due to its action on cannabinoid receptors CBr1 and CBr2 -widely distributed throughout various organs and tissues that, together with endogenously produced cannabionids and the regulatory enzymes of synthesis and degradation, constitute the endocannabinoid system (ECS) [19,27]. The ECS is a neuromodulatory system, detected from the earliest embryonic stage and throughout preand postnal development, responsible for several controls related to the regulation of many important function, since its receptors has been found to play a key role in neuronal progenitor cell proliferation, pyramidal specification, axon pattering modulation of dendritic arbor, and promotion of neuronal differentiation [5,20,28,29]. Also, the ECS influences metabolism and physiology of multiple systems with its anabolic action, leading to protein and glycogen synthesis and fat deposition [30].…”

“…Also, the ECS influences metabolism and physiology of multiple systems with its anabolic action, leading to protein and glycogen synthesis and fat deposition [30]. Moreover, plays a fundamental role in pregnancy outcome and fetal development, and overstimulation of CBr1 in the placenta can impair fetal growth by inhibiting cytotrophoblastic proliferation [5,28,31]. The endocannabinoid receptors can be found on both presynaptic neurons and postsynaptic locations and are densely expressed in various regions within the brain [4], and its key function in mature neurons is modulate the release of neurotransmitters [18].…”

“…Cannabis consumption during pregnancy may negatively impact the fetus since the effects may be subtle and do not be detectable for many months to years after birth [28]. Cannabis can affect the normal transport functions and physiologic status of the placenta where it arrives by passive diffusion or, less commonly, through active transport or pinocytosis [2,19], and its concentrations varies by the permeability and biological capacity of the placenta.…”