All but the small pipe calibration factor are higher than typical cigarette smoke calibration factors. By calibrating our instruments to machine-smoked cigarette smoke, we may have underestimated the true PM2.5 concentration in the dispensary. Our findings show that allowing customers to smoke cannabis indoors can create conditions that are known to be hazardous. Improvements to the ventilation system during the experiment had no effect on the PM2.5 concentrations. Exposure to PM2.5 from cannabis consumption is likely to have negative effects on the respiratory andcardiovascular health of the employees and may have negative effects of the respiratory and cardiovascular health of vulnerable patrons. Cannabis is the most commonly used illicit psychoactive drug in the United States with an estimated 9.6% of the population aged 12 and older reporting use in the past month.The majority of new users are under 18 years of age, and cannabis use has increased among youth and teens since 2007. In addition, pregnant women are increasingly using it to mitigate morning sickness. In the U.S., between 2002–2003 and 2016–2017, the adjusted prevalence of past-month cannabis use increased from 3.4 to 7.0% among pregnant women overall and from 5.7 to 12.1% among pregnant women during the first trimester. A recent national survey suggested that the public perception of “great risk” from weekly cannabis use has dropped from 50.4% in 2002 to 33.3% in 2014. Another recent survey found that 81% of U.S. adults believe that cannabis has at least one health benefit, such as use in pain management, disease treatment, or relief of anxiety, stress, or depression. While 91% of U.S. adults also believe cannabis use has at least one risk, including those associated with legal issues, 9% believe it has no risks, and the American public has an overall favorable view of cannabis drying racks. Cannabis is composed of over 400 chemicals, of which over 60 are cannabinoid compounds. The four major compounds include Δ9 -tetrahydrocannabinol , cannabidiol , Δ8 -tetrahydrocannabinol, and cannabinol. The major psychoactive cannabinoid in cannabis, THC, targets the endocannabinoid system, which regulates biological processes involved in development and neuroplasticity. It mimics eCB action, exerting most of its effects via cannabinoid receptors s 1 and 2.
CBR1 is one of the most abundant G protein-coupled receptors in the adult brain, and it is localized inregions important in movement, cognition, attention, emotion, and memory. In animals, expression begins early in the central nervous system during embryonic development. One study found CBR1 expressed in the human fetal brain at 20 weeks, with high expression in the hippocampus and amygdala. In contrast, CBR2 is mainly expressed in immune cells. Male mitotic germ cells also express a high level of CBR2, whose activation promotes their differentiation and progresses spermatogenesis.During adolescence, the eCB system continues to facilitate neurodevelopment through its involvement in neuroplasticity and synaptic function. Levels of CBRs fluctuate during adolescence and depend on the brain region. For instance, there is a rapid, sustained increase in CBR binding sites in the striatum that is reduced by half in early adulthood, as well as high levels in limbic related regions that gradually decrease by adulthood. Tightly regulated biosynthetic pathways ensure proper signaling throughout development, and correct brain function depends heavily on the temporal and spatial layout of the eCB system. Thus, exposure to THC, especially during critical windows of brain development, has the potential to disrupt the tightly regulated system. Parallel to the increase in adolescent cannabis use, the percentage of adolescents and young adults experiencing certain types of psychiatric disorders has risen in the United States over the past decade, despite the lack of increase in adults.In human studies, THC has been shown to disrupt the development and function of the brain, and in animals, THC has been experimentally shown to lead to molecular impairments that are heritable and extend into subsequent generations, thus increasing the risk of offspring developing a psychiatric disease. Three different routes of multi-generational transmission have been summarized in a prior review; they include fetal programming , germline transmission , and behavioral or social transfer . The first route is typical for prenatal exposure, the second route is typical for pregestational exposure, while the third route is typical for both. In a recent commentary, which was published in response to a study examining the epigenetic impact of cannabis use on rat and human sperm, the authors highlighted that the epigenomic toxicology of cannabinoids should have priority on the research agenda, especially considering the potential transgenerational health implications.
A review published in 2016 focused on the epigenetic effects of cannabis exposure. The authors noted that the majority of addiction-related epigenetic neurobiological studies had targeted the adult brain, while there was a dearth of literature on the potential intergenerational impacts of cannabis. Another article published in 2018 provided an overview of the current data regarding vulnerabilities of the developing brain to cannabinoid exposure during sensitive windows of development, especially with regard to epigenetic changes associated with cannabis use. Since that time, additional studies were published that address research gaps and have the potential to better inform clinical guidelines, preventative policy, and public opinion related to cannabis use during specific time points of the life course. Heritable molecular impairments include epigenetic modifications, such as DNA methylation, histone modifications, and changes in non-coding RNA , which regulate patterns of gene expression by altering DNA accessibility and chromatin structure. DNA methylation occurs when a methyl group is added at a cytosine nucleotide that precede guanines , influencing DNA function by activating or repressing transcriptional activity of a gene and by altering chromatin accessibility and remodeling. DNA methylation in the promoter region of a gene usually downregulates its expression, while higher DNA methylation in a gene body may promote expression of a gene. In most instances, DNA methylation represses gene expression by preventing the binding of transcription factors, or recruiting proteins that bind to methylated DNA. Histones are large groups of protein complexes that help DNA condense into chromatin. Histone modifications include methylation and acetylation of lysine residues on histone tails, which affect gene expression by altering chromatin structure and accessibility. In addition, ncRNA, such as micro RNA and long non-coding RNA, control DNA availability and transcription, regulate RNA processing and splicing, and form a scaffold upon which layers of DNA regulation are built. Some epigenetic modifications are passed down to offspring through genomic imprinting , in which offspring only inherit one working copy of a gene. Imprinted genes are silenced via DNA methylation in either the egg or sperm. Other modifications are passed down when genes escape epigenetic reprogramming, a process that occurs during the formation of primordial germ cells and in the early embryo soon after fertilization, in which genomic potential resets and epigenetic memory is erased. In this review, we provide an analysis of the recent literature relating to pre-gestational and prenatal cannabinoid exposure and its effect on genes and molecular pathways. Along with the studies discussed in the review, additional animal studies are summarized in Tables 1 and 2, in which molecular changes are observed in the F0 generation of adolescent brain tissue.
Since 2002, there has been an increase in pregnant women in the U.S. reporting daily cannabis use, use in the past-month, as well as an increase in the number of days during pregnancy that they report using cannabis. Pregnant women report using cannabis most frequently during the first trimester, in order to mitigate morning sickness. Studies have confirmed that THC readily crosses the placenta, distributes into the fetal compartment, and crosses the fetal blood-brain barrier. A handful of studies in both human subjects and animal models have indicated that the embryonic nervous system patterning is particularly susceptible to maternal cannabis use. Its use during pregnancy has been associated with an increased risk of various cognitive, behavioral, and neuropsychiatric defects. Use during pregnancy has also been associated with an increased risk of preterm birth in some studies, as well as decreased birth weight. This section highlights recent studies that have examined the epigenetic mechanisms by which prenatal cannabis exposure increases the risk of postnatal psychiatric disease.Considering that maternal cannabis grow tray use during pregnancy is associated with long-term adverse behavioral outcomes and addiction vulnerability in offspring, it is possible that epigenetic changes established in utero that affect dopaminergic reward signaling are involved. The striatal dopamine system, composed of medium spiny neurons enriched in cannabinoid receptors, is implicated in the pathogenesis of neuropsychiatric disorders. One study tested the neurobiology underlying the risk of addiction vulnerability in humans by examining mRNA expression in fetal brain specimens of the putamen and nucleus accumbens , from mothers who underwent elective abortions between 18 and 22 weeks of gestation. Half of the fetal brain specimens were those from mothers who had positive maternal self-report and/ or maternal urine that tested positive for THC and/or fetal meconium positive for THC, while the other half had no cannabis exposure. Not only did fetuses exposed prenatally to cannabis have decreased dopamine receptor D2 mRNA levels in the NAc, compared to controls, but there was also a dose response observed in which greater maternal use was correlated with decreased DRD2 mRNA levels. In contrast, there was no difference in DRD2 mRNA levels in the putamen. There was also no difference in DRD1 mRNA levels, or mRNA levels of the opioid neuropeptides proenkephalin and prodynorphin in the putamen or NAc, between the exposed and unexposed groups. The NAc core and shell are important components of motor and reward circuits, respectively, and disruptions in these signaling pathways could lead to adverse psychiatric outcomes. Additional studies were conducted on the same fetal brain specimens used in the study discussed above. In these analyses, decreased DRD2 mRNA levels were observed in the amygdala basal nucleus of fetuses exposed prenatally to cannabis compared to controls, which was consistent with the reduced levels observed in the NAc.In addition, fetal brain specimens with maternal cannabis exposure had reduced PENK expression in the caudal putamen, and PENK mRNA levels were inversely correlated with amount of maternal cannabis intake during pregnancy.
Disruptions in the opioid system during development contribute to the development of psychiatric disorders and persist into adulthood, increasing vulnerability to opiate-seeking behavior. Dysregulation of DRD2 is implicated in addiction risk and other psychiatric disorders, and its alteration was a consistent finding in the animal studies, as well as the human studies. Another recent study evaluated whether prenatal cannabis exposure is associated with DNA methylation of dopamine receptor D4 promoter in buccal cells from the neonates of maternal subjects with either cannabis or no cannabis use anytime during pregnancy.Buccal epithelial cells have the same developmental origins as neuronal cells, and prior studies provide support for buccal cells as a proxy for neurodevelopmental phenotypes. There was no association between DNA methylation at individual CpG sites in DRD4 after correction for multiple testing. It is unclear if the null findings were due to the relatively small sample size , the tissue specificity, or a lack of biological relevance. Certain genetic polymorphisms of DRD4 increase risk of drug use and severity of ADHD symptoms in children, both of which have been associated with cannabis exposure. Future candidate gene studies should examine the association between prenatal cannabis exposure and epigenetic changes in DRD4 in brain or other target cells, instead of the buccal cell proxy, as well as account for genetic polymorphisms.A recent study evaluated the association between male rat exposure to synthetic CBR1 agonist WIN 55212-2 during adolescence and global DNA methylation in the prefrontal cortex of their offspring. The offspring were also subjected to unpredictable stress, variable stress, or no stress, in order to examine the interaction between pre-gestational WIN exposure and stress response. Increased global DNA methylation was observed in offspring with pregestational WIN exposure, compared to controls, regardless of presence or absence of stress exposure. In addition, increased DNA methyltransferase 1 mRNA levels were observed in offspring with pre-gestational WIN exposure, compared to unexposed controls in non-stressed animals only, while increased Dnmt3 mRNA levels were observed in offspring with pre-gestational WIN exposure, compared to unexposed controls, regardless of presence or absence of stress exposure. It is plausible that the increased global PFC DNA methylation observed in animals with pre-gestational WIN exposure, as well as in stressed animals, was mediated by the upregulation of DNMT enzymes, since these are responsible for epigenetic maintenance.