Therapeutic Role of Hemp (Cannabis sativa) Against Copper-Induced Toxicity in Labeo rohita and Cirrhinus mrigala.

For decades hemp has been used as a therapeutic agent for enhancing immunity in animals. Current study was conceptualized to find out the protective role of dietary hemp seed products (hemp seed oil (HO) and hemp seed (HS)) against copper-induced toxicity in fish. Fingerlings of Labeo rohita (Rohu) and Cirrhinus mrigala (Mrigal) were exposed to copper at 20% of the 96 h LC50 (1.34 and 1.52 ppm, respectively) for 30 days. Following Cu exposure, fish were maintained on two types of hemp (Cannabis sativa)-supplemented feeds, on graded levels of hemp seed oil (HO: 1%, 2%, 3%) and hemp seed (HS: 5%, 10%, 15%) for 50 days, while one group was the control (without any copper exposure as well as any supplementation). Copper exposure significantly increased (P < 0.05) WBCs, hematocrit, MCHV, eosinophils, and lymphocytes in L. rohita and also in C. mrigala as compared to control. Copper exposure also significantly (P < 0.05) changed lysozymes, plasma protein, and IgM in both species, in comparison to control. Moreover, alkaline phosphatase, bilirubin, serum glutamic-pyruvic transaminase, and aspartate transaminase were significantly (P < 0.05) changed by copper exposure in comparison to control in both species. Additionally, Antioxidant enzymes like catalase, superoxide dismutase, glutathione reductase, and glutathione peroxidase were also significantly (P < 0.05) increased in the brain, gills, liver, and muscle of copper-exposed group in both species as compared to control. Interestingly, all the altered parameter of blood, serum, liver function tests, and antioxidant enzymes (in different organs) because of copper toxicity were successfully reverted to normal level in hemp seed oil (HO) and hemp seed (HS)-supplemented fed groups of both species. In conclusion, hemp seed supplementation showed significant (P < 0.05) improved results against copper toxicity. Thus, it could be recommended as an animal feed ingredient for its therapeutic role.

Birth outcomes following in utero co-exposure to tobacco and marijuana.

BACKGROUND: With recent changes in tobacco and marijuana use patterns, it becomes crucial to understand how the prenatal co-use of these substances impacts birth outcomes. The goal of this study was to examine the risk of adverse birth outcomes among infants born to women who used tobacco and marijuana concurrently throughout pregnancy compared to infants of women who used tobacco alone. METHODS: This study involved a retrospective chart review of pregnant women identified via self-report or biochemical testing who used tobacco products alone (N = 71) or tobacco and marijuana simultaneously (N = 127) at any point throughout pregnancy. Differences in birth outcomes between these groups, including APGAR (appearance, pulse, grimace, activity, and respiration) scores, respiratory distress, neonatal intensive care unit admission, intrauterine growth restriction, birth weight, birth length, head circumference, gestational age, and length of hospital stay, were analyzed using linear regression and odds ratio analysis. RESULTS: There were no significant differences in outcomes for infants of women who used tobacco and marijuana compared to infants of women who used tobacco alone during pregnancy. Rates of adverse birth outcomes were high among women who used tobacco compared to what would be expected in unexposed pregnancies. CONCLUSIONS: Tobacco and marijuana co-use during pregnancy was not associated with an additional risk of adverse birth outcomes compared to tobacco use alone. Women should be educated on potential risks of marijuana, and especially, tobacco use during pregnancy. These results will inform clinical recommendations for pregnant women using tobacco and marijuana, aiming to decrease preventable adverse outcomes for patients and infants.

In vitro evaluation of cell viability and expression profile of growth factors in mouse Sertoli cells exposed to Delta-9-tetrahydrocannabinol: a mechanistic insight into the cannabinoid-induced testicular toxicity.

The potentially adverse effects of cannabis (marijuana), a common leisure compound, on male reproductive performance are a reason for concern. δ-9-tetrahydrocannabinol (THC), the primary active component of marijuana alters testicular cells' proliferation and function which affects male fertility and causes testicular cells dysfunction and apoptosis. The main objective of this study was to investigate the possible mechanism underlying the toxic effects of THC with a mechanistic insight into Sertoli cell-based reproductive dysfunction. The Mus musculus Sertoli cell line (TM4) was cultured and exposed to different concentrations of THC and, MTT (3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was then performed for evaluating cell viability. The expression of caspase-3 gene and genes related to growth factors were analyzed by real-time RT-PCR. Western blotting was performed for evaluating protein expression level. THC concentration-dependently decreased the TM4 viability with a significant effect starting at concentration of 1 µM and reaching about 75% of the control level at the concentration of 50 µM (IC25). Moreover, caspase-3 mRNA expression levels significantly increased while growth factors mRNA levels decreased in THC-exposed cells compared to unexposed cells. There was also a significant reduction in related protein levels in THC group. Administration of the THC promotes cytotoxic and apoptotic effects on TM4 cells partly through down-regulation of growth factors expression. Increased apoptosis, over expression of caspase-3, and down-regulation of growth factors expression in Sertoli cells exposed to THC may be a reflection of THC-induced testicular toxicity, which may be partly involved in infertility associated with marijuana smoking or medical cannabis use.

Time- and temperature-dependent postmortem ∆9-tetrahydrocannabinol concentration changes in rabbits following controlled inhaled cannabis administration.

ostmortem redistribution (PMR), a well-known phenomenon in forensic toxicology, can result in substantial changes in drug concentrations after death, depending on the chemical characteristics of the drug, blood collection site, storage conditions of the body and postmortem interval (PMI). Limited PMR data are available for ∆9-tetrahydrocannabinol (THC), the primary psychoactive component in Cannabis sativa. PMR was evaluated after controlled cannabis inhalation via a smoking machine and exposure chamber in New Zealand white rabbits. Necropsies were performed on five control rabbits immediately after euthanasia, whereas 27 others were stored at room temperature (21°C) or refrigerated conditions (4°C) until necropsy at 2, 6, 16, 24 or 36 h after death. THC and its Phase I and glucuronidated Phase II metabolites were quantified in blood, vitreous humor, urine, bile and tissues by liquid chromatography-tandem mass spectrometry (LC-MS-MS). Under refrigerated temperature, heart blood THC concentrations significantly increased at PMI 2 h in rabbits, whereas peripheral blood THC concentrations showed a significant increase at PMI 16 h. Central:peripheral blood and liver:peripheral blood ratios for THC ranged from 0.13 to 4.1 and 0.28 to 8.9, respectively. Lung revealed the highest THC concentrations, while brain and liver exhibited the most stable THC concentrations over time. This report contributes much needed data to our understanding of postmortem THC behavior and can aid toxicologists in the interpretation of THC concentrations in medicolegal death investigations.

Subchronic oral toxicity assessment of a cannabis extract.

Cannabidiol (CBD) is present in Cannabis Sativa L. and has been used in medicines and foods to deliver beneficial health effects. Despite this, research on CBD safety utilising modern testing methods is lacking. Therefore three separate safety experiments were performed on a CBD isolate. Sprague-Dawley rats were used to investigate prenatal development, a 14-day toxicity sighting study, and an OECD compliant 90-day subchronic oral toxicity trial, with 35-day off-dose recovery. The prenatal screening study demonstrated reduced body weights and food consumption in the highest dose group, but no substance-related changes in pregnancy rate, maternal or placental gross abnormalities, or premature deliveries. The 14-day study indicated tolerance up to 460 mg/kg bw/d of CBD isolate. Based on these findings, a 90-day repeated dose oral toxicity study was performed at doses of 0, 30, 115, 230, and 460 mg/kg bw/d of CBD, followed by a 35-day off-dose recovery period. In the 90-day study, some non-adverse organ and tissue changes were observed. With the exception of the high dose group, these fully reversed during the recovery period. Based on these findings, sub-chronic consumption of highly purified isolate results in a CBD NOAEL of 460 mg/kg bw/d for males and 230 mg/kg bw/d for females.

Oral toxicity evaluation of cannabidiol.

Use of cannabidiol (CBD) in humans has increased considerably in recent years. While currently available studies suggest that CBD is relatively safe for human consumption, data from publicly available studies on CBD conducted according to modern testing guidelines are lacking. In the current study, the potential for toxicity following repeated oral exposure to hemp-derived CBD isolate was evaluated in male and female Sprague Dawley rats. No adverse treatment-related effects were observed following administration of CBD via oral gavage for 14 and 90 days at concentrations up to 150 and 140 mg/kg-bw/d, respectively. Microscopic liver and adrenal gland changes observed in the 90-day study were determined to be resolved after a 28-day recovery period. CBD was well tolerated at these dose levels, and the results of this study are comparable to findings reported in unpublished studies conducted with other CBD isolates. The current studies were conducted as part of a broader research program to examine the safety of CBD.

Increased vulnerability to atrial and ventricular arrhythmias caused by different types of inhaled tobacco or marijuana products.

BACKGROUND: The emergence of a plethora of new tobacco products marketed as being less harmful than smoking, such as electronic cigarettes and heated tobacco products, and the increased popularity of recreational marijuana have raised concerns about the potential cardiovascular risk associated with their use. OBJECTIVE: The purpose of this study was to investigate whether the use of novel tobacco products or marijuana can cause the development of proarrhythmic substrate and eventually lead to arrhythmias. METHODS: Rats were exposed to smoke from tobacco, marijuana, or cannabinoid-depleted marijuana, to aerosol from electronic cigarettes or heated tobacco products, or to clean air once per day for 8 weeks, following by assays for blood pressure, cardiac function, ex vivo electrophysiology, and histochemistry. RESULTS: The rats exposed to tobacco or marijuana products exhibited progressively increased systolic blood pressure, decreased cardiac systolic function with chamber dilation, and reduced overall heart rate variability, relative to the clean air negative control group. Atrial fibrillation and ventricular tachycardia testing by ex vivo optical mapping revealed a significantly higher susceptibility to each, with a shortened effective refractory period and prolonged calcium transient duration. Histological analysis indicated that in all exposure conditions except for air, exposure to smoke or aerosol from tobacco or marijuana products caused severe fibrosis with decreased microvessel density and higher level of sympathetic nerve innervation. CONCLUSION: These pathophysiological results indicate that tobacco and marijuana products can induce arrhythmogenic substrates involved in cardiac electrical, structural, and neural remodeling, facilitating the development of arrhythmias.

Animal evidence considered in determination of cannabis smoke and Δ9 -tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint): Part III. Proposed neurodevelopmental mechanisms of action.

This review summarizes the most common potential pathways of neurodevelopmental toxicity due to perinatal exposure to Δ9 -tetrahydrocannabinol (Δ9 -THC) that lead to behavioral and other adverse outcomes (AOs). This is Part III in a set of reviews highlighting the animal-derived data considered by California's Developmental and Reproductive Toxicant Identification Committee (DARTIC) in 2019. The Hazard Identification Document (HID) provided to the DARTIC included a summary of human, whole animal, and mechanistic data on the neurodevelopmental toxicity of cannabis smoke and Δ9 -THC. The literature search for mechanistic data has been updated through 2020. We focus on mechanistic pathways relating to behavioral and other neurodevelopmental outcomes of perinatal exposure to Δ9 -THC. The endocannabinoid system (EC system) plays a crucial role in many processes involved in neurodevelopment and exposure to Δ9 -THC can alter these processes. Whole animal studies report changes in cognitive ability, behavior, and motor function after prenatal exposure to Δ9 -THC. Findings from mechanistic studies add to this evidence and further provide information regarding the pathways leading to these outcomes. Neuromechanistic studies can bridge the gaps between molecular initiating events and apical neurodevelopmental endpoints caused by a chemical. They offer insight into potential alterations in the same pathways by other chemicals that can also result in AOs. Studies of cannabinoid receptor agonist-induced molecular alterations and provide deep biological plausibility at the mechanistic level for the cognitive, behavioral, and motor impairments observed in animal studies after perinatal exposure to Δ9 -THC.

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

OBJECTIVES: On December 11, 2019, California's Developmental and Reproductive Toxicant Identification Committee (DARTIC) met to consider the addition of cannabis smoke and Δ9 -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. Δ9 -THC can interfere with these functions. Mechanistic studies employed techniques including: blocking Δ9 -THC binding to endocannabinoid (EC) receptors, inhibiting Δ9 -THC metabolism, and/or using animals expressing knockout mutations of EC receptors. Apical somatic effects of cannabis smoke or Δ9 -THC reported in whole animal studies included decreases in offspring viability and growth. Mechanistic studies discussed in Part I focused on Δ9 -THC effects on early embryos and implantation, immune development, and bone growth. CONCLUSIONS: In reaching its decision to list cannabis and Δ9 -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.

Intoxicación accidental por marihuana en pediatría. Serie de 3 casos / Accidental poisoning by marijuana in pediatrics. Series of 3 cases

Resumen La marihuana o cannabis es la sustancia psicoactiva ilícita de mayor consumo. Una consecuencia no deseada de la regulación de su cultivo y la difusión popular de su uso medicinal y recreativo, es su asociación con el aumento de la disponibilidad de cultivos en la población general y de productos, como alimentos y fármacos elaborados con infusiones de esta planta, con concentraciones desconocidas de delta-9-tetrahidrocannabinol (A9THC), su principal componente psicoactivo. Se presenta una serie de 3 pacientes expuestos a esta sustancia de forma no intencional, por vía digestiva, asistidos de forma presencial por los servicios de Toxicología y Emergencias del Hospital Interzonal de Agudos Especializado en Pediatría "Sor María Ludovica" de La Plata. A diferencia de la absorción por vía inhalatoria, por vía digestiva se producen concentraciones mucho más variables y ciclos temporales mayores de A9THC y sus metabolitos, que ejercen sus efectos sobre los receptores CB1, dispuestos en el sistema nervioso central, incluido tronco encefálico, región con mayor presencia de éstos en niños, lo que justifica las manifestaciones neurológicas frecuentes y de mayor gravedad en este grupo etario, en relación a los adultos. La sospecha clínica, la anamnesis y la detección temprana de cannabinoides en orina son los pilares fundamentales para establecer el diagnóstico temprano. El tratamiento consiste en medidas de sostén y sintomáticas, que se implementan según la gravedad del cuadro. Debe considerarse la posibilidad de exposición a esta sustancia frente a cuadros de letargo o somnolencia de aparición brusca, con ataxia, modificaciones del humor, alteraciones sensoperceptivas, convulsiones o coma, con o sin insuficiencia respiratoria, con taquicardia o bradicardia. Es de fundamental importancia la educación y concientización de los adultos a cargo de niños sobre estos riesgos.

Abstract Marijuana or cannabis is the illicit psychoactive substance most widely used. An unwanted consequence of the regula-tion of its cultivation and the popular diffusion of its medicinal and recreational use, is the association with an increase in the avail-ability of crops in the general population, products, foods and medicines made with cannabis infusions, with unknown concentra-tions of delta-9-tetrahydrocannabinol (A9THC), the most important psychoactive component. We present a series with 3 patients with unintentional exposure to this substance through the digestive tract, assisted by the Toxicology and Emergency services of the Interzonal Hospital for Acute Specialized in Pediatrics "Sor María Ludovica". Unlike absorption through the inhalation route, more variable concentrations and greater temporal cycles of A9THC and its metabolites are produced through the digestive route, which exert their effects on CB1 receptors, arranged in the central nervous system, including brainstem, the region with greatest presence of this receptors in children, that justifies the frequent and more serious neurological manifestations in children, compared to adults. Clinical suspicion, anamnesis and early detection of cannabinoids in urine are the fundamental pillars to establish an early diagnosis. Treatment consists in supportive and symptomatic measures, that are implemented according to the severity of the condition. The possibility of exposure to this substance must be estimated in the face of sudden onset of lethargy or drowsi-ness, with ataxia, mood modifications, sensory-perceptual disturbances, seizures or coma, with or without respiratory failure, with tachycardia or bradycardia. The education and awareness of caretakers adults, about these risks is of fundamental importance.

Metabolites of Cannabis Induce Cardiac Toxicity and Morphological Alterations in Cardiac Myocytes.

Cannabis is one of the most commonly used recreational drugs worldwide. Rrecent epidemiology studies have linked increased cardiac complications to cannabis use. However, this literature is predominantly based on case incidents and post-mortem investigations. This study elucidates the molecular mechanism of Δ9-tetrahydrocannabinol (THC), and its primary metabolites 11-Hydroxy-Δ9-THC (THC-OH) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH). Treatment of cardiac myocytes with THC-OH and THC-COOH increased cell migration and proliferation (p < 0.05), with no effect on cell adhesion, with higher doses (250-100 ng/mL) resulting in increased cell death and significant deterioration in cellular architecture. Conversely, no changes in cell morphology or viability were observed in response to THC. Expression of key ECM proteins α-SMA and collagen were up-regulated in response to THC-OH and THC-COOH treatments with concomitant modulation of PI3K and MAPK signalling. Investigations in the planarian animal model Polycelis nigra demonstrated that treatments with cannabinoid metabolites resulted in increased protein deposition at transection sites while higher doses resulted in significant lethality and decline in regeneration. These results highlight that the key metabolites of cannabis elicit toxic effects independent of the parent and psychoactive compound, with implications for cardiotoxicity relating to hypertrophy and fibrogenesis.

Marijuana toxicosis in 2 donkeys.

Marijuana toxicosis is typically seen by companion animal veterinarians. However, with increased marijuana availability, there is a greater potential for toxicosis in other species. Herein we describe a case of suspected marijuana toxicosis in a female and a male American Mammoth donkey, aged 8 y and 20 y, respectively, fed cannabis buds. Both cases were presented because of depression and lethargy. However, the jenny had ataxia, mild colic, tachycardia, tachypnea, and decreased tongue tone. Plasma samples from the jenny on presentation and 3 d following hospitalization were submitted to the Kansas State Veterinary Diagnostic Laboratory to be screened for cannabinoids using high-pressure liquid chromatography coupled with tandem mass spectroscopy (HPLC-MS/MS). A single serum sample from the jack was taken on presentation and submitted to the Animal Health Diagnostic Center at Cornell University for Δ9-tetrahydrocannabinol (THC) and cannabidiol analysis using HPLC-MS/MS. THC was detected in all samples. Clinical signs were noted 24-36 h after ingestion, which included mild-to-moderate neurologic deficits, mild colic, tachycardia, tachypnea, and decreased tongue tone. Both donkeys recovered uneventfully within 24 h of peak effects. Utilizing a cannabinoid screening assay in collaboration with a veterinary diagnostic laboratory may be useful when an equine practitioner suspects marijuana toxicosis in a patient.

Marijuana toxicosis in dogs in Melbourne, Australia, following suspected ingestion of human faeces: 15 cases (2011-2020).

This retrospective case series describes a novel and unexpected source for marijuana toxicosis in dogs; suspected ingestion of human faeces containing Δ9 -tetrahydrocannabinol (THC). Medical records from four, 24-h veterinary emergency hospitals in Melbourne, Australia, were reviewed and 15 dogs met the criteria for inclusion in this case series. Clinical signs of marijuana toxicosis included ataxia (n = 13), mydriasis (n = 6), hyperaesthesia (n = 5), urinary incontinence (n = 4) and stupor (n = 3). A urine drug screening test was performed for eight dogs and all were positive for THC. Confirmation of ingestion of human faeces was based on owner-witnessed ingestion (n = 7) or the presence of faecal material within vomit (n = 8). Sites of human faecal exposure were recorded to be a local park (n = 10), beach (n = 1), camp site (n = 1) and walking trail (n = 1). Time from exposure to development of clinical signs ranged between 3 and 6 h (n = 4). All dogs survived to discharge. Ingestion of human faeces containing THC may lead to marijuana toxicosis in dogs. Veterinary staff and owners should be attentive in regard to using appropriate hygiene measures when managing these dogs.

Vapor Cannabis Exposure Generationally Affects Male Reproductive Functions in Mice.

This study was performed to examine whether vapor exposure to cannabis plant matter negatively impacts male reproductive functions and testis development in mice. Adult CD-1 male mice (F0) were exposed to air (control) or 200 mg of vaporized cannabis plant matter 3×/day over a 10-day period. Subsequently, F0 males were bred with drug-naïve CD-1 females to generate F1 males, and F1 offspring were used to generate F2 males. Cannabis vapor exposure decreased sperm count and/or motility in F0 and F1 males and disrupted the progression of germ cell development, as morphometric analyses exhibited an abnormal distribution of the stages of spermatogenesis in F0 males. Although plasma levels of testosterone were not affected by cannabis exposure in any ages or generations of males, dysregulated steroidogenic enzymes, Cyp11a1 and Cyp19a1, were observed in F0 testis. In the neonatal testis from F1 males, although apoptosis was not altered, DNA damage and DNMT1, but not DNMT3A and DNMT3B, were increased in germ cells following cannabis exposure. In contrast, the alterations of DNA damage and DNMT1 expression were not observed in F2 neonatal males. These results suggest that cannabis vapor exposure generationally affects male reproductive functions, probably due to disruption of spermatogenesis in the developing testis.

Cannabis exposure during adolescence: A uniquely sensitive period for neurobiological effects.

Adolescence is a crucial developmental period where neural circuits are refined and the brain is especially vulnerable to external insults. The endocannabinoid (eCB) system undergoes changes during adolescence which affect the way in which it modulates the development of other systems, in particular dopamine circuits, which show protracted development into adolescence. Given the rise of cannabis use by adolescents and young people, as well as variants containing increasingly higher concentrations of THC, it is now crucial to understand the unique effects of adolescent exposure to cannabis on the developing brain and it might shape future adult vulnerabilities to conditions such as psychosis, schizophrenia, addiction and more. Here we discuss the development of the eCB system across the lifespan, how CB1 receptors modulate dopamine release and potential neurobiological and behavioral effects of adolescent THC exposure on the developing brain such as alterations in excitatory/inhibitory balance during this developmental period.

Mechanisms of cannabis impairment: Implications for modeling driving performance.

Past research on cannabis has been limited in scope to THC potencies lower than legally available and efforts to integrate the effects into models of driving performance have not been attempted to date. The purpose of this systematic review is to understand the implications for modeling driving performance and describe future research needs. The risk of motor vehicle crashes increases 2-fold after smoking marijuana. Driving during acute cannabis intoxication impairs concentration, reaction time, along with a variety of other necessary driving-related skills. Changes to legislation in North America and abroad have led to an increase in cannabis' popularity. This has given rise to more potent strains, with higher THC concentrations than ever before. There is also rising usage of novel ingestion methods other than smoking, such as oral cannabis products (e.g., brownies, infused drinks, candies), vaping, and topicals. The PRISMA guidelines were followed to perform a systematic search of the PubMed database for peer-reviewed literature. Search terms were combined with keywords for driving performance: driving, performance, impairment. Grey literature was also reviewed, including congressional reports, committee reports, and roadside surveys. There is a large discrepancy between the types of cannabis products sold and what is researched. Almost all studies that used inhalation as the mode of ingestion with cannabis that is around 6% THC. This pales in comparison to the more potent strains being sold today which can exceed 20%. Which is to say nothing of extracts, which can contain 60% or more THC. Experimental protocol is another gap in research that needs to be filled. Methodologies that involve naturalistic (real world) driving environments, smoked rather than vaporized cannabis, and non-lab certified products introduce uncontrollable variables. When considering the available literature and the implications of modeling the impacts of cannabis on driving performance, two critical areas emerge that require additional research: The first is the role of cannabis potency. Second is the route of administration. Does the lower peak THC level result in smaller impacts on performance? How long does potential impairment last along the longer time-course associated with different pharmacokinetic profiles. It is critical for modeling efforts to understand the answers to these questions, accurately model the effects on driver performance, and by extension understand the risk to the public.

Paternal Cannabis Exposure Prior to Mating, but Not Δ9-Tetrahydrocannabinol, Elicits Deficits in Dopaminergic Synaptic Activity in the Offspring.

The legalization and increasing availability of cannabis products raises concerns about the impact on offspring of users, and little has appeared on the potential contribution of paternal use. We administered cannabis extract to male rats prior to mating, with two different 28-day exposures, one where there was a 56-day interval between the end of exposure and mating ("Early Cannabis"), and one just prior to mating ("Late Cannabis"); the extract delivered 4 mg/kg/day of the main psychoactive component, Δ9-tetrahydrocannabinol. We then assessed the impact on dopamine (DA) systems in the offspring from the onset of adolescence (postnatal day 30) through middle age (postnatal day 150), measuring the levels of DA and its primary metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) in various brain regions. Paternal cannabis with either regimen elicited a profound and persistent deficit in DA utilization (DOPAC/DA ratio) in the offspring, indicative of subnormal presynaptic activity. However, the two regimens differed in the underlying mechanism, with Early Cannabis reducing DOPAC whereas Late Cannabis increased DA and elicited a smaller reduction in DOPAC. Effects were restricted to male offspring. The effects of cannabis were not reproduced by equivalent exposure to its Δ9-tetrahydrocannabinol, nor did we see the effects with perinatal exposure to tobacco smoke or some of its fetotoxic contributors (benzo[a]pyrene without or with nicotine). Our studies provide some of the first evidence for adverse effects of paternal cannabis administration on neurodevelopment in the offspring, and reinforce the important consequences of paternal drug use in the preconception period.

Epidemiological overview of multidimensional chromosomal and genome toxicity of cannabis exposure in congenital anomalies and cancer development.

Cannabis and cannabinoids are implicated in multiple genotoxic, epigenotoxic and chromosomal-toxic mechanisms and interact with several morphogenic pathways, likely underpinning previous reports of links between cannabis and congenital anomalies and heritable tumours. However the effects of cannabinoid genotoxicity have not been assessed on whole populations and formal consideration of effects as a broadly acting genotoxin remain unexplored. Our study addressed these knowledge gaps in USA datasets. Cancer data from CDC, drug exposure data from National Survey of Drug Use and Health 2003-2017 and congenital anomaly data from National Birth Defects Prevention Network were used. We show that cannabis, THC cannabigerol and cannabichromene exposure fulfill causal criteria towards first Principal Components of both: (A) Down syndrome, Trisomies 18 and 13, Turner syndrome, Deletion 22q11.2, and (B) thyroid, liver, breast and pancreatic cancers and acute myeloid leukaemia, have mostly medium to large effect sizes, are robust to adjustment for ethnicity, other drugs and income in inverse probability-weighted models, show prominent non-linear effects, have 55/56 e-Values > 1.25, and are exacerbated by cannabis liberalization (P = 9.67 × 10-43, 2.66 × 10-15). The results confirm experimental studies showing that cannabinoids are an important cause of community-wide genotoxicity impacting both birth defect and cancer epidemiology at the chromosomal hundred-megabase level.