Examining the hepatotoxic potential of cannabidiol, cannabidiol-containing hemp extract, and cannabinol at consumer-relevant exposure concentrations in primary human hepatocytes.

Hemp extracts and consumer products containing cannabidiol (CBD) and/or other phytocannabinoids derived from hemp have entered the marketplace in recent years. CBD is an approved drug in the United States for the treatment of certain seizure disorders. While effects of CBD in the liver have been well characterized, data on the effects of other cannabinoids and hemp extracts in the liver and methods for studying these effects in vitro are limited. This study examined the hepatotoxic potential of CBD, CBD concentration-matched hemp extract, and cannabinol (CBN), at consumer-relevant concentrations determined by in silico modeling, in vitro using primary human hepatocytes. Primary human hepatocytes exposed to between 10-nM and 25-µM CBD, CBN, or hemp extract for 24 and 48 h were evaluated by measuring lactate dehydrogenase release, apoptosis, albumin secretion, urea secretion, and mitochondrial membrane potential. Cell viability was not significantly affected by CBD, CBN, or the hemp extract at any of the concentrations tested. Exposure to hemp extract induced a modest but statistically significant decrease in albumin secretion, urea secretion, and mitochondrial membrane potential at the highest concentration tested whereas CBD only induced a modest but statistically significant decrease in albumin secretion compared with vehicle control. Although this study addresses data gaps in the understanding of cannabinoid hepatoxicity in vitro, additional studies will be needed to determine how these results correlate with relevant consumer exposure and the biological effects of cannabinoids in human liver.

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.

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.

A geospatiotemporal and causal inference epidemiological exploration of substance and cannabinoid exposure as drivers of rising US pediatric cancer rates.

BACKGROUND: Age-adjusted US total pediatric cancer incidence rates (TPCIR) rose 49% 1975-2015 for unknown reasons. Prenatal cannabis exposure has been linked with several pediatric cancers which together comprise the majority of pediatric cancer types. We investigated whether cannabis use was related spatiotemporally and causally to TPCIR. METHODS: State-based age-adjusted TPCIR data was taken from the CDC Surveillance, Epidemiology and End Results cancer database 2003-2017. Drug exposure was taken from the nationally-representative National Survey of Drug Use and Health, response rate 74.1%. Drugs included were: tobacco, alcohol, cannabis, opioid analgesics and cocaine. This was supplemented by cannabinoid concentration data from the Drug Enforcement Agency and ethnicity and median household income data from US Census. RESULTS: TPCIR rose while all drug use nationally fell, except for cannabis which rose. TPCIR in the highest cannabis use quintile was greater than in the lowest (ß-estimate = 1.31 (95%C.I. 0.82, 1.80), P = 1.80 × 10- 7) and the time:highest two quintiles interaction was significant (ß-estimate = 0.1395 (0.82, 1.80), P = 1.00 × 10- 14). In robust inverse probability weighted additive regression models cannabis was independently associated with TPCIR (ß-estimate = 9.55 (3.95, 15.15), P = 0.0016). In interactive geospatiotemporal models including all drug, ethnic and income variables cannabis use was independently significant (ß-estimate = 45.67 (18.77, 72.56), P = 0.0009). In geospatial models temporally lagged to 1,2,4 and 6 years interactive terms including cannabis were significant. Cannabis interactive terms at one and two degrees of spatial lagging were significant (from ß-estimate = 3954.04 (1565.01, 6343.09), P = 0.0012). The interaction between the cannabinoids THC and cannabigerol was significant at zero, 2 and 6 years lag (from ß-estimate = 46.22 (30.06, 62.38), P = 2.10 × 10- 8). Cannabis legalization was associated with higher TPCIR (ß-estimate = 1.51 (0.68, 2.35), P = 0.0004) and cannabis-liberal regimes were associated with higher time:TPCIR interaction (ß-estimate = 1.87 × 10- 4, (2.9 × 10- 5, 2.45 × 10- 4), P = 0.0208). 33/56 minimum e-Values were > 5 and 6 were infinite. CONCLUSION: Data confirm a close relationship across space and lagged time between cannabis and TPCIR which was robust to adjustment, supported by inverse probability weighting procedures and accompanied by high e-Values making confounding unlikely and establishing the causal relationship. Cannabis-liberal jurisdictions were associated with higher rates of TPCIR and a faster rate of TPCIR increase. Data inform the broader general consideration of cannabinoid-induced genotoxicity.

Different Effects of Cannabis Abuse on Adolescent and Adult Brain.

Cannabis abuse is a common phenomenon among adolescents. The dominant psychoactive substance in Cannabis sativa is tetrahydrocannabinol (THC). However, in the past 40 years the content of the psychoactive ingredient THC in most of the preparations is not constant but has increased due to other breeding and culturing conditions. THC acts as the endocannabinoids at CB1 and CB2 receptors but pharmacologically can be described as a partial (not a pure) agonist. Recent evidence shows that activation of the CB1 receptor by THC can diminish the production of neuronal growth factor in neurons and affect other signalling cascades involved in synapsis formation. Since these factors play an important role in the brain development and in the neuronal conversion processes during puberty, it seems reasonable that THC can affect the adolescent brain in another manner than the adult brain. Accordingly, in adolescent cannabis users structural changes were observed with loss of grey matter in certain brain areas. Moreover, recent studies show different effects of THC on adolescent and adult brains and on behaviour. These studies indicate that early THC abuse can result in neuropsychological deficits. This review gives an overview over the present knowledge in this field.

The perceived impact of legalized cannabis on nursing workload in adult and pediatric emergency department visits: A qualitative exploratory study.

OBJECTIVE: To investigate changes in emergency nursing workload related to cannabis ingestion or inhalation by adult and pediatric patients in states and bordering states where recreational cannabis is legal. DESIGN: Qualitative exploratory design using data collected from focus groups. SAMPLE: Twenty-four English-speaking emergency nurses over the age of 18 who provide direct care to patients and work in US emergency departments located in a state, or bordering state, where recreational cannabis use is legal. MEASUREMENTS: Qualitative data were gathered using a semi-structured interview format and analyzed using situational analysis. RESULTS: The legalization of recreational cannabis in some US states is reported as resulting in an increase in patients presenting with cyclic vomiting syndromes, and increased difficulty in managing both associated behaviors and repetitive ED presentations. New presentations also include unintentional intoxication in both pediatric and geriatric populations. An unexpected finding was the displacement of local homeless populations by younger, indigent "cannabis tourists"; social services agencies might consider this while planning for cannabis legalization in their state or territory. CONCLUSIONS: To protect public health and safety, regulatory efforts to standardize the formulation, dosing and labeling of cannabis products would be beneficial along with educational initiatives for both consumers and health care providers.

A 21st Century Problem: Cannabis Toxicity in a 13-Month-Old Child.

BACKGROUND: Cannabis is one of the most abused drugs worldwide, with more than 20 million users in the United States (US). As access to cannabis products increases with expanding US legislation and decriminalization of marijuana, emergency physicians must be adept in recognizing unintentional cannabis toxicity in young children, which can range from altered mental status to encephalopathy and coma. CASE REPORT: We report the case of a 13-month-old female presenting with self-limiting altered mental status and lethargy, with a subsequent diagnosis of tetrahydrocannabinol exposure on confirmatory urine gas chromatography-mass spectrometry. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Considering caretakers rarely report possible cannabis exposure, history-taking must review caretakers' medicinal and recreational drug exposures to prevent inadvertently missing the diagnosis. In the young child with altered mental status, prompt urine screening for cannabinoid detection can prevent further invasive and costly diagnostic investigations, such as brain imaging and lumbar puncture.

Sudden onset unexplained encephalopathy in infants: think of cannabis intoxication.

UNLABELLED: The use of cannabis as both a therapeutic agent and recreational drug is common, and its availability is increasing as a result of legalization in many countries. Among older children, the manifestations of cannabis intoxication are numerous and include both neurological and systemic manifestations that are frequently non-specific. There have been only a few reports detailing cannabis intoxication in infants and toddlers. We describe three infants who presented to the emergency department with encephalopathic signs without prominent systemic manifestations. During the initial interview of caregivers, no history of exposure to neurotoxic agents was obtained. All three patients were subsequently diagnosed with cannabis intoxication based on urine toxic screens for delta-9-tetrahydrocannabinol (THC). The infants recovered with supportive care that included fluids and monitoring. The non-specific symptomatology of cannabis intoxication in infants together with the wide differential for unexplained acute onset encephalopathy may delay diagnosis and lead to inappropriate procedures and interventions such as antimicrobial treatments and imaging studies. CONCLUSION: Healthcare personnel of emergency rooms, urgent care centers, and general clinics should be aware of the potential risk of cannabis ingestion in young infants. A thorough medical history and toxic screen are warranted in all infants with unexplained decreased sensorium.

[Marijuana: A toxicological approach]. / Marihuana: visión toxicológica.

From an adult perspective, both marijuana and alcohol consumption are becoming natural. Among illegal substances, marijuana has disseminated all over the word and specially in Argentina. Thus, a scientifc approach towards this issue must be developed and we should spread what we know about toxicity and adverse effects, particularly among adolescents. The impact of this kind of toxic during the neurodevelopmental period, both in cognitive and impulse control areas, may involve negative consequences for users at a later age.

Notes from the Field: Death Following Ingestion of an Edible Marijuana Product--Colorado, March 2014.

In March 2014, the Colorado Department of Public Health and Environment (CDPHE) learned of the death of a man aged 19 years after consuming an edible marijuana product. CDPHE reviewed autopsy and police reports to assess factors associated with his death and to guide prevention efforts. The decedent's friend, aged 23 years, had purchased marijuana cookies and provided one to the decedent. A police report indicated that initially the decedent ate only a single piece of his cookie, as directed by the sales clerk. Approximately 30-60 minutes later, not feeling any effects, he consumed the remainder of the cookie. During the next 2 hours, he reportedly exhibited erratic speech and hostile behaviors. Approximately 3.5 hours after initial ingestion, and 2.5 hours after consuming the remainder of the cookie, he jumped off a fourth floor balcony and died from trauma. The autopsy, performed 29 hours after time of death, found marijuana intoxication as a chief contributing factor. Quantitative toxicologic analyses for drugs of abuse, synthetic cannabinoid, and cathinones ("bath salts") were performed on chest cavity blood by gas chromatography and mass spectrometry. The only confirmed findings were cannabinoids (7.2 ng/mL delta-9 tetrahydrocannabinol [THC] and 49 ng/mL delta-9 carboxy-THC, an inactive marijuana metabolite). The legal whole blood limit of delta-9 THC for driving a vehicle in Colorado is 5.0 ng/mL. This was the first reported death in Colorado linked to marijuana consumption without evidence of polysubstance use since the state approved recreational use of marijuana in 2012.

Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility.

Marijuana has the highest consumption rate among all of the illicit drugs used in the USA, and its popularity as both a recreational and medicinal drug is increasing especially among men of reproductive age. Male factor infertility is on the increase, and the exposure to the cannabinoid compounds released by marijuana could be a contributing cause. The endocannabinoid system (ECS) is deeply involved in the complex regulation of male reproduction through the endogenous release of endocannabinoids and binding to cannabinoid receptors. Disturbing the delicate balance of the ECS due to marijuana use can negatively impact reproductive potential. Various in vivo and in vitro studies have reported on the empirical role that marijuana plays in disrupting the hypothalamus-pituitary-gonadal axis, spermatogenesis, and sperm function such as motility, capacitation, and the acrosome reaction. In this review, we highlight the latest evidence regarding the effect of marijuana use on male fertility and also provide a detailed insight into the ECS and its significance in the male reproductive system.

High frequency of intracranial arterial stenosis and cannabis use in ischaemic stroke in the young.

BACKGROUND: Leading aetiologies of ischaemic stroke in young adults are cervico-cerebral arterial dissections and cardio-embolism, but the causes remain undetermined in a considerable proportion of cases. In a few reports, intracranial arterial stenosis has been suggested to be a potential cause of ischaemic stroke in young adults. The aim of our work was to evaluate the frequency, characteristics and risk factors of intracranial arterial stenosis in a prospective series of young ischaemic stroke patients. METHODS: The study was based on a prospective consecutive hospital-based series of 159 patients aged 18-45 years who were admitted to our unit for an acute ischaemic stroke from October 2005 to December 2010. A structured questionnaire was used in order to assess common vascular risk factors such as hypertension, diabetes, hypercholesterolemia, use of tobacco, alcohol and illicit drugs, migraine, and, in women, oral contraceptive use. A systematic screening was performed, including the following: brain magnetic resonance imaging or, if not feasible, brain computed tomography scan, carotid and vertebral Duplex scanning and trans-cranial Doppler sonography, 3D time-of-flight magnetic resonance cerebral angiography or cerebral computed tomography angiography. Long-duration electrocardiography, trans-thoracic and trans-oesophageal echocardiography were performed and laboratory blood investigations were extensive. Urine samples were screened for cannabinoids, cocaine, amphetamine and methylene-dioxy-methamphetamine. When this initial work-up was inconclusive, trans-femoral intra-arterial selective digital subtraction angiography with reconstructed 3D images was performed. RESULTS: In this series, 49 patients (31%) had intracranial arterial stenosis. Other defined causes were found in 91 patients (57%), including cardio-embolism in 32 (20%), cervical dissection in 23 (14%), extracranial atherosclerosis in 7 (4%), haematological disorders in 7 (4%), small vessel disease in 1, and isolated patent foramen ovale in 21 (13%); in 19 patients (12%), ischaemic stroke was related to an undetermined aetiology. Comparing risk factors between patients with intracranial arterial stenosis and those with other definite causes showed that there were only two significant differences: a lower age and a higher frequency of vasoactive substances (especially cannabis) in patients with intracranial arterial stenosis. All intracranial arterial stenosis in patients who used vasoactive substances were located in several intracranial vessels. CONCLUSIONS: Intracranial arterial stenosis may be an important mechanism of stroke in young patients and it should be systematically investigated using vascular imaging. Strong questioning about illicit drug consumption (including cannabis) or vasoactive medication use should also be performed. It should be emphasized for health prevention in young adults that cannabis use might be associated with critical consequences such as stroke.

Neuronal substrates and functional consequences of prenatal cannabis exposure.

Cannabis remains one of the world's most widely used substance of abuse amongst pregnant women. Trends of the last 50 years show an increase in popularity in child-bearing women together with a constant increase in cannabis potency. In addition, potent herbal "legal" highs containing synthetic cannabinoids that mimic the effects of cannabis with unknown pharmacological and toxicological effects have gained rapid popularity amongst young adults. Despite the surge in cannabis use during pregnancy, little is known about the neurobiological and psychological consequences in the exposed offspring. In this review, we emphasize the importance of maternal programming, defined as the intrauterine presentation of maternal stimuli to the foetus, in neurodevelopment. In particular, we focus on cannabis-mediated maternal adverse effects, resulting in direct central nervous system alteration or sensitization to late-onset chronic and neuropsychiatric disorders. We compare clinical and preclinical experimental studies on the effects of foetal cannabis exposure until early adulthood, to stress the importance of animal models that permit the fine control of environmental variables and allow the dissection of cannabis-mediated molecular cascades in the developing central nervous system. In sum, we conclude that preclinical experimental models confirm clinical studies and that cannabis exposure evokes significant molecular modifications to neurodevelopmental programs leading to neurophysiological and behavioural abnormalities.

[Cannabis-induced cognitive and psychiatric disorders]. / Les troubles cognitifs et psychiatriques liés à la consommation de cannabis.

Several studies have shown that Δ-9-THC the main psychoactive constituent of cannabis, can impair cognitive functions, especially attention, episodic memory, working memory and executive functions. These impairments have been related to the duration, frequency, dose and age at onset of cannabis use. Cognitive deficits may disappear with abstinence, but abnormalities may be long-lasting in subjects who began smoking cannabis before age 15. The lifetime prevalence of cannabis use disorders is about 1% in the general population. The main characteristics of cannabis use disorders are craving, persistent desire or unsuccessful efforts to cut down or control cannabis use, and persistent avoidance of familial, social occupational or recreational activities because of cannabis use. Nine prospective longitudinal studies in the generalpopulation have shown that cannabis use is associated with a two-fold increase in the risk of psychotic disorders, particularly schizophrenia, compared to controls. The risk of psychosis increases in a dose-related fashion. A higher risk of schizophrenia is predicted by earlier onset of cannabis use. The effects of cannabis are exerted primarily through THC interaction with cannabinoid (CB) 1 receptors in the brain. Cannabis exposure may disrupt the last steps of brain maturation, through the endocannabinoid system, thereby increasing the risk of psychosis during adolescence.

[Cannabis use among children and adolescents: impacts and consequences]. / Cannabis chez les enfants et les adolescents: impacts et conséquences.

A health policy for the prevention and treatment of cannabis-related disorders is urgently needed in France, given the high prevalence of cannabis use among children and adolescents. Such a policy will require a better understanding of the endo-cannabinoid system and the impact of exogenous cannabinoids in this fragile population. The brain continues to undergo significant development until the age of about 25 years, and cannabis consumption by young people therefore carries specific risks of dependence (frequency and intensity), and of neuroanatomical, cognitive and emotional damage. This article summarizes the available data and offers a medical view of the risks and consequences of cannabis use by children and adolescents.