Tetrahydrocannabinol Exposure Research Articles

In silico analyses of the involvement of GPR55, CB1R and TRPV1: response to THC, contribution to temporal lobe epilepsy, structural modeling and updated evolution.

The endocannabinoid (eCB) system is named after the discovery that endogenous cannabinoids bind to the same receptors as the phytochemical compounds found in Cannabis. While endogenous cannabinoids include anandamide (AEA) and 2-arachidonoylglycerol (2-AG), exogenous phytocannabinoids include Δ-9 tetrahydrocannabinol (THC) and cannabidiol (CBD). These compounds finely tune neurotransmission following synapse activation, via retrograde signaling that activates cannabinoid receptor 1 (CB1R) and/or transient receptor potential cation channel subfamily V member 1 (TRPV1). Recently, the eCB system has been linked to several neurological diseases, such as neuro-ocular abnormalities, pain insensitivity, migraine, epilepsy, addiction and neurodevelopmental disorders. In the current study, we aim to: (i) highlight a potential link between the eCB system and neurological disorders, (ii) assess if THC exposure alters the expression of eCB-related genes, and (iii) identify evolutionary-conserved residues in CB1R or TRPV1 in light of their function. To address this, we used several bioinformatic approaches, such as transcriptomic (Gene Expression Omnibus), protein-protein (STRING), phylogenic (BLASTP, MEGA) and structural (Phyre2, AutoDock, Vina, PyMol) analyzes. Using RNA sequencing datasets, we did not observe any dysregulation of eCB-related transcripts in major depressive disorders, bipolar disorder or schizophrenia in the anterior cingulate cortex, nucleus accumbens or dorsolateral striatum. Following in vivo THC exposure in adolescent mice, GPR55 was significantly upregulated in neurons from the ventral tegmental area, while other transcripts involved in the eCB system were not affected by THC exposure. Our results also suggest that THC likely induces neuroinflammation following in vitro application on mice microglia. Significant downregulation of TPRV1 occurred in the hippocampi of mice in which a model of temporal lobe epilepsy was induced, confirming previous observations. In addition, several transcriptomic dysregulations were observed in neurons of both epileptic mice and humans, which included transcripts involved in neuronal death. When scanning known interactions for transcripts involved in the eCB system (n = 12), we observed branching between the eCB system and neurophysiology, including proteins involved in the dopaminergic system. Our protein phylogenic analyzes revealed that CB1R forms a clade with CB2R, which is distinct from related paralogues such as sphingosine-1-phosphate, receptors, lysophosphatidic acid receptors and melanocortin receptors. As expected, several conserved residues were identified, which are crucial for CB1R receptor function. The anandamide-binding pocket seems to have appeared later in evolution. Similar results were observed for TRPV1, with conserved residues involved in receptor activation. The current study found that GPR55 is upregulated in neurons following THC exposure, while TRPV1 is downregulated in temporal lobe epilepsy. Caution is advised when interpreting the present results, as we have employed secondary analyzes. Common ancestors for CB1R and TRPV1 diverged from jawless vertebrates during the late Ordovician, 450 million years ago. Conserved residues are identified, which mediate crucial receptor functions.

Evaluation of pre-hospital cannabis exposure and hospital opioid utilization in a trauma population: A retrospective cohort

PurposeCannabis utilization has increased over time for recreational and medical purposes due to its legalization or decriminalization. The effects of cannabis use on opioid utilization are not well understood. The primary objective was to evaluate the total opioid utilization, measured in morphine milligram equivalents (MME), in hospitalized trauma patients that tested positive for tetrahydrocannabinol (THC) on a urine drug screen (UDS). MethodsThis was a retrospective, cohort study in a level 1 trauma center between 10/17/17 and 12/31/19. Adult trauma patients (aged 15 years and older) who had a UDS completed within 48 h of hospital arrival were eligible for inclusion. Patients were excluded for a hospitalization >14 days, death within 24 h, severe alcohol withdrawal, prescribed cannabinoids, high daily opioid use prior-to-arrival, or transitioned to hospice or palliative care. Group assignments were determined based on the presence or absence of THC on the UDS. ResultsThe analysis included 750 patients with 160 (21 %) THC positive patients. The population were primarily male (64.6 %), median age of 56 years [IQR 35–72], with blunt (93 %) injuries from motor vehicle crash or falls (79 %). The THC group was more likely to have other substances present, including amphetamines, benzodiazepines, opiates, and cocaine. The THC group had a higher median injury severity score (10 [IQR 5–17] vs. 9 [5–14], p = 0.0056), and maximum abbreviated injury score (3 [IQR 2–3] vs. 2 [IQR 2–3], p = 0.0009). The THC group had a total higher median opioid utilization during the hospitalization (155 [IQR 68–367] vs. 62 [IQR 13–175] MME; p < 0.0001), which included higher opioid use in the emergency department, floor, and intensive care unit. There were no significant differences in secondary outcomes except the THC group was more likely to receive an opioid prescription at discharge and more likely to require mechanical ventilation. Based on multivariable regression analyses, other variables were associated with increased opioid utilization. ConclusionPre-existing THC exposure may be associated with an increased hospital opioid utilization in a trauma population. However, other variables may also play a role in opioid utilization.

Five cases ofunintentional exposure to BZO-4en-POXIZID among nightclub attendees inNew York City.

A new class of synthetic cannabinoids called OXIZIDs has emerged in recent years. This class consists of compounds with oxindole cores and hydrazide/hydrazone linker moieties and has often been described as being designed to circumvent a Chinese class-wide ban that was effective as of 1 July 2021. However, through hair testing of nightclub attendees in New York City-a high-risk population for recreational drug use-we have evidence suggesting exposures to an OXIZID called BZO-4en-POXIZID (4en-pentyl MDA-19) prior to the effective ban. Through analysis of 6 cm segmented hair samples from attendees collected in 2021, we detected five cases of exposure. Specifically, we detected a cluster of three cases based on hair samples collected on 20 June 2021, and then two additional cases from samples collected on 16 July 2021. Four of these hair samples were long enough to analyze two 6 cm hair segments (representing approximately two 6-month timeframes) and three of four of these cases tested positive for repeated exposure (for an estimated exposure over 6 months prior to hair collection). All cases included young adult females reporting past-year cannabis use but all tested negative for tetrahydrocannabinol exposure. Three cases also reported past-year use of cocaine, ecstasy, and/or ketamine, and four cases tested positive for exposure to cocaine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), methamphetamine and/or eutylone. These subjects were exposed to BZO-4en-POXIZID-likely as an adulterant in other drugs, and these cases are among the first documented cases which occurred approximately half a year before the Chinese legislative ban.

Predicting Maternal and Infant Tetrahydrocannabinol Exposure in Lactating Cannabis Users: A Physiologically Based Pharmacokinetic Modeling Approach.

A knowledge gap exists in infant tetrahydrocannabinol (THC) data to guide breastfeeding recommendations for mothers who use cannabis. In the present study, a paired lactation and infant physiologically based pharmacokinetic (PBPK) model was developed and verified. The verified model was used to simulate one hundred virtual lactating mothers (mean age: 28 years, body weight: 78 kg) who smoked 0.32 g of cannabis containing 14.14% THC, either once or multiple times. The simulated breastfeeding conditions included one-hour post smoking and subsequently every three hours. The mean peak concentration (Cmax) and area under the concentration-time curve (AUC(0-24 h)) for breastmilk were higher than in plasma (Cmax: 155 vs. 69.9 ng/mL; AUC(0-24 h): 924.9 vs. 273.4 ng·hr/mL) with a milk-to-plasma AUC ratio of 3.3. The predicted relative infant dose ranged from 0.34% to 0.88% for infants consuming THC-containing breastmilk between birth and 12 months. However, the mother-to-infant plasma AUC(0-24 h) ratio increased up to three-fold (3.4-3.6) with increased maternal cannabis smoking up to six times. Our study demonstrated the successful development and application of a lactation and infant PBPK model for exploring THC exposure in infants, and the results can potentially inform breastfeeding recommendations.

How much cannabis is used in a joint in Australia? An experimental investigation into use by potency and frequency.

Cannabis use is highly prevalent in Australia, yet current survey metrics measure tetrahydrocannabinol (THC) exposure with limited accuracy. Often survey items measure cannabis quantity by assuming specific modes of use (i.e., 'how many joints do you use?'), which fail to capture variations in cannabis use and the diverse modes of use (e.g., joints, cones, spliffs). This study investigated how much cannabis is used in these modes of administration in an Australian sample. Participants (N = 31, Mage = 25.77; 51% university students) completed the Roll a Joint Paradigm in which they rolled joints, spliffs and packed cones as they would typically, using oregano as 'cannabis.' Participants then prepared each again but with cannabis of higher or lower potency. The amount of cannabis used across different modes of administration was variable: joints (range 0.10-1.25 g), spliffs (range 0.12-1.21 g) and cones (range 0.03-0.41 g). Participants who used cannabis daily rolled three times the amount of cannabis into a joint. The amount of cannabis used in common modes of administration may be highly variable. Daily use may be associated using larger quantities of cannabis. Titration attempts based on potency were not proportional or consistent across modes of administration. The results indicate people may adjust the quantity of cannabis based on perceived potency, however, not proportional to THC concentration. Inconsistency in the amount of cannabis used based on potency and within different modes of administration may represent a problem for self-report metrics which ask participants to report cannabis use in joints.

Understanding the Mechanism and Extent of Transplacental Transfer of (-)-∆9 -Tetrahydrocannabinol (THC) in the Perfused Human Placenta to Predict In Vivo Fetal THC Exposure.

Cannabis use during pregnancy may cause fetal toxicity driven by in utero exposure to (-)-∆9 -tetrahydrocannabinol (THC) and its psychoactive metabolite, (±)-11-hydroxy-∆9 -THC (11-OH-THC). THC concentrations in the human term fetal plasma appear to be lower than the corresponding maternal concentrations. Therefore, we investigated whether THC and its metabolites are effluxed by placental transporters using the dual cotyledon, dual perfusion, term human placenta. The perfusates contained THC alone (5 μM) or in combination (100-250 nM) with its metabolites (100 nM or 250 nM 11-OH-THC, 100 nM COOH-THC), plus a marker of P-glycoprotein (P-gp) efflux (1 or 10 μM saquinavir), and a passive diffusion marker (106 μM antipyrine). All perfusions were conducted with (n = 7) or without (n = 16) a P-gp/BCRP (breast-cancer resistance protein) inhibitor, 4 μM valspodar. The maternal-fetal and fetal-maternal unbound cotyledon clearance indexes (m-f-CLu,c,i and f-m-CLu,c,i ) were normalized for transplacental antipyrine clearance. At 5 μM THC, the m-f-CLu,c,i , 5.1 ± 2.1, was significantly lower than the f-m-CLu,c,i , 13 ± 6.1 (P = 0.004). This difference remained in the presence of valspodar or when the lower THC concentrations were perfused. In contrast, neither metabolite, 11-OH-THC/COOH-THC, had significantly different m-f-CLu,c,i vs. f-m-CLu,c,i . Therefore, THC appears to be effluxed by placental transporter(s) not inhibitable by the P-gp/BCRP antagonist, valspodar, while 11-OH-THC and COOH-THC appear to passively diffuse across the placenta. These findings plus our previously quantified human fetal liver clearance, extrapolated to in vivo, yielded a THC fetal/maternal steady-state plasma concentration ratio of 0.28 ± 0.09, comparable to that observed in vivo, 0.26 ± 0.10.

Prenatal alcohol and tetrahydrocannabinol exposure: Effects on spatial and working memory.

Alcohol and cannabis are widely used recreational drugs that can negatively impact fetal development, leading to cognitive impairments. However, these drugs may be used simultaneously and the effects of combined exposure during the prenatal period are not well understood. Thus, this study used an animal model to investigate the effects of prenatal exposure to ethanol (EtOH), Δ-9-tetrahydrocannabinol (THC), or the combination on spatial and working memory. Pregnant Sprague-Dawley rats were exposed to vaporized ethanol (EtOH; 68 ml/h), THC (100 mg/ml), the combination, or vehicle control during gestational days 5-20. Adolescent male and female offspring were evaluated using the Morris water maze task to assess spatial and working memory. Prenatal THC exposure impaired spatial learning and memory in female offspring, whereas prenatal EtOH exposure impaired working memory. The combination of THC and EtOH did not exacerbate the effects of either EtOH or THC, although subjects exposed to the combination were less thigmotaxic, which might represent an increase in risk-taking behavior. Our results highlight the differential effects of prenatal exposure to THC and EtOH on cognitive and emotional development, with substance- and sex-specific patterns. These findings highlight the potential harm of THC and EtOH on fetal development and support public health policies aimed at reducing cannabis and alcohol use during pregnancy.

Maternal and infant cannabis testing and associated birth outcomes.

The objective of the study was to determine any identifiable clinical utility of the practice of universal maternal and infant tetrahydrocannabinol (THC) testing at the time of birth. This was cross-sectional, retrospective cohort study comparing the following birth outcomes in relation to maternal and infant tetrahydrocannabinol (THC): APGAR scores, cord gases, NICU admission and need for immediate resuscitation. All births at the University of Maryland Medical Center between January 1, 2018 and December 31, 2020 were reviewed. Those that had either maternal or infant test results missing were excluded. Statistical analysis was performed using STATA v27. Birth outcomes were adjusted for gestational age at delivery and tobacco use. Infant resuscitation was considered the need for any respiratory support. A total of 4260 maternal/infant pairs were included. Of these, 314 (7.4%) birthing parents and 161 (3.8%) of infants tested positive for THC. Of the birth parents who tested positive for THC, 51.3% of their infants also tested positive for THC. Maternal/infant pairs that both tested positive for THC had the lowest need for immediate resuscitation and Neonatal Intensive Care Unit admission. Cord gases and APGAR scores were similar between the groups. Birth parents who tested positive for THC delivered infants at an earlier gestational age (37w6d v 38w5d, p = 0.001) and lower mean birth weight (2690gm v 3061gm, p = 0.001) than those who tested negative even after adjusting for confounders. When limited to only term births and broken down by weeks completed gestation, the mean birth weights were lower for every week in those who tested positive for THC versus those who tested negative. Our study shows that maternal and neonatal testing for THC at the time of birth is not predictive of important neonatal outcome parameters. Therefore, even though it is likely that there are some effects of in utero THC exposure on the neonate, we did not find any clinical benefits that would justify routine maternal and/or infant testing for THC at the time of birth.

Delta-8 tetrahydrocannabinol: a scoping review and commentary.

Delta-8 tetrahydrocannabinol (THC) is a psychoactive substance from the Cannabis plant that has been rising in popularity in the United States since the 2018 US Farm Bill implicitly legalized it. This study reviewed research from peer-reviewed and non-peer-reviewed (e.g. anecdotal and news) reports related to delta-8 THC to summarize current knowledge and implications for public health and safety. A scoping review was conducted using PubMed, Scopus, Google Scholar and Google as search engines, leading to the identification of 103 documents that were summarized. The themes that emerged were (1) legality, (2) use (popularity, motives, psychoactivity/potency, benefits/consequences), (3) synthesis (byproducts, laboratory testing) and (4) retail (availability, price, packaging, youth-oriented marketing). A second author independently coded 20% of the documents, which verified the categorization of articles by these emergent themes. Most research used animal/cell models or focused upon ways to identify the chemical structure of delta-8 THC in various products. Findings suggest that people often use delta-8 THC as a substitute for other substances. Anecdotally, delta-8 THC is a less potent psychoactive than delta-9 THC; however, several negative consequences have been reported. There is no federal age restriction for purchase/possession of delta-8 THC products. Delta-8 THC is readily accessible on-line, is typically less expensive than delta-9 THC and is often marketed in ways that would seemingly appeal to children. There are no regulations on synthesis, resulting in products being contaminated and/or yielding inconsistent effects. There have been thousands of calls to US poison control centers due to accidental delta-8 THC exposure among minors. Most research on delta-8 THC is largely anecdotal, not peer-reviewed and does not involve human subjects. Future research should examine delta-8 THC use using nationally representative samples to more clearly understand the prevalence and consequences of use. Laws are needed to mitigate the risks of using delta-8 THC, particularly quality control of synthesis and minimum purchase age.

Chronic Δ9-tetrahydrocannabinol impact on plasticity, and differential activation requirement for CB1-dependent long-term depression in ventral tegmental area GABA neurons in adult versus young mice.

The ventral tegmental area (VTA) mediates incentive salience and reward prediction error through dopamine (DA) neurons that are regulated by local VTA GABA neurons. In young mice, VTA GABA cells exhibit a form of synaptic plasticity known as long-term depression (LTD) that is dependent on cannabinoid 1 (CB1) receptors preceded by metabotropic glutamate receptor 5 (mGluR5) signaling to induce endocannabinoid production. This LTD was eliminated following chronic (7-10 consecutive days) exposure to the marijuana derived cannabinoid Δ9 -tetrahydrocannabinol (THC). We now examine the mechanism behind THC-induced elimination of LTD in adolescents as well as plasticity induction ability in adult versus young male and female mice using whole-cell electrophysiology experiments of VTA GABA cells. Chronic THC injections in adolescents resulted in a loss of CB1 agonist-mediated depression, illustrating chronic THC likely desensitizes or removes synaptic CB1. We noted that seven days withdrawal from chronic THC restored LTD and CB1 agonist-induced depression, suggesting reversibility of THC-induced changes. Adult mice continue to express functional mGluR5 and CB1, but require a doubling of the synaptic stimulation compared to young mice to induce LTD, suggesting a quantitative difference in CB1-dependent plasticity between young and adult mice. One potential rationale for this difference is changes in AMPA and NMDA glutamate receptors. Indeed, AMPA/NMDA ratios were increased in in adults compared to young mice. Lastly, we performed quantitative reverse-transcription PCR and identified that CB1, DAGLα, and GluA1 levels increased following chronic THC exposure. Collectively, our data demonstrate the first age-dependent GABA neuron plasticity in the VTA, which could have implications for decreased THC dependence capacity in adults, as well as the mechanism behind chronic THC-induced synaptic alterations in young mice.

Impaired Ghrelin Signaling Does Not Lead to Alterations of Anxiety-like Behaviors in Adult Mice Chronically Exposed to THC during Adolescence.

As marijuana use during adolescence has been increasing, the need to understand the effects of its long-term use becomes crucial. Previous research suggested that marijuana consumption during adolescence increases the risk of developing mental illnesses, such as schizophrenia, depression, and anxiety. Ghrelin is a peptide produced primarily in the gut and is important for feeding behavior. Recent studies have shown that ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR), play important roles in mediating stress, as well as anxiety and depression-like behaviors in animal models. Here, we investigated the effects of chronic tetrahydrocannabinol (THC) administration during late adolescence (P42-55) in GHSR (GHSR -/-) knockout mice and their wild-type littermates in relation to anxiety-like behaviors. We determined that continuous THC exposure during late adolescence did not lead to any significant alterations in the anxiety-like behaviors of adult mice, regardless of genotype, following a prolonged period of no exposure (1 month). These data indicate that in the presence of intact or impaired ghrelin/GHSR signaling, THC exposure during late adolescence has limited if any long-term impact on anxiety-like behaviors in mice.

Alterations in rat prefrontal cortex kynurenic acid levels are involved in the enduring cognitive dysfunctions induced by tetrahydrocannabinol exposure during the adolescence.

Cannabis abuse during adolescence is a risk factor for cognitive impairments in psychiatric disorders later in life. To date, the possible causal relationship between cannabinoids, kynurenic acid (KYNA; i.e., a neuroactive metabolite of tryptophan degradation) and cognition has not been investigated in adolescence. Early exposure to delta 9-tetrahydrocannabinol (THC; i.e., the main psychotropic component of cannabis) causes enduring cognitive deficits, which critically involve impaired glutamatergic function in the prefrontal cortex (PFC). In addition, prenatal cannabis exposure results in enduring increases in PFC KYNA levels. Based on these findings, the effects of chronic THC exposure in rats, during another critical period of neurodevelopment particularly sensitive to perturbation by exogenous stimuli, such as adolescence, have been investigated. Male Wistar rats were chronically treated with vehicle or ascending intraperitoneal (i.p.) doses of THC starting on postnatal day (PND) 35 until PND 45. In adulthood (PND 75), cognitive assessment (Y-maze) and extracellular KYNA/glutamate levels were measured in the PFC by in vivo microdialysis, before and after a challenge with KYN (5 mg/kg i.p., the biological precursor of KYNA). By using the selective, brain-penetrable KAT II inhibitor PF-04859989, we then examined whether blockade of KYNA neosynthesis prevents the cognitive impairment. Compared to vehicle-treated controls, extracellular basal KYNA levels were higher in the PFC of adult rats chronically exposed to THC in adolescence (p < 0.01). No changes were observed in extracellular glutamate levels. Following a challenge with KYN, extracellular KYNA levels similarly increased in both groups (i.e., vehicle- and THC-treated; p < 0.001 and p < 0.01, respectively). Chronic adolescent THC exposure negatively affected short-term memory (reduced spontaneous alternation), in adult animals (p < 0.001), while PF-04859989 (30 mg/kg i.p.) restored the cognitive impairment (p < 0.05). We propose that the observed alterations in PFC KYNA signaling might be involved in the cognitive dysfunction induced by the exposure to THC during the adolescence. In the translational realm, these experiments raise the prospect of prevention of KYNA neosynthesis as a possible novel approach to counteract some of the detrimental long-term effects of adolescence cannabis use.

Epidemiological association of cannabinoid- and drug- exposures and sociodemographic factors with limb reduction defects across USA 1989–2016: A geotemporospatial study

BackgroundReports of major limb defects after prenatal cannabis exposure (PCE) in animals and of human populations in Hawaii, Europe and Australia raise the question of whether the increasing use of cannabis in USA might be spatiotemporally associated with limb reduction rates (LRR) across USA. MethodsCongenital anomaly data was from the National Birth Defects Prevention Network, drug use data was taken from the National Survey of Drug Use and Health (NSDUH), cannabinoid concentration was estimated from Federal seizure data and ethnicity and income data were from the US Census bureau. Geotemporospatial analysis was conducted in R. Results436 LRR datapoints were obtained. LRR was significantly associated with cannabis use and tetrahydrocannabinol (THC) exposure and demonstrated prominent cannabis-use quintile effects. A sharp increase in LRR occurred from the fourth to fifth quintiles of cannabis exposure (mean ± S.E.M 3.78 ± 0.38 to 6.66 ± 0.56/10,000 live births, P = 5.22 × 10−9). In final lagged geospatial models adjusted for ethnicity and income interactive terms including cannabinoids were highly significant and robust to adjustment. States in which cannabis was not legalized had a lower LRR (4.28 v 5.01/10,000 live births, relative risk reduction = −0.15, (95%C.I. −0.25, −0.02), P = 0.021). Internationally 37–63% of cases are estimated to not be born alive. Their inclusion in these analyzes uniformly intensified the identified effects and the significance of the effect of the cannabis legalization paradigm rose from P = 0.0256 to P = 0.0146 to P = 0.0048 with silent factors of 0%, 36% and 63%, respectively. ConclusionTherefore a spatiotemporal and dose-dependent association between several cannabinoids including THC and cannabigerol and LRR is reported, is robust to adjustment, is consistent with pathophysiological and preclinical studies, accords with findings elsewhere, is markedly exacerbated in higher exposure quintiles, is exacerbated by cannabis legalization and evidences dose-related intergenerational sequaelae.

Effects of Oral Administration of Lepidium meyenii on Morphology of Mice Testis and Motility of Epididymal Sperm Cells After Tetrahydrocannabinol Exposure.

Background: Tetrahydrocannabinol (THC) administration is associated with testicular damage and reduced semen quality. Oral administration of Lepidium Meyenii (maca) improves spermatogenesis and sperm motility and count and reduces spermatogenic damage.Objectives: The aim of this study was to evaluate the effect of administration of THC, maca, and their combination on testicular tissue and semen parameters.Materials and Methods: Thirty-six-week-old male mice were classified into control, THC, Maca, and THC + Maca groups. The mice were subjected to Eco Color Doppler ultrasound examination of the testicles before and after treatment. After euthanasia, the epididymis, testes, liver, and kidney were collected for histological examination. For morphometry of the testis, tubular diameters and seminiferous epithelium height were measured. Sperm concentration and sperm motilities were assessed. Differences among the groups were assessed using the Kruskal–Wallis and Dunn's post-hoc test.Results: In all the groups, there were no significant changes in testicular morphology before and after treatment. Histological assessment of the testes showed no alterations in control, no significant alterations in Maca, mild to moderate alterations in THC, and mild alterations in THC + Maca groups. Histological examination of the other organs showed no significant differences among the groups. Tubular diameter showed significantly increased thickening for THC and THC + Maca compared with that for Maca and control. Moreover, seminiferous epithelium height decreased for THC compared with that in the control, Maca, and THC + Maca groups. No statistically significant reduction in the spermatogenic index was observed for THC compared with that for Maca and THC + Maca. Epididymal cross-sections of the groups showed no significant alterations. Sperm concentration and motility were higher for control and THC + Maca groups than in group THC and Maca.Conclusion: In vivo maca administration reduced the deleterious effect of THC on testicular parenchyma and semen production.

Frequent Δ9- tetrahydrocannabinol exposure during adolescence impairs sociability in adult mice exposed to an aversive painful stimulus

Early-life exposure to Δ9-tetrahydrocannabinol (Δ9-THC), the intoxicating constituent of cannabis, may produce enduring neurochemical changes in brain structures involved in the regulation of sociality but it is still unclear how such changes influence social behavior later in life. In the present study, we exposed male mice to moderate daily doses of Δ9-THC (5 mg/kg, intraperitoneal) during adolescence (postnatal day, PND, 30 to 43) and, when animals reached adulthood (PND70), we assessed their performance in the three-chamber social interaction task before and 3 weeks after injection of the chemical irritant formalin (1 % vol, intraplantar), which produces both immediate and persistent pain-related behaviors in mice. Prior Δ9-THC treatment did not alter social interaction in control adult mice but disrupted it in animals that developed lasting sensory abnormalities following formalin injection. The findings suggest that frequent exposure to Δ9-THC during adolescence causes in male mice a dormant dysfunction in social behavior which can be unmasked in adulthood when the animals experience an aversive state.

Cannabinoid Hyperemesis Syndrome Survey and Genomic Investigation.

Background:Cannabinoid hyperemesis syndrome (CHS) is a diagnosis of exclusion with intractable nausea, cyclic vomiting, abdominal pain, and hot bathing behavior associated with ongoing tetrahydrocannabinol (THC) exposure. Increasing cannabis use may elevate CHS prevalence, exacerbating a public health issue with attendant costs and morbidity.Objective, Design, and Data Source:This study, the largest contemporaneous database, investigated genetic mutations underlying CHS. Patients with CHS diagnosis and ongoing symptoms were compared with current cannabis users lacking symptoms.Target Population:A screening questionnaire was posted online. Of 585 respondents, 205 qualified as the CHS pool and 54 as controls; a reduced pool of 28 patients and 12 controls ultimately completed genomic testing.Results:Patients and controls were high-frequency users of cannabis flower or concentrates (93%), using multiple grams/day of THC-predominant material. Among patients, 15.6% carried diagnoses of cannabis dependency or addiction, and 56.6% experienced withdrawal symptoms. About 87.7% of patients improved after cannabis cessation, most suffering recurrence rapidly after resumption. Findings in patients included mutations in genes COMT {odds ratio, 12 (95% confidence limit [CL], 1.3–88.1) p=0.012}, transient receptor potential vanilloid receptor 1 (TRPV1) (odds ratio, 5.8 [95% CL, 1.2–28.4] p=0.015), CYP2C9 (odds ratio, 7.8 [95% CL, 1.1–70.1] p=0.043), gene coding dopamine-2 receptor (DRD2) (odds ratio, 6.2 [95% CL, 1.1–34.7] p=0.031), and ATP-binding cassette transporter gene (ABCA1) (odds ratio, 8.4 [95% CL, 1.5–48.1] p=0.012).Limitations:Some participants were reluctant to undergo genetic testing; only 28 of 99 CHS patients who agreed to testing ultimately returned a kit.Conclusion:This is the largest patient cohort of CHS examined to date, and first to note associated mutations in genes affecting neurotransmitters, the endocannabinoid system, and the cytochrome P450 complex associated with cannabinoid metabolism. Although the sample size was smaller than desired, these preliminary findings may contribute to the growing body of knowledge, stimulate additional investigation, help elucidate the pathophysiology of CHS, and, ultimately, direct future treatment.

European hemp-based food products – Health concerning cannabinoids exposure assessment

The latest report on tetrahydrocannabinol (THC) exposure assessment performed by European Food Safety Authority showed that THC levels in certain food categories are high. However, the performed study included uncertainties regarding occurrence data and hemp-food consumption patterns. The aim of the present study was to quantify the levels of “total” Δ 9 -THC, cannabidiol (CBD) and cannabinol (CBN) in hemp food products available on the market of countries mostly not assessed by the latest EFSA report, as well as to perform cannabinoids health risk assessment. The obtained results allowed us to identify hemp-seed oils as product type which might represent health concern. Furthermore, the analysis of hemp teas showed the possibility of Cannabis drug-type occurrence, but also questioned the justification of cannabinoids maximum transfer principle application for the exposure assessment. It was concluded, that hemp-based food products should not be consumed by population younger than 18 years. • Hemp seed oil may represent significant health risk in term of Δ 9 -THC. • Hemp tea can contain Cannabis species high in Δ 9 -THC. • Hemp-based food should not be consumed by underaged.

The role of Tetrahydrocannabinol in inducing disrupted signaling cascades, hippocampal atrophy and memory defects

Tetrahydrocannabinol (THC), a major psychoactive constituent of marijuana, can substantially change the function of several brain areas, leading to behavioral impairment including memory and learning dysfunction. Given the importance of hippocampus as one of the chief parts of the brain involved in memory processing, the present study seeks to investigate structural and histological alterations in hippocampus as well as behavioral defects provoked by THC treatment. Besides, using genome-wide sequencing, we adopted a pathway-based approach to discover dysregulated molecular pathways. Our results demonstrated remarkable hippocampal atrophy, and also interrupted memory function and long term potentiation (LTP) under THC exposure. We also detected several dysregulated signaling pathways involved in synaptic plasticity as well as cell-cell interaction in the hippocampus of THC-treated rats. Overall, the results indicate a potential correlation between disrupted signaling cascades, hippocampal atrophy and memory defects caused by THC treatment.

55715 Quantification of Neonatal THC Exposure Following Prenatal Marijuana Use

ABSTRACT IMPACT: Quantification of neonatal THC exposure will allow for better insight into how THC exposure correlates with neurodevelopmental outcomes. OBJECTIVES/GOALS: Tetrahydrocannabinol (THC) use has become increasingly prevalent in recent years, including among pregnant women. However, few, if any, clinical studies have quantified precise in utero exposure levels of THC during pregnancy. Our study aims to fill this gap by using analytical methods to quantify THC in mother and baby following prenatal THC use. METHODS/STUDY POPULATION: Pregnant women were asked to give a self-report of all cannabis and cannabinoid use during pregnancy, including dose, frequency, and route of consumption. Upon arrival at the labor and delivery unit, maternal blood samples were collected. Immediately following birth and 24 hours after birth, umbilical cord and neonatal blood samples were collected, respectively. All blood samples were analyzed using tandem liquid chromatography-mass spectrometry (LC-MS) for the presence of THC, tetrahydrocannabinol carboxylic acid (THC-COOH), and hydroxy-tetrahydrocannabinol (THC-OH). Maternal THC and metabolite levels were compared to both cord and neonate samples. RESULTS/ANTICIPATED RESULTS: To date, we have collected 3 mother-infant sample dyads and 4 mother-infant control samples. We anticipate collecting a total of 20 mother-infant samples from each group. We will quantify levels of THC and its metabolites in maternal samples and compare these to cord and infant samples. We expect that THC/metabolite levels will vary as a function of dose and frequency of consumption. We also expect that THC/metabolites will be higher in umbilical cord blood relative to neonatal blood. DISCUSSION/SIGNIFICANCE OF FINDINGS: This study is among the first to directly measure exposure in the neonate following prenatal cannabis use. Quantification of THC/metabolite concentrations will be supplemented with developmental evaluations of infants at 6 and 12 months of age in order to gain better insight into how THC exposure correlates with neurodevelopmental outcomes.

Detrimental effects of adolescent escalating low-dose Δ9 -tetrahydrocannabinol leads to a specific bio-behavioural profile in adult male rats.

Adolescent cannabis use is associated with adult psychopathology. When Δ9 -tetrahydrocannabinol (THC), mainly in high doses, is administered to adolescence rats there are also long lasting effects in adults. This study aims to determine the specific adult bio-behavioural profile after adolescent low-dose THC, which better mirrors adolescent recreational cannabis use. Adolescent male Sprague-Dawley rats were treated with escalating low-dose of THC. In adulthood, they were evaluated for their spontaneous locomotion, sensorimotor gating, higher order and spatial cognitive functions. Dopaminergic activity and cannabinoid receptor expression were measured in distinct brain regions. Hippocampal neurogenic activity of neural stem cells was determined and protein levels of neuroplasticity-related biomarkers were quantified. Adolescent low-dose THC exposure increased spontaneous open-field activity, without affecting prepulse inhibition and attentional set-shifting performance. Region-specific dopaminergic alterations and CB1 receptor up-regulation in the prefrontal cortex were observed. Impaired spatial memory, as assessed with the object location task and Morris water maze test, was associated with significantly decreased proliferative activity (SOX2-positive cells), neurogenic potential (decreased doublecortin-positive cells) in the adult hippocampus and defective neuroplasticity, including reduced BDNF expression in the hippocampus and prefrontal cortex. Our findings reveal the adverse impact of adolescent low-dose THC on the psychomotor profile, dopaminergic neurotransmission, compensatory cannabinoid receptor response, cognition-related neurobiological and behavioural functions. Our adolescent low-dose THC animal model does not induce tangible psychotic-like effects, such as those reported in high-dose THC studies, but it impairs cognitive functions and points to hippocampal vulnerability and disrupted neurogenesis.